Conditions: Recurrent Plasma Cell Myeloma Refractory Plasma Cell Myeloma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 5
Healthy volunteers: no

Brief summary:
This phase II trial studies how well daratumumab, azacitidine, and dexamethasone work in treating patients with multiple myeloma that has come back (recurrent) or has not responded to treatment (refractory) and was previously treated with daratumumab. Daratumumab is an antibody made up of immune cells that attaches to a protein on myeloma cells, called cluster of differentiation 38 (CD38). CD38 is found in higher levels on tumor cells than on normal cells. Daratumumab prevents the growth of tumors who have high levels of CD38 by causing those cells to die. Chemotherapy drugs, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Dexamethasone is a steroid that helps decrease inflammation and lowers the body's normal immune response to help reduce the effect of any infusion-related reactions. Giving azacitidine may help increase the levels of CD38 on the tumor cells to increase the function of daratumumab to attach to those tumor cells to help destroy them.

Detailed description:
PRIMARY OBJECTIVE:

I. To evaluate the efficacy of adding azacitidine to daratumumab and dexamethasone, as measured by the overall response rate in patients with relapsed refractory multiple myeloma (RRMM) previously treated with daratumumab.

SECONDARY OBJECTIVES:

I. To evaluate the duration of response per International Myeloma Working Group (IMWG) criteria.

II. To evaluate the safety and tolerability of azacitidine in combination with daratumumab and dexamethasone.

III. To evaluate progression free and overall survival in patients treated with azacitidine in combination with daratumumab and dexamethasone.

IV. To assess the changes in CD38 expression on plasma cells after treatment with azacitidine and correlate this change with the depth and duration of response of azacitidine in combination with daratumumab and dexamethasone.

OUTLINE:

PRE-INDUCTION (CYCLE 0): Patients receive azacitidine intravenously (IV) on days -7 to -3 in the absence of disease progression or unacceptable toxicity.

INDUCTION PHASE (CYCLES 1-2): Patients receive azacitidine IV on days 22-26 and dexamethasone IV or orally (PO) and daratumumab subcutaneously (SC) over 3-5 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION PHASE (CYCLES 3-6): Patients receive azacitidine IV on days 22-26 of cycle 3 and on days 1-5 of cycles 5-6 and dexamethasone IV or PO and daratumumab SC over 3-5 minutes on days 1 and 15. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE PHASE (CYCLES 7+): Patients receive azacitidine IV on days 1-5 and dexamethasone IV or PO and daratumumab SC over 3-5 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 4 weeks for up to 1 year.

Arms:
arm 1: PRE-INDUCTION (CYCLE 0): Patients receive azacitidine IV on days -7 to -3 in absence of disease progression or unacceptable toxicity.

INDUCTION (CYCLES 1-2): Patients receive azacitidine IV on days 22-26, dexamethasone IV or orally (PO), and daratumumab subcutaneously (SC) over 3-5 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity

CONSOLIDATION (CYCLES 3-6): Patients receive azacitidine IV on days 22-26 of cycle 3 and on days 1-5 of cycles 5-6, dexamethasone IV or PO, and daratumumab SC over 3-5 minutes on days 1 and 15. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity

MAINTENANCE (CYCLES 7+): Patients receive azacitidine IV on days 1-5, dexamethasone IV or PO, and daratumumab SC over 3-5 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity

Interventions: intervention 1: Azacitidine intervention 2: Daratumumab intervention 3: Dexamethasone
Intervention descriptions: intervention 1: Given IV intervention 2: Given SC intervention 3: Given IV or PO

Protocol document:
Prot_SAP_000.pdf: 
Proprietary and Confidential
The information in this document is considered privileged and confidential, and may not be disclosed to others except to the 
extent necessary to obtain Institutional Review Board approval and informed consent, or as required by federal and state laws.  
Persons to whom this information is disclosed should be informed that this information is privileged and confidential and that it 
should not be further disclosed. 
Phase II Study of Daratumumab in Combination with Azacitidine and 
Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients 
Previously Treated with Daratumumab
Protocol Number:  CC #20251
Investigational Product(s):  Daratumumab and Azacitidine
Version Number:  6.1
Version Date:  06/08/2022
IND Number:  EXEMPT
Principal Investigator (Sponsor-Investigator)
Alfred Chung, MD
San Francisco, CA 94143
Co- Principal Investigator 
Swetha Kambhampati, MD
 
Statistician
Chiang-Yu Huang
Revision History
Protocol Version
Date
Version 1
07/22/2019
Version 2
10/03/2019
Version 3
11/08/2019
Version 4
01/16/2020
Version 5
04/06/2020
Version 6
11/06/2020
Version 6.1
06/08/2022
NCT# 04407442


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Protocol Signature Page
Protocol No.: 20251
1.
I agree to follow this protocol version as approved by the UCSF Protocol Review Committee (PRC), Institutional 
Review Board (IRB), and Data and Safety Monitoring Committee (DSMC). 
2.
I will conduct the study in accordance with Good Clinical Practices (ICH-GCP) and the applicable IRB, ethical, 
federal, state, and local regulatory requirements. 
3.
I certify that I, and the study staff, have received the required training to conduct this research protocol. 
4.
I agree to maintain adequate and accurate records in accordance with IRB policies, federal, state and local laws 
and regulations.
UCSF Principal Investigator 
Swetha Kambhampati, Alfred Chung
Printed Name
Signature
Date


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Abstract
Title
A Phase II Study of Daratumumab in Combination with Azacitidine and 
Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients Previously Treated 
with Daratumumab 
Study Description
This is a single-arm, 2-stage, phase II study of the safety and efficacy of daratumumab 
in combination with azacitidine and dexamethasone in relapsed/refractory multiple 
myeloma (RRMM) patients who have previously been exposed to daratumumab. Based 
on pre-clinical data we hypothesize that azacitidine, by upregulating the expression of 
CD38, can potentially increase the antibody-dependent cell-mediated cytotoxicity and 
efficacy of daratumumab on multiple myeloma cells and help reverse daratumumab 
resistance. This study aims to assess the efficacy and safety of daratumumab and 
azacitidine in relapsed refractory multiple myeloma.
Phase of Study
Phase 2
Investigational 
Products
Daratumumab and Azacitidine
Study population
Patients ≥ 18 years of age with relapsed or refractory multiple myeloma (RRMM) who 
have progressed on ≥ 2 lines of prior therapy, including an immunomodulatory drugs 
(IMiD) and proteasome inhibitor, and have previously been treated with daratumumab, 
with most recent daratumumab treatment being at least 6 months prior to enrollment to 
allow for CD38 normalization. 
Primary Objective

To evaluate the efficacy, as determined by the overall response rate (ORR) of 
daratumumab in combination with azacitidine and dexamethasone in RRMM 
patients who have previously been exposed to daratumumab 
Secondary Objectives

To evaluate duration of response per IMWG response criteria.

To assess the safety and toxicity of azacitidine in combination with 
daratumumab and dexamethasone

To assess the 1-year OS and PFS of daratumumab in combination with 
azacitidine and dexamethasone

To evaluate the change in CD38 expression on plasma cells induced by 
azacitidine in patients with RRMM and correlate this change with depth and 
duration of response


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Sample Size
Simon’s minimax two-stage design will be used. 
The overall study (including the safety lead-in) plans to enroll 23 patients. 
Safety Lead In: We expect to enroll 6 patients overall in the safety lead-in. 
Stage 1: We expect to enroll a total of 13 patients during Stage 1 (including the 6 
patients enrolled in the safety lead-in).  Depending on the clinical response in Stage 1, 
Stage 2 will commence.
Stage 2:  If there is ≥ 2 responses in 13 patients the study will enroll an additional 10 
patients. 
If there is ≤ 1 response in 13 patients the study will be stopped.
 
Duration of Study 
Treatment
Participants will continue study treatment until they are unable to tolerate treatment due 
to toxicities or demonstrate progression. We anticipate the duration of study treatment 
to be around 8 months.
Duration of Follow up
Patients will be followed until 1 year after the last patient has received the last 
administration of daratumumab. 
Unique Aspects of this 
Study
This is the first study to evaluate the safety and efficacy of azacitidine and daratumumab 
in combination with dexamethasone in patients with relapsed and refractory myeloma.


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List of Abbreviations
ADCC
AE
antibody-dependent cellular toxicity
adverse event
ALP
alkaline phosphatase
ALT
ANC
alanine aminotransferase
absolute neutrophil count
AST
Aza
BM
aspartate aminotransferase
Azacitidine
Bone marrow
BUN
blood urea nitrogen
CBC
CDC
complete blood cell (count)
complement dependent cytotoxicity
CNS
central nervous system
CR
CRC
complete response
clinical research coordinator
CRF
case report form
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTMS
Dara
Dexamethasone
Clinical Trial Management System
Daratumumab
Dexamethasone
DFS
disease-free survival
DLT
DMC
DOR
dose limiting toxicity
Data Monitoring Committee
duration of response
DSMC
Data and Safety Monitoring Committee
DSMP
Data and Safety Monitoring Plan
ECG/EKG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
FDA
Food and Drug Administration
FDG
Fluorodeoxyglucose
FLC
free light chain
GCP
Good Clinical Practice


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List of Abbreviations
GGT
gamma-glutamyl transferase
HBeAg
hepatitis B “e” antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HDFCCC
Helen Diller Family Comprehensive Cancer Center
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Conference on Harmonization
IND
investigational new drug application
IP
investigational product
IRB
Institutional Review Board
IV
intravenous
LDH
Mab/MoAb
MFI
MM
MR
MRI
lactate dehydrogenase
Monoclonal Antibody
Median fluorescent intensity
Multiple myeloma
Minor response
Magnetic resonance imaging
MRD
minimal residual disease
MTD
maximum tolerated dose
NCI
National Cancer Institute
ORR
OS
overall response rate
overall survival
PD
Pd
PFS
PI
disease progression
pharmacodynamics
progression free survival
principal investigator
PK
pharmacokinetics
PO
Per os (by mouth, orally)
PR
partial response
PRC
RRMM
Protocol Review Committee (UCSF)
Relapsed refractory multiple myeloma


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List of Abbreviations
SAE
serious adverse event
SD
stable disease
SGOT
serum glutamic oxaloacetic transaminase
SGPT
VGPR
WBC
serum glutamic pyruvic transaminase
very good partial response
white blood cell count


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Table of Contents
Protocol Signature Page.........................................................................................................................2
Abstract .................................................................................................................................................3
List of Abbreviations ..............................................................................................................................5
1
Introduction..................................................................................................................................11
1.1
Background on Indication...................................................................................................................11
1.2
Background on the Investigational Product(s) and Associated Known Toxicities.................................12
Daratumumab.......................................................................................................................................................................12
Azacitidine ............................................................................................................................................................................19
1.3
Rationale for the Proposed Study .......................................................................................................24
1.4
Rationale for the Dose Selection/Regimen .........................................................................................26
1.5
Correlative Studies .............................................................................................................................27
2
Study Objectives ...........................................................................................................................30
2.1
Hypothesis .........................................................................................................................................30
2.2
Primary, Secondary, and Exploratory Objective(s) ..............................................................................30
Primary Objectives:...............................................................................................................................................................30
Secondary Objectives: ..........................................................................................................................................................31
2.3
Primary, Secondary, and Exploratory Endpoint(s)...............................................................................31
Primary endpoints: ...............................................................................................................................................................31
Secondary Endpoints: ...........................................................................................................................................................31
3
Study Design.................................................................................................................................31
3.1
Characteristics....................................................................................................................................31
3.2
Eligibility Criteria ................................................................................................................................33
Inclusion Criteria...................................................................................................................................................................33
Exclusion Criteria ..................................................................................................................................................................35
3.3
Inclusion and Recruitment of Women and Minorities.........................................................................37
3.4
Duration of Treatment........................................................................................................................37
3.5
Duration of Follow Up ........................................................................................................................37
3.6
Primary Completion ...........................................................................................................................38
3.7
Study Completion...............................................................................................................................38
4
Investigational Products ...............................................................................................................38
4.1
Description, Supply and Storage of Investigational Products...............................................................38
Daratumumab.......................................................................................................................................................................38
Azacitidine ............................................................................................................................................................................39
Dexamethasone....................................................................................................................................................................40
4.2
Accountability Records for Investigational Product(s).........................................................................40


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4.3
Ordering Investigational Product(s) ....................................................................................................40
5
Treatment Plan.............................................................................................................................40
5.1
Dosage and Administration ................................................................................................................40
Daratumumab.......................................................................................................................................................................41
Azacitidine ............................................................................................................................................................................44
Dexamethasone....................................................................................................................................................................44
5.2
Treatment Compliance .......................................................................................................................45
5.3
Other Investigational Procedures/Modalities .....................................................................................46
5.4
Dose Limiting Toxicity.........................................................................................................................46
5.5
Dose Modifications and Dosing Delays ...............................................................................................47
Daratumumab.......................................................................................................................................................................47
Azacitidine ............................................................................................................................................................................48
Dexamethasone....................................................................................................................................................................51
5.6
Criteria for Permanent Discontinuation of Study Drug(s) ....................................................................52
5.7
Use of Concurrent/Concomitant Medications.....................................................................................53
Recommended Therapies.....................................................................................................................................................53
5.8
Dietary Restrictions............................................................................................................................54
5.9
Prohibited Medications ......................................................................................................................54
6
Study Procedures and Schedule of Events......................................................................................54
6.1
Study Calendar ...................................................................................................................................55
6.2
Participant Registration......................................................................................................................58
6.3
Schedule of Procedures and Observations..........................................................................................58
Pretreatment Period.............................................................................................................................................................58
Treatment Period..................................................................................................................................................................59
Post-treatment/ Follow-Up ..................................................................................................................................................64
6.4
Correlative Studies .............................................................................................................................64
CD38 Expression Changes.....................................................................................................................................................64
Methylation Pattern Changes...............................................................................................................................................65
Tumor Microenvironment Changes......................................................................................................................................65
7
Reporting and Documentation of Results......................................................................................67
7.1
Evaluation of Efficacy: Antitumor Effect – Hematologic Tumors..........................................................67
Response Categories.............................................................................................................................................................67
Measurement of Endpoints for Response............................................................................................................................69
Assessment of Disease Progression or Response .................................................................................................................69
Methods of Response Evaluation .........................................................................................................................................69
7.2
Evaluation of Safety............................................................................................................................70
7.3
Definitions of Adverse Events.............................................................................................................71
Adverse Event (AE) ...............................................................................................................................................................71
Adverse Events of Special Interest........................................................................................................................................71


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Serious Adverse Events (SAE) ...............................................................................................................................................72
Unlisted (Unexpected) Adverse Event/Reference Safety Information.................................................................................73
7.4
Recording of Adverse Events ..............................................................................................................73
7.5
Follow-up of Adverse Events ..............................................................................................................73
7.6
Adverse Events Monitoring ................................................................................................................73
7.7
Expedited Reporting...........................................................................................................................73
Reporting to the Data and Safety Monitoring Committee ...................................................................................................73
Reporting to Institutional Review Board ..............................................................................................................................73
Expedited Reporting to the FDA ...........................................................................................................................................74
Interventional IIS Janssen Scientific Affairs Requirements for Safety Data            Collection and Reporting .......................74
8
Statistical Considerations and Evaluation of Results .....................................................................78
8.1
Sample Size Determination.................................................................................................................78
8.2
Analyses.............................................................................................................................................79
Analyses Population..............................................................................................................................................................79
Safety Analysis ......................................................................................................................................................................79
Efficacy Analysis....................................................................................................................................................................80
Correlative Studies Analysis..................................................................................................................................................81
8.3
Interim Analyses and Study Stopping Rules ........................................................................................82
8.4
Accrual Estimates ...............................................................................................................................83
9
Study Management ......................................................................................................................83
9.1
Pre-study Documentation...................................................................................................................83
9.2
Institutional Review Board Approval ..................................................................................................83
9.3
Informed Consent...............................................................................................................................83
9.4
Changes in the Protocol......................................................................................................................83
9.5
Handling and Documentation of Clinical Supplies ...............................................................................84
9.6
Case Report Forms (CRFs)...................................................................................................................84
9.7
Oversight and Monitoring Plan...........................................................................................................84
9.8
Record Keeping and Record Retention................................................................................................85
10
Protection of Human Subjects.......................................................................................................85
10.1
Protection from Unnecessary Harm....................................................................................................85
10.2
Protection of Privacy ..........................................................................................................................85
Appendix 1
Performance Status Criteria...........................................................................................86
Appendix 2
Data and Safety Monitoring Plan ..................................................................................87
Appendix 3
Prohibited Medications List............................................................................................90
References ...........................................................................................................................................91


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1
Introduction
1.1
Background on Indication
In the last decade, the introduction of proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) has 
significantly prolonged survival of patients with multiple myeloma (MM).1,2 However, despite numerous advances in 
treatment, multiple myeloma is still considered an incurable disease with an overall 5-year survival rate of 51%.3 
Daratumumab , the first-in-class CD38 monoclonal antibody, has significantly improved the treatment response of 
MM, due to plasma cell overexpression of protein CD38.4,5 Daratumumab binds CD38 with high affinity and induces 
tumor cell death through a variety of immune-mediated mechanisms of including complement-dependent cytotoxicity 
(CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC).6,7 Daratumumab monotherapy was approved for 
heavily pretreated relapsed refractory multiple myeloma (RRMM) patients8 based on the open-label, phase I/II 
GEN501 study and phase II SIRIUS study which showed overall response rates of 36% and 29%.9,10 Daratumumab, 
in the randomized open-label trials POLLUX and CASTOR, was also shown to have high response rates in RRMM 
when combined with Lenalidomide and Bortezomib, respectively, with a 63% and 61% risk reduction of disease 
progression or death.11,12 More recently, trials such as ALCYONE13 and MAIA14 have lead to approval of front-line 
daratumumab combination therapies for untreated transplant-ineligible myeloma patients. ALCYONE showed that 
daratumumab, bortezomib, melphalan, and prednisone combination in this patient population had an overall response 
rate of 90.9% in the daratumumab group as opposed to 73.9% in the control group13, while MAIA study showed that 
daratumumab, lenalidomide, and dexamethasone had a complete response of 47.6% in the daratumumab group as 
opposed to 24.9% in the control group14. Given the favorable results from the CASSOPEIA trial in Europe showing 
that daratumumab in combination with bortezomib, thalidomide, and dexamethasone (VTd), the frontline therapy 
standard of care in Europe in transplant eligible myeloma patients, resulted in 29% stringent complete response rate 
as opposed to 20% in the control non-daratumumab group15. There is an ongoing phase II GRIFFIN trial assessing the 
safety and efficacy of daratumumab in combination with revlimid, velcade, and dexamethasone (RVd) in frontline 
transplant eligible patients (NCT02874742). Preliminary data has indicated that this study has met its primary 
endpoint, demonstrating a higher percentage of stringent complete response (sCR) in patients in the daratumumab 
group compared to the control RVd group. While we are still awaiting the final results from this trial, if these 
preliminary results are confirmed in the final analysis, we anticipate daratumumab to be approved in the future in 
combination with the current standard of care RVd in frontline transplant-eligible myeloma patients. Now 
daratumumab is also approved in the subcutaneous form, based on the results of 
the COLUMBA study. The subcutaneous form provides several additional 
benefits for both patients and healthcare providers including shorter 
administration time, lower rate of infusion related reactions, additional flexibility, 
and reduction in treatment burden to the patient as well as lower risk of volume 
overload in patients with cardiac or renal insufficiency. 
While daratumumab is well tolerated and has high efficacy, not all 
patients respond, and many patients eventually develop progressive disease and 
resistance to daratumumab. A retrospective study showed that these patients have 
poor prognosis with a median overall survival of 5.3 months and a post-
daratumumab regimen overall response rate of 34% with limited treatment 
options.16 Another retrospective study analyzing outcomes of 275 multiple 
myeloma patients at 14 academic centers with disease refractory to CD38 
monoclonal antibodies (MoABs), either daratumumab or isatuximab, found that this patient population had a median 
overall survival (OS) of 8.6 months, ranging from 11.2 months for patients not simultaneously refractory to an 
immunomodulatory (IMiD) agent and a proteasome inhibitor to 5.6 months for penta-refractory patients who are 


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refractory to CD38 MoABs, 2 proteasome inhibitors, and 2 IMiDs.17 These studies highlight that heavily pre-treated 
MM patients who are resistant to daratumumab have overall poor prognosis. Thus, research has focused on 
understanding markers and predictors of daratumumab response and mechanisms of daratumumab resistance, which 
will prove to be even more important as daratumumab is being moved to frontline therapy.
1.2
Background on the Investigational Product(s) and Associated Known Toxicities
Daratumumab
Non-clinical studies
Daratumumab, the first-in-class CD38 monoclonal antibody, has significantly improved the treatment response of 
MM, due to plasma cell overexpression of protein CD38. CD38 is highly expressed on myeloma cells but is 
expressed at relatively low levels on normal lymphoid and myeloid cells and in some tissues of non-hematopoietic 
origin, making it a relevant target for the treatment of multiple 
myeloma. Daratumumab is an immunoglobulin G1kappa (IgG1k) 
human mAb that binds to a unique CD38 epitope on CD38-expressing 
cells with high affinity and was developed by the immunization of 
human  immunoglobulin transgenic mice with recombinant CD38 
protein.7,18 Daratumumab binds CD38 with high affinity and induces 
tumor cell death through a variety of immune-mediated mechanisms 
including complement-dependent cytotoxicity, antibody-dependent 
cell-mediated cytotoxicity, and antibody-dependent cellular 
phagocytosis, direct apoptosis after cross-linking, and can modulate 
CD38 enzymatic activity.7,19 Preclinical studies have showed that 
daratumumab’s ADCC is highly specific to CD38 given daratumumab has not shown to induce ADCC in CD38 
negative cells. Preclinical studies have also shown that daratumumab is effective at inducing both CDC and ADCC 
against MM cells in the presence of bone marrow stromal cells suggestive of daratumumab’s activity in the bone 
marrow microenvironment.7,18 Daratumumab has also shown to induce apoptosis with cross-linking. In addition, 
studies have shown that daratumumab has additional antimyeloma effects through immunomodulation and by 
eliminating a population of highly immunosuppressive CD38+ Tregs, T-cell MDSCs, and Bregs and thus stimulating 
T-cell effector functions.19 The immunomodulatory effects of daratumumab not only include reduction of CD38+ 
immunosuppressive cellular populations, but also include concomitant induction of helper and cytotoxic T-cell 
expansion, production of IFN-gamma in response to viral peptides, and increased TCR clonality and T-cell 
functional response suggestive of an improved adaptive immune response.19 
In-vitro studies, using bone marrow mononuclear cells from patients with multiple myeloma (MM), demonstrated 
increased killing of tumor cells when daratumumab was combined with lenalidomide or bortezomib as well as with 
both lenalidomide and bortezomib. Additionally, the upregulation of CD38 by pomalidomide or lenalidomide can 
enhance the activity of anti-CD38 antibodies including daratumumab. These observations suggest a strong potential 
for the treatment of CD38-expressing malignancies using daratumumab as monotherapy and in combinations.
The potential toxicity of daratumumab was evaluated in a repeat dose study in chimpanzees. The primary toxicities 
identified in chimpanzees were infusion-related reactions during the first, but not subsequent, daratumumab infusions 
and thrombocytopenia. The binding affinity of daratumumab is ≥15-fold higher for chimpanzee platelets than for 
human platelets, suggesting that thrombocytopenia may be less pronounced in humans. Depletion of specific 
lymphocyte phenotypic cell populations, as expected, based on the intended pharmacological effect of daratumumab, 
was observed in chimpanzees. No genotoxicity, chronic toxicity, carcinogenicity, or reproductive toxicity testing has 
been conducted.


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Clinical Studies and Efficacy
The promising preclinical data demonstrating the immunomodulatory effects of daratumumab has lead to extensive 
clinical trials testing the safety and efficacy of daratumumab in initially RRMM and now more recently newly 
diagnosed MM both transplant eligible and transplant ineligible. 
Daratumumab was initially approved in 2015 as monotherapy for patients with MM who have received at least 3 lines 
of therapy, including a proteasome inhibitor, IMiD, or who are double-refractory to a proteasome inhibitor and IMiD.9 
Pooled analysis of GEN501 and SIRIUS trials evaluating daratumumab monotherapy show an ORR of 31%, median 
DOR of 7.6 months, median PFS and OS of 4 months and 20.1 months respectively in heavily pretreated RRMM 
patients.10,20 The DRd and DVd regimens are approved by the FDA for use in patients with MM who have received at 
least one prior therapy based on the POLLUX and CASTOR trials respectively.11,21 POLLUX trial showed a higher 
ORR in the daratumumab arm, 93% vs 76%, and superior PFS of 83% vs 60%.11 CASTOR trial showed higher ORR 
of 84% vs 63% in the daratumumab arm and improved PFS of 16.7 vs 7.1 months.21 DPd is approved for use in patients 
with MM who have received at least two prior therapies including lenalidomide and a proteasome inhibitor with an 
ORR of 60% based on the EQUULEUS trial.22 Daratumumab is also approved in combination with bortezomib, 
melphalan, and prednisone (VMP) for the treatment of newly diagnosed MM patients who are ineligible for autologous 
stem cell transplant (ASCT) based on the ALCYONE study which showed a 50% reduction in the risk of progression 
or death compared with VMP alone.13 Daratumumab in combination with lenalidomide and dexamethasone was 
recently approved in newly diagnosed MM patients who are ineligible for ASCT based on the MAIA trial showing a 
superior ORR in the daratumumab arm of 92.9% vs 81.3% and showing reduced risk of disease progression or death 
by 44% in the daratumumab arm.14 The CASSIOPEIA trial in Europe found that daratumumab in combination with 
VTd compared to VTd alone demonstrated superior sCR of 29% vs 20%, superior CR of 39% vs 26%, and superior 
achievement of minimal residual disease (MRD) negativity of 64% vs 44%.15 This lead to the recent FDA approval of 
D-VTD for the treatment of newly diagnosed patients with MM who are eligible for ASCT. Given this was the first 
study showing the clinical benefit of daratumumab plus standard of care in frontline treatment of transplant eligible 
patients with newly diagnosed MM, this has lead to the ongoing GRIFFIN trial studying daratumumab plus standard 
of care in United States VRd in frontline treatment of transplant eligible patients (NCT02874742). 
Daratumumab by intravenous (IV) infusion is currently approved in over 90 countries worldwide for the treatment 
of relapsed or refractory, and frontline MM. Daratumumab subcutaneous (SC) was developed to provide several 
potential benefits for both patients and healthcare providers and was approved based on the phase 3 non-inferiority, 
randomized COLUMBA study. Both co-primary endpoints, overall response rate and Ctrough at Cycle 3 Day 1, were 
non-inferior for SC daratumumab, compared to IV daratumumab. Advantages  of the subcutaneous form include 
shorter administration time of 3 to 5 minutes (compared with 4 to 7 hours for IV infusion) and the lower rate of 
infusion related reactions (IRRs) give additional flexibility and reduction in treatment burden to the patient, as well 
as reducing health care professional time spent on administration. The smaller administration volume for 
daratumumab SC reduces the risk of volume overload in patients with cardiac or renal insufficiency.
There is very little data at this time regarding the re-treatment of daratumumab in patients with RRMM who have 
previously been treated with daratumumab. There was a retrospective analysis recently published regarding the safety 
and efficacy of daratumumab in combination with pomalidomide and dexamethasone in patients who were 
daratumumab and/or pomalidomide-refractory. Cohort 1 (12 patients) was daratumumab- and POM-naive, and cohort 
2 (22 patients) was daratumumab- and/or POM-refractory. A subgroup of 12 patients in cohort 2 (cohort 3) was 
daratumumab- and pomalidomide-refractory. The overall response rates (ORRs) were 91.7%, 40.9%, and 33.3% in 
cohorts 1, 2, and 3, respectively.23 There is no published data regarding retreatment with daratumumab monotherapy. 
There is an ongoing trial, Son of SAR study (NCT02514668), evaluating the efficacy of isatuximab monotherapy, 


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another CD38 monoclonal antibody with similar efficacy to daratumumab monotherapy24, in patients previously 
treated with daratumumab. Preliminary unpublished results of this ongoing trial show a response rate of < 10%. 
Overall, an estimated 5,528 subjects have received daratumumab in the clinical development program from 37 studies, 
ie, 8 completed, 19 studies with completed primary analysis (of these, 3 studies have ongoing cohorts), and 10 full 
ongoing monotherapy and combination therapy clinical studies in newly diagnosed MM, smoldering MM, 
relapsed/refractory MM, and also non-myeloma diseases, including myelodysplastic syndrome (MDS), amyloidosis, 
lung cancer, acute lymphoblastic leukemia, natural killer T-cell lymphoma (NKTCL), and non-Hodgkin’s lymphoma 
(NHL), as well as an early-access study and healthy volunteers. Of these, 1,756 subjects were exposed to daratumumab 
from monotherapy studies and 3,772 subjects were exposed to daratumumab from combination therapy (IB; version 
16, dated 20 December 2019).
Pharmacokinetics
Daratumumab is given intravenously (IV) at 16 mg/kg dose and when given as monotherapy for MM, is given once 
weekly for total of 8 doses (weeks 1-8), every 2 weeks for 8 doses (weeks 9-24), and every 4 weeks thereafter (starting 
week 25 and onwards). A study that reported the pharmacokinetic data from GEN501 and SIRIUS studies found that 
in both studies, daratumumab exhibited nonlinear pharmacokinetic characteristics. Decreasing daratumumab 
clearance with increasing dose suggests saturation of target-mediated clearance at higher dose levels, whereas 
decreasing clearance over time with repeated dosing may be due to tumor burden reductions as CD38-positive cells 
are eliminated. These and other pharmacokinetic data analyses support the use of the recommended dose regimen 
of daratumumab (16 mg/kg weekly for 8 weeks, every 2 weeks for 16 weeks, and every 4 weeks thereafter) to 
rapidly saturate target-mediated clearance during weekly dosing and maintain saturation when dosing every 2 or 
4 weeks.25 
Analysis of daratumumab pharmacokinetics have showed that daratumumab exhibits typical pharmacokinetics for 
an IgG1 monoclonal antibody. Mean serum concentrations of daratumumab peaked at the end of the first infusion 
and then declined in an apparent bi-exponential manner. V Z estimates indicate that daratumumab is confined 
primarily in the vascular system, with limited extravascular tissue distribution. Following the first full 
infusion, C max increased in approximate proportion to the increasing dose of daratumumab 1–24 mg/kg, and 
increased in a greater than dose-proportional manner after multiple doses. AUC increased in a greater than dose-
proportional manner after the first and multiple doses. Following the 16 mg/kg recommended dosing regimen 
(weekly for 8 weeks, every 2 weeks for 16 weeks, and every 4 weeks thereafter), accumulation of daratumumab 
continued throughout the weekly dosing period and decreased slightly as patients entered the less intense dosing 
periods. Following the end of treatment, daratumumab remained detectable in most patients in the SIRIUS 16 mg/kg 
group at 8 weeks post-treatment. No subjects in the GEN501 or SIRIUS studies developed antibodies to 
daratumumab during treatment suggesting a low risk for immunogenicity with this therapeutic agent.25
Over the dose range from 1 to 24 mg/kg as monotherapy or 1 to 16 mg/kg in combination with other treatments, 
increases in area under the curve (AUC) were more than dose-proportional. Clearance was rapid at low doses and 
slower at higher doses; clearance also decreased with multiple doses. This PK profile was consistent with target-
mediated disposition indicating target saturation at higher doses.26 Decreasing clearance over time with repeated 
dosing may be due to a reduction of tumor burden as CD38+ cells are eliminated.25 The PK of daratumumab was 
similar following monotherapy and combination therapies in multiple myeloma. The mean ± SD estimated terminal 
half-life of daratumumab associated with linear clearance was 18 ± 9 days when administered as monotherapy and 23 
± 12 days when administered as combination therapy.
Exposure-response analyses described elsewhere (Xu et al, submitted)26 indicates that most patients (approximately 
80%) following the recommended 16 mg/kg dose regimen were expected to achieve daratumumab serum 
concentrations correlated with 99% target (CD38) saturation and 90% of the maximal effect on ORR.25 


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The clinical pharmacology assessment of daratumumab SC monotherapy data are available from 
daratumumab SC-dosed subjects in a Phase 1/1b study MMY1004 [Part 2]) and Phase 3 study 
(MMY3012), Phase 2 combination therapy study MMY2040 and population pharmacokinetics and 
exposure-response analyses. In MMY1004, the 1800 mg dose achieved maximum Ctrough (Cycle 3 Day 1 
predose) values that were similar or greater than the maximum Ctrough observed for the approved 16 
mg/kg IV dose following the same dose schedule. The PK data from Part 2 supported the daratumumab SC 
1800 mg dose selection for the Phase 3 study. The PK data from MMY3012 study demonstrated that 
daratumumab SC 1800 mg is non-inferior to daratumumab IV 16 mg/kg in terms of maximum Ctrough 
(Cycle 3 Day 1 predose), with the lower bound of the 90% CI for the geometric means ratio for 
daratumumab SC versus daratumumab IV for maximum Ctrough (Cycle 3 Day 1 predose) exceeding 80%, 
thereby meeting the predefined non-inferiority criterion. 
Additionally, daratumumab SC 1800 mg monotherapy consistently produced lower peak-to-trough 
fluctuations, similar or slightly higher trough levels over time, and lower peak concentrations compared 
with daratumumab IV 16 mg/kg monotherapy. Overall, consistent daratumumab concentrations were 
observed across the body weight ranges. As expected, slightly higher concentrations were observed for 
subjects with lower body weights. There was no apparent relationship between exposure and safety 
endpoints (SAEs, Grade 3 or higher TEAEs and neutropenia).
The simulated trough concentrations following 6 weekly doses of daratumumab SC 1800 mg for
combination therapy (daratumumab SC, bortezomib, melphalan, and prednisone [D-VMP],
daratumumab SC, lenalidomide, and dexamethasone [D-Rd], daratumumab SC, bortezomib,
lenalidomide, and dexamethasone [D-VRd]) were similar to monotherapy.
Overall, daratumumab SC was well-tolerated with manageable side effects and a significantly reduced 
incidence of IRRs relative to daratumumab IV. The safety profile of daratumumab administered 
subcutaneously at a flat dose of 1800 mg continued to be generally comparable to that of the 16 mg/kg IV 
formulation.
Safety
The most frequently reported adverse reactions (reported at a rate of  20%) in the POLLUX trial were infusion 
reactions, diarrhea, nausea, fatigue, pyrexia, upper respiratory traction infections, muscle spasm, cough, and dyspnea.11 
The most frequently reported adverse events (reported at a rate of  20%) in the CASTOR trial were infusion reactions, 
diarrhea, peripheral edema, upper respiratory tract infection, and peripheral sensory neuropathy. Neutropenia and 
thrombocytopenia are also side effects of daratumumab.21
The safety results from all ongoing studies of daratumumab are summarized (through June 2017) below:
Table 1-1 Available Safety Findings in Ongoing Daratumumab Clinical Trials Through 30 
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Study Number (N 
exposed 
to 
Daratumumab)
Safety Results
Daratumumab Monotherapy Trials
MMY2002, GEN501, and 
MMY1002
(Relapsed/Refractory MM,
156)
Integrated analysis

Most common TEAEs: fatigue (40%), nausea and anemia (28% each), back 
pain (26%), cough (24%), neutropenia (23%), pyrexia (22%), upper respiratory 
tract infection (22%), and thrombocytopenia (21%).

