Phase II Study of Daratumumab Based Response Adapted Therapy for Older Adults With Newly Diagnosed Multiple Myeloma
Phase: PHASE2
Conditions: Multiple Myeloma
Sponsor: H. Lee Moffitt Cancer Center and Research Institute

i 
 
Phase II study of daratumumab based response adapted therapy for 
older adults with newly diagnosed multiple myeloma 
Protocol Number:  20130 
NCT Identified Number: 04151667 
 
 
 
Drug and Funding by: Janssen Scientific Affairs LLC  
Version Number: 9.0 
September 2 2022 
Principal Investigator: 
Rachid Baz, MD 
Sponsor Institution 
H. Lee Moffitt Cancer Center & Research Institute 
IND/IDE Sponsor/IND number 
144902 
Biostatistician: 
Jongphil Kim, PhD 

  
ii 
1 
CONTENTS 
STATEMENT OF COMPLIANCE ................................................................................................................. 5 
1 
PROTOCOL SUMMARY ................................................................................................................... 6 
1.1 
Synopsis ................................................................................................................................... 6 
1.2 
Schema .................................................................................................................................. 11 
1.3 
Schedule of Activities (SoA)................................................................................................... 12 
INTRODUCTION ......................................................................................................................................... 15 
1.4 
Study Rationale ...................................................................................................................... 15 
1.5 
Background ............................................................................................................................ 16 
1.5.1 
Daratumumab ...................................................................................................... 16 
1.6 
Risk/Benefit Assessment ....................................................................................................... 21 
1.6.1 
Known Potential Risks ......................................................................................... 21 
1.6.2 
Known Potential Benefits ..................................................................................... 21 
1.6.3 
Assessment of Potential Risks and Benefits ....................................................... 21 
2 
OBJECTIVES AND ENDPOINTS .................................................................................................... 22 
3 
STUDY DESIGN .............................................................................................................................. 23 
3.1 
Overall Design ....................................................................................................................... 23 
3.2 
End of Study Definition .......................................................................................................... 24 
4 
STUDY POPULATION .................................................................................................................... 24 
4.1 
Inclusion Criteria .................................................................................................................... 24 
4.2 
Exclusion Criteria ................................................................................................................... 25 
4.3 
Screen Failures ...................................................................................................................... 26 
4.4 
Strategies for Recruitment and Retention .............................................................................. 26 
5 
STUDY INTERVENTION ................................................................................................................. 26 
5.1 
Daratumumab ........................................................................................................................ 26 
5.1.1 
Daratumumab ...................................................................................................... 26 
5.1.2 
Daratumumab Dosing and Administration ........................................................... 26 
5.1.3 
daratumumab handling / storage and accountability ........................................... 28 
5.2 
Dexamethasone ..................................................................................................................... 28 
5.2.1 
Dexamethasone ................................................................................................... 28 
5.2.2 
Dexamethasone dosing and administration ......................................................... 28 
5.2.3 
Dexamethasone Preparation / handling / storage and accountability ................. 28 
5.2.4 
DEXAMETHASONE DOSE REDUCTION ........................................................... 28 
5.3 
Lenalidomide .......................................................................................................................... 30 
5.3.1 
Lenalidomide ........................................................................................................ 30 
5.3.2 
Lenalidomide dosing and administration ............................................................. 30 
5.3.3 
Lenalidomide Preparation / handling / storage and accountability ...................... 30 
5.3.4 
LENALIDOMIDE DOSE REDUCTION................................................................. 30 
5.4 
Bortezomib ............................................................................................................................. 32 
5.4.1 
Bortezomib ........................................................................................................... 32 
5.4.2 
Bortezomib Dosing and administration ................................................................ 33 
5.4.3 
bortezomib Preparation / handling / storage and accountability .......................... 33 
5.4.4 
BORTEZOMIB DOSE reducTION ....................................................................... 33 
5.5 
Study Intervention Compliance .............................................................................................. 34 
5.6 
Concomitant Therapy ............................................................................................................. 34 
6 
Correlative studies ........................................................................................................................... 35 
6.1 
EMMA .................................................................................................................................... 35 
6.2 
immune profiling ..................................................................................................................... 37 
6.3 
geriatric assessment .............................................................................................................. 38 

  
iii 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ......................................................................................................... 39 
7.1 
Discontinuation of Study Intervention .................................................................................... 39 
7.2 
Participant Discontinuation/Withdrawal from the Study ......................................................... 39 
7.3 
Lost to Follow-Up ................................................................................................................... 40 
8 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................. 40 
8.1 
Efficacy Assessments ............................................................................................................ 40 
8.2 
Safety and Other Assessments ............................................................................................. 41 
8.3 
Adverse Events and Serious Adverse Events ....................................................................... 41 
8.3.1 
Definition of Adverse Events (AE) ........................................................................ 42 
8.3.2 
Definition of Serious Adverse Events (SAE) ........................................................ 42 
8.3.3 
Classification of an Adverse Event ...................................................................... 42 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up .................... 43 
8.3.5 
Adverse Event Reporting ..................................................................................... 44 
8.3.6 
Serious Adverse Event Reporting ........................................................................ 44 
8.3.7 
Events of Special Interest .................................................................................... 44 
8.3.8 
Special reporting situations .................................................................................. 45 
8.4 
Unanticipated Problems ......................................................................................................... 45 
8.4.1 
Definition of Unanticipated Problems (UP) .......................................................... 45 
8.4.2 
Unanticipated Problem Reporting ........................................................................ 46 
8.4.3 
Reporting Unanticipated Problems to Participants .............................................. 46 
9 
STATISTICAL CONSIDERATIONS ................................................................................................ 47 
9.1 
Statistical Hypotheses ............................................................................................................ 47 
9.2 
Sample Size Determination ................................................................................................... 47 
9.3 
Populations for Analyses ....................................................................................................... 48 
9.4 
Statistical Analyses ................................................................................................................ 48 
9.4.1 
General Approach ................................................................................................ 48 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ....................................................... 48 
9.4.3 
Analysis of the Secondary Endpoints .................................................................. 48 
9.4.4 
Safety Analyses ................................................................................................... 49 
9.4.5 
Baseline Descriptive Statistics ............................................................................. 49 
9.4.6 
Planned Interim Analyses .................................................................................... 49 
9.4.7 
Sub-Group Analyses ............................................................................................ 49 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................... 49 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ..................................................... 49 
10.1.1 
Informed Consent Process .................................................................................. 49 
10.1.2 
Study Discontinuation and Closure ...................................................................... 50 
10.1.3 
Future Use of Stored Specimens and Data ......................................................... 50 
10.1.4 
Key Roles and Study Governance ....................................................................... 51 
10.1.5 
Safety Oversight................................................................................................... 51 
10.1.6 
Clinical Monitoring ................................................................................................ 51 
10.1.7 
Quality Assurance and Quality Control ................................................................ 51 
10.1.8 
Data Handling and Record Keeping .................................................................... 52 
10.1.9 
Protocol Deviations .............................................................................................. 52 
10.1.10 
Publication and Data Sharing Policy .................................................................... 53 
10.1.11 
Conflict of Interest Policy ..................................................................................... 53 
10.2 
Abbreviations ......................................................................................................................... 54 
10.3 
Protocol Amendment History ................................................................................................. 55 
11 
REFERENCES ................................................................................................................................ 57 
12 
APPENDIX A: IMWG response criteria ........................................................................................... 60 

  
iv 
13 
APPENDIX B: IMWG Geriatric assessment .................................................................................... 62 
13.1.1 
Activities of Daily Living (ADL) and Intrumental Activity of Daily Living (IADL) ... 62 
13.1.2 
Charlson Comorbidity Index (CCI) ....................................................................... 62 
13.1.3 
IMWG frailty scoring ............................................................................................. 63 
13.1.4 
Timed up and go (gait speed) .............................................................................. 63 
13.1.5 
Senior Adult Oncology Clinic questionnaire ......................................................... 63 
14 
APPENDIX C: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth 
Control Methods .......................................................................................................................................... 66 
15.  
APPENDIX D: Worksheet for Revised International Staging System (R-ISS) and Classification of 
FISH Findings……………………………………………………………………………………………………….68 
 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
Version 9.0 
 