Grade 3/4 TEAEs in 57% of subjects; most common were anemia (17%), 
thrombocytopenia (14%), neutropenia (12%), lymphopenia and pneumonia 
(6%), leukopenia and hypertension (5% each), hypercalcemia (3%).

TEAEs leading to DC of study treatment in 4% of subjects; none considered 
drug related.

SAEs in 34% of subjects; most common were pneumonia (6%) and pyrexia, 
general physical health deterioration, and hypercalcemia (3% each).

Deaths due to progressive disease (7%), and 3 (2%) due to TEAEs 
(cardiorespiratory arrest in the setting of H1N1 influenza, general physical 
health deterioration secondary to aspiration pneumonia, and pneumonia). 
None of the fatal TEAEs were considered related to daratumumab.
SMM2001 (smoldering 
MM, 122)

SAEs were reported for 15 subjects (24% in the long intense, 2% in 
intermediate, and 10% in short intense treatment groups). No IRRs or deaths.
MMY1004 -
Relapsed/Refractory MM 
(subcutaneous 
administration, 53)

A total of 8 subjects received daratumumab-MD 1200 mg and 45 subjects 
received daratumumab- MD 1800 mg.

Most common TEAEs (≥20% of all subjects): upper respiratory tract infection 
(1200 mg: 38%; 1800 mg: 22%), insomnia (1200 mg: 38%; 1800 mg: 11%), 
decreased appetite (1200 mg: 38%; 1800 mg: 7%), thrombocytopenia (1200 mg: 
38%; 1800 mg: 18%), viral upper respiratory tract infection (1200 mg: 25%; 1800 
mg: 13%), vomiting (1200 mg: 25%; 1800 mg: 13%), hyperuricaemia (1200 mg: 
25%; 1800 mg: 2%), hypokalaemia (1200 mg: 25%; 1800 mg: 4%), blood 
creatinine increased (1200 mg: 25%; 1800 mg: 4%), anemia (1200 mg: 25%; 
1800 mg: 33%), fatigue (1200 mg: 25%; 1800 mg: 20%), pyrexia (1200 mg: 25%; 
1800 mg: 27%), diarrhea (1200 mg: 25%; 1800 mg: 22%), headache (1200 mg: 
25%; 1800 mg: 18%), cough (1200 mg: 25%; 1800 mg: 13%), epistaxis (1200 
mg: 25%; 1800 mg: 4%), hypertension (1200 mg: 25%; 1800 mg: 7%), rhinitis 
allergic (1200 mg: 25%; 1800 mg: 2%), nasal congestion (1200 mg: 25%; 1800 
mg: 2%), rectal hemorrhage (1200 mg: 25%; 1800 mg: 0%), and asthenia (1200 
mg: 13%; 1800 mg: 20%),

Grade 3/4 TEAEs: in 63% and 49% of subjects in the 1200 mg and 1800 mg 
cohorts, respectively. The most frequently reported Grade 3 or 4 TEAEs were in 
the Blood and Lymphatic System Disorders System Organ Class (SOC), reported 
in 38% and 31% of subjects in the 1200 mg and 1800 mg cohorts, respectively. 
Two of 8 (25%) subjects in the 1200 mg cohort and 4% in the 1800 mg cohort 
had Grade 3 or 4 hypertension.

SAEs: SAEs were reported in 26% of all subjects: 50% and 31% of subjects in 
the 1200 mg and 1800 mg cohorts, respectively. The most frequently reported 
serious TEAEs were in the Infections and Infestations SOC (1200 mg: 38%, 
1800 mg: 16%), the Nervous System Disorders SOC (1200 mg: 13%, 1800 mg: 
4%), and the Respiratory, thoracic and mediastinal disorders (1200 mg: 13%, 
1800 mg: 2%).

No TEAEs leading to DC of study treatment. One subject in the 
daratumumab-MD 1800 SC cohort died within 30 days of the last dose of 
study drug from progressive disease.


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MMY3010
(Relapsed/Refractory MM,
687)

SAEs in 38% of subjects; most common were pneumonia (4%), hypercalcemia 
(3%), pyrexia (3%), dyspnea (2%), thrombocytopenia (2%), acute kidney injury 
(2%), and back pain (2%).

Deaths: Forty-eight subjects (7%) reported TEAEs with an outcome of death.
LYM2001 (non-Hodgkin’s
lymphoma, 36)

All subjects had at least 1 or more TEAE. Most common TEAEs were reported 
from SOC of respiratory, thoracic and mediastinal disorders; cough (DLBCL 
cohort: 47%; FL cohort: 38%; MCL cohort: 80%); SOC of gastrointestinal 
disorders: abdominal pain (DLBCL cohort: 13%; FL cohort: 31%; MCL cohort: 
20%), and nausea (DLBCL cohort: 33%; FL cohort: 6%; MCL cohort: 40%), and 
SOC of general disorders and administration site conditions; fatigue (DLBCL 
cohort: 27%; FL cohort: 19%; MCL cohort: 20%), and pyrexia (DLBCL cohort: 
13%; FL cohort: 25%; MCL cohort: 40%)

SAEs in 15 subjects. All SAEs were reported in 1 subject each, except for 
febrile neutropenia, pneumonia, general physical health deterioration, and 
pyrexia (2 subjects each).

Deaths in 4 subjects: 2 due to progressive disease and 2 due to an adverse event 
(chronic kidney disease and pneumonia).

IRRs – none.
Daratumumab Combination Trials
GEN503 and MMY3003
(integrated; 
daratumumab 
in 
combination 
with 
lenalidomide 
and 
dexamethasone (318)

Most common TEAEs (DRd treatment group): neutropenia (64%), diarrhea 
(53%), upper respiratory tract infection (37%), fatigue (37%), anemia (36%), 
cough (34%), muscle spasms (31%), constipation (31%), thrombocytopenia 
(29%), viral upper respiratory tract infection (29%), nausea (28%), and pyrexia 
(25%).

Grade 3/4 TEAEs (DRd treatment group): 89%; most common, neutropenia 
(58%), anemia (16%), and thrombocytopenia (14%).

TEAEs leading to DC of treatment in 13% of subjects in the DRd treatment 
group; most common were pneumonia (4 subjects, 1.3%), general physical 
health deterioration (3 subjects, 0.9%), and septic shock (2 subjects, 0.6%).

SAEs (DRd treatment group) in 63% of subjects; most common were 
pneumonia (13%), influenza, febrile neutropenia (4%) and pyrexia (4% each), 
and bronchitis, pulmonary embolism, lower respiratory tract infection, diarrhea 
(3% each).

Deaths (DRd treatment group):7% of subjects died within 30 days of the last 
dose of study drug: 21 due to TEAEs and 1 due to disease progression.
MMY1001
(daratumumab 
in 
combination 
with 
pomalidomide 
and 
dexamethasone, 240)

Most common TEAEs: neutropenia (81%), anemia (55%), fatigue (52%), 
diarrhea (50%), thrombocytopenia (43%), cough (41%), leukopenia (39%), 
constipation (36%), nausea (34%), dyspnea (33%), pyrexia (33%), upper 
respiratory tract infection (32%), muscle spasms (29%), vomiting (28%), 
arthralgia (26%).

Grade 3 or 4 TEAEs in 99% of subjects; most common were neutropenia 
(79%), anemia (28%), leukopenia (24%), thrombocytopenia (19%), 
lymphopenia (14%), and pneumonia and fatigue (13% each).

TEAEs leading to DC of treatment in 16% of subjects (no single AE reported 
in >1 subject).

SAEs in 57% of subjects; most common were pneumonia (12%), sepsis (7%), 
febrile neutropenia (5%), fall (4%), anemia, dyspnea, small intestinal 
obstruction, and urinary tract infection (3% each).

Deaths: 9% of subjects died during study treatment or within 30 days after the 
last dose of study drug; 7 due to AEs and 2 deaths due to disease progression.


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MMY1001 
(daratumumab 
plus 
bortezomib 
and 
dexamethasone, 30)

SAEs were reported for 3 subjects in the DVd arm (Hyperglycemia [1 subject], 
soft tissue infection, pneumonia, prerenal failure, diarrhea, respiratory failure 
[1 subject], laboratory test interference [1 subject]. In DVMP arm, SAEs were 
reported in 1 subject (cardiac failure). No subjects in the D-VTd arm were 
reported to have SAEs.

No deaths reported.
MMY1001 (daratumumab 
in 
combination 
with 
carfilzomib/dexamethasone
+/- lenalidomide DKd = 
20, DKRd = 20)

AEs of Interest – Cardiac Events: In the DKd arm, cardiac disorder TEAEs of 
interest were reported in 15% of subjects; 4 (5%) subjects had a Grade 3 or 
Grade 4 event. No cardiac disorder TEAEs of Grade 5 was reported. In the 
DKRd arm, cardiac disorder TEAEs of interest were reported in 41% of 
subjects, with 1 subject (5%) having a Grade 3 or Grade 4 event (congestive 
heart failure) that was also an SAE. No Grade 5 events were reported.

SAEs reported in 32% of subjects in the DKd arm (n=85); most common was 
pneumonia (7%). SAEs were reported in 46% of subjects in the DKRd arm 
(n=22). The most frequently reported SAEs were pulmonary embolism (n=3; 
14%) and influenza and pyrexia (n=2; 9% each). All other SAEs were reported 
in 1 subject each.

One death in the DKd arm due to progressive disease.
MMY1005 
(daratumumab 
in 
combination with
bortezomib 
and 
dexamethasone; Japan, 8)

SAEs in 3 subject each (herpes zoster, prostate cancer, nasopharyngitis).

No IRRs.

No deaths.
MMY3004 
(daratumumab 
in 
combination 
with 
bortezomib 
and 
dexamethasone, 243)

Most common TEAEs were thrombocytopenia (60%), peripheral sensory 
neuropathy (50%), diarrhea (35%), upper respiratory tract infection (33%), 
anemia (28%), and cough (28%).

Grade 3/4 AEs were reported in 81% of subjects; most common were 
thrombocytopenia (46%), anemia (15%), and neutropenia (14%).

TEAEs leading to DC of treatment were reported for 10% of subjects; most 
common were pneumonia (4 subjects; 2%), and cardiac failure congestive
(2 subjects; 0.8%).

SAEs in 50% of subjects; most common were pneumonia (10%), and anemia, 
bronchitis, thrombocytopenia, atrial fibrillation, upper respiratory tract infection, 
and pyrexia (3% each).

Deaths:15 subjects died within 30 days of the last dose of study drug; 13 deaths 
were due to TEAEs and 2 were due to disease progression.
MMY3007 (daratumumab 
in 
combination 
with 
bortezomib, melphalan and 
prednisone, 700)

Most common TEAEs were thrombocytopenia (51%), neutropenia (51%), 
anemia (33%), peripheral sensory neuropathy (31%), diarrhea (24%), pyrexia 
(22%), nausea (21%), upper respiratory tract infection (20%) and constipation 
(18%).

Grade 3/4 TEAEs were reported in 74% of subjects, with neutropenia (39%) 
and thrombocytopenia (36%) being the most frequently reported.

SAEs were reported in 37% of subjects, with pneumonia being the most 
frequent (7%).

Deaths: Thirty-eight (5%) subjects had a Grade 5 TEAE.
MMY3008 
(daratumumab 
in 
combination 
with 
lenalidomide 
and 
dexamethasone, 729)

Most common TEAEs were neutropenia (39%), diarrhea (34%), constipation 
(33%), fatigue (28%), anemia (25%), nausea and edema peripheral (24% each), 
insomnia (22%), muscle spasms (21%), and asthenia (20%).

Grade 3/4 TEAEs were reported in 70% of subjects, with neutropenia being the 
most frequently reported (32%).

SAEs were reported in 50% of subjects; most common were pneumonia (6%), 
pyrexia and pulmonary embolism (3% each).

Deaths Thirty-four subjects (5%) had a Grade 5 TEAE. 


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Monitoring response on Daratumumab
Daratumumab has been found to interfere with serum protein electrophoresis (SPEP) and immunofixation 
electrophoresis (IFE) assays due to co-migration of daratumumab with patients’ M protein which impedes accurate 
quantification of endogenous M proteins.18,27 Given this can pose a problem when SPEP and IFE assays are needed to 
measure disease response, a clinical assay known as the daratumumab IFE reflex assay (DIRA) has been developed 
to mitigate daratumumab interference with IFE.27 DIRA uses a mouse anti-daratumumab antibody that binds to 
daratumumab and shifts the migration of daratumumab away from the M protein.27 The DIRA assay has been utilized 
in clinical trials of daratumumab to confirm disease response, and the assay’s specificity, reproducibility, and ability 
to distinguish daratumumab mAb from endogenous M protein has been validated.9
In summary, daratumumab has been well tolerated and has demonstrated encouraging response rates in clinical trials 
both as a single agent and in combination regimens in the relapsed/refractory setting and now more recently in the 
frontline setting. Moreover, daratumumab in combination regimens has maintained a favorable safety profile without 
significant increase in toxicities. 
Azacitidine
Azacitidine is FDA approved for the treatment of all subtypes of myelodysplastic syndrome (MDS) and was recently 
approved in 2018 in combination with venetoclax for newly diagnosed AML in patients who were  75 years of age 
or had comorbidities that precluded the use of intensive induction chemotherapy. 
Azacitidine is thought to have two main mechanisms of antineoplastic action—cytotoxicity, resulting from 
incorporation into RNA and DNA, and DNA hypomethylation, restoring normal growth control and differentiation in 
hematopoietic cells. Induction of DNA hypomethylation appears to require lower 
azacitidine doses than does cytotoxicity, as the concentration of azacitidine required for 
maximum inhibition of DNA methylation in vitro does not suppress DNA synthesis. Upon 
uptake by cells, azacitidine is phosphorylated to 5-azacytidine monophosphate by uridine-
cytidine kinase and then to diphosphate and triphosphate by pyrimidine monophosphate 
and diphosphate kinases, respectively. 5-azacitidine triphosphate is incorporated into 
RNA, disrupting nuclear and cytoplasmic RNA metabolism and inhibiting protein 
synthesis. 5-azacitidine diphosphate is reduced by ribonucleotide reductase to 5-
azacitidine-deoxycytidine diphosphate, which is then phosphorylated by nucleoside 
diphosphate kinases to 5-azadeoxycitidine triphosphate, which is incorporated into 
DNA. As a result, DNA synthesis is inhibited. Azacitidine is most toxic during the 
S-phase of the cell cycle, but the predominant mechanism of cytotoxicity has not been established. Azacitidine inhibits 
methylation of replicating DNA by stoichiometric binding with DNA methyltransferase 1, resulting in DNA 
hypomethylation. DNA hypermethylation at the CpG islands has been described in myelodysplastic syndrome (MDS), 
acute myelogenous leukemia (AML), and other malignancies.
Clinical Studies
Effectiveness of azacitidine in high risk MDS was demonstrated in azacitidine-001, a Phase III international, 
multicenter, randomized controlled trial comparing azacitidine administered subcutaneously (SubQ) at 75 mg/m2 for 
7 consecutive days every 28 days to conventional care regimen (CCR) which included either best supportive care, low 
dose cytarabine, or intensive chemotherapy as selected by investigators before randomization for 358 patients with 
high risk MDS.28 After a median follow-up of 21.1 months, the median overall survival was 24.5 months for the 
Molecular structure of Aza


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azacitidine group vs 15 months for the conventional care group. Azacitidine resulted in higher rates of hematologic 
responses assessed by International Working Group (IWG) 2000 criteria and longer durations of response with median 
of 13.6 months in the azacitidine group compared to 5.2 months in the conventional care group. At 2 years, 50.8% of 
patients in the azacitidine group were alive compared with 26.2% in the conventional group.28 Azacitidine prolonged 
OS compared with CCR regardless of IPSS cytogenetic risk group. Subset analysis of the data has shown that the drug 
can be used safely in even the oldest patients with MDS and is superior to treatment with other established regimens, 
such as low-dose cytarabine.29 Azacitidine-001 showed that achievement of hematologic response was associated with 
improved OS with azacitidine treatment, and patients who achieved a hematologic response to azacitidine had 
significantly prolonged OS and reduced risk of death versus patients who achieved a response to CCR. In addition, 
stable disease or achievement of complete response (CR), marrow CR (mCR), partial response (PR) or hematologic 
response with alternative dosing schedules of azacitidine has been shown to significantly reduce the risk of death 
versus disease progression. In the azacitidine-001 study, the median time to first response with azacitidine was 2 cycles 
(range: 1–16), with 91% of responding patients achieving first response within 6 cycles and all but 1 achieving first 
response by cycle 12. Continued treatment improved response quality in 48% of patients, with a median of 3 cycles 
from first to best response. By cycle 12, 92% of responding patients achieved their best response.28 Based on this 
experience, some clinicians have advised administering at least six cycles of azacitidine, and the National 
Comprehensive Cancer Network guidelines for MDS recommend at least four to six cycles of azacitidine before 
assessing for treatment failure. 
Studies performed by Cancer and Leukemia Group B (CALGB) demonstrated that azacitidine had activity in MDS 
and AML when given at 75 mg/m2 by intravenous infusion (CALGB 8421) or subcutaneous injection (CALGB 8921 
and 9221) daily for 7 days in a 28-day cycle.30,31 The crossover phase III CALGB 9221 trial which was a multicenter 
randomized, open-label trial designed to compare the safety and efficacy of subcutaneous azacitidine with supportive 
care (observation group) in patients with any of the five subtypes of MDS, showed a significant effect of azacitidine 
on response rates (P< 0.0001), with an overall response rate of 60% in patients receiving azacitidine compared with 
5% in those receiving only supportive care. Median time to leukemic transformation or death was 21 months for 
azacitidine arm versus 13 months for supportive care arm. Transformation to acute myelogenous leukemia occurred 
in 15% of patients on the azacitidine arm and in 38% of patients in the supportive care arm. Median OS was 18 months 
for azacitidine and 11 months for supportive care arm.30,31 Response rates in these CALGB trials were similar in 
subjects with all MDS subtypes and with AML.
In a sub-analysis of azacitidine-001 of low-blast- count AML (20%–30% blasts) the 2-year OS rate for patients treated 
with azacitidine was 50%, and the median OS was 24.5 months compared with 16.0 months for patients treated with 
CCR and 16.4 months for patients not preselected to receive intensive chemotherapy (best supportive care or low-dose 
cytarabine). Survival benefits with azacitidine may not require CR because CR rates were similar for azacitidine versus 
CCR (18% vs. 16%), whereas rates of red blood cell transfusion independence were significantly higher with 
azacitidine (41% vs. 18%).32
Recently, the global phase III randomized open-label azacitidine- AML-001 study of azacitidine (75 mg/m2 per day 
on days 1–7 in 28-day cycles) versus CCR extended these findings in patients aged 65 years with newly diagnosed 
AML with >30% blasts. Azacitidine treatment demonstrated a clinically meaningful improvement in median OS of 
10.4 months versus 6.5 months with CCR. Azacitidine significantly improved 1-year survival: 46.5% versus 34.2% 
with CCR, a 12.3% difference. In patients who did not achieve CR, median OS was prolonged from 6.9 months with 
azacitidine versus 4.2 months with CCR.33
Azacitidine in combination with venetoclax was approved in newly diagnosed AML in elderly patients  75 years of 
age or patients who had comoribidities that precluded the use of intensive induction chemotherapy based on M14-358 
(NCT02203773), a large multicenter phase 1b dose-escalation and expansion study showing that the novel 


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combination of venetoclax with decitabine or azacitidine was effective and well tolerated in elderly patients with 
AML. With a median time on study of 8.9 months, 67% of patients (all doses) achieved complete remission (CR) + 
CR with incomplete count recovery (CRi), with a CR + CRi rate of 73% in the venetoclax 400 mg + HMA cohort. 
Patients with poor-risk cytogenetics and those at least 75 years old had CR + CRi rates of 60% and 65%, respectively. 
The median duration of CR + CRi (all patients) was 11.3 months, and median overall survival (mOS) was 17.5 months; 
mOS has not been reached for the 400-mg venetoclax cohort.34
Azacitidine in Multiple Myeloma
While azacitidine is currently not approved in MM, there have been pre-clinical studies studying the role of azacitidine 
and DNMTi in MM. Studies have found that the DNA methylation score can predict for the sensitivity of human 
myeloma cell lines and primary MM cells of patients to DNMTi.35 Azacitidine has also been shown to exert apoptosis-
inducing and growth-inhibiting effects on MM cell lines and its mechanism may be related to the decrease of BCL-
2/BAX ratio, caspase-3 activation, and the arrest of the cell cycle.36 Another study found that azacitidine induces 
apoptosis of MM cells by downregulating two crucial cell survival pathways in MM by inhibiting the elaboration of 
IL-6 receptor alpha and IL-6 resulting in reduced expression of phosphor-STAT3 and Bcl-xl and by inhibiting both 
nuclear factor-kappaB nuclear translocation and DNA binding.37
Clinically DNMTi’s such as azacitidine are currently being investigated in MM as monotherapy and in combination 
with standard therapies such as lenalidomide and dexamethasone (NCT01155583, NCT01050790). A recent phase 1b 
single center 3 x 3 dose escalation study looking at oral azacitidine (CC-486) in combination with lenalidomide and 
dexamethasone in patients with RRMM who had previously failed lenalidomide found the ORR was 37.5% at the 
MTD and clinical benefit rate was 50%. Median OS was 10.3 months and median PFS was 2.6 months. This study 
found that oral azacitidine, lenalidomide, and dexamethasone produced meaningful clinical responses in heavily 
treated Len refractory MM patients.38 However to this data there has been no trial assessing the safety and efficacy of 
daratumumab in combination with azacitidine and dexamethasone.
Standard Dosing
The standard dose of azacitidine, based on the trials leading to its approval in AML and MDS, is 75 mg/m2 
intravenously or subcutaneously for 7 days every 28 days.28,30,31,34 Because of the difficulty of continued administration 
for 7 days, in a randomized trial, MDS patients were given azacitidine subcutaneously in one of three schedules every 
4 weeks for six cycles: azacitidine 5-2-2 (75 mg/m2 daily for 5 days, followed by 2 days of no treatment, and then 75 
mg/m2 daily for 2 days for a total dose of 525 mg/m2 per cycle), azacitidine 5-2-5 (50 mg/m2 daily for 5 days, followed 
by 2 days of no treatment, and then 50 mg/m2 daily for 5 days for a total dose of 500 mg/m2 per cycle), or azacitidine 
5 (75 mg/m2 for 5 days for a total dose of 375 mg/m2).39 All three alternative dosing regimens produced hematological 
improvements, red blood cell transfusion independence, and safety responses consistent with the approved azacitidine 
regimen. However, results suggest that the azacitidine 5 dosing regimen may be better tolerated with a more convenient 
dosing schedule than the two alternative dosing regimens.39
Safety
With respect to safety of azacitidine, in the CALGB 9921 trial, >95% patients in both groups reported treatment-
associated adverse events. azacitidine-treated subjects reported more frequently than observation arm subjects 
gastrointestinal events (nausea, vomiting, diarrhea, constipation, and anorexia), neutropenia, febrile neutropenia, 
thrombocytopenia, injection site events, arthralgia, dizziness, dyspnea, cough, and myalgia. Serious adverse events 
occurred more frequently in azacitidine-treated patients (60%) than in observation patients (36%). Serious adverse 
events most commonly resulting in hospitalization were thrombocytopenia, febrile neutropenia, fever, and pneumonia. 
There were no deaths attributed to azacitidine treatment. During the study periods, half of the deaths in the three trials 
were probably related to MDS and the other half were unrelated to MDS.31


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The most common reasons for azacitidine discontinuation, dose reduction, or therapy interruption were leukopenia, 
neutropenia, and thrombocytopenia. Patients who developed CR or PR first had further decreases in hematologic 
parameters. Most patients in both treatment arms received packed RBC and/or platelet transfusions and medications 
to treat adverse events. The frequency of adverse events decreased after the first two cycles of azacitidine therapy.31
The data described below reflect exposure to azacitidine for injection in 443 MDS patients from 4 clinical studies. 
Study 1 was a supportive-care controlled trial (subcutaneous administration), Studies 2 and 3 were single arm studies 
(one with subcutaneous administration and one with intravenous administration), and Study 4 was an international 
randomized trial (subcutaneous administration).
Table below presents adverse reactions occurring in at least 5% of patients treated with azacitidine for Injection in 
Study 4. Similar to Studies 1 and 2 described above, duration of exposure to treatment with azacitidine for Injection 
was longer (mean 12.2 months) compared with best supportive care (mean 7.5 months).
Table 1-2 Adverse Reactions Occurring In At Least 5% of Patients Treated With Azacitidine for 
Injection
Number (%) of Patients
Any Grade
Grade 3/4
Body 
System 
Adverse Reactionsa
Azacitidine 
for Injection
(N=175)
Best 
Supportive 
Care Only
(N=102)
Azacitidine 
for Injection
(N=175)
Best 
Supportive
Care Only 
(N=102)
Blood and lymphatic system disorders
Anemia
90 (51)
45 (44)
24 (14)
9 (9)
Febrile neutropenia
24 (14)
10 (10)
22 (13)
7 (7)
Leukopenia
32 (18)
2 (2)
26 (15)
1 (1)
Neutropenia
115 (66)
29 (28)
107 (61)
22 (22)
Thrombocytopenia
122 (70)
35 (34)
102 (58)
29 (28)
Gastrointestinal disorders
Abdominal pain
22 (13)
7 (7)
7 (4)
0
Constipation
88 (50)
8 (8)
2 (1)
0
Dyspepsia
10 (6)
2 (2)
0
0
Nausea
84 (48)
12 (12)
3 (2)
0
Vomiting
47 (27)
7 (7)
0
0
General disorders and administration 
site conditions
Fatigue
42 (24)
12 (12)
6 (3)
2 (2)
Injection site bruising
9 (5)
0
0
0
Injection site erythema
75 (43)
0
0
0
Injection site hematoma
11 (6)
0
0
0
Injection site induration
9 (5)
0
0
0
Injection site pain
33 (19)
0
0
0
Injection site rash
10 (6)
0
0
0
Injection site reaction
51 (29)
0
1 (1)
0
Pyrexia
53 (30)
18 (18)
8 (5)
1 (1)
Infections and infestations
Rhinitis
10 (6)
1 (1)
0
0
Upper respiratory tract infection
16 (9)
4 (4)
3 (2)
0
Urinary tract infection
15 (9)
3 (3)
3 (2)
0
Investigations
Weight decreased
14 (8)
0
1 (1)
0


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Metabolism and nutrition disorders
Hypokalemia
11 (6)
3 (3)
3 (2)
3 (3)
Nervous system disorders
Lethargy
13 (7)
2 (2)
0
1 (1)
Psychiatric disorders
Anxiety
9 (5)
1 (1)
0
0
Insomnia
15 (9)
3 (3)
0
0
Renal and urinary disorders
Hematuria
11 (6)
2 (2)
4 (2)
1 (1)
Respiratory, thoracic and mediastinal
disorders
Dyspnea
26 (15)
5 (5)
6 (3)
2 (2)
Dyspnea exertional
9 (5)
1 (1)
0
0
Pharyngolaryngeal pain
11 (6)
3 (3)
0
0
Skin and subcutaneous tissue disorders
Erythema
13 (7)
3 (3)
0
0
Petechiae
20 (11)
4 (4)
2 (1)
0
Pruritus
21 (12)
2 (2)
0
0
Rash
18 (10)
1 (1)
0
0
Vascular disorders
Hypertension
15 (9)
4 (4)
2 (1)
2 (2)
In Studies 1, 2 and 4 with subcutaneous administration of azacitidine for injection, adverse reactions of neutropenia, 
thrombocytopenia, anemia, nausea, vomiting, diarrhea, constipation, and injection site erythema/reaction tended to 
increase in incidence with higher doses of azacitidine for injection. Adverse reactions that tended to be more 
pronounced during the first 1 to 2 cycles of subcutaneous treatment compared with later cycles included 
thrombocytopenia, neutropenia, anemia, nausea, vomiting, injection site erythema/pain/bruising/reaction, 
constipation, petechiae, dizziness, anxiety, hypokalemia, and insomnia. There did not appear to be any adverse 
reactions that increased in frequency over the course of treatment.
Overall, adverse reactions were qualitatively similar between the intravenous and subcutaneous studies. Adverse 
reactions that appeared to be specifically associated with the intravenous route of administration included 
infusion site reactions (e.g. erythema or pain) and catheter site reactions (e.g. infection, erythema, or 
hemorrhage).
Most Commonly Occurring Adverse Reactions (Subcutaneous or Intravenous Route): nausea, anemia, 
thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia, 
ecchymosis. The most common adverse reactions by intravenous route also included petechiae, rigors, weakness 
and hypokalemia.
Pharmacokinetics
In terms of pharmacology of azacitidine, it is rapidly absorbed following subcutaneous administration. Maximum 
plasma concentration is attained in about 30 minutes. Azacitidine is widely distributed, and is rapidly eliminated, with 
a mean plasma half-life of about 41 minutes.40
Metabolism of azacitidine involves deamination by cytidine deaminase followed by opening of the ring structure.41 
Azacitidine and its metabolites are primarily excreted by the kidneys. The effects of intrinsic factors such as age, 
gender, race, renal impairment, or hepatic impairment on the pharmacokinetics of azacitidine have not been studied. In 


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vivo drug-drug interaction studies have not been conducted.40 In vitro studies in cultured human hepatocytes indicate 
that azacitidine at a clinically relevant concentrations is not an inducer of CYP 1A2, 2C19, or 3A4/5.40
1.3
Rationale for the Proposed Study
While daratumumab is well tolerated and has high efficacy, not all patients respond and many patients eventually 
develop progressive disease and resistance to daratumumab. These patients often have poor prognosis and limited 
treatment options. A retrospective study presented at ASH 2018 looking at MM patients who have progressed on 
daratumumab found that these patients have a median OS of 5.3 months and a post-daratumumab regimen ORR of 
34% with limited treatment options. Another study analyzing outcomes of 275 MM patients at 14 academic centers 
with disease refractory to CD38 MoABs (daratumumab and isatuximab) found a median OS for the entire cohort of 
8.6 months ranging from 11.2 months for patients not simultaneously refractory to an IMiD agent and a proteasome 
inhibitor to 5.6 months for penta-refractory patients (refractory to CD38 MoAb, 2 PIs, and 2 IMiDs). Overall response 
rate to first regimen after relapse post CD38 MoAB was 31% with median PFS and OS of 3.5 and 9.3 months. These 
studies demonstrate that MM patients refractory to CD38 MoAb such as daratumumab have poor prognosis and limited 
treatment options. Thus developing ways to improve the efficacy of daratumumab and overcome the resistance to 
daratumumab are very much in need, especially as trials have progressively lead to daratumumab’s approval not only 
in the relapsed refractory setting but also in the frontline setting for MM patients. 
Pre-clinical data shows that CD38 expression on MM cells is associated with response to daratumumab therapy and a 
significant association has been seen between CD38 expression and daratumumab-mediated antibody-dependent 
cellular cytotoxicity (ADCC) as well as complement-dependent cytotoxicity (CDC) in ex vivo patients’ samples with 
MM.42,43 Pre-clinical data also shows that there is rapid but reversible loss of cell surface CD38 expression on MM 
cells during daratumumab treatment which may subsequently lead to immune escape and resistance to daratumumab 
and thus disease progression.19,43 There are several possible explanations for the reduction of CD38 levels during 
daratumumab treatment: 1) daratumumab may select for tumor cells with lower CD38 expression while preferentially 
eliminating MM cells with high CD38 levels 2) downregulation of CD38 may be an active process to evade 
daratumumab-mediated killing 3) in vitro studies suggest that binding of daratumumab to CD38 may cause 
redistribution of CD38 molecules 4) trogocytosis of CD38-daratumumab complexes and direct internalization may 
also result in a loss of CD38. This pre-clinical data showing that CD38 is a predictor of response to daratumumab and 
that loss of CD38 occurs during daratumumab treatment, suggests that methods to upregulate CD38 expression can 
increase the efficacy of daratumumab and decrease the resistance and immune escape to daratumumab. Thus efforts 
are underway to study the regulation of CD38 in MM.
Recent studies have shown that DNA methylation patterns change during MM progression, and clinically aggressive 
subtypes such as plasma cell leukemias and high risk (4,14) MM have hypermethylation.44-46 DNA hypermethylation 
has been associated with heterochromatin formation and inactivation of tumor suppressor genes.47 DNA 
methyltransferases (DNMTs) methylate cytosine residues in CpG islands and remodel chromatin. Currently two 
DNMT inhibitors (DNMTis) have been approved for treatment of acute myeloid leukemia and myelodysplastic 
syndrome: azacitidine and decitabine (DEC). These cytidine analogs function by incorporating into genome of 
proliferating cells during DNA synthesis, covalently binding 
DNMTs, targeting them for proteasomal degradation and causing 
passive loss of cytosine methylation in daughter cells.47 
Based on analysis of publicly-available ENCODE data, Dr. Arun 
Wiita’s lab at UCSF found a CpG island in the first exon of CD38 
and hypothesized that DNA methylation represses CD38 
expression. CD38 was previously identified as a differentially 
methylated region in myeloma patient samples with a negative 
CpG island, DNA methylation and expression of CD38 gene


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correlation between gene expression and DNA methylation.45 Dr. Wiita’s lab performed additional analysis of DNA 
methylation and gene expression data in three 
independent MM datasets and found an inverse 
correlation between CD38 promoter methylation status 
and gene expression between normal plasma cells and 
malignant plasma cells in MM. These findings 
supported 
our 
hypothesis 
of 
methylation-level 
regulation of CD38 transcription, and suggested that 
DNMTi treatment with azacitidine may be able to increase 
CD38 transcription in MM cells and that this increase can be 
exploited to augment the efficacy of daratumumab-mediated lysis of MM cells.
To test the role of DNA methylation in regulation of CD38 expression, a panel of MM cell lines were treated with 
increasing doses of DNMTi azacitidine, and CD38 cell surface expression was measured by flow cytometry. Cells 
were treated for either 3 days or 5 days with flow cytometry analysis at 7 days, which allowed for DNMTi 
incorporation into newly synthesized DNA in replicating cells leading to DNMT degradation and loss of DNA 
methylation. This has induced a 1.2-2.4 increase in CD38 MFI in a dose dependent manner across all four cell lines. 
Importantly, at doses of > 1M azacitidine appears to upregulate CD38 equally if not more than previously 
investigated doses of the known inducers ATRA and Panobinostat.42,48 
Next we determined whether upregulated CD38 MFIs 
increased functional daratumumab efficacy. Using an 
immortalized transgenic NK cell line to mediate lysis, we 
observed a significant increase in antibody dependent 
cellular cytotoxicity (ADCC) against DNMTi treated vs 
control. Importantly, this increase in ADCC was 
consistent with CD38 MFI upregulation. For example, 2 
M azacitidine increased CD38 MFI 1.37  0.03 fold and 
increased ADCC lysis to 50.23  6.84 %. In addition, the 
additive effect of DNMTi and ATRA on CD38 
upregulation was also seen in ADCC assays.
Pre-clinical data from Dr. Wiita’s lab shows that by de-
repressing the transcription of CD38 and upregulating the 
expression of CD38 on MM plasma cells, azacitidine can potentially increase the ADCC and efficacy of daratumumab 
in MM patients and help reverse daratumumab resistance that develops over time caused by loss of CD38 expression. 
However, there is no prior trial that has assessed the safety and efficacy of daratumumab combined with azacitidine 
for treatment of MM. This is the first study designed to assess the safety and efficacy of azacitidine combined with 
daratumumab and dexamethasone to see if the synergy of azacitidine and daratumumab, through upregulation of CD38 
expression, can improve the efficacy of daratumumab alone and overcome the resistance to daratumumab that 
develops over time. 
The main risk of this trial and combining azacitidine and daratumumab is toxicity, particularly cytopenias and 
infections, though we anticipate that the combination will be safe and there are clear dose modifications and safety 
stopping rules in place for DLTs. The safety lead-in to the trial will allow for formal safety analysis in the beginning 
of the trial and mitigate the risks of toxicity and ensure that the patients enrolled in this phase II study are treated with 
a dose combination of azacitidine and daratumumab with an acceptable safety profile. Daratumumab has already been 
approved in MM and demonstrated adequate safety in combination with other agents such as revlimid, pomalidomide, 
and velcade. Azacitidine is approved in MDS and leukemia and demonstrated an acceptable safety profile in other 
non-myeloma hematologic malignancies in combination with other agents that also cause cytopenias such as 
venetoclax.34 It is anticipated that the combination of daratumumab and azacitidine, which have acceptable safety 
Aza treatment increases CD38 cell surface expression
Treatment with Aza significantly increases ADCC of Dara and 
the effect is additive with ATRA


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profiles for currently approved indications, will have a manageable safety profile in combination. We believe that the 
potential benefits of improving response rates, CR rates, PFS and OS of relapsed refractory MM patients with poor 
prognosis by combining daratumumab and azacitidine outweighs the risks of possible increased toxicity with this 
combination.
1.4
Rationale for the Dose Selection/Regimen 
Daratumumab will be administered subcutaneously at the currently approved dose of 1800 mg, once weekly for 8 
doses, then every two weeks for 8 doses, and then every 4 weeks thereafter until disease progression or unacceptable 
toxicity.  First dose will be administered on Day 1 of Cycle 1. The rationale behind this dosing regimen stems from 
the GEN501 and SIRIUS trials that evaluated the safety and efficacy of daratumumab monotherapy.10,20 An analysis 
to understand and justify the recommended dose and dosing schedule for daratumumab in MM patients from a 
quantitative pharmacologic perspective was done. This analysis found that there was a maximum effect relationship 
between daratumumab exposure (i.e. maximal trough concentration) and overall response rate (ORR) and between 
daratumumab and target saturation. 
The daratumumab subcutaneous dose of 1800 mg was chosen based on the COLUMBA study49 which showed that 
subcutaneous daratumumab was non-inferior to intravenous daratumumab in terms of efficacy and pharmacokinetics 
and had a consistent safety profile to that of intravenous daratumumab in patients with relapsed refractory multiple 
myeloma An overall response was seen in 108 (41%) of 263 patients in the subcutaneous group and 96 (37%) of 259 
in the intravenous group (relative risk 1·11, 95% CI 0·89–1·37).  The geometric means ratio for Ctrough was 107·93% 
(90% CI 95·74–121·67), and the maximum Ctrough was 593 μg/mL (SD 306) in the subcutaneous group and 522 
μg/mL (226) in the intravenous group. 
Azacitidine will be given subcutaneously or IV at standard dose 75 mg/m2 for 5 days consecutively every 4 weeks 
starting day -7 to day -3 of Cycle 1 (before first dose of daratumumab). The starting dose regimen of 75 mg/m2 is 
based on prior trials leading to azacitidine approval in MDS and AML, including the azacitidine-00128 and CALGB 
8421, 8921, and 9221 trials.30,31 The dosing of azacitidine for 5 days consecutively (instead of 7) will be used for both 
patient convenience and to minimize toxicity. This is based on a study that showed that 5 days of consecutive 
azacitidine had similar efficacy to 7 days.39 Azacitidine prescribing information created by Celgene suggests dose 
adjustments for azacitidine based on hematologic toxicity and our dose de-escalation follows these 
recommendations.50 Dexamethasone 40 mg will be given orally once weekly on days 1, 8, 15, and 22 of each four-
week cycle starting day 1 of cycle 1 for at least the first two cycles. Dose modifications for azacitidine and 
dexamethasone based on toxicities are outlined in Section 5.5 There will be no dose modification for daratumumab. 
Treatment will be continued until progression or patient unable to tolerate treatment due to toxicities.


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1.5
Correlative Studies
The correlative studies for this trial stem from preclinical work done in Dr. Arun Wiita’s lab at UCSF. Dr. Priya 
Choudhry and Dr. Arun Wiita’s work was recently published in Leukemia and is described below.
1)
To determine the in vivo change in CD38 expression on plasma cells in MM patients exposed to azacitidine 
(primary objective)
Hypothesis:  Exposure to azacitidine will result in an increased surface expression of CD38, as determined by flow 
cytometry. 
Pre-clinical work done in Dr. Arun Wiita’s lab where a panel of MM cell lines (RPMI-8226, MM.1S, XG-1, KMS12-
PE) were treated with increasing doses of azacitidine and CD38 cell surface expression was analyzed by flow 
cytometry, showed that azacitidine consistently increased an increase in D38 median fluorescent intensity (MFI) in all 
cell lines. Wiita’s lab treated cells for either 3 days or 5 days with flow cytometry analysis at 7 days (3d+4 or 5d+ 2, 
respectively). This extra time allowed for DNMTi incorporation into newly synthesized DNA in replicating cells over 
two doublings, leading to DNMT degradation and loss of DNA methylation. 3d+4 and 5d+2 treatments induced a 1.2-
2.4 fold increase in CD38 MFI in a dose dependent manner for all four cell lines. 3 uM azacitidine, which is clinically 
equivalent to 75 mg/m2, consistently induced at least a 2 fold increase in CD38 MFI in all cell lines, in both the 3d+4 
and 5d+2 treatments. 
Figure: Azacitidine upregulates CD38 transcript 
expression. (A) Bar graph showing fold change in 
CD38 RNA (red) and cell surface protein (blue) in 
RPMI-8226 cells upon drug treatments. Data from 
3d+4 and 5d+2 azacytidine treatments are grouped 
together and compared to ATRA and panobinostat 
treatment. Data is presented as mean ± SD from a 
representative experiment from two independent 
experiments. (B) CD38 expression on primary MM 
cells upon azacytidine treatment. Grey lines separate 
different patient samples (IDs on x-axis). Colors in the 
legend indicate the drug and concentration used. The 
percentage of CD138+ cells in each sample are given 
in brackets underneath the IDs. Data are presented as 
mean ± SD from 3 replicate wells.


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The preclinical work done in Dr. Wiita’s lab further demonstrates that azacitidine also increases CD38 transcription 
in treated RPMI-8226 cells using qRT-PCR thus leading to its increased expression. Intriguingly, treatment with 
azacitidine appeared to induce higher fold changes in CD38 expression at the RNA level compared to cell surface 
expression. This indicates that there may be additional mechanisms regulating CD38 expression post-
transcriptionally. Though azacitidine is cleared very rapidly with respect to its pharmacokinetics, we hypothesize 
that the transcriptional effects of azacitidine will be prolonged and long-lasting due to incorporation into DNMT's 
and subsequent effects of drug on methylation after cellular division.
The following correlative studies will be done contingent upon funding.
2)
To assess in vivo changes in whole genome methylation, including CD38 specific methylation, after treatment 
with azacitidine via performing whole genome reverse-phase bisulfite sequencing. 
Hypothesis: Exposure to azacitidine will result in decreased overall methylation of the plasma cell genome and thus 
indirectly lead to increased CD38 expression.
Historically, determination of DNA methylation was largely confined to only a small fraction of the DNA 
methylome, usually to regulatory regions like gene promoters which are frequently associated with the CpG-rich 
CpG islands.51 Initially, based on analysis of publicly-available ENCODE data, Dr. Wiita’s lab found a CpG island in 
the first exon of CD38 and hypothesized that DNA methylation represses CD38 expression. CD38 was previously 
identified as a differentially methylated region in myeloma patient samples with a negative correlation between gene 
expression and DNA methylation. They further performed additional analyses of DNA methylation and gene 
expression data in three independent MM datasets (GSE43860, GSE17306 and GSE12453) and found an inverse 
correlation between CD38 promoter methylation status and gene expression between normal plasma cells and 
malignant plasma cells in MM. These findings suggested that DNMTs may regulate CD38 transcription. 
However, surprisingly in Dr. Wiita’s pre-clinical work, targeted bisulfite sequencing of the CD38 CpG island revealed 
almost complete hypomethylation at baseline in RPMI-8226 and KMS12-PE cells. Thus it was hypothesized that 
DNMTi treatment might instead upregulate CD38 indirectly. It was tested whether azacitidine upregulates CD38 via 
transcription factors PU.1 or ATF2 or through activation of interferon response, but this was not found to be true. It 
was tested whether DNMTi might function via TNF upregulation given TNF is regulated by DNA methylation 
and is known to upregulate CD38 expression in airway smooth muscle cells. Co-treatment with a TNF-neutralizing 
antibody completely abrogated azacitidine-induction of CD38 upregulation. Furthermore, azacitidine treatment indeed 
induced TNF secretion from RPMI-8226 cells. Finally, recombinant TNF increased surface CD38 in RPMI-8226 
Figure: Azacitidine treatment increases CD38 cell surface 
expression. (A) Bar graph of CD38 expression and cell 
survival upon treatment with azacytidine in the indicated cell 
lines. For each cell line the 3d, 3d+4 and 5d+2 treatments are 
compared side-by-side. Height of the bars indicates the fold 
change in CD38 MFI (left y-axis) and bold black line shows % 
cell viability (right y-axis). Both are normalized to DMSO 
treatment. Colors indicate the concentration of azacytidine 
used. Data are presented as mean ± SD from 2-3 independent 
experiments with triplicates in each experiment.  * indicates a 
significant difference from DMSO treatment (p  0.05 using a 
paired student’s t-test). (B) shows the histogram plots for CD38 
expression for one representative experiment in XG1 cells. 
Histograms from 3d+4 azacytidine treatment are compared to 
the known CD38 upregulators ATRA and Panobinostat. The 
drugs used are indicated on the left, and fold change in CD38 
MFI compared to DMSO control is given on the right. The grey 
dotted line indicates MFI in DMSO treated cells. 


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cells. These results therefore confirm that indirect mechanisms can mediate DNMTi-induced CD38 upregulation and 
suggest the TNF pathway may play a leading role in this process. We anticipate that there may be other indirect 
mechanisms by which DNMTi treatment upregulates CD38 and by doing whole genome reverse-phase bisulfite 
sequencing in patients pre and post azacitidine treatment, we hope to assess for other genes that may be involved in 
CD38 upregulation that are regulated by methylation. Many approaches to analyze the DNA methylome include a 
bisulfite conversion step during which unmethylated cytosines are converted to uracil, while methylated cytosines 
remain as cytosines. Subsequent PCR manifests unmethylated cytosines as thymines, thus, allowing discrimination 
between the unmethylated and methylated cytosines. The gold standard to address the complete DNA methylome 
is whole genome bisulfite sequencing (WGBS).51 
 
3)
To assess the in vivo changes in multiple myeloma tumor microenvironment with treatment of azacitidine via 
CyTOF
Hypothesis: Azacitidine will lead to changes in the multiple myeloma bone marrow tumor microenvironment that 
may have immunoregulatory and anti-tumor effects
CD38 CpG methylation at baseline. Targeted Bisulfite seq data visualized in UCSC browser. CD38 RefSeq RNAs and CpG island are depicted in blue and green 
respectively. The CpG Methylation track highlights each CpG site as a vertical bar. The label on the left of each CpG bar indicates the methylation ratio followed by percent 
methylation in brackets. For example, the first CpG labeled ‘4/6932 (0%)’ indicates 4 reads were methylated in 6932-fold sequencing read depth of coverage at this site, 
amounting to 0% methylation ratio. Data for RPMI-8226 is depicted here as an example. KMS12PE cell line was similarly completely hypomethylated. 
AZA induces CD38 upregulation via TNF upregulation. (A) RPMI-
8266 were co-treated with 3 M AZA treatment and either IgG1 
(control) or a neutralizing anti-TNF antibody (TNF). Data are 
represented as Fold Change in CD38 cell surface expression upon 3 
M AZA treatment normalized to DMSO treatment for the same 
Antibody treatment. TNF completely blocks surface induction of 
CD38 after Aza treatment. * indicates a significant difference between 
CD38 Fold change in IgG1- versus TNF- treated cells in individual 
experiments (p  0.05 using a paired student’s t-test). (B) TNF 
concentrations were measured in supernatants from RPMI-8266 cell 
line after Aza treatment. Data are represented as fold change in TNF 
concentration compared to DMSO.  X and Y represent independent 
experiments, and data are presented as mean ± SD from triplicate 
wells. X-norm and Y-norm are data from independent replicate 
experiments X and Y normalized to the live cell concentration 
measured at the time of supernatant collection. * indicates a significant 
difference between values from 3 M AZA treatment and DMSO 
control (p  0.05 using a paired student’s t-test). (C) Fold change in 
CD38 cell surface expression after 72-hour treatment of RPMI-8226 
cells with exogenously added recombinant TNF. Data are 
represented as mean ± SEM of two independent experiments. * 
indicates a significant difference (p  0.05 using a paired student’s t-
test).


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Azacitidine may upregulate expression of CD38 indirectly through altering the bone marrow tumor microenvironment, 
specifically through upregulation of inflammatory cytokines such as TNF alpha. Given the limited clinical data with 
regards to the use of azacitidine in multiple myeloma patients, there is very little known about the in vivo impact of 
azacitidine on bone marrow stromal tumor microenvironment. In leukemia, pre-clinical data shows that azacitidine 
has a variety of immunomodulatory effects on leukemic cell lines including upregulation of CD86, downregulation of 
INDO, downregulation of PI-9, downregulation of MHC-class I molecules, upregulation of PD-1, and increase of 
CXCR4.52Another study looking at azacitidine’s epigenetic effects found that azacitidine inhibits T-cell proliferation 
and activation, blocking cell cycle in the G0 to G1 phase and decreasing the production of proinflammatory cytokines 
such as tumor necrosis factor alpha and interferon gamma. The immunomodulatory effects of azacitidine have lead to 
an exploration of its role in the allogeneic transplantation setting in prevention of graft versus host disease. Pre-clinical 
studies have shown that azacitidine has a direct effect on immune response through affecting T-cell activation, 
proliferation, and secretion of proinflammatory cytokines. The effect of 5-azaC in T lymphocytes, which is caused by 
both an early effect on the expression of genes related to T-cell proliferation and activation and a delayed effect on the 
methylation pattern of genes such as FOXP3, lead to the hypothesis 5-azaC may play a role in the allogeneic 
transplantation setting as an immunomodulatory drug.53 A clinical study of 27 patients who had undergone a reduced 
intensity allogeneic transplantation for acute myeloid leukemia and were treated with monthly courses of azacitidine, 
found that administration of azacitidine increased the number of Tregs within the first 3 months after transplantation 
compared with a control population. azacitidine administration also induced a cytotoxic CD8(+) T-cell response to 
several tumor antigens and thus this study further examined the role of azacitidine after transplantation as a mechanism 
of augmenting a graft versus leukemia effect without a concomitant increase in graft versus host disease.54 
Given that much of Dara’s effects are mediated based on interactions with NK cells and macrophages (to clear the 
CD38-coated plasma cells) or modulating the microenvironment (potentially depleting specific NK subsets and 
Tregs), examining shifts in immune microenvironment after Azacitidine could play an important role in dissecting 
clinical effects of azacitidine and may help explain either increased or decreased efficacy of dara combination 
beyond that expected from CD38 upregulation alone. These findings could also inform possible combinations of 
azacitidine with other immunotherapies in the future.
We propose to use CyTOF (Fluidigm) or mass cytometry to better understand the effects of azacitidine on the bone 
marrow tumor microenvironment. CyTOF, is a variation of flow cytometry in which antibodies are labeled with heavy 
metal ion tags rather than fluorochromes. Readout is by time-of-flight mass spectrometry.  This allows for the 
combination of many more antibody specificities in a single samples, without significant spillover between channels.  
2
Study Objectives 
2.1
Hypothesis
We hypothesize that in patients with relapsed and refractory multiple myeloma who have previously progressed on 
daratumumab, the combination of azacitidine, daratumumab, and dexamethasone will be effective and safe and lead 
to improved response rates through upregulation of CD38.
2.2
Primary, Secondary, and Exploratory Objective(s)
Primary Objectives:
The primary objective of this study is to evaluate the efficacy of adding azacitidine to daratumumab and 
dexamethasone, as measured by the overall response rate in patients with relapsed refractory multiple myeloma 
(RRMM) previously treated with daratumumab. 


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Secondary Objectives:

To evaluate the duration of response per IMWG criteria.

To evaluate the safety and tolerability of azacitidine in combination with daratumumab and dexamethasone.

To evaluate progression free and overall survival in patients treated with azacitidine in combination with 
daratumumab and dexamethasone.

To assess the changes in CD38 expression on plasma cells after treatment with azacitidine and correlate this 
change with the depth and duration of response of azacitidine in combination with daratumumab and 
dexamethasone.
2.3
Primary, Secondary, and Exploratory Endpoint(s)
Primary endpoints: 

Rate of overall response (ORR) defined as sCR+CR+VGPR + PR as best response utilizing IMWG Uniform 
Response Criteria55 calculated in the time period from initiation of study treatment until discontinuation of 
treatment 
Secondary Endpoints:

Adverse events, as graded by National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE version 5.0), assessed from the initiation of study treatment until discontinuation of treatment

Duration of response (DOR) defined as the duration from the date of initial documentation of a response (PR 
or better) according to the IMWG criteria to the date of first documented evidence of progressive disease 
according to the IMWG criteria or death due to PD whichever occurred first.

Overall survival which is defined from the date of first dose of study treatment to the date of death due to any 
cause or censored based on the date of last encounter if patient is alive or lost to follow-up. 

Progression-free survival which is defined as the duration from the date of first dose of study treatment to the 
date of first documented evidence of progressive disease or death, whichever occurs first. 

Change in CD38 surface expression of plasma cells after azacitidine treatment (the CD38 expression of plasma 
cells pre and post first cycle of azacitidine treatment in this trial will be compared)

Number of patients who achieve at least 1.5 fold increase in their CD38 expression by flow cytometry after 
azacitidine treatment

Correlation of change in CD38 expression after azacitidine treatment to response including depth of response 
and duration of response
3
Study Design
3.1
Characteristics
This is a single-arm, open label, 2-stage phase II study of the safety and efficacy of daratumumab in combination with 
azacitidine and dexamethasone in RRMM patients who have previously been treated with daratumumab with a safety 
lead-in cohort. Screening data will be reviewed to determine subject eligibility. Subjects who meet all inclusion criteria 
and none of the exclusion criteria will be entered into the study.


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Patients will need a washout period of at least 6 months from their most recent exposure to daratumumab prior to first 
dose of daratumumab on the trial.  This 6 month washout period will allow for CD38 normalization56, and hence will 
enable the measurement of the change in CD38 expression on plasma cells secondary to azacitidine (secondary 
endpoint correlative study for this trial) and eliminate the confounding factor of daratumumab’s effect on CD38 
expression. Patients will receive azacitidine at the standard 75 mg/m2 dose 5 days consecutively every 4 weeks starting 
day -7 to day -3 of Cycle 1 and then Day 22-26 of Cycle 1-3, and subsequently Day 1-5 of Cycle 5 and thereafter, with 
dose modifications for toxicities as outlined in Section 5.5. Daratumumab will be administered at the standard dose of 
1800 mg subcutaneously, with first dose administered on day 1. Daratumumab will be dosed in standard fashion: 
weekly for 8 doses (induction phase), every two weeks for 8 doses (consolidation phase), and then every 4 weeks 
thereafter (maintenance phase). There will be no dose modifications for daratumumab.  Dexamethasone at a dose of 
40 mg PO (or IV if PO is not available) will be given weekly for Cycle 1 and 2. This dose may be reduced or stopped 
after Cycle 2 on non-daratumumab administration weeks and as a pre-medication on daratumumab administration 
weeks. Further dose reduction is permitted based on dose modification criteria outlined in Section 5.5. Bone marrow 
biopsies will be done within 14 days of Cycle 1 day -7 (first azacitidine dose) and on Cycle 1 day 1 prior to first 
daratumumab administration (or after completion of first 5 days of azacitidine and prior to first daratumumab 
administration), for correlative studies. Please see Section 5 for more details on dosing of study treatment and Section 
6 for more details regarding correlative studies.
A Simon’s minimax 2-stage design will be used for this study.  The study will have an interim halting for safety 
analysis after enrollment of 6 patients and an interim halting for efficacy analysis after completion of Simon’s Stage I 
with enrollment of 13 patients. Please refer to Section 8 for further details regarding interim analysis, stopping rules, 
and statistics supporting this design. Safety monitoring will be done throughout the trial per Study Procedures and 
Schedule of Events.
Response to treatment will be evaluated according to the International Myeloma Working Group (IMWG) response 
criteria,55via standard indices including SPEP, UPEP, immunoglobulin levels, immunofixation, and free light chain 
assay, at the end of each treatment cycle during induction and consolidation phase and at the end of every two treatment 
cycles during maintenance phase. See Section 7 for more details on response measurements. Patients will remain on 
study until they are unable to tolerate treatment due to toxicities or demonstrate progression. At the time of progression, 
repeat bone marrow biopsy can be obtained at the discretion of the treating hematologist but will not be required by 
the study. 
Dara, Aza, and Dex dosing schedule 
Green arrow= Bone marrow biopsy # 1 on Day -7 
or within 1 week before first Aza dose
Purple arrow= Bone marrow biopsy #2 on Day 1 
before Dara first dose


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The anticipated duration of subject participation in this trial is estimated to be 8 months. Patient accrual is estimated 
to be 12-18 months. Patients will be followed for one year after the last patient has received the last administration of 
daratumumab. The anticipated duration of the entire study is 3 years.
3.2
Eligibility Criteria
Inclusion Criteria
1. Age ≥18 years 
2.
Patients must have a known diagnosis of multiple myeloma with evidence of measurable disease, AND have 
evidence of disease progression based on IMWG criteria55:
o
Serum M-protein ≥0.5 g/dL, or urine M-protein ≥200 mg/24 hours. OR 
o
In the absence of measurable M-protein, Serum immunoglobulin free light chain ≥10 mg/dL, and 
abnormal serum immunoglobulin kappa lambda free light chain ratio. 
3.
Relapsed from or refractory to 2 or more different prior therapies, including immunomodulatory drugs 
(IMiDs; eg, thalidomide, lenalidomide) and proteasome inhibitors, chemotherapy-based regimens, 
monoclonal antibodies, or autologous stem cell transplantation (ASCT). 
o
Relapse is defined as progression of disease after an initial response (MR or better) to previous 
treatment, more than 60 days after cessation of treatment
o
Refractory disease is defined as <25% reduction in M-protein or progression of disease during 
treatment or within 60 days after cessation of treatment
4.
Prior exposure to daratumumab, with most recent dose being at least 6 months prior to trial enrollment
5.
ECOG performance status <2 (Karnofsky >60% (see Appendix 1)
6.
Demonstrates adequate organ function as defined below within 7 days of first dose of drug:
Adequate bone marrow function:
absolute neutrophil count
≥1,500/mcL
platelets
≥75,000/mcL
Adequate hepatic function:
total bilirubin
within normal institutional limits, unless elevated 
due to Gilbert’s syndrome and direct bilirubin is 
within normal limits
AST(SGOT)
≤3 X institutional upper limit of normal
ALT(SGPT)
≤3 X institutional upper limit of normal
Adequate renal function:
creatinine
≤ 1.5 x within institutional upper limit of normal


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OR
creatinine clearance
GFR ≥ 60 mL/min/1.73 m2, calculated using the 
Cockcroft-Gault 
equation, 
unless 
data 
exists 
supporting safe use at lower kidney function values, 
no lower than 30 mL/min/1.73 m2 
7.
Life expectancy of at least 3 months.
8.
Women of childbearing potential must have at least one negative highly sensitive serum (β eta-human 
chorionic gonadotropin [β eta-hCG]) during screening, within one week prior to the first dose of any 
component of study treatment 
9.
Before enrollment, a woman must be either:
a. 
Not of childbearing potential defined as:
o
Postmenopausal:
-
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone level (>40 IU/L or mIU/mL in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy, however in the absence of 12 months of amenorrhea, a single 
follicle stimulating hormone measurement is insufficient.
o
Permanently Sterile
-
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal 
occlusion/ligation procedures, and bilateral oophorectomy.
OR
b. Of childbearing potential and
o
Practicing 2 highly effective user-independent methods of contraception (failure rate of <1% per year 
when used consistently and correctly
-
Examples of highly effective user-independent methods of contraception include:

implantable progesterone-only hormone contraception associated with inhibition of ovulation; 
intrauterine device (IUD); intrauterine hormone-releasing system (IUS); vasectomized partner; sexual 
abstinence (sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the subject.)
-
Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for subjects participating in 
clinical studies.
-
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the 
efficacy of the contraceptive method.
o
Agrees to remain on a highly effective method for 4 weeks before the first dose of any component of 
study treatment, throughout the study (including during dose interruptions), and for 4 weeks following 
discontinuation of azacitidine, and for 3 months after last daratumumab dose 
Note: If the risk of pregnancy changes (eg, a woman who is not heterosexually active becomes active), a woman 


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must begin a highly effective method of contraception, as described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
o
Agrees to not breast feed for the duration of the study (including during dose interruptions), and for 4 
weeks following discontinuation of azacitidine, and for 3 months after last daratumumab dose
10. Women must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study 
(including during dose interruptions), and for 4 weeks following discontinuation of azacitidine, and if receiving 
daratumumab, for 3 months after the last dose. 
11. Due to the teratogenicity of azacitidine and the lack of adequate reproductive toxicity data for daratumumab, 
in addition to the user independent highly effective method of contraception, a male or female condom with or 
without spermicide, diaphragm, or cervical cap is required. Male condom and female condom should not be 
used together (due to risk of failure with friction).
12. During the study (including during dose interruptions), and for 4 weeks following discontinuation of 
azacitidine, and for 3 months after the last daratumumab dose, in addition to the user independent highly 
effective method of contraception (even if he has undergone a successful vasectomy), a man
o
Who is sexually active with a woman of childbearing potential must agree to use a barrier 
method 
of 
contraception 
(ie, 
latex 
or 
synthetic 
condom 
with 
spermicidal 
foam/gel/film/cream/suppository)
o
Who is sexually active with a woman who is pregnant must use a latex or synthetic condom.
o
Must agree not to donate sperm
13. Willing and able to adhere to the prohibitions and restrictions specified in this protocol and referenced in the 
ICF.
14. Must sign an ICF (or their legally acceptable representative must sign) indicating that he or she understands 
the purpose of, and procedures required for, the study and is willing to participate in the study.
Any potential subject who meets any of the following criteria will be excluded from participating in the study:
Exclusion Criteria
1.
Diagnosed or treated for malignancy (either solid tumor or hematologic) other than multiple myeloma, except:
o
Malignancy treated with curative intent and with no known active disease
at enrollment.
o
Adequately treated non-melanoma skin cancer, lentigo maligna or in situ
malignancies (including but not limited to, cervical, breast) with no
       
evidence of disease.
2.
Received daratumumab therapy less than 6 months prior to trial enrollment
3.
Primary refractory to prior daratumumab
4.
Subject is:
a.
seropositive for human immunodeficiency virus (HIV)
b.
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 