9/2/2022 
 
5 | P a g e  
STATEMENT OF COMPLIANCE 
 
 
The trial will be conducted in accordance with the ICH E6, the Code of Federal Regulations on the 
Protection of Human Subjects (45 CFR Part 46), and the Supporting Agency Terms. The Principal 
Investigator will assure that no deviation from, or changes to the protocol will take place without prior 
agreement from the sponsor and documented approval from the Institutional Review Board, except where 
necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved in the conduct 
of this study have completed Human Subjects Protection Training. 
 
I agree to ensure that all staff members involved in the conduct of this study are informed of their 
obligation to meet the above commitments. 
 
 
Principal Investigator: 
   
  
Rachid Baz, M.D. 
 
 
Signed:    
 Date: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 6  
1 
 
PROTOCOL SUMMARY 
1.1 SYNOPSIS  
Title: 
Phase II study of daratumumab based response adapted therapy for older 
adults with newly diagnosed multiple myeloma 
Study Description: 
In this response adapted approach, older adults with newly diagnosed 
symptomatic multiple myeloma will receive daratumumab and 
dexamethasone for 2 months. Patients who achieve a partial response or 
better will continue on daratumumab. Patients who achieve less than a 
partial response will have lenalidomide or bortezomib added to their 
therapy. Patients who experience progressive disease on daratumumab 
after the initial 2 months of monotherapy or on the combination of 
daratumumab and either lenalidomide or bortezomib will come off study.  
Objectives: 
Primary Objective:  
1- Efficacy of this response adapted approach in older adults with newly 
diagnosed myeloma 
 
Secondary Objectives:  
1- Safety profile of daratumumab based therapy in older adults with newly 
diagnosed myeloma 
2- Identification of potential biomarkers for the prediction of response  
 
 
Endpoints: 
Primary Endpoint: Best response per the IMWG Uniform response criteria 
for the response adapted approach (partial response (PR) or better) based 
on investigator assessment 
 
Secondary Endpoints:  
1- The 1 and 2 years progression free survival (PFS) of the study 
population 
2- Overall response rate (partial response or better) after 2 cycles of 
daratumumab 
3- Proportion of patients who continue on daratumumab monotherapy 
after 2 cycles.  
4- Proportion of patients who are without minimal residual disease (MRD-) 
using Next Generation sequencing (NGS) 
5- The 2 year overall survival of this response adapted approach 
6- Safety profile of subcutaneous daratumumab based therapy in older 
adults newly diagnosed multiple myeloma 
7- Agreement between actual responses and responses as predicted by 
an Ex Vivo Mathematical Myeloma Advisor (EMMA) 
Exploratory endpoints/ correlative: 
1- Immune profiling at baseline and after daratumumab dexamethasone 
for newly diagnosed myeloma. 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 7  
2- Validate EMMA in silico predictions of daratumumab response.  
3- Incorporate clinical parameters and early dynamics of monoclonal 
paraprotein response to therapy to extend EMMA’s capacity to include 
longer term predictions of patient outcomes. 
4- Correlation between a simplified geriatric assessment (frailty) and 
grade 3 and 4 (hematologic and non-hematologic) toxicity from therapy 
as well as discontinuation due to adverse events 
5- Evaluation potential molecular biomarkers of clinical response to trial 
associated therapy.   
 
 
Study Population: 
Eligible patients:  
Subjects must meet all of the following inclusion criteria to be eligible for 
enrollment into the study: 
1. Understand and voluntarily sign an informed consent form. 
2. Age 65 years and presence of coexisting conditions which in the 
opinion of the treating physician are likely to result in the development 
of unacceptable side effects associated with high-dose chemotherapy 
with stem-cell transplantation 
3. Able to adhere to the study visit schedule and other protocol 
requirements. 
4. Diagnosed with multiple myeloma and be considered to have active 
disease with either CRAB criteria or myeloma defining events (bone 
marrow ≥ 60% plasma cells, sFLC ratio≥ 100 or MRI or PET defined 
lesions) (Appendix C). Patients must not have received an active 
chemotherapy regimen. Patients may have received palliative 
radiotherapy at least 2 weeks prior to the study start. Dexamethasone 
up to 160 mg total dose is allowed prior to participation 
5. Measurable myeloma paraprotein levels in serum (≥ 0.5 g/dL), urine (≥ 
0.2 g excreted in a 24-hour urine collection sample) or by serum free 
light chains (involved free light chain greater than 100mg/L) 
6. Eastern Cooperative Group (ECOG) Performance Status of 0 - 2. 
7. Serum bilirubin levels 1.5 times the upper limit of the normal range for 
the laboratory (ULN).  
8. Serum AST or serum ALT] levels 2 x ULN 
9. Must have adequate bone marrow function:   
a. Absolute neutrophil count > 1,000 cells/mm3 (1.0 x 109/L).  
b. Platelets  75,000 /mm3.  

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 8  
10. Hemoglobin > 8 g/dL (transfusions are allowed) 
11. Calculated creatinine clearance ≥ 30ml/min by Cockcroft-Gault formula.   
12. Men must agree to use a latex condom during sexual contact with a 
female of child bearing potential even if they have had a successful 
vasectomy.  See Appendix C: Risks of Fetal Exposure, Pregnancy 
Testing Guidelines and Acceptable Birth Control Methods. 
Exclusion criteria 
The presence of any of the following will exclude a subject from study 
enrollment:  
1. Ongoing severe infection requiring intravenous antibiotic treatment. 
2. Prior malignancy, except for adequately treated basal cell or squamous 
cell skin cancer, in-situ cervical cancer, or other cancer from which the 
subject has been disease-free for at least 2 years. 
3. Solitary bone or solitary extramedullary plasmacytoma as the only 
evidence of plasma cell dyscrasia. 
4. Patients with known COPD with a forced expiratory volume in 1 second 
(FEV1) <50% of predicted normal and , moderate or severe persistent 
asthma within the past 2 years or uncontrolled asthma. Patients with a 
history of COPD will have pulmonary function testing to include FEV1  
5. Uncontrolled medical problems such as diabetes mellitus, congestive 
heart failure, coronary artery disease, hypertension, unstable angina, 
arrhythmias), pulmonary, hepatic and renal diseases unless renal 
insufficiency is felt to be secondary to multiple myeloma.  
6. Any serious medical condition, laboratory abnormality, or psychiatric 
illness that would prevent the subject from signing the informed consent 
form. 
7. Pregnant or lactating females. 
8. Any condition, including the presence of laboratory abnormalities, 
which places the subject at unacceptable risk if he/she were to 
participate in the study or confounds the ability to interpret data from 
the study.   
9. Concurrent use of other anti-cancer agents or treatments with the 
exception for hormonal therapy which is allowed. 
10. Known allergy or hypersensititvity or intolerance to any of the study 
drugs, hyaluronidase, mAbs, human proteins, or their excipients (refer 
to daratumumab IB), or known sensitivity to mammalian-derived 
products 
11. Seropositive for human immunodeficiency virus (HIV) 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 9  
12. Seropositive for hepatitis B (defined by a positive test for hepatitis B 
surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects 
who are HBsAg negative but positive for antibodies to hepatitis B core 
antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-
HBs]) must be screened using real-time polymerase chain reaction 
(PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who 
are PCR positive will be excluded. EXCEPTION: Subjects with 
serologic findings suggestive of HBV vaccination (anti-HBs positivity as 
the only serologic marker) AND a known history of prior HBV 
vaccination, do not need to be tested for HBV DNA by PCR. 
13. 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). 
 