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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.
c.
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).
5.
Known chronic obstructive pulmonary disease with a forced expiratory volume in 1 second (FEV1) <50% of 
predicted normal to minimize daratumumab-related pulmonary toxicities.
Note: FEV1 testing is required for subjects suspected of having chronic obstructive pulmonary disease and 
asthma. Subjects must be excluded if FEV1 <50% of predicted normal.
6.
Known moderate or severe persistent asthma within the past 2 year or currently has uncontrolled asthma of 
any classification.
Note: Subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are 
allowed in the study. FEV1 testing is required for subjects suspected of having asthma.
7.
Concurrent medical condition or disease (eg, active systemic infection) that is likely to interfere with study 
procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in 
this study. 
8.
Clinically significant cardiac disease, including:
a.
Myocardial infarction within 6 months before Cycle 1, Day -7, or unstable or uncontrolled 
disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart 
failure, New York Heart Association Class IIIIV).
b.
Uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology Criteria for 
Adverse Events [NCI-CTCAE] Version 5.0 Grade 2 or higher) or clinically significant 
electrocardiogram (ECG) abnormalities.
c.
Screening 12-lead ECG showing a baseline corrected QT interval (QTc) >470 msec.
9.
Known allergies, hypersensitivity, or intolerance to monoclonal antibodies or human proteins, daratumumab 
or its excipients (refer to Investigator’s Brochure), or known sensitivity to mammalian-derived products.
10. Concurrent plasma cell leukemia, Waldenström’s macroglobulinemia, POEMS syndrome (polyneuropathy, 
organomegaly, endocrinopathy, monoclonal protein, and/or skin changes), or light chain amyloidosis.
11. Known or suspected of not being able to comply with the study protocol (eg, because of alcoholism, drug 
dependency, or psychological disorder) or the subject has any condition for which, in the opinion of the 
investigator, participation would not be in the best interest of the subject (eg, compromise their well-being) 
or that could prevent, limit, or confound the protocol-specified assessments.
12. Contraindications to the use of daratumumab, azacitidine or dexamethasone per local prescribing 
information
13. Taken any disallowed therapies as noted in Section 6, Pre-study and Concomitant Therapy before the 
planned first dose of study drug
14. Received any therapy to treat cancer (including radiation, chemotherapy, biologics, cellular therapies, and/or 
steroids at doses > 20 mg) or undergone a major surgical procedure within 14 days, or within 5 half-lives of 


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an anticancer drug, prior to the first dose of study treatment, whichever is longer (with the exception of 
palliative radiotherapy for symptomatic management but not on measurable extramedullary plasmacytoma). 
15. Participated in an interventional clinical trial(s) and received an investigational drug (including 
investigational vaccines) or used an invasive investigational medical device within 4 weeks before Cycle 1, 
Day -7 or 5 pharmacokinetic half-lives, whichever is longer
16. Had major surgery within 2 weeks before Cycle 1, Day -7, or will not have fully recovered from surgery, or 
has surgery planned during the time the subject is expected to participate in the study or within 2 weeks after 
the last dose of study drug administration.
Note: Subjects with planned surgical procedures to be conducted under local anesthesia may participate. 
Kyphoplasty is not considered a major surgery
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. If a subject’s clinical 
status changes (including any available laboratory results or receipt of additional medical records) after screening but 
before Cycle 1 Day -7 (first dose of azacitidine) such that he or she no longer meets all eligibility criteria, then the 
subject should be excluded from participation in the study. 
3.3
Inclusion and Recruitment of Women and Minorities
Individuals of any sex/gender, race, or ethnicity may participate.
The study recruitment strategy aims to achieve representation of minority groups that reflects the demographics of the 
affected population in the catchment area.
3.4
Duration of Treatment
In the absence of treatment delays due to adverse events, treatment may continue indefinitely or until:

Disease progression which requires discontinuation of the study treatment;

Inter-current illness that prevents further administration of treatment;

Unacceptable adverse event(s);

Participant decides to withdraw from the study;

Significant participant non-compliance with protocol;

If the participant meets an exclusion criterion (either newly developed or not previously; or, recognized) that 
precludes further study participation

General or specific changes in the participant’s condition render the participant unacceptable for further 
treatment in the judgment of the investigator.
3.5
Duration of Follow Up
Each subject will be followed until 1 year after his/her last dose of study treatment, until death or withdrawal of consent 
for study participation, whichever occurs first. The end of study is defined as when all subjects have completed either 
at least 1 year of follow-up, or until death or withdrawal of consent for study participation, whichever occurs first. 
Further details regarding the long-term follow-up phase are detailed in Section 6.3.3.


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3.6
Primary Completion 
The estimated primary completion is 18 months after the study opens to accrual.
3.7
Study Completion
The expected study completion date is 30 months after the study opens to accrual.
4
Investigational Products
4.1
Description, Supply and Storage of Investigational Products
Daratumumab
Classification
Anti-CD38 Antibody
Mechanism of Action
Daratumumab is an IgG1κ human monoclonal antibody directed against CD38. CD38 is a cell surface glycoprotein 
which is highly expressed on myeloma cells, yet is expressed at low levels on normal lymphoid and myeloid cells 
(Lokhorst 2015). By binding to CD38, daratumumab inhibits the growth of CD38 expressing tumor cells by inducing 
apoptosis directly through Fc mediated cross linking as well as by immune-mediated tumor cell lysis through 
complement dependent cytotoxicity, antibody dependent cell mediated cytotoxicity, and antibody dependent cellular 
phagocytosis.
Metabolism
None known
Contraindications
History of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any component of the formulation.
Formulation, Appearance, Packaging, and Labeling
Daratumumab and hyaluronidase-fihj, daratumumab-SC will be provided as a fixed-dose (1800 mg), combination 
drug product containing rHuPH20 drug substance (2000 U/mL) and daratumumab drug substance (120 mg/mL) in a 
single vial. The daratumumab supplied for this study is a colorless to yellow liquid and sterile concentrate of 120 
mg/mL as a liquid vial. It will be manufactured and provided under the responsibility of the sponsor. Refer to the 
Investigator’s Brochure for a list of excipients.
Packaging
Daratumumab is supplied as glass vials containing daratumumab at a concentration of 120 mg/mL for subcutaneous 
administration. 
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements. Each vial will contain a 
study-specific label with a unique identification number.


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Availability
Daratumumab is being obtained as study supply provided by Janssen.
Storage and handling
Daratumumab is stored at the original carton in a refrigerator at controlled temperatures ranging from 2°C to 8°C. 
Daratumumab must not be utilized after the expiry date printed on the label. The daratumumab product must be 
protected from light and must not be frozen. Daratumumab does not contain preservatives; therefore, any unused 
portion remaining in the vial must be discarded.
Refer to the study site investigational product and procedures manual for additional guidance on-study drug 
preparation, handling, and storage.
Side Effects
Complete and updated adverse event information is available in the Investigational Drug Brochure (IB) and/or product 
package insert. 
Azacitidine
Classification
Hypomethylating agent
Mechanism of Action
Antineoplastic effects may be a result of azacitidine's ability to promote hypomethylation of DNA, restoring normal 
gene differentiation and proliferation. Azacitidine also exerts direct toxicity to abnormal hematopoietic cells in the 
bone marrow.
Metabolism
None known
Contraindications
Hypersensitivity to azacitidine, mannitol, or any component of the formulation; advanced malignant hepatic tumors
Formulation, Appearance, Packaging, and Labeling
Azacitidine for injection is supplied as a lyophilized powder in 100 mg single-dose vials packaged in cartons of 1 vial 
(NDC 0591-2897-49).
Availability
Azacitidine is being obtained as commercial supply 
Storage and handling
Azacitidine is stored at unreconstituted vials at 25ºC (77º) with excursions permitted to 15º to 30ºC (59º to 86ºF). 
Discard unused portion.
Please refer to the package insert 
.
Side Effects
Complete and updated adverse event information is available in the current IB and/or product package insert. 


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Dexamethasone
Classification
Dexamethasone is a potent steroid and direct toxin for malignant plasma cells.
Mechanism of Action
Dexamethasone is a long acting corticosteroid with minimal sodium-retaining potential. It decreases inflammation by 
suppression of neutrophil migration, decreased production of inflammatory mediators, and reversal of increased 
capillary permeability; suppresses normal immune response. Dexamethasone's mechanism of antiemetic activity is 
unknown.
Metabolism
Substrate of CYP3A4 (major), P-glycoprotein/ABCB1; Note: Assignment of Major/Minor substrate status based on 
clinically relevant drug interaction potential; Induces CYP3A4 (weak)
Contraindications
Hypersensitivity to dexamethasone or any component of the formulation; systemic fungal infections. Documentation 
of allergenic cross-reactivity for corticosteroids is limited. However, because of similarities in chemical structure 
and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.
Formulation, Appearance, Packaging, and Labeling
Dexamethasone is supplied as 40 mg tablets for oral administration. 
Availability
Dexamethasone is being obtained as commercial supply.
Storage and handling
Dexamethasone is stored at room/ambient temperature. Please refer to manufacturer’s product information for 
handling and storage conditions of dexamethasone.
Side Effects
Complete and updated adverse event information is available in the current IB and/or product package insert. 
4.2
Accountability Records for Investigational Product(s)
UCSF Investigational Drug Services (IDS) will manage drug accountability records for UCSF.
4.3
Ordering Investigational Product(s)
UCSF will obtain daratumumab directly from pharmaceutical company and azacitidine as commercial supply. 
5
Treatment Plan
5.1
Dosage and Administration
Treatment will be administered on an outpatient basis.


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Daratumumab
Preparation
Daratumumab-SC will be provided as a fixed-dose (1800 mg), combination drug product containing rHuPH20 drug 
substance (2000 U/mL) and daratumumab drug substance (120 mg/mL) in a single vial. Manuals with detailed 
descriptions for preparation and administration of daratumumab will be supplied to the pharmacy and site.
Treatment Schedule and Administration
Daratumumab SC should be given  according to product information: 
Daratumumab (1800 mg) will be administered by SC injection by manual push over approximately 3 – 5 minutes in 
the abdominal subcutaneous tissues in the left/right locations, alternating between individual doses. The volume of the 
SC solution will be 15 mL for the 1800 mg dose. Reasons for continued observation after daratumumab injection may 
include but are not limited to the following: subjects with a higher risk of respiratory complications (e.g., subjects with 
mild asthma or subjects with COPD who have an FEV1 < 80% at screening or developed FEV1 < 80% during the 
study without any medical history), subjects with IRR with the first injection of study drug, subject with decreased 
condition on day of dosing compared to prior dosing day. The dose of daratumumab will remain constant throughout 
the study. 
All administration will be planned as outpatient visits. Subjects will receive pre-injection medications and post-
injection medications as detailed in the protocol.
Daratumumab will be administered weekly during induction treatment in Cycles 1 to 2 (Days 1, 8, 15, 22), every 2 
weeks during consolidation treatment in Cycles 3 to Cycle 6 (Day 1, 15), and every 4 weeks during maintenance 
treatment in Cycle 7 (Day 1) and beyond. This schedule is provided below in Table 5-1.
Table 5-1. Daratumumab Administration Schedule 
Weeks
Cycle (every 4 weeks)
Schedule
Weeks 1 to 8 (induction)
Cycle 1-2
weekly (total of 8 doses)
Weeks 9 to 24a (consolidation)
Cycle 3-6
every two weeks (total of 8 doses)
Weeks 25 onwards until disease 
progressionb (maintenance)
Cycle 7 and onwards
every four weeks
a First dose of the every-2-week dosing schedule is given at week 9
b First dose of the every-4-week dosing schedule is given at week 25
As noted in the Study Procedures and Schedule of Events, vital signs should be monitored extensively on Cycle 1, 
Day 1 before, during, and after the first administration of daratumumab. For all other administrations, vital signs 
should be measured before the start of the injection and at the end of the injection. These vital signs will be measured 
by standard daratumumab subcutaneous protocol. If a subject experiences any significant medical event, then the 
investigator should assess whether the subject should stay overnight for observation. If the subject has not experienced 
a significant medical event but is hospitalized overnight only for observation, then the hospitalization should not be 
reported as a serious adverse event.
If an IRR develops, then the injection should be temporarily interrupted or slowed down. In the event of a life-


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threatening IRR (which may include pulmonary or cardiac events) or anaphylactic reaction, dara-SC should be 
discontinued, and no additional dara-SC should be administered to the participant. See section below for instructions 
on the management of IRR and local ISRs.
Guidelines for Prevention and Management of Administration-Related Reactions and Local Injection-
site Reactions of Daratumumab-SC
Pre-dose Medication
All participants will receive the following medications 1 to 3 hours prior to each study drug administration: 

An antipyretic: paracetamol (acetaminophen) 650-1000 mg IV or PO

An antihistamine: diphenhydramine 25-50 mg IV or PO or equivalent. Avoid IV use of promethazine. 
o
After Cycle 6, if a participant has not developed an administration-related reaction and is intolerant 
to antihistamines, modifications are acceptable as per investigator discretion.

Corticosteroids (Long-acting or intermediate-acting): 
o
Dexamethasone dosing as part of combination therapy: 

Administer 40 mg dexamethasone (or equivalent) prior to every daratumumab injection in the 
first two cycles. Since dexamethasone is also the background regimen specific corticosteroid 
for this treatment regimen, the dexamethasone treatment dose will instead serve as pre-
medication on daratumumab administration days. 

Dexamethasone is given orally or intravenously prior to the first daratumumab injection and 
oral administration may be considered prior to subsequent injections. 
o
If the subject does not experience a major systemic administration-related reaction after the first 8 
doses of daratumumab, consider discontinuing the administration of corticosteroids as a pre-
medication (excluding any background regimen-specific corticosteroid or treatment-specific 
dexamethasone as determined by the primary treating provider).
o
Further dose reduction of dexamethasone is permitted based on dose modification criteria outlined in 
Section 5.5.
Pre-dose administration of a leukotriene inhibitor (montelukast 10 mg PO or equivalent) is optional in Cycle 1 Day 1 
and can be administered up to 24 hours before administration as per investigator discretion. 
If necessary, all PO pre-administration medications may be administered out of the clinic on the day of the 
administration, provided they are taken within 3 hours before the administration. 
Post-dose Medication
Administer post-dose medication to reduce the risk of delayed administration and injection related reactions as follows: 
o
Consider administering low-dose methylprednisolone (≤ 20 mg) or equivalent, the day after the 
administration. 
o
For participants with a higher risk of respiratory complications (e.g. participants with mild asthma or 
participants with COPD who have an FEV1 < 80% at screening or developed FEV1 < 80% during the 
study without any medical history) the following post-administration medication should be 
considered: 

Antihistamine (diphenhydramine or equivalent) 

Leukotriene inhibitor (montelukast or equivalent) 

Short-acting β2 adrenergic receptor agonist such as salbutamol aerosol

Control medications for lung disease (e.g. inhaled corticosteroids ± long-acting β2 adrenergic 


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receptor agonists with asthma; long-acting bronchodilators such as tiotropium or salmeterol 
± inhaled corticosteroids for participants with COPD)
o
Investigators may prescribe bronchodilators, H1-antihistamines, and corticosteroids that are deemed 
necessary to provide adequate supportive care in the event a bronchospasm occurs after participants 
are released from the hospital/clinic. If an at-risk participant experiences no major administration-
related reactions, then these post-administration medications may be waived after 4 doses at the 
investigator’s discretion. 
o
Any post-injection medication will be administered after the injection has completed. 
Management of Administration-related Reactions and Local Injection-site Reactions of Daratumumab-SC
Injection-related Reactions (IRRs)
Injection-related reactions (IRRs) are systemic reactions related to daratumumab administration. Participants should 
be observed carefully during daratumumab administrations. Trained study staff at the clinic should be prepared to 
intervene in case of any IRRs, and resources necessary for resuscitation (e.g., agents such as epinephrine and 
aerosolized bronchodilator, medical equipment such as oxygen tanks, tracheostomy equipment, and a defibrillator) 
must be available at the bedside. Attention to staffing should be considered when multiple participants will be dosed 
at the same time. If an IRR develops during Dara SC administration, then the administration should be temporarily 
interrupted. Participants who experience AEs during Dara-SC administration must be treated for their symptoms. 
Participants should be treated with paracetamol (acetaminophen), antihistamine, or corticosteroids, as needed. 
Intravenous saline may be indicated. For bronchospasm, urticaria, or dyspnea, participants may require antihistamines, 
oxygen, corticosteroids, or bronchodilators. For hypotension, participants may require vasopressors. In the event of a 
life-threatening IRR (which may include pulmonary or cardiac events) or an anaphylactic reaction, Dara-SC should 
be discontinued.
Injection-related Reactions Grade 1 or Grade 2: 
If the investigator assesses a Grade 1-2 IRR to be related to administration of study intervention, then the Dara-SC 
administration should be interrupted. When the participant's condition is stable, Dara-SC administration may be 
restarted at the investigator's discretion. Refer to the SIPPM for further details regarding continuation of Dara-SC 
administration. 
If the participant experiences a Grade 2 or higher event of laryngeal edema, or a Grade 2 or higher event of 
bronchospasm that does not respond to systemic therapy and does not resolve within 6 hours from onset, then the 
participant must be permanently discontinued from Dara-SC treatment.
Injection-related Reactions Grade 3 or Higher: 
For IRR AEs (other than laryngeal edema or bronchospasm) that are Grade 3, the Dara-SC administration must be 
stopped, and the participant must be observed carefully until resolution of the AE or until the intensity of the event 
decreases to Grade 1, at which point the Dara-SC administration may be restarted at the investigator’s discretion. Refer 
to the SIPPM for further details regarding continuation of Dara-SC administration. 
If the intensity of the AE returns to Grade 3 after restart of the Dara-SC administration, then the participant must be 
permanently discontinued from Dara-SC treatment. 
For IRR AEs that are Grade 4, the Dara-SC administration must be stopped, and the participant permanently 
discontinued from Dara-SC treatment.


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Recurrent Injection-related Reactions: 
If a Grade 3 IRR (or Grade 2 or higher event of laryngeal edema, or a Grade 2 or higher event of bronchospasm) recurs 
during or within 24 hours after a subsequent Dara-SC administration, the participant must be permanently discontinued 
from Dara-SC treatment.
Injection Site Reactions: 
In clinical studies, SC administration of daratumumab was associated with local injection site reactions, such as 
induration and erythema, in some subjects. The reactions usually resolved within 60 minutes. Local injection-site 
reactions should be managed per institutional standards.
Recommended Concomitant Therapy: 

Prophylaxis for Herpes Zoster Reactivation: 
o
Prophylaxis for herpes zoster reactivation is recommended during the Treatment Phase, as per 
institutional guidelines. Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 
week after starting study treatment and continue for 3 months following study treatment. Acceptable 
antiviral therapy includes acyclovir (eg 400 mg given orally 3 times a day, or 800 mg given orally 2 
times a day or per institutional standards), famcyclovir (eg, 125 mg given orally, twice a day or per 
institutional standards), or valacyclovir (eg, 500 mg given orally, twice a day or per institutional 
standards), initiated within 1 week after the start of study drug.

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 participants at risk for HBV reactivation. 
o
In patients who develop reactivation of HBV while on study treatment, suspend treatment with study 
treatment and any concomitant steroids, chemotherapy, and institute appropriate treatment. 
Resumption of study treatment in patients whose HBV reactivation is adequately controlled should 
be discussed with physicians with expertise in managing HBV.
Azacitidine
Azacitidine should be given at 75mg/m2 IV/SC for 5 consecutive days starting in cycle 1 day -7 to -3. Subsequently 
azacitidine will be given for 5 consecutive days on days 22-26 of cycles 1-3. Patients should be premedicated for 
nausea and vomiting. Cycles should be repeated every 4 weeks with dose modifications as needed per parameters 
outlined below in Section 5.5.2.1. Starting cycle 5, azacitidine will be given for 5 consecutive days on days 1-5 to 
coordinate with daratumumab dosing. This protocol uses azacitidine 5 day dosing as opposed to the standard 7 day 
dosing used in MDS and AML, given that studies have shown equivalent efficacy with 5 day dosing and we hope to 
minimize cumulative toxicities.39 Treatment may be continued as long as the patient continues to benefit.
Dexamethasone
Dexamethasone at a dose of 40 mg PO (or IV if PO is not available) will be given weekly for Cycle 1 and 2.  This 
dose may be reduced or stopped after Cycle 2 on both non-daratumumab administration weeks and as a pre-medication 
on daratumumab administration weeks as per treating physician discretion. Further dose reduction is permitted based 
on dose modification criteria outlined in Section 5.5. 


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Subjects may receive low-dose methylprednisolone (≤20 mg) orally (or equivalent in accordance with local standards) 
for the prevention of delayed IRRs as clinically indicated.
Dose modifications, dose delays, and dose interruptions for study drugs are described in Section 5.5.
5.2
Treatment Compliance
Study drug (daratumumab) will be administered as a subQ injection and study drug (azacitidine) will be administered 
either as IV or subQ by qualified staff and the details of each administration will be recorded in APEX, the electronic 
medical record system used at UCSF. Additional details are provided in the study site investigational product and 
procedures manual. Subjects will be provided with a diary to record intake of dexamethasone; sites will use 
information to complete exposure information in the CRF. The drug diary will be returned to clinic staff at the end of 
each month.


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Table 5-2. Regimen Description
Investigational 
Product
Premedication; 
precautions
Dose
Route
Schedule
Cycle 
Length
Daratumumab
Pre-medication with 
corticosteroid, 
acetaminophen, 
diphenhydramine, and 
monteleukast 1-3 hours 
prior to administration 
(See section 5.1.1.3 for 
further details)
1800 mg
SC
D1, D8, D15, D22 for 
Cycle 1-2
D1, D15 Cycle 3-6
D1 Cycle 7 and 
onwards
Azacitidine
Premedicate with 
antiemetics
75 mg/m2 or 
MTD
IV/SubQ
Day -7 to Day -3 
Cycle 1, Day 22-26 
Cycle 1-3, Day 1-5 
Cycle 5 and onwards
Every 4 
weeks
Dexamethasone
Take prior to daratumumab 
administration on days of 
daratumumab 
administration and may 
also be given weekly on 
weeks without 
daratumumab
40 
mg 
(or 
lower 
after 
Cycle 2)
PO
Dexamethasone 40 
mg PO (or IV if PO is 
not available) weekly 
for Cycle 1 and 2.  
This dose may be 
reduced or stopped 
after Cycle 2 both on 
non-daratumumab 
administration weeks 
and on daratumumab 
administration weeks 
(as pre-medication). 
Further dose 
reduction is permitted 
based on dose 
modification criteria 
outlined in Section 
5.5.
See Dosing Schedule Diagram in Section 3.1.
5.3
Other Investigational Procedures/Modalities
There will be no other investigational procedures/modalities (e.g surgery, radiotherapy, hematopoietic stem cell 
transplantation) used in the protocol study treatment, if applicable.
5.4
Dose Limiting Toxicity 
Dose-limiting toxicities are defined as the following toxicities if they occur anytime within the first 5 weeks of starting 
azacitidine (anytime within Cycle 1) and are thought to be secondary to azacitidine in combination with daratumumab:
o
Grade 4 neutropenia lasting more than 7 days.
o
Grade 4 thrombocytopenia lasting more than 7 days despite transfusion support.


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o
Grade 3 or higher non-hematological toxicity except:

Grade 3 nausea, vomiting or diarrhea that can be controlled within 48 hours with maximal supportive 
care.

Grade 3 hyperglycemia that can be controlled within 48 hours with appropriate supportive care.

Asymptomatic new Grade 3 or higher electrolyte disturbances that can be controlled with repletion or 
other medical management within 24 hours.
Severity of AEs will be graded according to CTCAE Version 5.0. As described in Section 8.2.2, interim analysis will 
occur after accrual of 6 patients in the safety cohort. Study accrual will be stopped until these 6 patients have completed 
at minimum 5 weeks of treatment after starting azacitidine (ie completed Cycle 1), at which point a formal interim 
safety analysis will be performed with assessment for DLTs as defined above and safety stopping bounds for DLTs as 
described in Section 8.2.2. Guidelines for dose reductions of azacitidine due to toxicity or dose delays/holding for 
daratumumab toxicity are detailed in Section 5.5. 
5.5
Dose Modifications and Dosing Delays
Daratumumab
Dose Modification
No daratumumab dose modification (increase or decrease) will be permitted unless the subject’s weight changes more 
than 10% from Cycle 1 Day 1 or the most recent weight used for dose calculation. Subject’s weight will be recorded 
on all daratumumab dosing days.
Daratumumab-Related Toxicity Management and Dose Delay
ONLY if any of the following criteria are met and the event cannot be attributed to azacitidine, or underlying multiple 
myeloma, the daratumumab administration must be held to allow for recovery from toxicity. The criteria for a dose 
delay are:
-
Grade 4 hematologic toxicity (except for Grade 4 lymphopenia), or Grade 3 or higher
thrombocytopenia with bleeding
-
Febrile neutropenia of any grade
-
Grade 4 Neutropenia with any grade infection
-
Grade 3 or higher non-hematologic toxicities with the following exceptions:
o
Grade 3 nausea or Grade 3 vomiting that responds to antiemetic treatment within 48 hours of 
supportive care
o
Grade 3 diarrhea that responds to antidiarrheal treatment within 48 hours of supportive care
o
Grade 3 fatigue or asthenia that was present at baseline and lasts for <7 days after the
last administration of daratumumab
o
Grade 3 or 4 electrolyte disturbances which can be managed with replacement therapy
If daratumumab administration does not commence within the prespecified window of the scheduled administration 
date, then the dose will be considered a missed dose. See Table 5-3 Daratumumab-Related Dose Delay Time 
Chart.


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Administration may resume at the next planned dosing date. See Section 5.5.1.4, Interruption or Missed Doses for 
additional information.
Table 5-3 Daratumumab-Related Dose Delay Time Chart
Weeks
Frequency
Missed Dose
Dosing Resumption
Weeks 1-8 (induction)
Weekly
> 3 days
Next planned weekly 
dosing date
Weeks 9-24 
(consolidation)
Every 2 weeks
> 14 days
Next planned every 2 
week dosing date
Week 25 onwards until 
disease progression 
(maintenance)
Every 4 weeks
>  14 days
Next planned every 4 
week dosing date
A missed dose will not be made up. Any adverse event listed above deemed to be related to daratumumab that requires 
a dose hold of more than 3 doses will result permanent discontinuation of daratumumab and patient’s withdrawal from 
this study. 
Dose Delay
A dose is deemed to have been delayed if the treatment is 2-3 days beyond the theoretical day of treatment for weekly 
dose, 3-14 days beyond the theoretical day of treatment for Q2W dose, and 4-14 days beyond the theoretical day of 
treatment for Q4W dose. The reason for dose delay will be captured.
Interruption or Missed Doses
A daratumumab dose held for more than 3 days during induction, 14 days during consolidation, or 14 days during 
maintenance from the per protocol administration date for any reason other than toxicities suspected to be related to 
daratumumab should be brought to the attention of the sponsor at the earliest possible time. Subjects who miss ≥3 
consecutive planned doses of daratumumab for reasons other than toxicity will be withdrawn from treatment, unless, 
upon consultation with the sponsor and the review of safety and efficacy, continuation is agreed upon.
Azacitidine
Dose modification
The dose for azacitidine can be reduced as follows, based on counts for any given cycle:
Table 5-4 Dosage Adjustment for Azacitidine Based on Hematology Laboratory Values:
Counts
% Dose Administered in 
the Next Cycle
ANC (x 10^9/L)
Platelets (x10^9/L)


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<0.5 (Gr 4)
<25 (Gr 4)
50%
0.5 – 1.5 (Gr 2-3)
25-50 (Gr 3)
67%
> 1.5 (Gr 0-1)
> 50 (Gr 0 -2)
100%
Dosage Adjustment Based on Renal Function and Serum Electrolytes during treatment (not at baseline): 
If unexplained reductions in serum bicarbonate levels to less than 20 mEq/L occur, the dosage should be reduced by 
50% on the next cycle. Similarly, if unexplained elevations of BUN or serum creatinine occur, the next cycle should 
be delayed until values return to normal or baseline and the dose should be reduced by 50% on the next treatment 
cycle. 
Use in Geriatric Patients: 
Azacitidine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to 
this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have 
decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
For any other non-hematologic  grade 3 AE thought to be secondary to azacitidine, dose should be held until recovery 
defined as improvement to at least grade 1, and resumed at 50% dose on the next treatment cycle. If non-hematologic 
 grade 3 AE or hematologic  grade 4 AE lasting more than 7 days thought to be secondary to azacitidine occurs at 
azacitidine dose < 25 mg/m2, then azacitidine will be stopped and patient will withdraw from study. Guidelines for 
DLTs within the first cycle (ie within the first 5 weeks of starting azacitidine) are detailed in Section 5.4.
Further dose modifications or dose delays for azacitidine based on adverse events during treatment will be left to the 
discretion of the treating provider. In the event that the investigator feels deviation from the recommendations above 
is required, please consult the study chair to discuss for approval.
If the dose of azacitidine is reduced, at the investigator’s discretion, the dose of azacitidine may be re-escalated after 
2 cycles of a dose reduction in the absence of a recurrence of the toxicity that led to the reduction. Dose changes must 
be recorded in the Dose Administration eCRF.
Dose Delay
A dose is deemed to have been delayed if the treatment is  4 days beyond the theoretical day of treatment for this 
Q4W dose. The reason for dose delay will be captured. 
Interruption or Missed Doses
An azacitidine dose held for more than 2 times for any reason other than toxicities suspected to be related to 
azacitidine will be reviewed by the study team at the earliest possible time. Subjects who miss ≥3 consecutive 
planned doses of azacitidine for reasons other than toxicity will be withdrawn from treatment. Any missed dose of 
azacitidine will not be made up.
The following dose modification rules will be used with respect to potential toxicity. Toxicity will be assessed 
according to the NCI CTCAE version 5.0.


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If a participant experiences several adverse events and there are conflicting recommendations, the investigator 
should use the recommended dose adjustment that reduces the dose to the lowest level.
Table 5-5.  Dose Modifications and Dosing Delays Tables for Specific Adverse Events
Dose modifications for AEs thought to be secondary to either drug, azacitidine or daratumumab, will be made as 
below:
Adverse Events: Neutropenia
Grade of Event
Management/Next Dose for 
Azacitidine
Management/Next Dose for 
Daratumumab
≤ Grade 1
No change in dose
No change in dose
Grade 2
Administer 67% of dose during next 
treatment course 
No change in dose
Grade 3
Administer 67% of dose during next 
treatment course
No change in dose
Grade 4
Administer 50% of dose during next 
treatment course
Dose delay until recovery to at least 
Grade 1, can resume at same dose*
*Toxicity criteria for holding daratumumab dose are detailed above in Section 5.5.1.2
** Participants having Grade 4 AE at azacitidine dose  < 25 mg/m2 should go off study
Recommended management:  

Use G-CSF as needed (except for Cycle 1 when it can only be used if patient develops ≥ Grade 
3 neutropenia), start prophylactic antimicrobials and anti-fungals, and monitor closely for 
fevers and infection
Adverse Events: Thrombocytopenia
Grade of Event
Management/Next Dose for 
Azacitidine
Management/Next Dose for 
Daratumumab
≤ Grade 1
No change
No change
Grade 2
No change
No change
Grade 3
Administer 67% of dose during next 
treatment course
No change
Grade 4
Administer 50% of dose during next 
treatment course
Dose delay until recovery to at least 
Grade 1, can resume at same dose*
*Toxicity criteria for holding daratumumab dose are detailed above in Section 5.5.1.2
** Participants having Grade 4 AE at azacitidine dose  < 25 mg/m2 should go off study
Recommended management:  
- Transfuse platelets as needed and monitor for bleeding
Adverse Events: Renal toxicity during treatment
Grade of Event
Management/Next 
Dose 
for 
Azacitidine
Management/Next Dose for 
Daratumumab
≤ Grade 1
No change
No change


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Adverse Events: Neutropenia
Grade of Event
Management/Next Dose for 
Azacitidine
Management/Next Dose for 
Daratumumab
Grade 2
No change
No change
Grade 3
Hold dose until recovery to at least 
Grade 1, then resume dose at 50%
Dose delay until recovery to at least 
Grade 1, can resume at same dose*
Grade 4
Hold dose until recovery to at least 
Grade 1, then resume dose at 50%
Dose delay until recovery to at least 
Grade 1, can resume at same dose*
*Toxicity criteria for holding daratumumab dose are detailed above in Section 5.5.1.2
** Participants having ≥ Grade 3 AE at a dose  < 25 mg/m2 should go off study
Recommended management:  
- Hydrate with fluids, minimize other nephrotoxic agents, and monitor urine output
Adverse Events: Other non-hematologic toxicity during treatment
Grade of Event
Management/Next Dose for 
Azacitidine
Management/Next Dose for 
Daratumumab
≤ Grade 1
No change
No change
Grade 2
No change
No change
Grade 3
Hold dose until recovery to at least 
Grade 1, then resume dose at 50%
Dose delay until recovery to at least 
Grade 1, can resume at same dose*
Grade 4
Hold dose until recovery to at least 
Grade 1, then resume dose at 50%
Dose delay until recovery to at least 
Grade 1, can resume at same dose*
*Toxicity criteria for holding daratumumab dose are detailed above in Section 5.5.1.2
** Participants having ≥ Grade 3 AE at a dose  < 25 mg/m2 should go off study
Dexamethasone 
Dexamethasone Toxicity
For management of dexamethasone toxicity see table below. If dexamethasone is permanently discontinued due to 
toxicity, pre- and post-administration doses administered on the day of daratumumab dosing may be given at the 
investigators’ discretion. This table represents suggested dose modifications of dexamethasone, but physician 
discretion and clinical judgment should prevail.


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Table 
5-6 
Dexamethasone Toxicity Management Chart


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5.6
Criteria for Permanent Discontinuation of Study Drug(s)
Subjects who are experiencing a clinical benefit should remain on study if possible, unless significant toxicity puts the 
subject at risk, routine noncompliance puts the study outcomes at risk, the subject withdraws consent, or one of the 
treatment discontinuation reasons referred to in Section 5.5 occurs.
5.7
Use of Concurrent/Concomitant Medications
Throughout the study, investigators may prescribe any concomitant medications or treatments deemed necessary 
to provide adequate supportive care except for those listed in Section 5.9, Prohibited Therapies. The principal 
investigator must be notified in advance (or as soon as possible thereafter) of any instances in which prohibited 
therapies are administered. Systemic use of the following concomitant medications will be collected in the CRF 
and recorded in the source documents beginning with signing of the ICF to 30 days after the last dose of the last 
study treatment or until the start of next-line anticancer treatment, if earlier: growth factors, transfusions, anti-
infective medications (antibacterials, antivirals, and antimycotics), steroids, anti-arrhythmic medications and 
other cardiac supportive therapy, anti-epileptic medications, centrally acting psychiatric medications, anti-
histamines and other medications targeting post-administration systemic reactions, and any anticancer therapy 
(including radiation).


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Recommended Therapies
Prophylaxis for Bacterial Infection
Prophylaxis for bacterial infections should be considered per institutional guidelines and treating physician 
preference, especially for subjects with a history of recurrent bacterial infections or severe 
hypogammaglobulinemia.
Prophylaxis for Herpes Zoster Reactivation
Prophylaxis for herpes zoster reactivation is recommended unless contraindicated.
Prevention of Steroid Induced Gastritis
Dexamethasone and other steroids may induce gastritis. Medications to prevent gastritis are permitted per 
institutional guidelines, for example proton pump inhibitors (omeprazole or equivalent) or sucralfate, or H2 
blockers (ranitidine or equivalent).
Management of Hepatitis B Virus Reactivation
Primary antiviral prophylaxis is permitted as per local standard of care.  Per protocol, HBV DNA testing by PCR is 
mandatory for subjects at risk for HBV reactivation see Section 6.3
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.
Permitted Therapies
In addition, subjects are to receive full supportive care. The following medications and supportive therapies are 
examples of support therapies that may be used at any time during the study:

Antiviral medications should be considered per institutional guidelines.

Colony stimulating factors and erythropoietin may be used as needed at the discretion of the treating 
provider (except for Cycle 1 when they can only be used if patient develops ≥ Grade 3 neutropenia or 
≥ Grade 3 anemia respectively rather than pre-emptively to avoid interference with DLT monitoring 
in Cycle 1)

Transfusion of platelets and RBCs per institutional goals

It is important to prevent constipation (eg, adequate hydration, high-fiber diet, and stool softeners if 
needed).

Adequate hydration is recommended for prevention of myeloma-related kidney disease.

Intravenous immunoglobulin (IVIG) may be considered for subjects with recurrent infection related 
to hypogammaglobulinemia.

Prophylactic antiemetics, with the exception of corticosteroids

Loperamide is recommended for the treatment of diarrhea, starting at the time of the first watery stool. 
The loperamide dose and regimen is according to institutional guidelines. Prophylactic loperamide is 
not recommended.


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5.8
Dietary Restrictions
There are no specific dietary restrictions for study participants.
5.9
Prohibited Medications
Concomitant administration of any other antineoplastic therapy for the intention of treating multiple myeloma is 
prohibited, including medications that target CD38, as well as medications used for other indications that have anti-
myeloma properties (for example, interferon). Any non-study chemotherapy, anticancer immunotherapy, experimental 
therapy, or radiotherapy are prohibited while the subject is receiving azacitidine treatment. 
Concomitant participation in an interventional clinical trial(s) or use of investigational agent(s) as well as medical 
devices is prohibited. Administration of commercially available agents with activity against or under 
investigation for multiple myeloma, including systemic corticosteroids (>10 mg prednisone per day or 
equivalent) (other than those given for IRRs as described in Section 5.1.1.3, Management of Injection-Related 
Reactions) should be avoided. Nonsteroidal anti-inflammatory agents should be avoided to prevent myeloma-
related kidney disease.
Typically, IV contrast is not used in CT scanning of subjects with secretory multiple myeloma because of the risk to 
the kidney. If administration of IV contrast is necessary, then adequate precautions including hydration are indicated.
6
Study Procedures and Schedule of Events
The study-specific procedures and assessments are detailed in this section and outlined in the Study Procedures and 
Schedule of Events.
Screening assessments must be performed within 28 days prior to the first dose of investigational product, unless 
otherwise noted.  Any results falling outside of the reference ranges may be repeated at the discretion of the 
investigator. 
All on-study visit procedures are allowed a window of ± 7 days unless indicated otherwise on Table 6.1.  Treatment 
or visit delays for public holidays or weather conditions do not constitute a protocol violation.


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6.1
Study Calendar
Period/
Procedure
Scre
enin
g
Cycl
e 1a
(Pre-
Indu
ction 
Phas
e)
Cycle 1-2a (Induction 
Phase)
Cycle 3a 
(Consolidation Phase)
Cycle 4a 
(Consolidation Phase)
Cycle 5-6a (Consolidation 
Phase)
Cycle 7a 
and 
Onwards 
(Mainten
ance 
Phase)
End of 
Treatment
Follow-
upt
Study Day/Visit 
Day
D -27 
to D-8
D -7 
to D-3 
D1 
(± 1 
day
)
D8 
(± 1 
day) 
D15 
(± 1 
day) 
D22 
(± 1 
day) 
D1 
(± 2 
day
s)
D8 
(± 2 
day
s)
D15 
(± 2 
day
s)
D22 
(± 2 
day
s)
D1 
(± 2 
days
)
D8 
(± 2 
days
)
D15 
(± 2 
days
)
D22 
(± 
2 
days)
D1 
(± 2 
day
s)
D8 
(± 2 
days
)
D15 
(± 2 
days
)
D22 (± 
2 days)
D1 
(± 
3 
days)
Study Treatment/Drug
Daratumumabb
x
x
x
x
x
x
x
x
x
x
x
Azacitidinec
x
x
x
x
x
Dexamethasoned
x
x
x
x
x
x
x
x
x
x
x
Administrative Procedures
Informed 
Consent
x
Clinical Evaluation
Physical Exam
x
x
x
x
x
x
x
Medical History
x
Vital signs
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Weight/heighte
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant 
medications
x
Continuously throughout study period
AE assessmentf
x
Continuously throughout study period
Performance 
statusg
x
x
x
x
x
x
x
Laboratory Assessments
Pregnancy Testh
x
x
x
x
x
x
x
Type and 
Screeni
x
Hepatitis B 
(HBV) 
Serologyj
x
HBV DNA 
Testingk
x
Q12W during treatment for patients who meet criteria
x
x
Blood 
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


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Chemistryl
Hematologym
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Disease Evaluationm
Immunoglobulin
sn
x
x
x
x
x
x
x
Serum M 
proteino
x
x
x
x
x
x
x
sFLCp
x
x
x
x
x
x
x
serum IFEq
x
x
x
x
x
x
x
Urine M protein 
(24 hour urine)r
x
x
Skeletal Survey
Only as clinically indicated by standard of care
PET/CT/MRI
Only as clinically indicated by standard of care
Study Procedure/Correlative Studies
Bone Marrow 
Biopsys
x
x
a Cycle: Every cycle is 28 days (except for Cycle 1 which extends from day -7 to day 28). The treatment window is ± 1 days for induction phase, ± 2 days for consolidation phase, ± 3 days 
for maintenance phase
b Daratumumab: Daratumumab dose scheduling, pre-medications, dose modification, and DLTs are detailed in Section 5. 
c Azacitidine: Azacitidine dose scheduling, dose modification, and DLTs are detailed in Section 5. Azacitidine will be given for 5 consecutive days starting Cycle 1 day -7 to day -
3, Cycle 1-2 Day 22 – 26, Cycle 5 and onwards Day 1-5
d Dexamethasone: Dexamethasone 40 mg PO (or IV if PO is not available) weekly for Cycle 1 and 2.  This dose may be reduced or stopped after Cycle 2 on both non-
daratumumab administration weeks and on daratumumab administration weeks (as premedication) based on investigator’s discretion. Further dose reduction is permitted based on 
dose modification criteria outlined in Section 5.5.
e Weight/height: Height is required at screening/baseline only. Weight is required at screening and with every daratumumab and first day out of 5 consecutive days of azacitidine 
administration
f AE assessment: All AEs including adverse events of new onset as well as worsening signs and symptoms are to be reported from the signing of the informed consent to 30 days 
following the last administration of study treatment. After the 30 days all ongoing related non-serious AEs, ongoing SAE, and new related AE/SAEs are to be followed up to 
resolution or stabilization. 
g Performance Status: This will be measured by ECOG
h Pregnancy Test: Women of child bearing potential must have a negative serum pregnancy within 7 days prior to first study drug administration and D1 of every cycle of 
treatment starting Cycle 2 (does not need to be performed Cycle 1 Day 1) and at the EOT visit as part of standard of care.
I Type and Screen: Type and screen study must be done at the time of screening
j Hepatitis B (HBV) Serology: Local testing for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (Anti-HBs), and hepatitis B core antibody (Anti-HBc). 
k HBV DNA Testing: 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. For these patients, HBV DNA testing PCR must be done Q12W during treatment, at the End of Treatment Visit, and Q12W for up to 6 months after the 
last dose of study treatment.
l Blood chemistry: To be done at screening/baseline, then within 3 days prior to every daratumumab administration and cycle of azacitidine,  at the EOT visit, and as clinically 


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indicated. Blood chemistry includes: SGOT (AST), SGPT (ALT), total bilirubin, alkaline phosphate, lactate dehydrogenase (LDH), sodium, potassium chloride, 
bicarbonate/carbon dioxide, calcium, magnesium, phosphate, uric acid, blood urea nitrogen (BUN), serum creatinine, albumin, and total protein
m Hematology: To be done at screening/baseline and then within 3 days prior to every daratumumab administration and cycle of azacitidine, at the EOT visit, and as clinically 
indicated. Hematology includes hemoglobin, hematocrit, RBC, WBC with differential, and platelet counts. 
n-r Disease evaluations: All lab tests including M-protein quantification (serum and 24-hour urine), immunoglobulins (IgG, IgA, IgM), serum immunofixation, serum free light 
chains should be performed at screening/baseline. Serum M-protein quantification, immunoglobulins, serum immunofixation, and serum free light chains should also be performed 
on Cycle 1 D -7 (unless completed within 14 days of this day during screening phase) and every cycle on D1 starting Cycle 2 (Do not need to be performed Cycle 1 Day 1). If 
UPEP is positive at screening, then repeat UPEP can be done at investigator’s discretion. All radiologic assessments are to be performed as clinically indicated and not required by 
the study. Response is assessed on the basis of clinical and laboratory findings on D1 of every cycle starting C2 prior to study drug administration, whenever disease progression is 
suspected (eg, symptomatic deterioration) and at the EOT visit. The availability of the results must not prevent the initiation of the next cycle. Response will be assessed against 
baseline values obtained during screening. 
s Bone Marrow Biopsy: Bone marrow biopsy for correlative studies will be performed prior to C0, D-7 (within 14 days of first azacitidine dose) and again at C1, D1 (or after 
completion of first 5 days of azacitidine and prior to first daratumumab administration) and only as clinically indicated at time of progression (though not required by study)
t Disease assessments during follow-up period: are only required for patients with PR or better who have discontinued treatment for reasons other than disease progression and 
have not yet started treatment with another anti-cancer therapy. Patients will be followed every month for progression during this period. Disease assessments required every 
month include evaluation of serum M-protein, serum free light chains, and serum immunoglobulins. A bone skeletal survey and PET/CT/MRI are only required if clinically 
indicated to confirm response or progression according to IMWG criteria. Disease assessments are not required in the follow-up period by this study for patients who have 
discontinued treatment due to progression or once patients starts treatment with another anti-cancer therapy. For patients who are off study due to disease progression, they will 
receive a phone call at minimum per study every 4 weeks for one year post last study drug treatment to assess survival


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6.2
Participant Registration
A written, signed, informed consent form (ICF) and a Health Insurance Portability and Accountability Act 
(HIPAA) authorization must be obtained before any study-specific assessments are initiated.  A copy of the 
signed ICF will be given to the subject and a copy will be filed in the medical record.  The original will be 
kept on file with the study records.  
All participants consented to the study will be registered in OnCore®, the UCSF Helen Diller Family 
Comprehensive Cancer Center Clinical Trial Management System (CTMS).  The system is password 
protected and meets HIPAA requirements.
6.3
Schedule of Procedures and Observations
The Study Calendar summarizes the frequency and timing of study procedures and assessments 
applicable to this study.
Study assessments will be performed only after written informed consent is obtained. At each visit, 
study assessments should be completed before the administration of any treatment. All PRO 
assessments should be conducted/completed before any tests, procedures, or other consultations to 
prevent influencing subject perceptions.
Throughout the study, subjects will be closely monitored for adverse events, laboratory abnormalities, 
and clinical response. Clinical evaluations and laboratory studies may be repeated more frequently, if 
clinically indicated.
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time during 
the subject’s participation in the study.
Medical resource utilization data will be collected.
 Pretreatment Period
Screening Assessments 
The Screening procedures and assessments must be completed within 28 days of initiating study 
treatment, unless otherwise noted. The signed ICF must be obtained before any study-specific 
procedures are performed. The screening phase begins when the ICF is signed. During the screening 
phase, eligibility criteria will be reviewed and a complete clinical evaluation will be performed. 
Results of tests such as skeletal survey, radiologic tests (eg, MRI) to document baseline size of known 
or suspected extramedullary plasmacytomas; or chest X-rays) performed up to 6 weeks (42 days) 
before enrollment may be used if these tests have been performed as part of routine follow-up for the 
subject’s disease. A bone marrow biopsy will need to be done within 14 days prior to first azacitidine 
dose.

History and Physical Examination
o
Including Vital Signs, weight/height, concomitant meds, AE assessment, performance 
status

Laboratory Assessments:
o
Pregnancy Test: women of child-bearing potential must have a negative serum pregnancy 


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test result within 7 days prior to first IMP administration
o
Type and screen must be done prior to first daratumumab administration
o
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.  HBV serology is not required at Screening if this was performed as part of 
standard of care within 3 months prior to first dose.
o
HBV DNA Tests: Subjects who are positive for Anti-HBc or Anti-HBs will undergo testing 
for hepatitis B DNA by PCR. Subjects with serologic findings suggestive of HBV 
vaccination (Anti-HBs positivity as the only serologic marker) and a known history of prior 
HBV vaccination do not need to be tested for HBV DNA by PCR. During and following 
study treatment, subjects who have history of HBV infection will be closely monitored for 
clinical and laboratory signs of reactivation of HBV as specified in the Study Calendar 
(Section 6.1) Where required by local law, the results of HBV testing may be reported to 
the local health authorities.
o
Blood Chemistry: SGOT (AST), SGPT (ALT), total bilirubin, alkaline phosphatase (AP), 
lactate dehydrogenase (LDH), sodium, potassium, chloride, bicarbonate/carbon dioxide, 
calcium, corrected serum calcium, magnesium, phosphate, uric acid, blood urea nitrogen 
(BUN), serum creatinine, albumin and total protein
o
Hematology: hemoglobin, hematocrit, red blood cell (RBC), white blood cell (WBC) with 
differential, platelet count

Adverse events/serious adverse events are to be reported from the signing of the informed consent

Disease Assessment:  (all lab assessments to be performed within 28 days and all radiologic 
assessments as clinically indicated prior to first azacitidine administration) 
o
M-protein quantification (serum and 24-hr urine) 
o
Serum IFE
o
Serum free light chain levels 
o
Immunoglobulins: IgG, IgA, IgM, 
o
Radiologic imaging (PET/CT/MRI scan) of plasmacytoma (medullary and extramedullary), 
if clinically indicated 
o
Skeletal survey (X-ray; including skull, rachis, all long bones, pelvis and chest), if clinically 
indicated.

Correlative study procedure: baseline bone marrow biopsy prior to first azacitidine dose (within 
14 days prior to first dose of azacitidine) 
Treatment Period
The same evaluations as performed at screening/baseline will be performed for each of the required 
evaluations. Disease evaluations will be performed every cycle. 
Subjects with platelet counts ≤30,000/μL at the beginning of any cycle will be required to have 
platelet assessment 2 times per week until the end of treatment cycle. Any patient with platelets 
>30,000/μL at the beginning of any cycle who develops platelets ≤ 20,000/μL at any point during 
cycle should begin having platelets evaluated two times per week each cycle until patient has a cycle 
where nadir is > 20,000/μL. If Grade 4 neutropenia, assess ANC every 2-3 days until ANC   ≥ 0.5   x   
109/L    and    at    least weekly   thereafter   until   ANC   ≥1.0   x    109/L. 
Otherwise will plan to check complete blood count and chemistry panel with every daratumumab 
administration and every cycle of azacitidine. 


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Cycle 1 Day -7 to -3
-
History and Physical Examination 
-
Weight
-
Vital Signs*
-
Performance Status (ECOG)
-
AE/SAE assessment
-
Concomitant medications.
-
Laboratory Assessments:
•
Blood Chemistry (not required to be repeated if screening labs were 
performed within 3 days prior to first study drug administration),
•
Hematology (not required to be repeated if screening labs were performed within 3 
days prior to first study drug administration),
-
Disease assessment (not required to be repeated if screening labs were performed within 14 
days prior to first study drug administration)
•
M-protein quantification (serum)
•
Serum free light chain levels 
•
Immunoglobulin quantification 
•
Serum IFE
-
Administration of azacitidine 75 mg/m2*
*Occur daily Day -7 to -3 as clarified in footnote of table, while the other items only needed on 
Day -7
Cycle 1, Day 1
-
Physical Examination
-
Weight.
-
Vital Signs.
-
Performance Status (ECOG)
-
AE/SAE assessment
-
Concomitant medications.
-
Laboratory Assessments:
•
Blood Chemistry (not required to be repeated at Cycle 1 if labs were performed within 
3 days prior to first study drug administration),
•
Hematology (not required to be repeated at Cycle 1 if labs were performed within 3 days 
prior to first study drug administration) 
-
Correlative Study procedure: Bone Marrow Biopsy # 2 prior to daratumumab first dose 
-
Administration of daratumumab 1800 mg subcutaneous
-
Administration of dexamethasone 40 mg PO/IV (32 mg on Day 1, 4 mg on Day 2 and 
Day 3)


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Cycle 1, Day 8  (repeat same Cycle 1, Day 15, Cycle 2, Days 8 and 15, Cycles 3-6,  Day 15)
-
Weight.
-
Vital Signs.
-
AE/SAE assessment
-
Concomitant medications.
-
Laboratory Assessments:
•
Blood Chemistry (can be performed within 3 days of study drug administration),
•
Hematology (can be performed within 3 days of study drug administration),
-
Administration of daratumumab 1800 mg subcutaneous
-
Administration of dexamethasone 40 mg PO/IV for Cycle 1 and Cycle 2 (can be 
reduced or stopped at discretion of treating provide for subsequent cycles)
Cycle 1, Day 22 (repeat on Cycle 2, Day 22)
-
Weight
-
Vital Signs*
-
AE/SAE assessment
-
Concomitant medications.
-
Laboratory Assessments:
•
Blood Chemistry (can be performed within 3 days of study drug administration),
•
Hematology (can be performed within 3 days of study drug administration),
-
Administration of azacitidine 75 mg/m2 (or modified dose based on AEs)*
-
Administration of daratumumab 1800 mg subcutaneous 
-
Administration of dexamethasone 40 mg PO/IV
*Occur daily Day 22- 26 as clarified in footnote of table, while the other items only needed on 
Day 22
Cycle 2, Day 1, (repeat on Cycle 3, Day 1 and Cycle 4, Day 1)
-
Physical Examination
-
Weight.
-
Vital Signs.
-
Performance Status (ECOG)
-
AE/SAE assessment
-
Concomitant medications.
-
Laboratory Assessments:
•
Blood Chemistry (can be performed within 3 days prior to study drug administration),
•
Hematology (can be performed within 3 days prior to study drug administration)
•
Serum pregnancy test
-
Disease assessment
•
M-protein quantification (serum) (can be performed within 3 days of study drug 
administration),
•
Serum free light chain levels (can be performed within 3 days of study drug 


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administration)
•
Immunoglobulin quantification (can be performed within 3 days of study drug 
administration)
•
Serum IFE
-
Administration of daratumumab 1800 mg subcutaneous 
-
Administration of dexamethasone 40 mg PO/IV for Cycle 2 (can be reduced or stopped 
at discretion of treating provide for subsequent cycles)
Cycle 3, Day 22
-
Weight
-
Vital Signs*
-
AE/SAE assessment
-
Concomitant medications.
-
Laboratory Assessments:
•
Blood Chemistry (can be performed within 3 days of study drug administration),
•
Hematology (can be performed within 3 days of study drug administration),
-
Administration of azacitidine 75 mg/m2 (or modified dose based on AEs)*
*Occur daily Day 22- 26 as clarified in footnote of table, while the other items only needed on 
Day 22
Cycle 5, Day 1 (repeat on Day 1 of Cycle 6)
-
Physical Examination
-
Weight
-
Vital Signs*
-
Performance Status (ECOG)
-
AE/SAE assessment
-
Concomitant medications.
-
Laboratory Assessments:
•
Blood Chemistry (can be performed within 3 days prior to study drug administration),
•
Hematology (can be performed within 3 days prior to study drug administration)
•
Serum pregnancy test
-
Disease assessment
•
M-protein quantification (serum) (can be performed within 3 days of study drug 
administration),
•
Serum free light chain levels (can be performed within 3 days of study drug 
administration)
Immunoglobulin quantification (can be performed within 3 days of study drug 
•
administration)
•
Serum IFE
-
Administration of azacitidine 75 mg/m2 (or modified dose based on AEs)*
-
Administration of daratumumab 1800 mg subcutaneous 
-
Administration of dexamethasone at discretion of treating provider


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*Occur daily Day 1-5 as clarified in footnote of table, while the other items only needed on Day 
1
Cycle 7, Day 1 (repeat on Day 1 of subsequent cycles)
-
Physical Examination
-
Weight
-
Vital Signs*
-
Performance Status (ECOG)
-
AE/SAE assessment
-
Concomitant medications.
-
Laboratory Assessments:
•
Blood Chemistry (can be performed within 3 days prior to study drug administration),
•
Hematology (can be performed within 3 days prior to study drug administration)
•
Serum pregnancy test
-
Disease assessment
•
M-protein quantification (serum) (can be performed within 3 days of study drug 
administration),
•
Serum free light chain levels (can be performed within 3 days of study drug 
administration)
Immunoglobulin quantification (can be performed within 3 days of study drug 
•
administration)
•
Serum IFE
-
Administration of azacitidine 75 mg/m2 (or modified dose based on AEs)*
-
Administration of daratumumab 1800 mg subcutaneous 
-
Administration of dexamethasone at discretion of treating provider
*Occur daily Day 1-5 as clarified in footnote of table, while the other items only needed on Day 
1
End of Treatment
-
Weight

Vital Signs 

Concomitant medications

Adverse events/serious adverse events

Laboratory Assessments:
o
Serum Pregnancy Test 
o
HBV DNA Test
o
Blood Chemistry
o
Hematology

Disease Assessment:
o
M-protein quantification (serum and 24-hr urine) 
o
Serum free light chain levels (sFLC)
o
Immunoglobulins: IgG, IgA, IgM, 
o
Serum IFE


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o
Radiologic imaging (PET/CT/MRI scan) of plasmacytoma (medullary and extramedullary), 
if clinically indicated 
o
Skeletal survey (X-ray; including skull, rachis, all long bones, pelvis and chest), if clinically 
indicated.
Post-treatment/ Follow-Up 
Each subject will be followed until 1 year after his/her last dose of study treatment, until death or withdrawal 
of consent for study participation, whichever occurs first. The end of study is defined as when all subjects 
have completed either at least 1 year of follow-up, or until death or withdrawal of consent for study 
participation, whichever occurs first. 
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. For these patients, HBV DNA 
testing PCR must be done Q12W during treatment, at the End of Treatment Visit, and Q12W for up to 6 
months after the last dose of study treatment.
After confirmed disease progression or the start of a new treatment for multiple myeloma, subjects will at 
minimum be contacted by telephone every 12 weeks for follow- up assessments (ie, other malignancies, 
next-line therapy, PD on next-line therapy, and survival, as applicable) until death, withdrawal of consent 
for study participation, or the end of the 1 year follow-up period, whichever occurs first. Following disease 
progression on the next-line therapy, subjects will only be followed for survival. 
If the information on other malignancies, next-line therapy, PD on next-line therapy, and survival is 
obtained via telephone contact, written documentation of the communication must be available for review 
in the source documents. If the subject has died, the date and cause of death will be collected and 
documented on the CRF. 
Investigators may recontact the subject to obtain long-term follow-up information regarding the subject’s 
safety or survival status as noted in the ICF.
Subjects will be instructed that study drug (ie, daratumumab) will not be made available to them after they 
have completed/discontinued study drug and that they should return to their primary physician to determine 
standard of care. 
6.4
Correlative Studies 
There will be two bone marrow biopsies performed for correlative studies. The first bone marrow biopsy 
will be performed within 14 days prior to the first azacitidine dose (during the screening phase) and the 
second bone marrow biopsy will be performed after completion of first 5 days of azacitidine treatment and 
prior to first dose of daratumumab treatment.   
Refer to laboratory manual for specific specimen collection instructions. The correlative studies below and 
the analysis will be performed in batched samples. Samples will be retained and stored at the end of the 
study.
CD38 Expression Changes
Pharmacodynamic analysis of surface CD38 Expression on primary plasma cells (Secondary 
Objective)


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Assessment of CD38 regulation with treatment of azacitidine in this study population is one of the 
secondary objectives of this study. Bone marrow (BM) samples will be collected as described above.  BM 
mononuclear cells (MNCs) will be subject to ficol separation and stained with CD38-FITC, CD138-APC 
R700 and Propidium Iodide among other markers. Cells will be washed with PBS, resuspended in 5% FBS-
PBS and analyzed by flow cytometry on BD Cytoflex. CS&T (Becton Dickinson) and Rainbow calibration 
beads (Spherotech) will be used to calibrate the instrument and fluorescence intensity of sequential samples. 
MFIs will be calculated on Flow Jo software. This will be done in Dr. Arun Wiita’s laboratory. Please see 
Section 8.2.5.1 for further details on analysis.
Methylation Pattern Changes
Analysis of methylation pattern changes induced by Aza on primary plasma cells (Exploratory 
Objective, contingent upon funding)
Assessment of methylation of plasma cell whole genome and CD38 specific genome will be performed via 
whole genome reduced representation bisulfite sequencing in collaboration with Zymo Research. BM 
samples will be obtained before and after exposure to Aza and DNA will be extracted via the Quick DNA 
miniprep kit (Zymo Research).  200ng of genomic DNA will be bisulfite converted using EZ DNA 
Methylation-Gold Kit (Zymo Research). Subsequently, a region of the CD38 CpG island will be PCR 
amplified and cloned into the TOPO cloning vector (Life Technologies). Clones will be verified by PCR 
and 10 verified clones will be sequenced for analysis of CpG content and methylation levels.
Tumor Microenvironment Changes
Assessment of tumor microenvironment changes induced by Aza (Exploratory Objective, 
contingent upon funding)
Analysis of bone marrow microenvironment changes induced by Aza will be performed via CyTOF assay. 
BM samples will be obtained as described above and samples will be stained and processed in collaboration 
with Dr. Matthew Spitzer’s laboratory. Dr. Matthew Spitzer is one of the leaders in cancer immunotherapy 
and his laboratory is part of the Cancer Immunotherapy Program (CIP) as well as the Parker Institute for 
Cancer Immunotherapy. The mass cytometry (CyTOF) experiments will be performed in Dr. Matt Spitzer’s 
lab at UCSF. Dr. Matt Spitzer is one of the leading researchers in tumor immunology.
CyTOF assay enumerates  98% of peripheral immune cells with 4 positively identifying antigens among 
a reference panel of 33 antibodies to cover major cell subsets quantifying activation and immune checkpoint 
molecules in a single assay.  Spitzer et al.57 established a reference panel of 33 anti-human antibodies (see 
Appendix 4 for full list of antibodies) for mass cytometry that can easily be incorporated into routine 
immunophenotyping studies in the context of cancer immunotherapy. The selected target antigens are 
distributed broadly across immune cell types and thus ensure that all major immune cell lineages and 
various functional subsets can be identified robustly and unambiguously. Using automated analysis, we 
will be able to identify stratifying immune signatures and compare the immune signatures pre and post Aza 
treatment. 
Mass cytometry workflow57:
Sample preparation
Cryopreserved bone marrow biopsy samples will be thawed into 10mL of cold cell culture medium 
(RPMI-1640 (life technologies), 10% FBS, 1x L-glutamine, 1x penicillin/streptomycin (Thermo Fisher)) 


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supplemented with 20 U/ml sodium heparin and 0.025 U/ml benzonase (Sigma) and washed once (250 g, 
4°C).
Cellular barcoding
Where indicated, samples will be barcoded and combined into a composite sample before surface 
staining. Barcoding will be performed employing either a palladium-based barcoding approach applicable 
to fixed cells or a live cell barcoding methodology involving antibodies against the surface molecules 
beta-2-microglobulin and a sodium-potassium pump (CD298) as described.
 