Phase: 
Phase II, open label 
Description of 
Sites/Facilities 
Enrolling Participants: 
H. Lee Moffitt Cancer Center & Research Institute  
Description of Study 
Intervention: 
Patient will receive daratumumab (1800 mg in 15 ml) premixed with 
recombinant human hyaluronidase enzyme (rHuPH20 30,000 units) to be 
administered by manual subcutaneous injections over 3-5 minutes on the 
following schedule: weekly for the first 8 injections 
In the event of a partial response or better, patient will continue on arm A 
and receive SC daratumumab every 2 weeks for the next 8 injections and 
monthly thereafter. Supportive medicine including antihistamine 
acetaminophen, and corticosteroids will be per standard of care 
premedications for daratumumab. On the weeks when the patient is not to 
receive daratumumab, dexamethasone 20 mg PO will be given only.  
In the event of less than a partial response (stable disease, minimal 
response or progressive disease) after 2 cycles, lenalidomide or bortezomib 
will be added. The decision to use bortezomib or lenalidomide will be at the 
discretion of the treating physician (based on which agent is expected to be 
better tolerated), the patient preference and informed by EMMA (after a 
repeat bone marrow aspiration)  
If lenalidomide is to be added to daratumumab (arm B), lenalidomide will be 
used at a starting dose of 10-25 mg PO D1-21 every 28 days. The starting 
dose of lenalidomide will be 10 mg if the creatinine clearance is < 50 ml/min 
or the patient is over 80 years of age, 15 mg if the patient is 75 years of age 
or older and the creatinine clearance is >50 ml/min; and 25 mg if the patient 
is <75 years and with a creatinine clearance of 50 ml/min. During the first 4 
cycles of lenalidomide, daratumumab will be given every 2 weeks and after 
the first 4 cycles of lenalidomide, daratumumab will be administered every 
month. On the weeks when the patient is not to receive daratumumab, 
dexamethasone 20 mg PO will be given. 
If bortezomib is to be added to daratumumab and dexamethasone, patients 
will receive weekly SC bortezomib at a starting dose of 1.3 mg/m2 on days 
1,8,15 every 28 days in combination with daratumumab every 2 weeks for 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 10  
the next 4 cycles (each cycle is 28 days) and then monthly daratumumab 
after. On the weeks when the patient is not to receive daratumumab, 
dexamethasone 20 mg PO will be given (figure 2). After 8 cycles of 
bortezomib based therapy (cycle 10 of the trial), patients may receive a less 
frequent maintenance dose of bortezomib (including discontinue 
bortezomib) at the discretion of the treating physician.  
Treatment will be continued until progressive disease.  
Commercial supply of lenalidomide and bortezomib will be used for this 
study. 
 
Study Duration: 
It is estimated that accrual will be completed in 2 years. In that case the 
data would need another year to mature.  
Participant Duration: 
Treatment will be continued until progressive disease or unacceptable 
toxicity. The estimated median PFS for newly diagnosed older adults with 
multiple myeloma was 25 months in a study of lenalidomide and 
dexamethasone 
 
 
 
 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 11  
1.2 
SCHEMA 
Screening 
bone marrow 
biopsy 
(EMMA)
Weekly 
Daratumumab* 
Dexamethasone 
X 2 month
≥PR
<PR
Repeat bone 
marrow 
biopsy 
(EMMA)
Continue Daratumumab 
& Dexamethasone 
per usual Dara schedule*
until PD
Addition of weekly SC 
bortezomib§ or dose 
adjusted lenalidomide¥
informed by EMMA 
prediction until PD 
* Daratumumab SC weekly x 8, then every 2 weeks x 8 and then monthly. Dexamethasone 20 
mg weekly starting dose)
§ Bortezomib 1.3 mg/m2 SC D1,8,15/28 days
¥ Lenalidomide 10‐25 mg PO D1‐21/28 days (dosing based on frailty / CrCl)
Bortezomib and lenalidomide based therapy per standard of care, administration could be done at local oncologist office 
(given safety of combination per CASTOR and POLLUX). All Daratumumab to be administered at MCC given study drug. 
PD: progression of disease; EMMA: Ex Vivo Mathematical Myeloma Advisor (CLIA based), PR: Partial Response
Bone 
marrow 
at PD
Treatment / Study Schema
 
Dara SC 1800 mg: daratumumab (1800 mg in 15 
ml) premixed with recombinant human 
hyaluronidase enzyme (rHuPH20 30,000 units) 
to be administered by manual subcutaneous 
injections over 3‐5 minutes 
Response 
Assessment 
Arm A (≥PR): Daratumumab dexamethasone 
Arm B (<PR): Lenalidomide daratumumab dexamethasone
Every 2 weeks
Every month
Every 2 weeks
Every month
Len
Daratumumab 
weekly x 8
Len
Len
Len
Len
Lenalidomide 10‐25 mg 
21 days /28 days PO
Len
Len
Len
Len
Arm C (<PR): Bortezomib daratumumab dexamethasone
Every 2 weeks
Every month
Bortezomib 1.3 mg/m2 SC 
weekly D1,8,15/ 28 days
 
After 8 cycles of bortezomib based therapy (cycle 10 of the trial), patients may receive a less frequent 
maintenance dose of bortezomib (including discontinue bortezomib) at the discretion of the treating 
physician.  
 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 12  
 
1.3 
SCHEDULE OF ACTIVITIES (SOA) 
The following assessment will be performed for safety but not collected on electronic case report forms 
after the baseline / screening evaluation (abnormalities / adverse events noted in the assessments below 
however will be collected on the AE log): vital signs, hematology, serum chemistry, concomitant 
medication review, pregnancy tests when applicable, height and weight.    
Arm A 
Procedures 
Screening 
Day ‐28 to ‐1 
Enrollment/Baseline 
Cycle 1 Day 1 
Cycle 1 Days 8, 15, 22 
+/‐1 day 
Cycle 2 Day1 
Day 28 +/‐ 1 day 
Cycle 2 Days 8,15 
+/‐1 day 
Cycle 2 Day 22 
+/‐ 1 day  
Cycles 3,4,5,6 Days 1 
Every 28 days +/‐7 day 
Cycle 3,4,5,6 Days 15 
+/‐4 day 
Cycle 7+ Day 1 
Every 28 days +/‐7 day 
End of study 
+/‐28 days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Myeloma Response 
Assessment a  
X 
x 
 
x 
 
x 
x 
 
x 
x 
Bone marrow biopsy / 
aspirate b 
X  
 
 
 
 
x 
 
 
 
x 
B2 microglobulin 
X  
 
 
 