Viability staining
Cisplatin (Sigma) will be resuspended to 100mM in DMSO, pre-conditioned for 48 h at 37°C and stored 
at 20°C. Viability staining will be performed by resuspending the sample in 1mL of PBS and adding 
cisplatin to a final concentration of 500 nM, followed by incubation for 5 min at RT and washing with 
CSM. Where indicated, cells will be fixed with 1.6% PFA in PBS for 10 min at RT and washed twice 
with cell staining medium (CSM: PBS with 0.5% BSA and 0.02% sodium azide (all Sigma)) before 
staining. In case live cell barcoding is employed, viability assessment will be performed by substituting 
cisplatin with DCED-palladium (Sigma) and following the protocol
as described here.
Antibody staining
Cell-surface antibody master-mix (2x) will be prepared by adding appropriate dilutions of all cell-surface 
antibodies into 50 mL CSM per sample. If samples contained more than 3 x 106 cells, antibody volume 
(but not total CSM volume) will be increased accordingly (e.g., 2-fold for up to 6 x106 cells). The 
antibody master-mix will be then filtered through a prewetted 0.1 µm spin-column (Millipore) to remove 
antibody aggregates and 50 mL will be added to the sample resuspended in 50 mL of CSM. After 
incubation for 30 min at RT, cells will be washed once with CSM. For intracellular staining, cells will be 
fixed using the FoxP3 / transcription factor staining buffer set (Thermo Fisher Scientific) to fix for 1 h at 
RT. After fixation, samples will be washed once with CSM and once with 1x permeabilization buffer 
(Thermo Fisher Scientific) by centrifugation for 5 min, 600 g at 4°C. Intracellular antibody master-mix 
(2x) will be prepared analogously to the surface antibody mix by adding appropriate dilutions of all 
intracellular antibodies into 50 ul permeabilization buffer per sample. 50 mL of 2x antibody master mix 
will be added to the samples in 50 mL permeabilization buffer and incubated for 1 h at RT. Cells will be 
washed once with permeabilization buffer and once with CSM. Finally, samples will be resuspended in 
intercalation solution (1.6% PFA in PBS and 0.5 µM iridium-intercalator (Fluidigm)) for 20 min at RT or 
overnight at 4°C.
Data acquisition
Before acquisition, samples will be washed once in CSM and twice in ddH2O and filtered through a cell 
strainer (Falcon). Cells will be then resuspended at 1 3 106 cells/mL in ddH2O supplemented with 1x EQ 
four element calibration beads (Fluidigm) and acquired on a CyTOF2 mass cytometer (Fluidigm).
Flow cytometry
Bone marrow samples will be thawed as described above and subsequently treated with Fc blocking 
reagent (BioLegend) for 10 min at 4°C. Antibody cocktails will be then added for 30 min and incubated at 
4°C. All samples will be washed with PBS containing BSA (0.5%), then fixed with 1.6% PFA for 10 min 
at RT. Finally, the samples will be washed and analyzed on an LSRII flow cytometer (BD Biosciences) 
equipped with 405, 488, 561, and 640nm lasers.
Quantification and statistical analysis from the CyTOF assay will be described in detail in Section 8.2.


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7
Reporting and Documentation of Results
7.1
Evaluation of Efficacy: Antitumor Effect – Hematologic Tumors
Disease response and progression will be based on assessments according to the IMWG Guidelines55 as 
defined in Section 7.1.1, Response Categories. Daratumumab detection on serum IFE has been 
demonstrated in subjects treated with 16 mg/kg and may interfere with the traditional IMWG criteria of 
negative serum IFE for CR or sCR. To mitigate this interference, daratumumab-specific IFE testing will 
be performed as clinically indicated in patients with IgG Kappa myeloma. This daratumumab-specific 
IFE testing utilizes anti-idiotype antibody to bind daratumumab and confirm its interference on IFE (see 
laboratory manual). For all subjects on study with VGPR, a serum IFE positive for IgG Kappa, and a 
negative M-protein by SPEP, daratumumab-specific IFE testing will be performed as clinically indicated 
if CR is suspected, to confirm the presence or absence of daratumumab on IFE. In addition, in subjects 
with IgG Kappa myeloma and an M protein on SPEP of ≤0.2 g/dL, the daratumumab specific IFE testing 
will also be performed to determine whether the paraprotein identified on SPEP/IFE is monoclonal 
daratumumab or the subject’s endogenous myeloma protein.
Response Categories
Disease evaluations by laboratory tests must be performed per the schedule noted in the Study Procedures 
and Schedule of Events. This study will use the IMWG consensus recommendations for multiple myeloma 
treatment response criteria presented in table below. For quantitative Ig, M-protein, and IFE measurements 
in serum and 24-hour urine, the investigator will use results provided by the central laboratory. 


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Table 7-1 International Uniform Response Criteria Consensus Recommendations
FLC = free light chain; IMWG = International Myeloma Working Group; M-protein = monoclonal paraprotein; PC = plasma
cell.
All response categories (CR, sCR, VGPR, PR, and PD) require 2 consecutive assessments made at any time before the
institution of any new therapy; CR, sCR, VGPR, PR, and SD categories also require documentation of no known evidence of
progressive or new bone lesions if radiographic studies were performed. VGPR and CR categories require serum and urine studies regardless of 
whether disease at baseline was measurable on serum, urine, both, or neither. Radiographic studies are not required to satisfy these response 
requirements. Bone marrow assessments need not be confirmed. For PD, serum M component increases of more than or equal to 1 g/dL are sufficient 
to define relapse if starting M-component is ≥5 g/dL.
Disease progression based on 1 of the laboratory tests alone must be confirmed by at least 1 repeat investigation. Clinical
judgment should prevail; however, repeat assessments after 1 to 3 weeks can be used as a general guideline.
       a       Presence/absence of clonal cells is based upon the kappa/lambda ratio. An abnormal kappa/lambda ratio by
immunohistochemistry or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio
reflecting presence of an abnormal clone is kappa/lambda of >4:1 or <1:2.
        b         Clarifications to IMWG criteria for coding CR and VGPR in subjects in whom the only measurable disease is by serum
FLC levels: CR in such subjects indicates a normal FLC ratio of 0.26 to 1.65 in addition to CR criteria listed above. VGPR
in such subjects requires a >90% decrease in the difference between involved and uninvolved FLC levels.


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     c Clarifications to IMWG criteria for coding PD: Bone marrow criteria for PD are to be used only in subjects without
measurable disease by M-protein and by FLC levels; “25% increase” refers to M-protein, FLC, and bone marrow results,
and does not refer to bone lesions, soft tissue plasmacytomas, or hypercalcemia and the “lowest response value” does not
need to be a confirmed value.
Clinical Relapse
Clinical relapse is defined using the definition of clinical relapse in the IMWG criteria.55 In the IMWG criteria, clinical
relapse is defined as requiring one or more of the following direct indicators of increasing disease or end-organ dysfunction
that are considered related to the underlying plasma cell proliferative disorder:
      1. Development of new soft tissue plasmacytomas or bone lesions on skeletal survey, magnetic resonance imaging, or other
          imaging
      2. Definite increase in the size of existing plasmacytomas or bone lesions. A definite increase is defined as a 50% (and at
          least 1 cm) increase as measured serially by the sum of the products of the cross-diameters of the measurable lesion
      3. Hypercalcemia (>11.5 mg/dL; >2.875 mM/L)
      4. Decrease in hemoglobin of more than 2 g/dL (1.25 mM) or to less than 10 g/dL
      5. Rise in serum creatinine by more than or equal to 2 mg/dL (≥177 mM/L)
      6. Hyperviscosity
      In some subjects, bone pain may be the initial symptom of relapse in the absence of any of the above features. However, bone
      pain without imaging confirmation is not adequate to meet these criteria in studies.
Measurement of Endpoints for Response
The primary endpoint for response in this study is ORR as best response by the end of the study treatment. 
ORR is defined as the proportion of patients with stringent complete response (sCR), complete response 
(CR), very good partial response (VGPR), and partial response (PR) based on responses as assessed using 
the International Myeloma Working Group (IMWG) Uniform Response Criteria. Response evaluation will 
be performed on a monthly basis. Disease progression by paraprotein should be confirmed within the first 
4 weeks after last assessment. DOR is defined as the time from the date of the first response to the date of 
subsequent PD or death due to PD, whichever happens earlier. In the absence of the confirmation of 
subsequent disease progression or death before the analysis cut-off date, the DOR will be censored at the 
date of the last valid assessment performed before the analysis cut-off date or date of initiation of new 
anticancer treatment, whichever is earlier. DOR is determined only for patients who have achieved a 
response of ≥PR. DOR will not be calculated for patients that do not achieve a response. 
Assessment of Disease Progression or Response
Disease progression must be consistently documented using the criteria in table in Section 7.1.1. Disease 
progression based on 1 of the laboratory tests alone must be confirmed by at least 1 repeat investigation. 
Clinical judgment should prevail; however, repeat assessments after 1 to 3 weeks can be used as a general 
guideline. Disease progression based on imaging, bone marrow plasma cell percentage, or hypercalcemia 
(not attributable to any other cause) do not need to be confirmed. Bone marrow biopsy to assess morphology 
(aspirate and biopsy) at the time of progression will be at the discretion of the individual provider and not 
required by the study. 
For subjects who discontinue study treatment before disease progression, disease evaluations should 
continue to be performed as described every 4 weeks until confirmed disease progression, death, the start 
of a new treatment for multiple myeloma, withdrawal of consent for study participation, or the end of study, 
whichever occurs first. 
Methods of Response Evaluation
Response evaluation will include:


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
M-protein quantification (serum and 24-hr urine)

Serum free light chain (FLC) levels

Bone marrow biopsy/aspiration (not required)
Myeloma Protein Measurements in Serum and Urine
Blood and 24-hour urine samples will be collected for serum quantitative Igs, serum and urine M-protein 
measurements, serum and urine IFE measurements, and serum FLC assay in screening phase (within 28 
days of first azacitidine administration). If urine samples cannot be collected, then serum markers will be 
used alone. Serum quantitative immunoglobulins, serum M-protein measurements, serum IFE, and serum 
FLC assay will be performed on Cycle 1 Day -7 (prior to first azacitidine dose), unless screening disease 
evaluation labs were performed within 14 days prior to this first azacitidine administration, and every 
subsequent cycle on D1 starting cycle 2 (disease evaluation labs do not need to be repeated on Cycle 1 Day 
1) until off study and at EOT. 
Blood (and 24-hour urine, as determined by the treating physician) samples for disease evaluation will be 
collected until the development of confirmed disease progression. Progression of disease based on serum 
markers will need to be confirmed by at least 1 repeat investigation. Progression of disease based on urine 
markers does not need to be confirmed. Clinical judgment should prevail; however, repeat assessments after 
1 to 3 weeks can be used as a general guideline. 
For subjects with VGPR and suspected daratumumab interference (see Section 7.1.1, Response categories), 
reflex serum IFE using the anti-idiotype monoclonal antibody can be used as clinically indicated to confirm 
daratumumab migration on the IFE. Subjects that meet all other IMWG criteria for CR, and whose positive 
IFE is confirmed to be daratumumab, will be considered complete responders.
Bone Marrow Biopsy
Bone marrow biopsy will be performed on Cycle 1 Day -7 (or within 14 days prior) and Cycle 1 Day 1 (or 
after completion of first 5 days of azacitidine and prior to first daratumumab administration). Bone marrow 
biopsies to assess response or progression will not be required by the study but will be left to the discretion 
of the individual provider.
7.2
Evaluation of Safety
Safety will be measured by adverse events reported to the investigators by participants, laboratory test 
results, and clinical evaluation. Toxicity will be assessed according to the NCI CTCAE version 5.0. Safety 
analyses will be performed for all participants who have completed at least one dose of treatment and will 
encompass the duration of each participant’s study treatment and until 30 days after last treatment. Please 
see Section 8.1.3 for further details on safety analysis.
Any clinically relevant toxicity ( ≥ grade 3 hematologic adverse events or any grade non-hematologic 
adverse events) as determined by the treating provider thought to be probably, possibly, or definitely 
related to daratumumab, azacitidine, or dexamethasone exposure should be reported. Any clinically 
significant abnormalities persisting at the end of the study/early withdrawal will be followed by the 
investigator until resolution or until a clinically stable endpoint is reached.
Overview


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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.
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.
Management of Safety Data
This Study has been designated as an interventional study.  As such, all adverse events, special situations 
including pregnancies and product quality complaints will be reported as described in this exhibit from 
the time a subject has signed and dated an Informed Consent Form (ICF) until 30 days after the last 
documented use of a product under study within the study. All subsequent AEs and SAEs will be 
collected after this period if the Principal Investigator considers the AE/SAE to be causally-related to the 
use of the study drug. 
For the purposes of this study, the J&J medicinal product is: DARZALEX® (daratumumab). The Celgene 
medicinal product is: VIDAZATM (azacitidine).
7.3
Definitions of Adverse Events 
Adverse Event (AE)
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational or non- investigational) product, whether or not related to that 
medicinal (investigational or non-investigational) product. (Definition per International Conference 
on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Adverse Events of Special Interest
Adverse events of special interest are events that Janssen Scientific Affairs, LLC is actively 
monitoring as a result of a previously identified signal (even if non-serious). These adverse events 
are:

Administration reactions: ≥ grade 3

Infections: ≥ grade 4 

HBV Reactivation

Cytopenias: ≥ grade 4 

Other malignancies


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Any Adverse Event of Special Interest that is to be reported to Janssen should be recorded on a 
Serious Adverse Event Report Form and be reported to Janssen within 24 hours of knowledge of the 
event.
Serious Adverse Events (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

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.] 


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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, section 6, Reference Safety Information
 
7.4
Recording of Adverse Events
Refer to the Data Safety Monitoring Plan, located in Appendix 2.
7.5
Follow-up of Adverse Events
All participants who experience adverse events will be followed with appropriate medical management 
until resolved or stabilized, as determined by the investigator, or until the initiation of new anti-cancer 
therapy, whichever occurs first.  For selected adverse events for which administration of the investigational 
product was stopped, a re-challenge of the subject with the investigational drug may be conducted if 
considered both safe and ethical by the investigator.
7.6
Adverse Events Monitoring
Refer to the Data Safety Monitoring Plan, located in Appendix 2.
Adverse events (with the exception of progression of multiple myeloma) will be reported by the 
subject (or, when appropriate, by a caregiver, surrogate, or the subject’s legally acceptable 
representative) for the duration of the study (ie, from the time a signed and dated informed consent if 
obtained until 30 days following the last dose of study treatment). 
7.7
Expedited Reporting 
Reporting to the Data and Safety Monitoring Committee
If a death occurs during the treatment phase of the study or within 30 days after the last administration of 
the study drug(s) and it is determined to be related either to the study drug(s) or to a study procedure, the 
Investigator or his/her designee must notify the DSMC Chair (or qualified alternate) within 1 business day 
of knowledge of the event.  The contact may be by phone or e-mail.
Reporting to Institutional Review Board
The UCSF PI must report events to the UCSF IRB according to institutional guidelines.


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UCSF IRB website for guidance in reporting adverse events: https://irb.ucsf.edu/adverse-event
Expedited Reporting to the FDA
If the study is being conducted under an IND, the Sponsor (or the Sponsor-Investigator) is responsible for 
determining whether or not the suspected adverse reaction meets the criteria for expedited reporting in 
accordance with federal regulations (21 CFR §312.32). 
The Sponsor (or Sponsor-Investigator) must report in an IND safety report any suspected adverse reaction 
that is both serious and unexpected. The Sponsor needs to ensure that the event meets all three definitions: 

Suspected adverse reaction 

Unexpected 

Serious 
If the adverse event does not meet all three of the definitions, it should not be submitted as an expedited 
IND safety report.
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after the 
Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 312.32(c)(1)). 
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no later than 
7 calendar days after the Investigator’s initial receipt of the information (21 CFR 312.32(c)(2)). 
Any relevant additional information that pertains to a previously submitted IND safety report will be 
submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the information is available 
(21 CFR 312.32(d)(2)). 
Interventional 
IIS 
Janssen 
Scientific 
Affairs 
Requirements 
for 
Safety 
Data
           Collection and Reporting
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 J&J 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 J&J medicinal 
product

Medication error (includes potential, intercepted or actual) involving a J&J product (with or 
without patient exposure to the J&J Product(s) under study , 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
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.


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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.
Individual Case Safety Report (ICSR)
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


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Pregnancy
All initial reports of pregnancy must be reported to Janssen Scientific Affairs, LLC by Principal Investigator 
within 24 hours of becoming aware of the event using the Serious Adverse Event Form. Abnormal 
pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, congenital anomaly, ectopic 
pregnancy) are considered serious adverse events and must be reported using the Serious Adverse Event 
Form. 
Any subject who becomes pregnant during the study must be promptly withdrawn from the study and 
discontinue further study treatment.
Because the effect of the J&J medicinal product on sperm is unknown, pregnancies in partners of male 
subjects exposed to a J&J medicinal product will be reported by Principal Investigator within 24 hours of 
their knowledge of the event using the Serious Adverse Event Form.  Depending on local legislation this 
may require prior consent of the partner.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the infant 
will be required.
Maintenance of Safety Information
All safety data should be maintained in a clinical database in a retrievable format. 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 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&J medicinal 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&J medicinal 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, Adverse Events of Special Interest and Special Reporting Situations
All serious adverse events that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject's participation in the study, must be followed until any of the following 
occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available


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
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)
Principal Investigator will transmit all SAEs, Adverse Events of Special Interest and special situations 
following exposure to a J&J product under study in a form provided by Janssen Scientific Affairs, LLC in 
accordance with Section 7.3, Transmission Methods, in English within 24-hours of becoming aware of 
the event(s).
In the event the study is blinded, 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, 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, Adverse Events of Special 
Interest, serious ADR or special situation is required.

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 extraordinary (not including routine initial or follow-up ICSR 
submission) correspondences with regulatory authorities and ethics committees regarding any 
and all serious adverse events, irrespective of association with the J&J Product under study, 
are to be provided to Janssen Scientific Affairs, LLC using a transmission method in Section 
7.4.4.9 within 24 hours of such report or correspondence being sent to applicable health 
authorities.
Non-serious AEs
All non-serious adverse events should be reported to Janssen Scientific Affairs, LLC according to the 
timeframe outlined in the Research Funding Agreement section entitled Reporting of Data.
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.


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All initial PQCs involving a J&J medicinal product under study must be reported to Janssen Scientific 
Affairs, LLC by Principal Investigator within 24 hours after being made aware 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, 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&J Medicinal Products
For SAEs, special reporting situations and PQCs following exposure to a non-J&J medicinal product 
under study, 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 J&J 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. 
8
Statistical Considerations and Evaluation of Results
8.1
Sample Size Determination
This is a single-arm, open-label, 2-stage phase II study designed to evaluate the efficacy of daratumumab 
in combination with azacitidine and dexamethasone in RRMM patients previously treated with 
daratumumab. A Simon’s two-stage design58 will be used for this study. The study will begin with accrual 
of 6 patients in a safety run-in. Safety monitoring bounds for study termination based on DLTs are described 
in Section 8.2.2. If the safety stopping bounds are not met, study will continue to accrue more Stage I 
patients. 
Sample size calculation was based on assessing the overall response rate (ORR) using Simon’s minimax 2-
stage design. Interim analysis for efficacy, using ORR, will be performed when the last patient enrolled to 
Stage 1 has received at least 2 cycles of treatment.
The overall target sample size of 23 patients is based upon having sufficient information to assess whether 
combined treatment of daratumumab with azacitidine and dexamethasone increases the ORR in this study 
population of RRMM patients with prior treatment with daratumumab. Data from ongoing clinical trial 
evaluating the safety, pharmacokinetics, and efficacy of isatuximab in patients with RRMM previously 
treated with daratumumab has shown preliminary results of ORR 8% (NCT02514668). Isatuximab is 
another CD38 monoclonal antibody with similar efficacy to daratumumab in RRMM patients.24 Based on 
these previous results, for this study we would be interested in detecting an improvement in the ORR 
from a null rate of 8% to 33% ORR, which is based on the daratumumab-pomalidomide-dexamethasone 


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combination study in patients with RRMM re-treated with daratumumab.23 Simon’s minimax two-stage 
design will be used. The null hypothesis that the true response rate is 8% will be tested against a one-
sided alternative that the true response rate is higher than 33%. In the first stage, 13 patients will be 
accrued. If there are 1 or fewer responses in these 13 patients, the study will be stopped. Otherwise, 10 
additional patients will be accrued for a total of 23. The null hypothesis will be rejected if 5 or more 
responses are observed in 23 patients. The design will have a 90% power to reject the null hypothesis, if 
the true response rate is 33%, at one-sided 5% significance level. Accounting for an approximate 10% 
drop-out/ineligibility rate, maximum target accrual should not exceed 25 participants.
8.2
Analyses
Analyses Population
Analysis of primary and secondary efficacy variables will be based on the response-evaluable 
population, which includes all subjects who have measurable disease and received at least 2 cycles of 
study treatment, and have at least 2 efficacy evaluation assessments. All safety analyses for AEs will 
be based on the safety analysis set, which includes all subjects who receive at least 1 cycle of study 
treatment. 
Safety Analysis
The study will begin with accrual of 6 patients in a safety run-in with interim safety analysis occurring after 
these 6 patients have completed at minimum Cycle 1 and further accrual stopped until safety analysis 
completed. If ≥ 2/6 patients in the safety cohort have dose limiting toxicities (DLTs) as defined in Section 
5.4, then further study accrual will be halted until the study PI, co-investigators, and the DSMC can review 
the data, and determine whether the study should continue, be amended with a lower starting dose of 
azacitidine, or be closed to further accrual. Toxicities will be monitored throughout the study using CTCAE 
5.0 criteria. Though we do not expect to observe DLTs during the study period, formal safety bounds based 
upon monitoring DLTs as defined in Section 5.4 will guide decisions about early stopping due to potential 
safety concerns. A Pocock-type sequential boundary59 will be used to monitor dose-limiting toxicities with 
the aim of keeping the probability of early stopping at around 90% if the true underlying toxicity rate is 
25%. If the number of dose-limiting toxicities is equal to or exceeds the stopping boundaries detailed in the 
following table at any point in the study, then accrual to the study will be suspended until the study PI, co-
investigators, and the DSMC can review the data, and determine whether the study should continue, be 
amended with a lower starting dose of azacitidine, or be closed to further accrual. With a toxicity rate of 
25%, the expected number of enrolled patients before stopping for excessive toxicities is 6.5.
Table 8-1. Table: Safety monitoring bounds for DLTs
 
Number of subjects
Stopping boundary
6-9
≥2
10-14
≥3
15-18
≥4
19-23
≥5


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Adverse Events
Adverse events for safety analysis will be monitored for the duration of patient’s treatment until 30 
days post completion of treatment. The verbatim terms used in the CRF by investigators to identify 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent adverse events are adverse events with onset during the induction/consolidation 
or maintenance treatment phase or that are a consequence of a pre-existing condition that has worsened 
since baseline. All reported adverse events will be included in the analysis. For each adverse event, 
the percentage of subjects who experience at least 1 occurrence of the given event will be 
summarized.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those subjects 
who die, who discontinue treatment due to an adverse event, or who experience a severe or a serious 
adverse event. These will be provided using the same formats as those used for adverse events. At 
study conclusion frequency, proportion and severity of adverse events, and DLTs by dose level will 
be tabulated. Point estimates and confidence intervals will be calculated for all dichotomous 
endpoints.
Efficacy Analysis
Response to study treatment and progressive disease will be evaluated by the IMWG response criteria. 55
Primary endpoints for efficacy 
Primary endpoints for efficacy will be assessed by ORR. See Section 2.3 for definitions. To account for the 
adaptive nature of Simon’s two-stage design, we will calculate the uniformly minimum-variance unbiased 
estimator, p-value and 95% CI for the response rates. The calculation will be performed using R clinfun 
package (www.r-project.org).
Secondary endpoints for efficacy
Secondary endpoints for efficacy will be assessed using duration of response (DOR), progression-free 
survival (PFS), and overall survival (OS). DOR is defined as the duration from the date of initial 
documentation of a response (PR or better) according to the IMWG criteria to the date of first documented 
evidence of progressive disease according to the IMWG criteria or death due to PD whichever occurred 
first. DOR for subjects who have not progressed will be censored at the last disease evaluation before the 
start of any subsequent anti-myeloma therapy. PFS which is defined as the duration from the date of first 
dose of study treatment to the date of first documented evidence of progressive disease or death, whichever 
occurs first. Participants without a disease assessment will be censored at the date of first study treatment 
received. OS will be calculated as the time from the first dose of study treatment until death from any cause. 
Participants who have not died will be censored at the last time the participant was known to be alive. 
Distributions of DOR, PFS, and OS will be summarized using the Kaplan-Meier estimator. For each 
secondary efficacy endpoint, median even-free survival will be reported and the corresponding 
95% confidence interval will be calculated using Brookmeyer and Crowley method.


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Correlative Studies Analysis
CD38 regulation by azacitidine (Secondary Endpoint)
Change in CD38 surface expression in MM patients treated with azacitidine will be summarized using 
descriptive statistics and tested using the one-sample t-test. Two-sided p-value less than 0.05 will be 
considered statistically significant. The proportion of patients with at least a 1.5 fold increase in CD38 
expression after one cycle of azacitidine treatment will also be reported. This phase II sample size of 23 
will provide >99% statistical power to detect a fold change of 1.965 (SD: 0.299) in CD38 surface expression 
of MM patients treated with azacitidine based on a one-sample t-test at a two-sided type I error rate of 0.05. 
This estimated change in CD38 surface expression was calculated from our preliminary pre-clinical data. 
The association between the fold change in CD38 expression post azacitidine treatment and depth of 
response and duration of response will also be evaluated using logistic regression, linear regression 
methods, and Spearman’s correlation coefficient, as appropriate.
DNA methylation pattern changes with azacitidine (Exploratory Objective, contingent upon 
funding)
Paired t-tests will be used to compare the DNA methylation levels between the samples pre and post Aza 
treatment. Analysis will be corrected for multiple hypothesis testing by controlling the false discovery rate 
(FDR). The distribution of uncorrected p values will be analyzed and an FDR will be inferred for each 
differentially methylated region (DMR). The inference will be made using the q value method available in 
R/Bioconductor. The dependence between statistical tests carried out for neighboring CpGs will be modeled 
to increase statistical power. Statistical comparisons will be carried out on larger genomic regions rather 
than single CpGs, such that neighbouring CpGs with similar differences in DNA methylation reinforce each 
other and give rise to more significant results. Hierarchical models will be used to minimize small standard 
deviations that frequently arise by chance. Standard deviation of a given CpG or genomic region will be 
estimated as the average of observed and expected values to obtain more robust P values for DNA 
methylation comparisons. A ranked list of DMRs will be established by incorporating p values as well as 
the relative and absolute differences in DNA methylation between samples pre and post Aza treatment.
Assessment of bone marrow tumor microenvironment changes (Exploratory Objective, 
contingent upon funding)
CyTOF will be used to report the changes in bone marrow tumor microenvironment before and after 
treatment with Aza, one of the exploratory endpoints of the study. Data generation and analysis will be 
done in collaboration with Dr. Matt Spitzer’s laboratory at UCSF.  
Data normalization and gating
After acquisition, data from acquired samples will be bead-normalized using MATLAB-based software. 
Barcoded cells will be assigned back to their initial samples using MATLAB-based debarcoding software. 
Normalized data will be then uploaded onto the Cytobank analysis platform to perform initial gating and 
population identification using the indicated gating schemes.
Data visualization and analysis
For further downstream analysis, pre-gated data will be imported into the R environment using the flowCore 
package. Data will be transformed with an inverse hyperbolic sine (arcsinh) transformation using a cofactor 
of 5 and normalized to the 99.5th percentile of each respective channel before downstream tSNE and 
Scaffold analysis. Visualization of samples by tSNE dimensionality reduction will be calculated using the 
Rtnse package with default parameters: perplexity = 30, theta = 0.5, max_iter = 1000 using the indicated 


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channels. To build a reference scaffold, bead and percentile-normalized data from live, CD45+, single, non-
neutrophil cells will be imported into the statisticalScaffold package. All available channels will be used to 
build the reference maps. All population-relevant antigens will be included in the clustering analysis. 
Astrolabe analysis will be carried out by uploading bead-normalized data. Single-cell data will be clustered 
using the FlowSOM R package. Cell subset definitions follow. Cluster labeling method implementation, 
and visualization will be done through the Astrolabe Cytometry Platform (Astrolabe Diagnostics, Inc.).
Statistical analysis
In order to identify parameters of the immune system that are impacted by azacitidine treatment, we will 
use unbiased, unsupervised approaches that have been developed from mass cytometry (CyTOF) data. We 
will utilize an unsupervised clustering algorithm to identify immune cell subsets that is capable of handling 
large datasets and has been utilized previously for this purpose (clara, implemented in R, as in Spitzer et 
al.3). Changes in the abundance of each cluster will be evaluated using permutation-based statistical 
methods adapted previously for this purpose (SAM, implemented in R, as in Bruggner et al.,4 Gaudilliere 
et al.,5 Spitzer et al.6), which accommodate paired data (before and after) and handle multiple hypothesis 
testing. Immune cell subsets will be considered to change significantly when q ≤ 0.05. We will evaluate 
both changes in immune cell abundances as well as changes in immune cell proliferation (% Ki-67+ cells) 
in this way. We will further evaluate significant results by manually identifying cell populations in the raw 
data by gating. These results will form the basis for the evaluation of a validation cohort in the future.
Visualization
Plots will be created using the ggplot2 R package. Schematic representations will be created with biorender 
(https://biorender.com/). Figures will be prepared in Illustrator (Adobe).
8.3
Interim Analyses and Study Stopping Rules
As described in Section 8.2.2, interim analysis will occur after accrual of 6 patients in the safety lead-in. 
Study accrual will be stopped until these 6 patients have completed at minimum cycle 1 of treatment, at 
which point a formal interim safety analysis will be performed with assessment for DLTs as defined in 
Section 5.4 and safety stopping bounds for DLTs as described in Section 8.2.2 and included again in the 
table below. If 2/6 patients have DLTs, then further accrual to the study will be suspended until the study 
PI, co-investigators, and the DSMC can review the data, and determine whether the study should continue, 
be amended with a lower starting dose of azacitidine, or be closed for further accrual. Otherwise, study will 
continue. Safety monitoring will continue for the remaining duration of the trial. A Pocock-type sequential 
boundary59 will be used to monitor dose-limiting toxicities with the aim of keeping the probability of early 
stopping at around 90% if the true underlying toxicity rate is 25%. The accrual will be halted until further 
study investigation if excessive numbers of dose-limiting toxicities are observed, that is, if the number of 
dose-limiting toxicities is equal to or exceeds the stopping boundaries in the following table. With a toxicity 
rate of 25%, the expected number of enrolled patients before stopping for excessive toxicities is 6.5.
Table: Safety monitoring bounds for DLTs
Number of subjects
Stopping boundary
6-9
≥2
10-14
≥3
15-18
≥4
19-23
≥5
As described previously in Section 8.1, interim efficacy analysis will occur after completion of Simon’s 
Stage I. 13 patients will be enrolled in Simon’s Stage I. If there are 1 or fewer responses in these 13 patients, 
the study will be stopped. Otherwise, 10 additional patients will be accrued for a total of 23.


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8.4
Accrual Estimates
There are around 1500 active myeloma patients being seen at UCSF. We would expect to accrue about 2-3 
patients per month, which ideally would mean 8-12 months for patient accrual.
9
Study Management
9.1
Pre-study Documentation
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all applicable 
regulatory requirements.
Before initiating this trial, the PI will have written and dated approval from the Institutional Review Board 
for the protocol, written informed consent form, subject recruitment materials, and any other written 
information to be provided to participants before any protocol related procedures are performed on any 
participants.  
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the FDA has determined that the study is 
exempt from IND requirements. 
The PI must comply with the applicable regulations in Title 21 of the Code of Federal Regulations (21 CFR 
§50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory requirements.  The IRB must 
comply with the regulations in 21 CFR §56 and applicable regulatory requirements.
9.2
Institutional Review Board Approval
The protocol, the proposed informed consent form, and all forms of participant-facing materials related to 
the study (e.g. advertisements used to recruit participants) will be reviewed and approved by the UCSF 
IRB.  Prior to obtaining IRB approval, the protocol must be approved by the Helen Diller Family 
Comprehensive Cancer Center Site Committee and by the Protocol Review Committee (PRC).  The initial 
protocol and all protocol amendments must be approved by the IRB prior to implementation.  
9.3
Informed Consent
All participants must be provided a consent form describing the study with sufficient information for each 
participant to make an informed decision regarding their participation.  Participants must sign the IRB -
approved informed consent form prior to participation in any study specific procedure.  The participant 
must receive a copy of the signed and dated consent document.  The original signed copy of the consent 
document must be retained in the medical record or research file. 
9.4
Changes in the Protocol
Once the protocol has been approved by the UCSF IRB, any changes to the protocol must be documented 
in the form of an amendment.  The amendment must be signed by the PI and approved by PRC, IRB, and 
Janssen prior to implementation.  
If it becomes necessary to alter the protocol to eliminate an immediate hazard to participants, an amendment 
may be implemented prior to IRB approval.  In this circumstance, however, the PI must then notify the IRB 
according to institutional requirements.  