 
 
 
 
 
 
Administer SC daratumumab 
 
X 
X  
X  
X 
X  
X  
X 
X  
 
Dexamethasone  
 
X  
X  
X  
X  
X  
X  
X  
X  
 
Concomitant medication 
review 
X 
X‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐X 
 
Physical exam 
X 
X 
 
X  
 
 
X  
 
X  
X 
Vital signs 
X 
X 
 
X  
 
 
X  
 
X  
X 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
 
 
X  
 
 
X 
ECOG Performance status 
X 
X 
 
X 
 
 
X  
 
X  
X 
Hematology  
Xg 
X 
X 
X 
X 
X 
X 
X  
X 
X 
Serum chemistry c 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
Hepatitis B and C and HIV 
X  
 
 
 
 
 
 
 
 
 
Geriatric Assessmentd 
X 
 
 
 
 
X  
 
 
 
 
Adverse event review and 
evaluation 
X 
X‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐X 
X 
Bone survey or PET CTe 
X 
 
 
 
 
 
 
 
 
X 
Immune Profiling  f 
X 
 
 
 
 
X 
 
 
 
 
Complete Case Report Forms 
(CRFs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a: 
Serum protein electrophoresis, serum immunofixation, 24 h urine electrophoresis and immunofixation, 
serum free light chains. The 24 h urine protein electrophoresis does not need to be repeated on cycle 1 
day 1 if performed within 7 days of that date as part of screening.  
b:      Bone marrow biopsy at screening to include cytogenetics, FISH and for identification of a possible future 
MRD clone. EMMA assay to be performed on bone marrow aspirate sample obtained on screening and 
cycle 2 Day 22. In addition, bone marrow biopsy and aspirate will be performed in patients with VGPR or 
CR for MRD assessment and determination of CR (for VGPR, if the remainder M spike is consistent with 
daratumumab interference) 
c:      Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, 
LDH, potassium, total protein, AST, ALT, sodium. 
d: 
Geriatric assessment will include the IMWG geriatric assessment as well as a modified Balducci and 
testing for CRP and D‐ Dimer 
e:     If PET CT or bone survery has been performed within 28 days of cycle 1 day 1 but prior to screening (per 
standard of care) , it would not need to be repeated during screening 
f:      Immune profiling to be performed at screening and on cycle 2 day 22 
g:      A type and screen will be performed on screening only 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 13  
Arm B 
Procedures 
Screening 
Day ‐28 to ‐1 
Enrollment/Baseline 
Cycle 1 Day 1 
Cycle 1 Days 8, 15, 22 
+/‐1 day 
Cycle 2 Day1 
Day 28 +/‐ 1 day 
Cycle 2 Days 8,15 
+/‐1 day 
Cycle 2 Day 22 
+/‐ 1 day  
Cycles 3,4,5,6 Days 1 
Every 28 days +/‐7 day 
Cycle 3,4,5,6 Days 15 
+/‐4 days 
Cycle 7+ Day 1 
Every 28 days +/‐7 day 
End of study 
+/‐ 28 days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Myeloma Response 
Assessment a  
X 
x 
 
x 
 
x 
x 
 
x 
x 
Bone marrow biopsy / 
aspirate b 
X  
 
 
 
 
x 
 
 
 
x 
B2 microglobulin 
X  
 
 
 
 
 
 
 
 
 
Administer SC daratumumab 
 
X 
X  
X  
X 
X  
X  
X 
X  
 
Lenalidomide c 
 
  
  
  
  
  
X  
X  
X  
 
Dexamethasone  
 
X  
X  
X  
X  
X  
X  
X  
X  
 
Concomitant medication 
review 
X 
X‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐X 
 
Physical exam 
X 
X 
 
X  
 
 
X  
 
X  
X 
Collect diary 
 
 
 
X  
 
 
X  
 
X  
X  
Vital signs 
X 
X 
 
X  
 
 
X  
 
X  
X 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
 
 
X  
 
X  
X 
ECOG Performance status 
X 
X 
 
X 
 
 
X  
 
X  
X 
Hematology  
Xh 
X 
X 
X 
X 
X 
X 
X  
X 
X 
serum chemistry d 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
Hepatitis B and C and HIV 
X  
 
 
 
 
 
 
 
 
 
Geriatric Assessmente 
X 
 
 
 
 
X  
 
 
 
 
Adverse event review and 
evaluation 
X 
X‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐X 
X 
Bone survey or PET CTf 
X 
 
 
 
 
 
 
 
 
X 
Immune Profiling  g 
X 
 
 
 
 
X 
 
 
 
 
Complete Case Report Forms 
(CRFs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a: 
Serum protein electrophoresis, serum immunofixation, 24 h urine electrophoresis and immunofixation, 
serum free light chains. The 24 h urine protein electrophoresis does not need to be repeated on cycle 1 
day 1 if performed within 7 days of that date as part of screening. 
b:      Bone marrow biopsy at screening to include cytogenetics, FISH and for identification of a possible future 
MRD clone. EMMA assay to be performed on bone marrow aspirate sample obtained on screening and 
cycle 2 Day 22. In addition, bone marrow biopsy and aspirate will be performed in patients with VGPR or 
CR for MRD assessment and determination of CR (for VGPR, if the remainder M spike is consistent with 
daratumumab interference) 
c:       Patients will take lenalidomide orally on D1‐21 every 28 days cycle 
d:      Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, 
LDH, potassium, total protein, AST, ALT, sodium. 
e:      Geriatric assessment will include the IMWG geriatric assessment as well as a modified Balducci and 
testing for CRP and D‐ Dimer 
f:       If PET CT or bone survery has been performed within 28 days of cycle 1 day 1 but prior to screening (per 
standard of care) , it would not need to be repeated during screening. 
g:      Immune profiling to be performed at screening and on cycle 2 day 22 
h:      A type and screen will be performed on screening only 
 
 
 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 14  
Arm C 
Procedures 
Screening 
Day ‐28 to ‐1 
Enrollment/Baseline 
Cycle 1 Day 1 
Cycle 1 Days 8, 15, 22 
+/‐1 day 
Cycle 2 Day1 
Day 28 +/‐ 1 day 
Cycle 2 Days 8,15 
+/‐1 day 
Cycle 2 Day 22 
+/‐ 1 day  
Cycles 3,4,5,6 Days 1 
Every 28 days +/‐7 day 
Cycle 3,4,5,6 Day  8 
+/‐2 days 
Cycle 3,4,5,6 Days 15 
+/‐2 days 
Cycle 7+ Day 1 
Every 28 days +/‐7 
days 
Cycle 7+ Day 8,15 
Every 28 days +/‐2 
days 
End of study 
+/‐ 28 days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Myeloma Response 
Assessment a  
X 
X  
 
X  
 
X  
X  
 
 
X  
 
x 
Bone marrow biopsy / 
aspirate b 
X  
 
 
 
 
x 
 
 
 
 
 
x 
B2 microglobulin 
X  
 
 
 
 
 
 
 
 
 
 
 
Administer SC daratumumab 
 
X 
X  
X  
X 
X  
X  
 
X 
X  
 
 
Administer SC bortezomib c 
 
  
  
  
  
 
X   
X  
X  
X  
X  
 
Dexamethasone  
 
X  
X  
X  
X  
X  
X  
 
X  
X  
X  
 
Concomitant medication 
review 
X 
X‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐X 
 
Physical exam 
X 
X 
 
X  
 
 
X  
 
 
X  
 
X 
Vital signs 
X 
X 
 
X  
 
 
X  
 
 
X  
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
 
 
X  
 
 
X  
 
X 
ECOG Performance status 
X 
X 
 
X 
 
 
X  
 
 
X  
 
X 
Hematology  
Xh 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
serum chemistry d 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
Hepatitis B and C and HIV 
X  
 
 
 
 
 
 
 
 
 
 
 
Geriatric Assessmente 
X 
 
 
 
 
X  
 
 
 
 
 
 
Adverse event review and 
evaluation 
X 
X‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐X 
X 
Bone survey or PET CTf 
X 
 
 
 
 
 
 
 
 
 
 
X 
Immune Profiling  g 
X 
 
 
 
 
X 
 
 
 
 
 
 
Complete Case Report Forms 
(CRFs) 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
a: 
Serum protein electrophoresis, serum immunofixation, 24 h urine electrophoresis and immunofixation, serum free light chains. 
The 24 h urine protein electrophoresis does not need to be repeated on cycle 1 day 1 if performed within 7 days of that date as 
part of screening. 
b:      Bone marrow biopsy at screening to include cytogenetics, FISH and for identification of a possible future MRD clone. EMMA 
assay to be performed on bone marrow aspirate sample obtained on screening and cycle 2 Day 22. In addition, bone marrow 
biopsy and aspirate will be performed in patients with VGPR or CR for MRD assessment and determination of CR (for VGPR, if 
the remainder M spike is consistent with daratumumab interference) 
c:      Bortezomib will be administered at a starting dose of 1.3 mg/m2 SC D1,8,15 every 28 days cycle. After 8 cycles of bortezomib 
based therapy (cycle 10 of the trial), patients may receive a less frequent maintenance dose of bortezomib (including 
discontinue bortezomib) at the discretion of the treating physician. 
d:      Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, potassium, total 
protein, AST, ALT, sodium. 
e:      Geriatric assessment will include the IMWG geriatric assessment as well as a modified Balducci and testing for CRP and D‐ Dimer 
f:      If PET CT or bone survery has been performed within 28 days of cycle 1 day 1 but prior to screening (per standard of care) , it 
would not need to be repeated during screening 
g:      Immune profiling to be performed at screening and on cycle 2 day 22  
h:      A type and screen will be performed on screening only 
 
 
 
 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 15  
 
INTRODUCTION 
 
1.4 STUDY RATIONALE  
 
The median age of diagnosis of patients with multiple myeloma is about 70 years of age and only about 
1/3 of myeloma patients at tertiary care centers receive high dose therapy and bone marrow 
transplantation. Despite the availability of novel agents, the outcome of older adults with multiple 
myeloma remains suboptimal and little improvements have been noted. Of particular note, several groups 
have evaluated a geriatric assessment of frailty in older adults with multiple myeloma and this 
assessment was one of the most powerful predictors of outcomes (as well as non-hematologic toxicity 
and discontinuation of therapy) for patients treated with immunomodulatory agents, proteasome inhibitors 
with or without alkylating agents1-3.  
The FIRST and UPFRONT trials have solidified lenalidomide and dexamethasone or bortezomib and 
dexamethasone respectively as the treatment of choice for first line therapy in older adults with myeloma4, 
5. Specifically in this patient population, the FIRST trial demonstrated superiority of continuous 
lenalidomide dexamethasone versus the combination of melphalan prednisone and thalidomide or a fixed 
duration (18 months) of lenalidomide dexamethasone4. The median PFS for lenalidomide and 
dexamethasone was 25.5 months and 59% of patients were alive at 4 years. The overall response rate of 
lenalidomide and dexamethasone was 75% with 15% of patients achieving a complete response4. The 
UPFRONT trial demonstrated similar outcomes with bortezomib dexamethasone versus bortezomib 
dexamethasone and melphalan or bortezomib dexamethasone and thalidomide although the doublet was 
associated with less adverse events5. In that trial, bortezomib dexamethasone resulted in a median PFS 
of 14.7 months and a median overall survival of 49.8 months. The overall response rate of bortezomib 
and dexamethasone was 73% and 3% of patients achieved a complete response5. 
Daratumumab is a human IgG kappa CD38 directed monoclonal antibody with multiple mechanisms of 
actions including direct antitumor effects and immunomodulatory effects resulting in the depletion of 
immunosuppressive cells and expansion of cytotoxic T cells . It results in a response rate of 30% in 
heavily pretreated myeloma patients and a response rate of about 50% in patients with smoldering 
myeloma6. Daratumumab was recently approved by the US FDA for the treatment of newly diagnosed 
multiple myeloma in combination with bortezomib melphalan and prednisone based on the ALCYONE 
trial comparing this therapy to bortezomib melphalan and prednisone7. In that trial daratumumab and 
bortezomib melphalan and prednisone resulted in an overall response rate of 90.9% and a complete 
response rate of 42%. The median PFS was not reached at the time of this report but the 12 months PFS 
was 87%7. Importantly, aside of infusion-related reactions (IRR), daratumumab is well tolerated and has 
little related non hematologic toxicities6-9. Infusion reactions are noted usually in the first or second 
infusions and can be decreased by subcutaneous administration of daratumumab. In fact the PAVO study 
noted IRR in 12% of patients which compares favorably with about 40% noted with IV administration.10 
Importantly the infusion time can be shortened significantly with SC administration without impacting 
efficacy10. An ongoing phase III clinical trial is comparing SC and IV daratumumab in patients with 
relapsed and refractory multiple myeloma (clinicaltrials.gov NCT03277105). Daratumumab monotherapy 
has not been evaluated in newly diagnosed myeloma.  
Given the mechanism of action of daratumumab and above safety data, we anticipate that this agent 
would be well tolerated by older adults with multiple myeloma and possibly would not be impacted by the 
frailty of the patients. Accordingly, we propose to evaluate a daratumumab based response adapted 
therapy for older adults with newly diagnosed symptomatic multiple myeloma. Specifically; eligible 
patients will receive 2 months of therapy with weekly SC daratumumab and dexamethasone. Patients 
who experience a partial response or better would continue on daratumumab and dexamethasone until 
progressive disease (every 2 weeks for 4 months and then monthly for daratumumab and weekly 
dexamethasone). For patients who experience less than a partial response, (MR, SD or PD); 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 16  
lenalidomide or bortezomib would be added to their treatment regimen. The choice of additional therapy 
(bortezomib or lenalidomide) would be informed by an Ex Vivo Mathematical Myeloma Advisor (EMMA) 
and by a discussion between the treating physician and the patient. The safety and efficacy of the 
combination of bortezomib or lenalidomide with daratumumab has been established in the Castor and 
Pollux studies, respectively8, 9. Importantly subcutaneous delivery of daratumumab would reduce the 
infusion duration and potential for infusion related adverse events which would be particularly of benefit 
for older adults with multiple myeloma 
 