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9.5
Handling and Documentation of Clinical Supplies
The PI will maintain complete records showing the receipt, dispensation, return, or other disposition of all 
investigational drugs at the site.  The date, quantity and batch or code number of the drug, and the 
identification of participants to whom the investigational product has been dispensed by participant number 
and initials will be included.  
The PI shall not make the investigational drug available to any individuals other than to qualified study 
participants.  Furthermore, the PI will not allow the investigational product to be used in any manner other 
than that specified in this protocol.
9.6
Case Report Forms (CRFs)
The PI and/or designee will prepare and maintain adequate and accurate participant case histories with 
observations and data pertinent to the study.  Study specific Case Report Forms (CRFs) will document 
safety and treatment outcomes for safety monitoring and data analysis.  All study data will be entered into 
OnCore® via standardized CRFs in accordance with the CTMS study calendar, using single data entry with 
a secure access account.  Study personnel will complete the CRFs; the PI will review and approve the 
completed CRFs. 
The information collected on CRFs shall be identical to that appearing in original source documents.  Source 
documents will be found in the participant’s medical records maintained by study personnel.  All source 
documentation should be kept in separate research files for each participant. 
In accordance with federal regulations, the PI is responsible for the accuracy and authenticity of all clinical 
and laboratory data entered onto CRFs.  The PI will approve all completed CRFs to attest that the 
information contained on the CRFs is true and accurate. 
The PI will be responsible for ensuring the accurate capture of study data.  At study completion, when the 
CRFs have been declared to be complete and accurate, the database will be locked.  Any changes to the 
data entered into the CRFs after that time can only be made by joint written agreement among the PI and 
the trial statistician.
All source documentation and CTMS data will be available for review/monitoring by the UCSF DSMC and 
regulatory agencies.
9.7
Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the monitoring entity for this 
study.  The UCSF DSMC will monitor the study in accordance with the NCI-approved Data and Safety 
Monitoring Plan (DSMP).  The DSMC will routinely review all adverse events and suspected adverse 
reactions considered “serious”.  The DSMC will audit study-related activities to ensure that the study is 
conducted in accordance with the protocol, local standard operating procedures, FDA regulations, and Good 
Clinical Practice (GCP).  Significant results of the DSMC audit will be communicated to the IRB and the 
appropriate regulatory authorities at the time of continuing review, or in an expedited fashion, as applicable.  
See Appendix 2 - Data and Safety Monitoring Plan.


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9.8
Record Keeping and Record Retention
The PI is required to maintain adequate records of the disposition of the drug, including dates, quantity, and 
use by subjects, as well as written records of the disposition of the drug when the study ends.  
The PI is required to prepare and maintain adequate and accurate case histories that record all observations 
and other data pertinent to the investigation on each individual administered the investigational drug or 
employed as a control in the investigation. Case histories include the case report forms and supporting data 
including, for example, signed and dated consent forms and medical records including, for example, 
progress notes of the physician, the individual's hospital chart(s), and the nurses' notes. The case history for 
each individual shall document that informed consent was obtained prior to participation in the study.
Study documentation includes all CRFs, data correction forms or queries, source documents, Sponsor-
Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., protocol and 
amendments, IRB correspondence and approval, signed participant consent forms).
Source documents include all recordings of observations or notations of clinical activities and all reports 
and records necessary for the evaluation and reconstruction of the clinical research study.
In accordance with FDA regulations, the PI shall retain records for a period of 2 years following the date a 
marketing application is approved for the drug for the indication for which it is being investigated; or, if no 
application is to be filed or if the application is not approved for such indication, until 2 years after the 
investigation is discontinued and FDA is notified.
10
Protection of Human Subjects
10.1
Protection from Unnecessary Harm 
Each clinical site is responsible for protecting all participants involved in human experimentation. This is 
accomplished through the IRB mechanism and the process of informed consent. The IRB reviews all 
proposed studies involving human experimentation and ensures that the participant’s rights and welfare are 
protected and that the potential benefits and/or the importance of the knowledge to be gained outweigh the 
risks to the individual. The IRB also reviews the informed consent document associated with each study in 
order to ensure that the consent document accurately and clearly communicates the nature of the research 
to be done and its associated risks and benefits. 
10.2
Protection of Privacy
Participants will be informed of the extent to which their confidential health information generated from 
this study may be used for research purposes. Following this discussion, they will be asked to sign the 
HIPAA form and informed consent documents. The original signed document will become part of the 
participant’s medical records, and each participant will receive a copy of the signed document. The use and 
disclosure of protected health information will be limited to the individuals described in the informed 
consent document.


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


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Appendix 2
Data and Safety Monitoring Plan 
Data and Safety Monitoring Plan for a Phase II or III Institutional Trial 
1.         Oversight and Monitoring Plan 
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for auditing data quality and participant safety for 
all HDFCCC institutional clinical trials.  A summary of DSMC activities for this trial includes:  

Semiannual auditing (depending on trial accrual) 

Review of serious adverse events 

Minimum of biennial regulatory auditing 
 
2. Monitoring and Reporting Guidelines 
Investigators will conduct a continuous review of data and participant safety at monthly site 
committee meetings where the results of each participant’s treatment are discussed and 
documented in the site committee minutes.   
All institutional Phase II and III therapeutic trials are audited on a semiannual basis, with all data 
from twenty percent of the enrolled participants audited by the DSMC 
Monitor/Auditor.  The assigned DSMC Monitor/Auditor will review no more than a total of 
10 participant charts during the course of auditing this trial. DSMC Monitor/Auditors will send a 
follow-up report to the study team within 20 business days after the auditing visit is complete for 
the PI and the study team to resolve all action items from this report within 20 business days.  An 
abbreviated regulatory review (i.e., reviewing protocol and consent versions, SAEs, PVs, DOA 
logs, 1572 forms, etc.) will occur at each participant monitoring review; however, a full 
regulatory review will occur on a biennially basis by the DSMC for regulatory compliance. 
Auditing of all enrolled participants in these trials will be complete after 20% of enrolled 
participants have been audited through five cycles of treatment.  However, regulatory reviews of 
the trial, safety reviews (i.e., Serious Adverse Event (SAE) reviews and Protocol Violation (PV) 
reviews), and audit/inspection preparation (as applicable) will continue until the trial is closed by 
the IRB.   
 
3. Review and Oversight Requirements 
3.1 Adverse Event Monitoring  
All Grade 3-5 adverse events (AEs), whether or not considered to be expected or 
unexpected and whether or not considered to be associated with the use of 
the investigational agent(s) or study procedure, will be entered into OnCore®, UCSF’s 
Clinical Trial Management System.   
Adverse events are graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE) as developed and revised by the Common Therapy Evaluation Program 
(CTEP) of the National Cancer Institute.  Adverse events are further given an assignment 
of attribution or relationship to investigational agent or study procedure.  Attribution 
categories are: 


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
Definite – The adverse event is clearly related to the investigational agent(s) 
or study procedure. 

Probable – The adverse event is likely related to the investigational agent(s) 
or study procedure. 

Possible – The adverse event may be related to the investigational agent(s) 
or study procedure. 

Unrelated – the adverse event is clearly not related to the investigational agent(s) 
or study procedure. 
 
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis 
at the Site Committee meetings.  The Site Committee will review and discuss the selected 
toxicity, the toxicity grade, and attribution assignment. 
3.2 Serious Adverse Event Reporting  
By definition, an adverse event is defined as a serious adverse event (SAE) according to 
the following criteria: 

Death. 

Life-threatening (i.e., results in an immediate risk of death). 

Requires inpatient hospitalization or prolongation of existing hospitalization, 

Permanent or significant disability/incapacity 

Gives rise to a congenital anomaly/birth defect, or cancer, or any experience that 
suggests a significant hazard, contraindication, side effect, or precaution that may 
require medical or surgical intervention to prevent one of the outcomes listed 
above.  

Event occurring in a gene therapy study. 

Event that changes the risk/benefit ratio of a study. 

Any other event the Principal Investigator judges to be serious or which would 
suggest a significant hazard, contraindication, side effect, or precaution. 
 
Serious adverse event reporting will be in accordance with all IRB regulations. For trials 
conducted under an investigational new drug (IND) application, the SAE will be reported 
in accordance with Code of Federal Regulation Title 21 Part 312.32 and will be reported 
on a Med Watch form.   
UCSF IRB website for guidance in reporting serious adverse events: 
https://irb.ucsf.edu/adverse-event  
 
Med Watch forms and information: 
www.fda.gov/medwatch/getforms.htm 
 
All serious adverse events are entered into OnCore®, as well as submitted to the IRB (per 
IRB guidelines).  The SAEs are reviewed and monitored by the Data and Safety 
Monitoring Committee on an ongoing basis and discussed at DSMC meetings, which 
take place every six weeks.  The date the SAE is sent to all required reporting agencies 
will be documented in OnCore®.  


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If the SAE involves a subject death, and is determined to be possibly, probably or 
definitely related to the investigational drug or any research related procedure, the event 
must be reported to the DSMC Chair (or Vice Chair) and DSMC Director within one 
business day.   
3.3 Review of Adverse Event Rates 
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in 
the Investigator Brochure or package insert) is noted in the study, the Principal 
Investigator will notify the DSMC via report at the time the increased rate is 
identified.  The report will indicate if the incidence of adverse events observed in the 
study is above the range stated in the Investigator Brochure or package insert. 
If at any time the Investigator voluntarily holds enrollment or stops the study due to 
safety issues, the DSMC Chair (or Vice Chair) and the DSMC Director must be notified 
within one business day and the IRB must be notified as per IRB reporting regulations. 
Data and Safety Monitoring Committee Contacts: 
 
  Katie Kelley, MD (DSMC Chair) 
 
  
 
  
 
  
  UCSF HDFCCC 
  San Francisco, CA 94158 
 
 
 
 
John McAdams (DSMC Director)  
 
 
UCSF HDFCCC 
San Francisco, CA 94143 
 
 


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Phase II – daratumumab and azacitidine
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Appendix 3
Prohibited Medications List 
Drug
Trade name (if applicable)
adalimumab
Humira
baricitinib
Olumiant
BCG
TheraCys and TICE BCG
certolizumab
Cimzia
clozapine
Clozaril
deferiprone
Ferriprox
etanercept
Enbrel
fingolimod
Gilenya
golimumab
Simponi
infliximab
Remicade
leflunomide
Arava
natalizumab
Tysabri
Samarium 
sm 
153 lexidronam
Quadramet
siponimod
Mayzent
Talimogene 
laherparepvec
Imlygic
teriflunomide
Aubagio
thalidomide
Thalomid
tofacitinib             Xeljanz


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Nijhof IS, Casneuf T, van Velzen J, et al: CD38 expression and complement 
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ICF_001.pdf: 
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PAGE 1 OF 30 
ALFRED CHUNG, MD
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
CONSENT TO PARTICIPATE IN A RESEARCH STUDY
Study Title: Phase II Study of Daratumumab in Combination with 
Azacitidine and Dexamethasone in Relapsed/Refractory Multiple Myeloma 
Patients Previously Treated with Daratumumab
Principal Investigator:
Alfred Chung, MD
San Francisco, CA 94143
This is a clinical research study.  Your study doctor(s) Swetha Kambhampati, MD and 
Alfred Chung, MD from the UCSF Department of Hematology, will explain the study to 
you.
STUDY SUMMARY
Introduction: We are asking you to consider taking part in a research study being done 
by Drs. Swetha Kambhampati and Alfred Chung at UCSF. You are being asked to take 
part in this study because you have relapsed and refractory multiple myeloma meaning 
your cancer has returned and it is no longer responding to treatment. 
The first part of this consent form gives you a summary of this study. We will give you 
more details about the study later in this form. The study team will also explain the study 
to you and answer any questions you have.
Research studies include only people who choose to take part. It is your choice whether 
or not you want to take part in this study. Please take your time to make a decision 
about participating. You can discuss your decision with your family, friends and health 
care team. 
Purpose of the study:  
The purpose of this study is to determine if the combination of daratumumab, 
azacitidine and dexamethasone is safe and effective for treating patients with relapsed 
and refractory multiple myeloma who were previously treated with daratumumab.
Study Procedures: 
You must be screened to see if you can be in this study. If you are in the study, you 
must provide two bone marrow biopsies, blood samples, and information about your 
current and past medications, treatments, and surgeries. 
IRB NUMBER: 19-29438
IRB APPROVAL DATE: 06/16/2022
IRB EXPIRATION DATE: 02/07/2023


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ALFRED CHUNG, MD
The main study is divided into four phases, Pre-Induction, Induction, Consolidation and 
Maintenance phases. Each phase is divided into four-week Cycles.
1. Pre-Induction, Cycle 1 Days -7 to -3: You will receive your first dose of 
azacitidine on 5 of the 7 days before Cycle 1 Day 1. Azacitidine is given by 
intravenous (IV) infusion or by injection under the skin (which is also called 
subcutaneous injection).
2. Induction, Cycles 1 and 2: On Days 1, 8, 15, and 22 of each Cycle you will 
receive daratumumab and dexamethasone. Daratumumab is given by injection 
under the skin. Dexamethasone is given by IV or taken by mouth. You will also 
receive azacitidine for five consecutive days of each Cycle, on Days 22 to 26. 
After Cycle 2, depending on your response to the study treatment the study 
doctor will tell you whether dexamethasone should continue weekly, be reduced, 
or stop.
3. Consolidation, Cycles 3-6: You will receive daratumumab on Days 1 and 15 of 
each Cycle.  You will receive dexamethasone as needed. During Cycle 3 you will 
receive azacitidine every day on Days 22 to 26. During Cycles 5 and 6 you will 
receive azacitidine every day on Days 1 – 5.
4. Maintenance, Cycles 7 and beyond: You will receive daratumumab on Day 1. 
You will receive dexamethasone as needed. You will also receive azacitidine 
every day on Days 1 to 5.
In addition, the main study procedures include two bone marrow biopsies, blood sample 
collection, and collecting information about your current and past medications, 
treatments and/or surgeries.
You will be in this study for about 20 - 24 months depending on how well you respond to 
the study treatment and you will visit the research site approximately 40 - 45 times. 
Possible Risks: There are risks to taking part in a research study. Some of the most 
likely risks of the study drugs include:
Daratumumab

Neutropenia (low neutrophil count) 

Thrombocytopenia (decrease in the number of platelets) 

Interference with pre-transfusion blood testing

Liver infection (hepatitis) in those patients who are carriers of the hepatitis B virus
Azacitidine 

Anemia which may require blood transfusion

Constipation, diarrhea, nausea, vomiting

Tiredness, fever
IRB NUMBER: 19-29438
IRB APPROVAL DATE: 06/16/2022
IRB EXPIRATION DATE: 02/07/2023


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ALFRED CHUNG, MD
Dexamethasone

High blood pressure, retaining water, changes in salt or potassium levels in your 
body

Changes in vision, trouble seeing, eye pain
There is also risk of loss of privacy.  We will test your blood during screening and if we 
find you have a new case of Hepatitis B/C we must report it to the San Francisco 
Health Department, as described on page 23.
We’ll tell you about the other risks later in this consent form.
Possible Benefits:
You may benefit from participating in the study, but this cannot be guaranteed.
Your Other Options: You do not have to participate in this study. Your other choices 
may include:

Getting treatment or care for your condition without being in a study. 

Taking part in another study.

Getting no treatment or receiving comfort care to relieve your symptoms and 
discomfort. 
Please talk to your doctor about your choices before agreeing to participate in this 
study.
The following section is a more complete description of this study. Please read this 
description carefully. You can ask any questions you want to help you decide whether to 
join the study. If you join this study, we will give you a signed copy of this form to keep 
for future reference.
DETAILED STUDY INFORMATION
This part of the consent form gives you more detailed information about what the study 
involves.
You are being asked to take part in this study because you have relapsed and refractory 
multiple myeloma (RRMM) meaning your cancer has returned and it is no longer 
responding to treatment. 
Why is this study being done?
The purpose of this study is to find out how your multiple myeloma responds to 
receiving daratumumab in combination with azacitidine and dexamethasone and what 
good and/or bad effects the combination has on patients with relapsed and refractory 
multiple myeloma.
IRB NUMBER: 19-29438
IRB APPROVAL DATE: 06/16/2022
IRB EXPIRATION DATE: 02/07/2023


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PAGE 4 OF 30 
ALFRED CHUNG, MD
Daratumumab is an antibody made up of immune cells that attaches to a protein on your 
myeloma cell, called CD38.  CD38 is found in higher levels on your tumor cells than on 
your normal cells. Daratumumab prevents the growth of tumors who have high levels of 
CD38 by causing those cells to die. Daratumumab is commercially approved for the 
treatment of multiple myeloma and AL amyloidosis. 
Azacitidine has been shown in studies to help restore normal cell function and growth in 
your cells.  Azacitidine is FDA approved for the treatment of myelodysplastic syndrome 
and in combination with venetoclax for newly diagnosed acute myeloid leukemia in 
patients who were  75 years of age or had comorbidities that prevented the use of 
intensive induction chemotherapy. In this study, we hope that azacitidine will help 
increase the levels of CD38 on your tumor cells to increase the function of 
daratumumab to attach to those tumor cells to help destroy them.
Dexamethasone is a steroid that helps decrease inflammation and lowers your normal 
immune response.  Dexamethasone is being used in this study to help reduce the effect 
of any injection-related reactions.
If you sign this consent form to participate in the study, you will do tests and procedures 
to make sure that it is okay for you to participate in this study- this is called screening. 
After screening, you will begin receiving the study drugs.
Azacitidine will be given for 5 consecutive days before the start of Cycle 1 during Days 
-7 to -3. During Cycles 1 to 3, you will be given azacitidine for 5 consecutive days on 
Days 22 - 26. Starting Cycle 5, azacitidine will be given for 5 consecutive days on Days 
1 to 5. Azacitidine is given by intravenous (IV) infusion or by injection under the skin 
(also called subcutaneous injection).
Daratumumab will be given weekly during the Induction phase of Cycles 1 to 2 on Days 
1, 8, 15, 22 and every 2 weeks during the Consolidation phase of Cycles 3 to Cycle 6 
on Days 1 and 15 and every 4 weeks during the Maintenance phase in Cycle 7 and 
beyond on Day 1. Daratumumab is given by injection under the skin.
Dexamethasone will be given by IV infusion or taken by mouth every week for the first 2 
Cycles of study treatment.  Before you are given daratumumab, you will be given 
dexamethasone as a pre--medication. During the weeks you are not receiving 
daratumumab, you may be told to take dexamethasone by mouth.  After Cycle 2, 
depending on your response to the study treatment, the study doctor will tell you 
whether dexamethasone should continue weekly, be reduced, or stop.
Janssen, the manufacturer of daratumumab, is supplying daratumumab at no cost to 
study participants, and is providing funding to UCSF for this study, which will be used by 
UCSF to purchase commercial supply of azacitidine for the study.
How many people will take part in this study?
IRB NUMBER: 19-29438
IRB APPROVAL DATE: 06/16/2022
IRB EXPIRATION DATE: 02/07/2023


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ALFRED CHUNG, MD
About 23 people will take part in this study.  
What will happen if I take part in this research study?
Before you begin the main part of the study:
You will need to have the following tests and procedures to find out if you can be in the 
main part of the study. Some of these tests and procedures are part of regular cancer 
care and may be done even if you do not join the study. If you have had some of them 
recently, they may not need to be repeated. This will be up to your study doctor.

You will have a complete physical exam (including height and weight) and your 
current symptoms will be reviewed.

You will have your vital signs checked (temperature, blood pressure, pulse, and 
breathing rate).

You will be asked about your medical history which includes a review of 
medications, assessment of your disease, past procedures, past treatments, and 
current baseline medical conditions.

You will be asked about your basic daily activities to determine your general 
health, how you have been feeling, and about your daily activities (performance 
status).

If you are a woman of child-bearing potential you will have a urine or blood (1 
teaspoon) pregnancy test within 7 days of starting the study drug(s).

You will have a total of 3 tablespoons of blood be taken by inserting a needle into 
a vein in your arm for routine safety tests, Hepatitis B/C, and assessment of your 
disease.

You will have a skeletal scan of your skull, spinal cord, long bones, pelvis and 
chest, if your study doctor finds it necessary. 

You will have an MRI, contrast-enhanced CT, or PET/CT imaging of the soft 
tissue or bony skeleton, if your study doctor finds it necessary.

MRI scan: A Magnetic Resonance Imaging (MRI) scan takes an image of your 
head or body to observe the location and size of your tumor. For the MRI scan, 
you may be given a ‘contrast material’ (a special dye that makes it easier for 
doctors to see different tissues in your body). Gadolinium is contrast material that 
causes some tumors to appear much brighter than normal tissue on MRI scans 
(these tumors may not be visible without gadolinium). The contrast material may 
be given to you in your arm through an intravenous catheter (a tiny tube inserted 
into a vein). You will then lie down on a narrow bed which will be placed in a 
tunnel that is 6 feet long by 22 inches wide and open at each end. You will lie 
there quietly for about one hour, during which time you will hear a loud machine- 
like noise. The MRI scan is done in the radiology department and takes 
approximately an hour and a half to complete.
IRB NUMBER: 19-29438
IRB APPROVAL DATE: 06/16/2022
IRB EXPIRATION DATE: 02/07/2023


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ALFRED CHUNG, MD

PET/CT scan: For this procedure, an IV is started in the hand. A small amount of 
radioactive chemical (glucose) is injected into the blood stream. Once the 
glucose is injected, you will be asked to wait for about an hour to allow for 
glucose to distribute in the body. Then you will be asked to lie down on a table 
and the body is scanned. The total time for this procedure is about 2-3 hours.

A CT scan uses special x-ray equipment to make detailed pictures of body 
tissues and organs. For the CT scan, you may be given a "contrast material" (a 
special dye that makes it easier for doctors to see different tissues in your body). 
The contrast material may be given orally, intravenously, or rectally (less likely). 
Oral contrast material is given to you to drink and is used to help outline the 
stomach and intestines. Intravenous (IV) contrast material is given to you by 
injecting the contrast material into a line which is attached to a needle in your 
arm, and is used to get clearer pictures of your body cavity. A rectal contrast fills 
up the loops of your lower bowel so the doctors can see your tumor better. After 
you have been given the contrast material (either by mouth, by vein, or rectum), 
you will lie flat on a table that will move you into the CT scan machine. You will 
be asked to lie still and may be asked to hold your breath for a few seconds. The 
CT scan is done in the Radiology Department and takes about half an hour.

You will have a biopsy within 14 days of you receiving azacitidine dose.  A 
sample of your bone marrow will be collected for disease assessment (to look for 
the presence of tumor cells inside the bone marrow) and to measure the amount 
of CD38, the marker which daratumumab binds to in order to kill your myeloma 
cells, is in your bone marrow. This test is done by inserting a needle into your hip 
bone to remove a sample of bone and bone marrow (about 2 teaspoons).  You 
will receive a medicine to numb the surface of your skin on your hip.  This will 
take about 15-30 minutes. 
During the main part of the study:
If the tests and procedures show that you can be in the main part of the study, and you 
choose to take part, then you will begin receiving azacitidine, daratumumab and 
dexamethasone.  The study is divided into four parts: Pre-Induction, Induction, 
Consolidation and Maintenance phases.
During the Pre-Induction phase, you will come in on Days -7 to -3 of Cycle 1 to receive 
your first dose of azacitidine for 5 consecutive days.  Azacitidine is given by IV infusion 
or by injection under the skin (also called subcutaneous injection).
During the Induction phase, you will come in on Days 1, 8, 15, and 22 during Cycles 1-2 
to receive daratumumab as well as receive dexamethasone.  Daratumumab is given by 
injection under the skin. Dexamethasone is given by IV or taken by mouth. You will also 
receive azacitidine for five consecutive days during Cycles 1 and 2 on Days 22 – 26.  
After Cycle 2, depending on your response to the study treatment, the study doctor will 
tell you whether dexamethasone should continue weekly, be reduced, or stop.
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IRB EXPIRATION DATE: 02/07/2023


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ALFRED CHUNG, MD
During the Consolidation phase, you will come in on Days 1 and 15 during Cycles 3 
through 6 to receive daratumumab. You will also receive azacitidine for five consecutive 
days on Days 22 – 26 during Cycle 3 and Days 1 – 5 during Cycles 5 – 6. 
During the Maintenance phase, you will come in on Day 1 during Cycles 7 and beyond 
to receive daratumumab. You will also receive azacitidine for five consecutive days on 
Days 1 to 5 during Cycles 7 and beyond.  
The following tests and procedures will be done during the main part of the study:
Pre-Induction Phase:
Cycle 1, Day – 7 (1 week before daratumumab administration)
Items marked with an asterisk (*) will occur daily on Day -7 to -3 while the other items are 
only performed on Day -7

You will have a complete physical exam (including weight) and your current 
symptoms will be reviewed.

You will have your vital signs checked (temperature, blood pressure, pulse, and 
breathing rate).*

You will be asked about the medications you are currently taking, including over-
the-counter medicines, vitamins, or herbal treatments.

 You will be asked about your medical history which includes a review of 
medications, assessment of your disease, past procedures, past treatments, and 
current baseline medical conditions.

You will be asked about your basic daily activities to determine your general 
health, how you have been feeling, and about your daily activities (performance 
status).

You will have a total of 3 tablespoons of blood be taken by inserting a needle into 
a vein in your arm for routine safety tests and assessment of your disease.

You will have an MRI, contrast-enhanced CT, PET/CT imaging of the soft tissue 
or bony skeleton, or skeletal survey (a series of x-rays to check for bone lesions), 
only if your study doctor finds it necessary for your myeloma as standard of care 

You will receive azacitidine via IV infusion or injection under the skin for 5 
consecutive days, (Cycle 1, Day – 7 through Cycle 1, Day – 3).*
Induction Phase: 
Cycles 1 and 2, Day 1

You will have a complete physical exam (including weight) and your current 
symptoms will be reviewed.

You will have your vital signs checked (temperature, blood pressure, pulse, and 
breathing rate).
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ALFRED CHUNG, MD

You will be asked about the medications you are currently taking, including over-
the-counter medicines, vitamins, or herbal treatments.

You will be asked about your basic daily activities to determine your general 
health, how you have been feeling, and about your daily activities (performance 
status).

If you are a woman of childbearing potential you will have a urine or blood (1 
teaspoon) pregnancy test before the administration of the study drug(s).

You will have a total of 3 tablespoons of blood be taken by inserting a needle into 
a vein in your arm for routine safety tests and assessment of your disease.

You will have an MRI, contrast-enhanced CT, PET/CT imaging of the soft tissue 
or bony skeleton, or skeletal survey (a series of x-rays to check for bone lesions) 
only if your study doctor finds it necessary for your myeloma as standard of care 

You will have a second bone marrow biopsy before you receive daratumumab. A 
sample of your bone marrow will be collected to measure the amount of CD38, 
the marker which daratumumab binds to in order to kill your myeloma cells, is in 
your bone marrow (Cycle 1, Day 1 only).

You will take dexamethasone by mouth or it will be given via an IV infusion 
before receiving daratumumab. 

You will receive daratumumab by injection under the skin.
Cycles 1 and 2, Days 8 and 15

You will have your weight recorded and your current symptoms will be reviewed.

You will have your vital signs checked (temperature, blood pressure, pulse, and 
breathing rate).

You will be asked about the medications you are currently taking, including over-
the-counter medicines, vitamins, or herbal treatments.

You will have a total of 2 tablespoons of blood be taken by inserting a needle into 
a vein in your arm for routine safety tests.

You will have an MRI, contrast-enhanced CT, PET/CT imaging of the soft tissue 
or bony skeleton, or skeletal survey (a series of x-rays to check for bone lesions) 
only if your study doctor finds it necessary for your myeloma as standard of care 

You will take dexamethasone by mouth or it will be given via IV infusion before 
receiving daratumumab. 

You will receive daratumumab by injection under the skin.
Cycles 1 and 2, Day 22
Items marked with an asterisk (*) will occur daily on Days 22 through 26 while the other 
items are only performed on Day 22

You will have your weight recorded and your current symptoms will be reviewed.

You will have your vital signs checked (temperature, blood pressure, pulse, and 
breathing rate).*
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ALFRED CHUNG, MD

You will be asked about the medications you are currently taking, including over-
the-counter medicines, vitamins, or herbal treatments.

You will have a total of 2 tablespoons of blood be taken by inserting a needle into 
a vein in your arm for routine safety tests.

You will have an MRI, contrast-enhanced CT, PET/CT imaging of the soft tissue 
or bony skeleton, or skeletal survey (a series of x-rays to check for bone lesions) 
only if your study doctor finds it necessary for your myeloma as standard of care 

You will take dexamethasone by mouth or it will be given via IV infusion before 
receiving daratumumab (Cycles 1 and 2, Days 22, only). After you complete Cycle 
2, Your study doctor will discuss with you reducing or stopping your dose of 
dexamethasone, depending on your response to study treatment.  

You will receive daratumumab by injection under the skin (Cycles 1 and 2, Days 
22, only). 

You will receive azacitidine via IV infusion or injection under the skin for 5 
consecutive days, (Cycles 1 and 2, Days 22 through 26).*
Consolidation Phase:
Cycles 3 and 4, Day 1

You will have a complete physical exam (including weight) and your current 
symptoms will be reviewed.

You will have your vital signs checked (temperature, blood pressure, pulse, and 
breathing rate).

You will be asked about the medications you are currently taking, including over-
the-counter medicines, vitamins, or herbal treatments.

You will be asked about your basic daily activities to determine your general 
health, how you have been feeling, and about your daily activities (performance 
status).

If you are a woman of childbearing potential you will have a urine or blood (1 
teaspoon) pregnancy test before the administration of the study drug(s).

You will have a total of 3 tablespoons of blood be taken by inserting a needle into 
a vein in your arm for routine safety tests and assessment of your disease.

If you have a resolved hepatitis infection, you will be asked to take a follow-up 
hepatitis test.

You will have an MRI, contrast-enhanced CT, PET/CT imaging of the soft tissue 
or bony skeleton, or skeletal survey (a series of x-rays to check for bone lesions) 
only if your study doctor finds it necessary for your myeloma as standard of care 

You will receive dexamethasone as needed, by mouth or via IV infusion.

You will receive daratumumab by injection under the skin. 
Cycles 3 and 4, Day 15
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ALFRED CHUNG, MD

You will have your weight recorded and your current symptoms will be reviewed.

You will have your vital signs checked (temperature, blood pressure, pulse, and 
breathing rate).

You will be asked about the medications you are currently taking, including over-
the-counter medicines, vitamins, or herbal treatments.

You will have a total of 2 tablespoons of blood be taken by inserting a needle into 
a vein in your arm for routine safety tests.

You will have an MRI, contrast-enhanced CT, PET/CT imaging of the soft tissue 
or bony skeleton, or skeletal survey (a series of x-rays to check for bone lesions) 
only if your study doctor finds it necessary for your myeloma as standard of care 

You will receive dexamethasone as needed, by mouth or via IV infusion.

You will receive daratumumab by injection under the skin. 
Cycle 3, Day 22
Items marked with an asterisk (*) will occur daily on Days 22 through 26 while the other 
items are only performed on Day 22

You will have your weight recorded and your current symptoms will be reviewed.

You will have your vital signs checked (temperature, blood pressure, pulse, and 
breathing rate).*

You will be asked about the medications you are currently taking, including over-
the-counter medicines, vitamins, or herbal treatments.

You will have a total of 2 tablespoons of blood be taken by inserting a needle into 
a vein in your arm for routine safety tests.

You will have an MRI, contrast-enhanced CT, PET/CT imaging of the soft tissue 
or bony skeleton, or skeletal survey (a series of x-rays to check for bone lesions) 
only if your study doctor finds it necessary for your myeloma as standard of care. 

You will receive azacitidine via IV infusion or by injection under the skin for 5 
consecutive days, (Cycle 3, Days 22 – 26, only).* 
Cycles 5 and 6, Day 1 
Items marked with an asterisk (*) will occur daily on Days 1 to 5 while the other items are 
only performed on Day 1

You will have a complete physical exam (including weight) and your current 
symptoms will be reviewed.

You will have your vital signs checked (temperature, blood pressure, pulse, and 
breathing rate).*

You will be asked about the medications you are currently taking, including over-
the-counter medicines, vitamins, or herbal treatments.