1.5 
BACKGROUND  
1.5.1 DARATUMUMAB 
 
1.5.1.1 Non clinical studies 
In mouse xenograft models, daratumumab reduced tumor growth in both preventive and therapeutic 
settings. Daratumumab had no effect on proliferation of human peripheral blood mononuclear cells 
(PBMCs), and cytokine release was similar to other marketed therapeutic antibodies. Hence, 
daratumumab can recruit multiple effector mechanisms to facilitate the lysis of malignant cells in vitro and 
in vivo. 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. 
1.5.1.2 Clinical Studies 
Daratumumab has being evaluated in multiple company sponsored clinical studies in subjects across the 
multiple myeloma disease continuum, ie, smoldering multiple myeloma, previously untreated multiple 
myeloma, relapsed/refractory multiple myeloma, and other diseases including myelodysplastic syndrome 
(MDS), lung cancer, natural killer (NK)/T-cell lymphoma and non-Hodgkin lymphoma. In addition, IV 
daratumumab is currently approved by the U.S. Food and Drug Administration for patients with untreated 
multiple myeloma as well as relapsed and refractory multiple myeloma. Over 2,700 subjects have been 
treated with daratumumab monotherapy or combination therapy in 14 clinical studies that contribute 
study-specific safety summaries to the current daratumumab Investigator Brochure (IB; version 17, dated 
17 December 2020). Of these subjects, daratumumab has been administered to approximately 1,160 
subjects as monotherapy in Studies GEN501, MMY1002, and MMY2002, SMM2001, LYM2001, 
MMY1004 (SC) and MMY3010. Daratumumab as combination therapy has been administered to 
approximately 1,533 subjects in Studies GEN503, MMY1001, MMY1005, MMY3003, MMY3004, 
MMY3007, and MMY3008. 
Monotherapy studies in subjects with relapsed/refractory multiple myeloma are: 
 
GEN501, MMY1002, MMY1004, MMY2002, SMM2001, MMY3010 
 Combination therapy studies are: 
 
Subjects with previously untreated and relapsed/refractory multiple myeloma: 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 17  
o 
MMY1001: daratumumab in combination with bortezomib-dexamethasone (Vd), 
bortezomib-thalidomide-dexamethasone (VTd), bortezomib-melphalan-prednisone 
(VMP), carfilzomib-lenalidomide-dexamethasone [KRd] in subjects with previously 
untreated multiple myeloma and pomalidomide dexamethasone [Pomdex] and 
carfilzomib-dexamethasone [Kd]) 
 
Subjects with relapsed/refractory multiple myeloma: 
o 
GEN503: daratumumab in combination with lenalidomide-dexamethasone (Rd) 
o 
MMY1005: daratumumab in combination with Vd (in Japan) 
o 
MMY3003: daratumumab in combination with Rd 
o 
MMY3004: daratumumab in combination with Vd 
• 
Subjects with previously untreated multiple myeloma: 
o 
MMY3007: daratumumab in combination with VMP 
o 
MMY3008: daratumumab in combination with Rd 
• 
Monotherapy Non-Hodgkin’s Lymphoma 
o 
LYM2001 
 
1.5.1.2.1 Pharmacokinetics 
 
For IV daratumumab, 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. 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. 
For SC daratumumab, Analysis showed a higher max Ctrough in the 1800 mg cohort in comparison to the 
max Ctrough achieved following IV DARA (16 mg/kg) (See figures below)10 
 
 
 
1.5.1.2.2 Efficacy 
Efficacy results for Study MMY2002 and Study GEN501 Part 2 (Part 1 was the dose-escalation phase of 
this first-in-human study), single-arm, open-label studies in which subjects with relapsed and refractory 
multiple myeloma were administered 16 mg/kg of daratumumab by intravenous (IV) route as 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 18  
monotherapy weekly for 8 weeks, every 2 weeks for an additional 16 weeks, and every 4 weeks 
thereafter until disease progression or unacceptable toxicity. Response and progressive disease 
assessment in both studies were evaluated based on the International Myeloma Working Group (IMWG) 
criteria. Efficacy results from the primary analysis of 148 subjects receiving daratumumab 16 mg/kg in 
Study MMY2002 (n = 106) and Study GEN501 Part 2 (n = 42) were integrated. After a median duration of 
follow-up of 20.7 months, the median overall survival (OS) was 20.1 months and an overall response rate 
(ORR) of 31%. Within the individual studies, the ORR was 36% in Study GEN501 and 29% in Study 
MMY2002. 
In Study GEN503, a Phase 1/2, open-label, dose-escalation study of DRd in subjects with 
relapsed/refractory MM, efficacy results from the primary analysis of 13 subjects (Part 1) and 32 subjects 
(Part 2) receiving daratumumab 16 mg/kg showed an ORR of 88% and very good partial response of 
53% after a median follow up of 7.8 months. Efficacy results from the final analysis showed ORR of 81% 
and VGPR or better of 69% after median follow-up of 32.5 months. Median PFS has not been established 
in this study. 
In study MMY3003, daratumumab in combination with lenalidomide and dexamethasone (DRd) in 
relapsed/refractory MM, the primary analysis showed a significant improvement in PFS and ORR for 
subjects in the DRd group, compared with the lenalidomide/dexamethasone (Rd) group. This represents 
a 63% reduction in the risk of disease progression or death for the DRd group compared with the Rd 
group. The ORR for the DRd group was 91% and 75%% for the Rd group.  
In Study MMY3004, daratumumab in combination with bortezomib and dexamethasone (DVd) in subjects 
with relapsed/refractory MM, the primary analysis showed a significant improvement in PFS for subjects 
in the DVd group, compared with the bortezomib/dexamethasone (Vd) group. This represents a 61% 
reduction in the risk of disease progression or death for the DVd group compared with the Vd group. The 
ORR was significant for the DVd group (79%) compared with the Vd group (60%). 
For SC daratumumab, the PAVO trials enrolled patients with relapsed and refractory myeloma who had 
received ≥2 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory drug 
(IMiD). The response rate of SC daratumumab was 52% suggesting efficacy is at least equal or possibly 
improved compared to IV daratumumab.  
 
1.5.1.2.3 Safety 
 
For IV daratumumab, in the MMY2002 monotherapy trial, the most common treatment emergent adverse 
events (TEAE) were 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 TEAE were noted in 57% of patients and are anemia (17%), thrombocytopenia (14%), 
neutropenia (12%), lymphopenia and pneumonia (6%), leukopenia and hypertension (5% each), and 
hypercalcemia (3%).  
For IV daratumumab in combination with lenalidomide and dexamethasone (MMY3003 and GEN503), 
most common TEAE included 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%). Whereas most 
common Grade 3/4 TEAEs: neutropenia (58%), anemia (16%), and thrombocytopenia (14%). 
For IV daratumumab in combination with bortezomib and dexamethasone (MMY3004), the 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%). 
Overall the rate of IRR for IV daratumumab ranges from 40-50% and IRR are mostly noted with the first 1-
2 infusions. Most IRR are grades 1 and 2.  

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 19  
For SC daratumumab, Infusion related reactions (IRRs) were reported in 9/41 pts (22%) mostly grade 1/2 
in severity including chills, fever, rigors, vomiting, itching, edema of the tongue, non-cardiac chest pain 
and wheezing. One patient developed grade 3 dyspnea and 1 patient required hospitalization due to fever 
and chills (both grade 2) after the first infusion. All IRRs developed during or within 6 hours of the first SC 
infusion and were controlled with antihistamine, corticosteroid, antiemetic, or bronchodilator treatment. No 
IRRs were reported with subsequent infusions. Overall, the adverse event profile of SC daratumumab 
was consistent with that of IV use. Grade 3 or higher drug-related adverse events were reported in 5/41 
(12%) pts including fatigue (2 pts), influenza, hypertension, dyspnea, and tumor lysis syndrome. SC 
administration of daratumumab was well tolerated at the abdominal wall injection site with 3/41 (7%) 
patients reporting grade 1 erythema, induration, or burning sensation. 
 