You will be asked about your basic daily activities to determine your general 
health, how you have been feeling, and about your daily activities (performance 
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ALFRED CHUNG, MD
status).

If you are a woman of child-bearing potential you will have a urine or blood (1 
teaspoon) pregnancy test before the administration of the study drug(s).

You will have a total of 3 tablespoons of blood be taken by inserting a needle into 
a vein in your arm for routine safety tests and assessment of your disease.

You will have an MRI, contrast-enhanced CT, PET/CT imaging of the soft tissue 
or bony skeleton, or skeletal survey (a series of x-rays to check for bone lesions) 
only if your study doctor finds it necessary for your myeloma as standard of care. 

You will receive dexamethasone as needed, by mouth or via IV infusion.

You will receive daratumumab by injection under the skin. 

You will receive azacitidine via IV infusion or by injection under the skin for 5 
consecutive days, (Cycles 5 and 6, Days 1 to 5). *
Cycles 5 and 6, Day 15

You will have your weight recorded and your current symptoms will be reviewed.

You will have your vital signs checked (temperature, blood pressure, pulse, and 
breathing rate).

You will be asked about the medications you are currently taking, including over-
the-counter medicines, vitamins, or herbal treatments.

You will have a total of 2 tablespoons of blood be taken by inserting a needle into 
a vein in your arm for routine safety tests.

You will have an MRI, contrast-enhanced CT, PET/CT imaging of the soft tissue 
or bony skeleton, or skeletal survey (a series of x-rays to check for bone lesions) 
only if your study doctor finds it necessary for your myeloma as standard of care 

You will receive dexamethasone as needed, by mouth or via IV infusion.

You will receive daratumumab by injection under the skin.
Maintenance Phase:
Cycles 7 and beyond, Day 1 
Items marked with an asterisk (*) will occur daily on Days 1 to 5 while the other items are 
only performed on Day 1

You will have a complete physical exam (including weight) and your current 
symptoms will be reviewed.

You will have your vital signs checked (temperature, blood pressure, pulse, and 
breathing rate).*

You will be asked about the medications you are currently taking, including over-
the-counter medicines, vitamins, or herbal treatments.

You will be asked about your basic daily activities to determine your general 
health, how you have been feeling, and about your daily activities (performance 
status).
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ALFRED CHUNG, MD

If you are a woman of child-bearing potential you will have a urine or blood (1 
teaspoon) pregnancy test before the administration of the study drug(s).

You will have a total of 3 tablespoons of blood be taken by inserting a needle into 
a vein in your arm for routine safety tests and assessment of your disease.

You will have an MRI, contrast-enhanced CT, PET/CT imaging of the soft tissue 
or bony skeleton, or skeletal survey (a series of x-rays to check for bone lesions) 
only if your study doctor finds it necessary for your myeloma as standard of care. 

You will receive dexamethasone as needed, by mouth or via IV infusion.

You will receive daratumumab by injection under the skin.

You will receive azacitidine via IV infusion or by injection under the skin for 5 
consecutive days (Cycles 7 and beyond, Days 1 to 5).* 
When you are finished receiving daratumumab and azacitidine:

You will have your vital signs checked (temperature, blood pressure, pulse, and 
breathing rate) and your current symptoms will be reviewed.

You will be asked about the medications you are currently taking, including over-
the-counter medicines, vitamins, or herbal treatments.

If you are a woman of childbearing potential you will have a urine or blood (1 
teaspoon) pregnancy test before the administration of the study drug(s).

You will have a total of 3 tablespoons of blood be taken by inserting a needle into 
a vein in your arm for routine safety tests and assessment of your disease.

If you have a resolved hepatitis infection, you will be asked to take a follow-up 
hepatitis test.

You will have an MRI, contrast-enhanced CT, PET/CT imaging of the soft tissue 
or bony skeleton, or skeletal survey (a series of x-rays to check for bone lesions) 
only if your study doctor finds it necessary for your myeloma as standard of care. 
You will be followed every 4 weeks for up to one year after stopping study treatment.  
You will be contacted by telephone or when you come to clinic at least every 4 weeks at 
minimum to assess your disease.
Study location: 
All study procedures will be done at the UCSF Helen Diller Family Comprehensive 
Cancer Center.
How long will I be in the study?
You will be asked to receive study drugs for about 20 - 24 months depending on how 
well you respond to the study treatment and you will visit the research site 
approximately 40 - 45 times. If the study drugs are stopped or you withdraw from the 
study, you will be followed until any side effects from the study drugs have resolved.
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ALFRED CHUNG, MD
Can I stop being in the study?
Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about 
stopping or decide to stop. She will tell you how to stop your participation safely. 
It is important to tell the study doctor if you are thinking about stopping so any risks from 
the daratumumab and azacitidine can be evaluated by your doctor. Another reason to 
tell your doctor that you are thinking about stopping is to discuss what follow-up care 
and testing could be most helpful for you.
The study doctor may stop you from taking part in this study at any time if she believes 
it is in your best interest, if you do not follow the study rules, or if the study is stopped.
What side effects or risks can I expect from being in the study?
You may have side effects while on the study. Everyone taking part in the study will be 
watched carefully for any side effects. However, doctors don't know all the side effects 
that may happen.  Side effects may be mild or very serious. Your health care team may 
give you medicines to help lessen side effects. Many side effects go away soon after 
you stop taking the daratumumab and azacitidine. In some cases, side effects can be 
serious, long lasting, or may never go away. There also is a risk of death.
You should talk to your study doctor about any side-effects you experience while taking 
part in the study.
Risks Associated with Daratumumab
Any drug has risks and side effects which may vary from person to person. Side effects 
may be mild or very severe. Most side effects will go away after treatment is stopped, but 
some may be long lasting. Side effects seen on research studies can result from a 
patient’s disease, the drug under study, other drugs you are taking, other diseases you 
have, or a combination of these. This section gives you the information known so far about 
side effects seen with daratumumab.
As of November 15, 2021, approximately 5839 clinical trial patients have been treated 
with daratumumab IV (intravenous directly into the vein) or SC (subcutaneous, 
underneath the skin of the abdomen). Of these 5839 patients about 1878 received 
daratumumab alone, and about 3961 patients received daratumumab in combination with 
other therapies.
Not all the possible side effects and risks related to daratumumab are known. New side 
effects may happen. You will be watched closely and you will receive appropriate care if 
side effects happen. Please tell your study doctor if you have any of the side effects 
described below or any other ones not listed. You will be told of any new findings that 
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ALFRED CHUNG, MD
may affect your decision to continue in this study.
The following side effects are observed when daratumumab was given to patients either 
alone or in combination with other drugs.
Very common side effects with daratumumab (affects more than 1 in 10 persons)

Infection of the upper respiratory tract such as nose, sinuses throat or upper 
airway 

Infection of the lungs (pneumonia)

Infection of the lower airway (bronchitis)

Low white blood cells (including neutrophils and lymphocytes); may increase the 
risk of getting an infection (see information below)

Low platelets; may increase the risk of bleeding and bruising (see information – 
“Blood Cell Effects” below)

Low red blood cells (anemia) 

Decreased appetite

Sleeplessness (insomnia)

Abnormal sensation including numbness/tingling of hands, feet or limbs (sensory 
neuropathy, paresthesia)

Headache

Cough

Shortness of breath (dyspnea), including wheezing 

Diarrhea

Constipation 

Nausea

Vomiting

Rash, a noticeable change in the texture or color of your skin

Back Pain

Joint pain

Muscle spasms

Swelling of hands, feet or limbs

Fatigue or lack of energy

Weakness, lack of strength

Fever
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ALFRED CHUNG, MD
Common side effects with daratumumab (affects 1 to 10 in 100 persons)

Urinary tract infection

Influenza or flu like symptoms

Sepsis (a life-threatening condition that arises when the body's response to an 
infection injures its own tissues and organs)

Hypogammaglobulinemia, a condition with your immune system in which not 
enough gamma globulin proteins (also known as antibodies) are produced. 
Decreases in gamma globulin proteins can increase the risk of infections

High blood glucose levels 

Low blood calcium levels 

Loss of body fluids, also known as dehydration

Dizziness

Fainting

Irregular heartbeat (atrial fibrillation)

High blood pressure 

Fluid in lungs (pulmonary edema)

Inflammation of the pancreas (pancreatitis)

Itchy skin

Muscular pain in the chest 

Chills 

Infusion-related reaction (see information – “Infusion-Related Reactions” below)

Injection site reaction: local reaction reported as mild pain or burning sensation at 
the site of injection in the abdominal wall. Redness and hardening of the skin at 
the injection site was also observed and usually disappeared within a few hours 
after the administration 
Uncommon side effects with daratumumab (affects 1 to 10 in 1,000 persons)

Cytomegalovirus infection (see information below)

Liver infection (hepatitis) in those patients who are carriers of the hepatitis B virus
Infusion-Related Reactions
An antibody is a large protein that is generated as part of the normal immune system to 
neutralize foreign objects such as bacteria and viruses. Daratumumab is an antibody 
designed to specifically target and eliminate a specific harmful object in your body, in 
this case cancerous plasma cells. A non-local, hypersensitivity reaction  to 
daratumumab that occurs during or shortly after an administration (IV or SC) is called an 
infusion-related reaction. It usually occurs during or within the first few hours after the 
start of the first administration. However, delayed reactions can happen up to 3-4 days 
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ALFRED CHUNG, MD
after the dose administration.  These reactions can be life-threatening and fatal 
outcomes have been reported.
Signs and symptoms of infusion-related reactions may include:

Respiratory symptoms, such as stuffy nose, cough, throat irritation 

Chills

Vomiting

Nausea
Most of the observed infusion-related reactions were mild or moderate, and ended by 
temporarily stopping the administration and/or giving medicines to treat the symptoms. 
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. 
Severe reactions have occurred, including narrowing and obstruction of the respiratory 
airway (bronchospasm), low level of oxygen (hypoxia), shortness of breath, high blood 
pressure, swelling in the throat and fluid 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 an anaphylactic 
reaction, the worst case of allergic reaction. 
Anaphylactic reaction
Anaphylactic reaction is a serious allergic reaction that can develop quickly (in minutes 
to a few hours) and may cause death. Usually a combination of the following side 
effects occurs: 

An itchy rash, throat or tongue swelling

Shortness of breath

Vomiting

Lightheadedness

Low blood pressure
This type of reaction is for example seen when one is allergic to a bee sting or certain 
foods like peanuts.
Please inform your doctor immediately if you experience any of these signs and 
symptoms.
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ALFRED CHUNG, MD
Anaphylactic reactions were rarely reported when commercially available daratumumab 
was used outside of clinical trials (also called post marketing experience). The reported 
cases of anaphylactic reaction were believed to be a more severe form of infusion-
related reactions. More than 227,000 patients globally have been treated with 
daratumumab. Anaphylactic reaction has not been reported in clinical studies; therefore, 
the frequency is not known.
The manufacturer will continue to monitor infusion-related reactions and make changes 
to the way daratumumab is administered and/or recommend additional medications as 
necessary.
Blood Cell Effects
Daratumumab can decrease white blood cell counts which help fight infections, and blood 
cells called platelets which help to clot blood. Tell your healthcare provider if you develop 
any symptoms of infection such as fever or any symptoms of decreased platelet counts 
such as bruising or bleeding.
Infection
Different kinds of infection have been seen in patients receiving daratumumab. Most of 
them are respiratory tract infections. If you have an infection now, have a history of 
frequent infections, or if you feel sick, you should tell your study doctor right away. The 
majority of the observed infections so far were mild or moderate. Severe infections such 
as pneumonia and sepsis have also been reported. 
Certain infections with viruses, such as shingles (Herpes Zoster virus) and 
cytomegalovirus, and liver infection (hepatitis B virus) have been observed with 
daratumumab. Patients who have had prior exposure to hepatitis B virus are at increased 
risk of recurrence of the virus. Your doctor will test you for the hepatitis B virus before 
beginning treatment on this study. If you test positive for the virus, you will be e closely 
monitored for signs of infections during daratumumab treatment and until 6 months after 
the last dose of daratumumab, and you will be treated, if appropriate, by your doctor. 
Heart problems in patients with light chain (AL) amyloidosis
Heart problems, in some cases fatal, have occurred. Your study doctor will monitor you 
closely during treatment with daratumumab. Call your study doctor right away if any of 
the following symptoms occur: chest pain, feeling faint, swollen legs, shortness of breath, 
or abnormal heart rhythm.
Blood transfusions:
If you need a blood transfusion, you will have a blood test first to match your blood 
types.
Daratumumab can affect the results of this blood test. These changes can last up to 6 
months after your last dose. Your doctor will therefore test your blood type before you 
start treatment with Daratumumab. The test result will be placed on the patient 
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ALFRED CHUNG, MD
identification wallet card you will carry for this study. Please tell all your health care 
providers that you are using Daratumumab before receiving a blood transfusion. 
Risks Associated with Dexamethasone
The most common side effects of dexamethasone that have been seen in humans with 
multiple myeloma are listed below:

High blood pressure, retaining water, changes in salt or potassium levels in your 
body

Cataracts or glaucoma (with long-term use)

Bone loss (with long-term use)

Allergic reaction: Itching or hives, swelling in your face or hands, swelling or 
tingling in your mouth or throat, chest tightness, trouble breathing

Changes in vision, trouble seeing, eye pain

Dark freckles, skin changes, coldness, weakness, tiredness, weight loss

Depression, unusual thoughts, feelings, or behaviors, trouble sleeping

Fast or slow, pounding heartbeat

Fever, chills, cough, sore throat, body aches

Rapid weight gain, swelling in your hands, ankles, or feet

Severe stomach pain, nausea, vomiting, or red or black stools

Trouble breathing

Trouble urinating

Worsened joint pain, swelling, or stiffness

Round, puffy face

Weight gain around your neck, upper back, breast, face, or waist
Risks Related to Azacitidine
Common, Some May Be Serious (affects more than 20 people in 100 people 
receiving azacitidine):

Anemia which may require blood transfusion

Constipation, diarrhea, nausea, vomiting

Tiredness, fever

Swelling and redness at the site of medication injection

Infection, especially when white blood cell count is low

Bruising, bleeding

Loss of appetite

Shortness of breath

Rash
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Occasional, Some May Be Serious (affects 4 to 20 people in 100 people receiving 
azacitidine):

Heart failure which may cause shortness of breath, swelling of ankles, and 
tiredness

Fluid around heart

Abnormal heartbeat

Swelling and redness of the eye

Pain

Heartburn, hemorrhoids

Difficulty swallowing or sleeping

Bleeding from multiple sites including the nose

Internal bleeding which may cause black tarry stool, blood in vomit or coughing 
up blood

Sores in mouth

Chills

Swelling of arms, legs

Weight loss

Muscle weakness

Dizziness, headache

Worry, confusion, depression

Cough, postnasal drip

Hair loss, itching

Increased sweating

Sores on the skin

Low blood pressure which may cause feeling faint

Pale skin
Rare, and Serious (affects 3 or fewer people in 100 people receiving azacitidine):

Allergic reaction which may cause rash, low blood pressure, wheezing, shortness 
of breath, swelling of the face or throat

Kidney damage which may cause swelling, may require dialysis
Risks related to Study Procedures
Blood Draws: The risks of drawing blood include temporary discomfort from the needle 
stick, bruising, and rarely, infection.
Bone Marrow Biopsy: When you have a bone marrow biopsy, there may be some 
discomfort during and after collection of the sample. You may experience pain, bleeding 
and swelling. Numbing medicine may be given with a syringe near the site of the bone 
marrow biopsy. You may have an increased risk of developing an infection at the sample 
site. 
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Hepatitis B and C Reporting: California regulations require laboratories to report new 
cases of Hepatitis B, and Hepatitis C infection to the county public health department. 
The reports include the patient’s name, social security number, and other identifying 
information. Information about these new infections is used to track these diseases 
statewide and nationwide. Other than this required reporting, your results will be treated 
confidentially by the study staff. Personally identifying information will not be reported to 
other departments or agencies.
No radiation risk beyond routine clinical care:  This study involves radiation 
exposure as part of routine clinical care.  You will not receive additional radiation as a 
result of participating in this study.  If you have any questions regarding the use of 
radiation or the risks involved, please consult the physician conducting the study.
Study Drug Combination: The side effects of the combination of daratumumab and 
azacitidine are not yet known.  It is possible that this combination of drugs will cause 
new or more serious side effects than taking these drugs separately. You will be 
monitored closely for side effects and your doctor may change your medications if it 
appears that this combination is causing serious side effects. You should tell your 
doctor about any side effects you experience while on this study.  When additional 
information about side effects is known, you will be notified of any further study drug 
related effects.  
Infusion Related Risks: As with most intravenous products, you may experience pain, 
irritation, swelling or bruising, or a slight chance of infection at the site where the 
intravenous catheter (small tube) is inserted into your vein. These side effects may also 
be observed at the site where blood is drawn for laboratory tests.  
Loss of Privacy: There is a risk of loss of privacy.  We will do our best to make sure 
that your personal information will be kept private. Your samples will be labeled with a 
code that cannot be used to identify you directly.  The list that links your identity to the 
code on the sample will be kept separate from the samples.  The researchers using 
your samples will never be given your identity.  
Reproductive Risks: The effects of daratumumab on fertility, the human embryo, the 
fetus, or the breast-fed infant are unknown. If you are a woman, taking part in the study 
might harm your unborn child or breast-fed baby. Thus, you must agree not to become 
pregnant while you are in this study. Also, you cannot take part in this study if you are 
pregnant or breastfeeding a child. If you are a man, the effect of daratumumab on your 
sperm is unknown.
If you are a woman and becoming pregnant is a possibility, you will be required to 
undergo a pregnancy test prior to taking daratumumab.  During the course of the study 
and for 3 months after the last dose of daratumumab both male and female patients 
must use effective methods of birth control and not donate sperm/eggs.
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ALFRED CHUNG, MD
The type of birth control you use must be discussed with, and approved by, the study 
doctor before you begin the study. If you become pregnant or father a child during the 
study, you must tell the study doctor immediately.
Are there benefits to taking part in the study?
Taking part in this study may or may not make your health better.  While doctors hope 
the combination of daratumumab, azacitidine, and dexamethasone will be more useful 
against cancer compared to the usual treatment, there is no proof of this.  We do know 
that the information from this study will help doctors learn more about whether the study 
drugs could be a treatment for this cancer.  This information could help future cancer 
patients.
What other choices do I have if I do not take part in this study?
Your other choices may include:

Getting treatment or care for your cancer without being in a study. 

Taking part in another study.

Getting no treatment.

Getting comfort care, also called palliative care.  This type of care helps reduce 
pain, tiredness, appetite problems and other problems caused by the cancer.  It 
does not treat the cancer directly, but instead tries to improve how you feel.  
Comfort care tries to keep you as active and comfortable as possible.
Please talk to your doctor about your choices before deciding if you will take part in this 
study.
How will my specimens and information be used? 
Researchers will use your blood and tissue specimens and information to conduct this 
study. Once the study is done using your specimens and information, we may share 
them with other researchers so they can use them for other cancer studies in the future. 
We will not share your name or any other personal information that would let the 
researchers know who you are. We will not ask you for additional permission to share 
the de-identified information and specimens.
Your blood and tissue specimens will be stored in a repository, also called a ‘tissue 
bank’, at UCSF. The manager of tissue bank and select tissue bank staff members will 
have access to your specimens and information about you, but they will not release any 
identifying information about you to researchers using your specimens. We may give 
your specimens and certain medical information about you (for example, diagnosis, 
blood pressure, age if less than 85) to other scientists or companies not at UCSF, 
including to an unrestricted or controlled-access government health research database, 
but we will not give them your name, address, phone number, or any other identifiable 
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ALFRED CHUNG, MD
information. Your specimens and information will be kept indefinitely until they are used 
up or destroyed. 
Research results from these studies will not be returned to you and will not be put in 
your medical record. The research will not change the care you receive.
Researchers may use your blood and tissue specimens to look at all of your DNA (this 
is called “whole genome sequencing”. DNA contains information that determines things 
like eye color, height, or disease risk that are passed on from parent to child. Genetic 
information (also known as genotype data) and the medical record data (also known as 
phenotype data) may be shared broadly in a coded form for future genetic research or 
analysis. 
Genetic Information Nondiscrimination Act (GINA) 
A Federal law, called the Genetic Information Nondiscrimination Act (GINA), effective May 
21, 2010, generally makes it illegal for health insurance companies, group health plans, 
and most employers to discriminate against you based on your genetic information. This 
law generally will protect you in the following ways: 
•
Health insurance companies and group health plans may not request your 
genetic information that we get from this research.
•
Health insurance companies and group health plans may not use your genetic 
information when making decisions regarding your eligibility or premiums. 
•
Employers with 15 or more employees may not use your genetic information that 
we get from this research when making a decision to hire, promote, or fire you or when 
setting the terms of your employment. 
Be aware that this new Federal law does not protect you against genetic discrimination 
by companies that sell life insurance, disability insurance, or long-term care insurance.
Donating data and specimens may involve a loss of privacy, but information about you 
will be handled as confidentially as possible. Study data will be physically and 
electronically secured. As with any use of electronic means to store data, there is a risk 
of breach of data security. Genetic information that results from this study does not have 
medical or treatment importance at this time. However, there is a risk that information 
about taking part in a genetic study may influence insurance companies and/or 
employers regarding your health. Taking part in a genetic study may also have a 
negative impact or unintended consequences on family or other relationships. It is 
possible that future research could one day help people of the same race, ethnicity, or 
sex as you. However, it is also possible through these kinds of studies that genetic traits 
might come to be associated with your group. In some cases, this could reinforce 
harmful stereotypes.
There will be no direct benefit to you from allowing your specimens and data to be kept 
and used for future research. However, we hope we will learn something that will 
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ALFRED CHUNG, MD
contribute to the advancement of science and understanding of health and disease. If 
your specimens, the data or any new products, tests or discoveries that result from this 
research have potential commercial value, you will not share in any financial benefits. 
If you decide later that you do not want your information to be used for future research, 
you can notify the investigator in writing or via phone at,
Swetha Kambhampati, MD
University of California San Francisco
 
Alfred Chung, MD
University of California San Francisco
  
and any remaining data will be destroyed.  However, we cannot retract any data that 
has been shared with other researchers.
How will information about me be kept confidential?
Participation in research involves some loss of privacy.  We will do our best to make 
sure that information about you is kept confidential, but we cannot guarantee total 
privacy.  Some information from your medical records will be collected and used for this 
study.  If you do not have a UCSF medical record, one will be created for you.  Your 
signed consent form and some of your research tests will be added to your UCSF 
medical record.  Therefore, people involved with your future care and insurance may 
become aware of your participation and of any information added to your medical record 
as a result of your participation.  Study tests that are performed by research labs, and 
information gathered directly from you by the researchers will be part of your research 
records and may be added to your medical record.  Your personal information may be 
given out if required by law.  If information from this study is published or presented at 
scientific meetings, your name and other personal information will not be used.
California regulations require laboratories to report new cases of hepatitis B, and 
hepatitis C infection to the county public health department. The reports include the 
patient’s name, social security number, and other identifying information. Information 
about these new infections is used to track these diseases statewide and nationwide. 
Other than this required reporting, your results will be treated confidentially by the study 
staff. Personally identifying information will not be reported to other departments or 
agencies.
Authorized representatives from the following organizations may review your research 
data for the purpose of monitoring or managing the conduct of this study:

Representatives of Janssen

Representatives of Multiple Myeloma Research Foundation

Representatives of the University of California
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ALFRED CHUNG, MD

Representatives of the Food and Drug Administration (FDA) 
Are there any costs to me for taking part in this study?
Janssen Pharmaceuticals will provide funding and daratumumab at no cost to you.  
Azacitidine will be provided by UCSF. Multiple Myeloma Research Foundation will 
provide funding for this study.
Two types of procedures will be done during this study. Some are part of your standard 
medical care and others are only for research. You or your insurer will be billed for the 
standard medical care. You will be responsible for your co-pays, deductibles, and any 
other charges that your insurer will not pay. There is a possibility that your insurer may 
not cover all standard medical care costs if you are receiving medical services out of 
network. Any procedures done only for research will not be charged to you or your 
insurer.
Will I be paid for taking part in this study?
You will not be paid for taking part in this study.
What happens if I am injured because I took part in this study?
It is important that you tell your study doctor (s), Dr. Swetha Kambhampati or Dr. Alfred 
Chung, if you feel that you have been injured because of taking part in this study. You 
can tell the Dr. Kambhampati or Dr. Chung in person or call 
 
Treatment and Compensation for Injury:  If you are injured as a result of being 
in this study, the University of California will provide necessary medical 
treatment.  The costs of the treatment may be billed to you or your insurer just 
like any other medical costs, or covered by the University of California, 
depending on a number of factors.  The University does not normally provide any 
other form of compensation for injury.  For further information about this, you may 
call the office of the Institutional Review Board at 415- 476-1814.
What are my rights if I take part in this study?
Taking part in this study is your choice. You may choose either to take part or not to 
take part in the study. If you decide to take part in this study, you may leave the study at 
any time. No matter what decision you make, there will be no penalty to you and you will 
not lose any of your regular benefits. Leaving the study will not affect your medical care. 
You can still get your medical care from our institution. 
We will tell you about new information or changes in the study that may affect your 
health or your willingness to continue in the study.
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ALFRED CHUNG, MD
In the case of injury resulting from this study, you do not lose any of your legal rights to 
seek payment by signing this form.
Who can answer my questions about the study?
You can talk to your study doctor about any questions, concerns, or complaints you 
have about this study.  Contact your study doctor(s) Dr. Swetha Kambhampati 
 or Dr. Alfred Chung 
.
If you wish to ask questions about the study or your rights as a research participant to 
someone other than the researchers or if you wish to voice any problems or concerns 
you may have about the study, please call the office of the Institutional Review Board at 
415-476-1814.  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This Web site will not include information that can identify 
you.  At most, the Web site will include a summary of the results.  You can search this 
Web site at any time.      
OPTIONAL RESEARCH
This section of the informed consent is about additional research studies that are 
being done with people who are taking part in the study. You may take part in these 
additional studies only if you want to. Everyone who is receiving study drug is 
being asked to take part in this optional study.
Optional Blood and Tissue Samples for Future Research
If there is any leftover blood or tissue from the blood draws and tissue biopsies required 
in this study after the study tests are done, we ask you to donate those left over 
samples for future research. If you do not want to take part in this optional portion of 
this study, you may still take part in the main study as described above.
If you agree, your samples and information about you may be made available to others 
to use for research. We may give your specimens and certain medical information 
about you (for example, diagnosis, blood pressure, age if less than 85) to other 
scientists or companies not at UCSF, including to an unrestricted or controlled-access 
government health research database, but we will not give them your name, address, 
phone number, or any other identifiable information. You will not receive any benefit 
as a result of the tests done on your samples.
Your samples may be helpful for research whether you do or do not have cancer. The 
research that may be done with your samples is not designed specifically to help you. 
It might help people who have cancer and other diseases in the future.
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Reports about research done with your samples will not be given to you or your doctor. 
These reports will not be put in your health record. The research will not have an effect 
on your care.
Things to Think About
The choice to let us keep the left over samples for future research is up to you. No 
matter what you decide to do, it will not affect your care.
If you decide now that your samples can be kept for research, you can change your 
mind at any time. Just contact us and let us know that you do not want us to use your 
samples. Then identifiable samples that remains will no longer be used for research.
In the future, people who do research may need to know more about your health. While 
the study doctor may give them reports about your health, they will not give them your 
name, address, phone number, or any other information that would let the researchers 
know who you are.
Sometimes samples are used for genetic research (about diseases that are passed 
on in families). Even if your sample is used for this kind of research, the results will 
not be put in your health records.
Benefits
There will be no direct benefit to you from donating your samples for future research.
The benefits of research using blood and/or tissue include learning more about what 
causes cancer and other diseases, how to prevent them, and how to treat them. Your 
samples will be used only for research and will not be sold. The research done with 
your samples may help to develop new products in the future.  New products may have 
commercial value but you will not receive any compensation for the development or 
sale of these products.
Risks
The greatest risk to you is the release of information from your health records. We will 
do our best to make sure that your personal information will be kept private. 
How will my genetic information be shared?
Genetic information (also known as genotype data) and the medical record data (also 
known as phenotype data) may be shared broadly in a coded form for future genetic 
research or analysis. We may give certain medical information about you (for example, 
diagnosis, blood pressure, age if less than 85) to other scientists or companies not at 
UCSF, including to a (public or controlled access) government health research 
database, but we will not give them your name, address, phone number, or any other 
identifiable information. Research results from these studies will not be returned to 
you.
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Donating data may involve a loss of privacy, but information about you will be handled 
as confidentially as possible. Study data will be physically and electronically secured. 
As with any use of electronic means to store data, there is a risk of breach of data 
security. Genetic information that results from this study does not have medical or 
treatment importance at this time. However, there is a risk that information about taking 
part in a genetic study may influence insurance companies and/or employers regarding 
your health. Taking part in a genetic study may also have a negative impact or 
unintended consequences on family or other relationships. It is possible that future 
research could one day help people of the same race, ethnicity, or sex as you. 
However, it is also possible through these kinds of studies that genetic traits might come 
to be associated with your group. In some cases, this could reinforce harmful 
stereotypes.
There will be no direct benefit to you from allowing your data to be kept and used 
for future research. However, we hope we will learn something that will contribute 
to the advancement of science and understanding of health and disease. If the 
data or any new products, tests or discoveries that result from this research have 
potential commercial value, you will not share in any financial benefits. If you 
decide later that you do not want your information to be used for future research, 
you can notify the investigator in writing or by phone, and any remaining data will 
be destroyed. 
However, we cannot retract any data has been shared with other researchers.
Swetha Kambhampati, MD
University of California San Francisco
 
Alfred Chung, MD
University of California San Francisco
 
 
Will I be contacted in the future about this or other research?
We, the local site study team, may want to contact you in the future. You 
can 
decide now whether or not you want to be contacted. You can also change your mind 
later.
If you agree, we may contact you for several reasons. For example, over time, stored 
samples may be used up or decrease in quality, so we may contact you to ask for more 
samples. We may also contact you to update basic information or request information 
about your health.
Additionally, we may want to contact you to see if you want to participate in other 
research. We will not notify you every time your samples and information are used. 
However, some researchers might apply to do a study for which they would need to 
contact you. For example, they might want to ask you to give another sample or to fill 
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ALFRED CHUNG, MD
out a survey, or they might ask you to do a phone interview or come in to be seen by 
a researcher or doctor. If a study like this is approved, someone from this project will 
contact you. They will tell you about the study so you can decide if you want to receive 
more information. There will be a new consent process just for that study. You can 
decide then to take part or not take part. If at any time you decide you no longer want 
to be contacted about future studies, please tell us.
Can I change my mind after I agree to let my samples be used?
You have the right to change your mind about the future use of your leftover blood 
and tissue samples and information at any time. If you want to leave the project, let us 
know. Just contact the study doctors, Swetha Kambhampati, MD, or Alfred Chung, MD 
in writing or by phone and let us know that you do not want us to keep your samples.
Making Your Choice
Please read each sentence below and think about your choice. After reading each 
sentence, put your initials in the "Yes" or "No" box. If you have any questions, please 
talk to your doctor or nurse, or call our Institutional Review Board at 415-476-1814.
No matter what you decide to do, it will not affect your care.
1. My excess tissue may be kept for use in research to learn about, prevent, or treat 
cancer and other diseases.
2. My excess blood may be kept for use in research to learn about, prevent, or treat 
cancer and other diseases.
3. Someone may contact me in the future to ask me to take part in more research.
YES
NO
YES
NO
YES
NO
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CONSENT
You have been given copies of this consent form and the Experimental Subject's Bill of 
Rights to keep.
You will be asked to sign a separate form authorizing access, use, creation, or 
disclosure of health information about you.
PARTICIPATION IN RESEARCH IS VOLUNTARY. You have the right to decline to 
participate or to withdraw at any point in this study without penalty or loss of benefits to 
which you are otherwise entitled.
If you wish to participate in this study, you should sign below.
Date
Participant's Signature for Consent
Date
Person Obtaining Consent
Person Obtaining Consent Name (Printed)
Date
Witness – Only required if the participant is a non-English speaker
Witness’s Name (Printed) – Only required if the participant is a 
non-English speaker
AND/OR:
Date
Legally Authorized Representative
Legally Authorized Representative Name (Printed)
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ALFRED CHUNG, MD
Date
Person Obtaining Consent
Person Obtaining Consent Name (Printed)
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