As of June 29, 2018, approximately 426 patients received SC daratumumab. In order for daratumumab to 
be absorbed into the body when injected under the skin, it is combined with a substance called rHuPH20 
(Hylenex®, recombinant hyaluronidase human injection), also known as co-formulated product. Hylenex® 
recombinant is used in combination with other medications (in this case, daratumumab) to improve 
absorption. rHuPH20 has been studied extensively with more than 2321 patients having received it in 
clinical studies and more than 1,737,832 patients having received the marketed product Hylenex® 
recombinant.  
 
The most commonly reported adverse events from recombinant human hyaluronidase when injected 
beneath the skin have been mild injection site reactions, such as redness, pain, bruising, itching, burning, 
tenderness, swelling, hardness, irritation, tingling, numbness and rash.  These reactions were temporary. 
Moderate injection site reactions have occurred less frequently, including burning, redness, pain, and 
tingling. Mild to moderate headache has also been reported. Hyaluronidase should not be injected into or 
around an infected or acutely inflamed area because of the danger of spreading a localized infection. 
Allergic reactions (urticaria or angioedema) have been reported in less than 0.1% of patients receiving 
hyaluronidase. Anaphylactic-like reactions following intravenous injections have occurred, rarely.  
 
For further information regarding the safety and efficacy of daratumumab, please refer to the investigator 
brochure. Daratumumab Hyaluronidase SC (DARZALEX FASPRO) was approved by the FDA for use in 
multiple myeloma in May 2020 in various combinations including with lenalidomide or with bortezomib.  
 
1.5.2 Lenalidomide 
 
Lenalidomide is approved by the U.S. FDA for the treatment of newly diagnosed multiple myeloma, 
relapsed and refractory multiple myeloma as well as maintenance therapy for multiple myeloma. 
Lenalidomide is an immunomodulatory drug that is thought to mediate anti-myeloma activity by 3 main 
mechanisms: 1) direct antitumor effect; 2) inhibition of the microenvironment support for tumor cells; and 
3) an immunomodulatory role.11 Importantly, it has also been shown that lenalidomide causes 
upregulation of natural killer (NK) cells in myeloma11 and enhances the effector cells of antibody-
dependent cell-mediated cytotoxicity, which is one mechanism of action of daratumumab shown in 
preclinical studies.  
Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study 
similar to birth defects caused by thalidomide in humans. If lenalidomide is used during pregnancy, it may 
cause birth defects or embryo-fetal death. Lenalidomide can cause significant neutropenia and 
thrombocytopenia. There is a significantly increased risk of deep vein thrombosis and pulmonary 
embolism, as well as risk of myocardial infarction and stroke in patients with multiple myeloma who 
receive lenalidomide with dexamethasone. Higher incidences of secondary primary malignancies were 
observed in controlled trials of subjects with multiple myeloma receiving lenalidomide. Additionally, 
administration of lenalidomide has been associated with hepatotoxicity (hepatic failure including fatalities); 
allergic reactions, including fatalities (hypersensitivity, angioedema, Stevens-Johnson syndrome, toxic 
epidermal necrolysis); tumor lysis syndrome including fatalities; and impaired stem cell mobilization (a 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 20  
decrease in the number of CD34+ cells collected after treatment [>4 cycles]). Most common adverse 
reactions (≥20%) include diarrhea, fatigue, anemia, constipation, neutropenia, peripheral edema, 
insomnia, muscle cramp/spasms, back pain, nausea, asthenia, pyrexia, upper respiratory tract infection, 
cough, rash, dyspnea, dizziness, decreased appetite, thrombocytopenia, and tremor. 
1.5.2.1 Daratumumab in combination with lenalidomide and dexamethasone 
The combination of daratumumab and lenalidomide dexamethasone resulted in a superior response rate, 
complete response rate, progression free survival than lenalidomide and dexamethasone in patients with 
relapsed and refractory myeloma8. Importantly the addition of daratumumab to lenalidomide and 
dexamethasone was associated with a tolerable safety profile: The most common adverse events of 
grade 3 or 4 during treatment were neutropenia (in 51.9% of the patients in the daratumumab group vs. 
37.0% of those in the control group), thrombocytopenia (in 12.7% vs. 13.5%), and anemia (in 12.4% vs. 
19.6%)8. Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients and were 
mostly of grade 1 or 28. 
1.5.3 Bortezomib 
Bortezomib is a proteasome inhibitor. It is a reversible inhibitor of the chymotrypsin-like activity of the 26S 
proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades 
ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the 
intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of 
the 26S proteasome prevents this targeted proteolysis, which can affect multiple signaling cascades 
within the cell. This disruption of normal homeostatic mechanisms can lead to cell death. Experiments 
have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro. Bortezomib 
causes a delay in tumor growth in vivo in nonclinical tumor models, including multiple myeloma. In 
addition, bortezomib-based treatment regimens have demonstrated significant improvements in 
response, progression-free survival (PFS), and OS compared with non-bortezomib-based therapy for 
multiple myeloma, both in newly diagnosed transplant ineligible patients and those suitable for induction 
and transplant.Administration of bortezomib has been associated with peripheral neuropathy, 
hypotension, cardiac toxicity (worsening of and development of cardiac failure), pulmonary toxicity (acute 
respiratory syndromes), posterior reversible encephalopathy syndrome, gastrointestinal toxicity (nausea, 
diarrhea, constipation, and vomiting), thrombocytopenia, neutropenia, tumor lysis syndrome, hepatic 
toxicity, and embryo-fetal risk. Most commonly reported adverse reactions (incidence ≥20%) in clinical 
studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, 
neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia.  
1.5.3.1 Daratumumab in combination with bortezomib and dexamethasone 
The combination of daratumumab bortezomib and dexamethasone resulted in a higher overall response 
rate, complete response rate, and progress free survival than bortezomib and dexamethasone in patients 
with relapsed and refractory myeloma9. Importantly, the safety of this combination has been established 
in the same trial with the most common grade 3 or 4 adverse events reported in the daratumumab group 
and the control group as follows: thrombocytopenia (45.3% and 32.9%, respectively), anemia (14.4% and 
16.0%, respectively), and neutropenia (12.8% and 4.2%, respectively). Infusion-related reactions that 
were associated with daratumumab treatment were reported in 45.3% of the patients in the daratumumab 
group; these reactions were mostly grade 1 or 2 (grade 3 in 8.6% of the patients), and in 98.2% of these 
patients, they occurred during the first infusion.  
1.5.4 Dexamethasone  
Dexamethasone is a corticosteroid used to decrease the nausea and vomiting associated with 
chemotherapy as well as for the prevention and treatment of infusion related reactions. Dexamethasone 
is also an integral part of myeloma therapy and responses to single agent high dose dexamethasone can 
be noted in nearly half of newly diagnosed patients. In combination with lenalidomide for newly diagnosed 
myeloma patients, high dose dexamethasone (40 mg PO D1-4, 8-11, 15-19) however results in a higher 
mortality and morbidity than low dose dexamethasone (40 mg PO D1,8,15,22) which is now the standard 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 21  
of care. Common adverse reactions include hyperglycemia, increased appetite and weight gain, 
irritability, insomnia, impaired wound healing, and cataracts and osteoporosis with long-term use. 
For further information regarding lenalidomide, bortezomib, and dexamethasone, refer to the individual 
prescribing information. 
1.6 
RISK/BENEFIT ASSESSMENT  
 
1.6.1 KNOWN POTENTIAL RISKS  
 
Potential risks of daratumumab  
The main risk with IV daratumumab is the potential for infusion related reaction (IRR). The risk of IRR is 
approximately 40-50% and mostly is noted with the first infusion of daratumumab. Available evidence, 
although limited in sample size, suggests that SC daratumumab is associated with a lower incidence of 
IRR (approximately 22%)10. Other risks include myelosuppression although it is hard to distinguish this 
toxicity from the signs of symptomatic myeloma. Additional risks of SC daratumumab include injection site 
reaction. Additional potential risks are included in the package insert / IB for IV and SC daratumumab 
respectively 
 
 
 
Potential risks for the response adapted approach 
The main potential risk of the response adapted approach is a longer time to response given patients will 
be receiving daratumumab for 2 months prior to the addition of lenalidomide or bortezomib. It is not likely 
that this potential delay in depth of response would impact the patient negatively but patients who have a 
more rapid worsening of their myeloma would be taken off study by the treating physician and standard of 
care therapy would be instituted. It is possible that the duration of benefit from daratumumab 
monotherapy in responding patient may be shorter than what is expected in patients who receive 
chemotherapy (lenalidomide or bortezomib). It is unclear however if this would impact the patient’s long 
term outcomes given that salvage therapy in myeloma is effective especially for patients who are 
lenalidomide or bortezomib naïve. In such light the SWOG 0232 study had randomized newly diagnosed 
myeloma patients to lenalidomide dexamethasone versus dexamethasone11. Patients randomized to 
dexamethasone had a very short median progression free survival (median 12 months) but did not 
experience a worse overall survival likely given the ability to cross over and receive active salvage 
therapy11.  
 
1.6.2 KNOWN POTENTIAL BENEFITS  
 
Potential benefit of daratumumab 
Daratumumab based therapy may be associated with improved outcomes for newly diagnosed myeloma 
patients who participate in this study. Daratumumab has known direct anti-myeloma effects as well as 
immunomodulatory effects which result in expansion of cytotoxic T cells and suppression of 
immunosuppressive cells. In addition, the experience with daratumumab suggests this agent is well 
tolerated.  
 
Potential benefit for the response adapted approach 
Potential participants will be able to receive daratumumab as part of their therapy for newly diagnosed 
myeloma. Patient will receive SC daratumumab which may be associated with less IRR. Importantly, 
patients who respond to daratumumab may enjoy a chemotherapy-free treatment on this response 
adapted approach.   
 
1.6.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 22  
While SC administration of daratumumab is not FDA approved; IV daratumumab, lenalidomide, 
bortezomib and dexamethasone are all approved by the US FDA for the treatment of newly diagnosed 
multiple myeloma patients who are not candidate for high dose melphalan and autologous stem cell 
transplant. Existing data with SC daratumumab suggests a similar efficacy and possibly an enhanced 
safety and ease of administration over IV daratumumab. SC administration of daratumumab has been 
FDA approved in May 2020 in various combinations including with lenalidomide or bortezomib 
combinations). 
  
One aim of this study is to determine the safety and efficacy of daratumumab (a chemotherapy free 
therapy) for patients with newly diagnosed multiple myeloma. However to minimize the risk of under 
treatment and in light of the fact that salvage therapy is effective, we have used a response adapted 
treatment design. As such, patients who don’t achieve a partial response to daratumumab in the first 2 
cycles (months) of therapy, will receive the addition of lenalidomide or bortezomib which represent 
standard of care as they are approved second line regimens. The decision to add bortezomib or 
lenalidomide will be at the discretion of the treating physician based on which agent is anticipated to have 
a better tolerance, the patient choice but also informed by ex vivo testing (EMMA).  If such therapy is 
shown to be safe and effective, it could prove to be a chemotherapy free regimen for patients with newly 
diagnosed myeloma and hence spare toxicity from patients (especially for older adults who are 
particularly at risk for such complications).  
 
2 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
Primary 
 
 
To evaluate the efficacy of a 
daratumumab based 
response adapted approach 
 
To determine the best response (Overall 
response rate: rate of partial response and 
better) to therapy per the uniform response 
criteria of the IMWG as assessed by the 
study investigators 
The overall response 
rate (ORR) assessment 
is a commonly used 
endpoint in newly 
diagnosed myeloma 
trials. This is because it 
can be assessed more 
rapidly than PFS and 
OS 
 
Secondary 
 
 
To evaluate the safety profile 
of daratumumab based 
therapy in older adults with 
newly diagnosed myeloma 
To identify potential 
biomarkers for the prediction 
of response to therapy in MM 
To determine the 1 and 2 years progression 
free survival (PFS) of the study population 
To determine the overall response rate 
(ORR) (partial response or better) after 2 
cycles of daratumumab 
To determine the 2 year overall survival of 
this response adapted approach 
The proportion of patients who remains on 
daratumumab monotherapy 
To evaluate the safety of this therapy using 
the NCI CTC version 5.0 with a particular 
While ORR is the 
primary endpoint, PFS 
and OS will be 
evaluated as well. The 
study will also allow the 
evaluation of the 
response to 2 cycles of 
daratumumab 
monotherapy.  
.  
Safety evaluation is a 
necessary component 
of MM studies given the 
non curative nature of 
therapy.  
We will evaluate a 
possible biomarker of 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 23  
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
attention to the rate of IRR with SC 
daratumumab 
To determine agreement between actual 
responses and responses as predicted by 
an Ex Vivo Mathematical Myeloma Advisor 
(EMMA) 
response (namely an 
ex vivo drug sensitivity 
testing termed EMMA) 
Tertiary/Exploratory  
 
 
 
To study changes in immune 
profiling with daratumumab 
therapy 
 
To attempt to validate EMMA 
in silico prediction and 
dynamics of response  
 
To evaluate a frailty index as 
a tool for older adults with 
myeloma treated with novel 
agents 
Explore changes in immune profiling at 
baseline and after daratumumab 
dexamethasone  
 
Validate EMMA in silico predictions of 
daratumumab response.  
 
Incorporate clinical parameters and early 
dynamics of monoclonal paraprotein 
response to therapy to extend EMMA’s 
capacity to include longer term predictions 
of patient outcomes. 
 
Correlate a simplified geriatric assessment 
(frailty) and grade 3 and 4 (hematologic and 
non-hematologic) toxicity from therapy as 
well as discontinuation due to adverse 
events 
 
To determine the proportion of patients who 
are without minimal residual disease (MRD-
) using Next Generation sequencing (NGS) 
 
 
Given daratumumab’s 
mechanism of action, 
immune profiling is an 
attractive tool to 
investigate.  
 
Geriatric assessments 
have not been 
validated with 
daratumumab based 
monotherapy for newly 
diagnosed myeloma 
patients 
 
MRD assessment are 
an important tool for 
newly diagnosed 
myeloma studies to 
better assess the depth 
of response. This will 
be done for patients 
who achieve VGPR or 
better. However it is 
unknown how many 
patients may require 
MRD testing with this 
approach and this is an 
exploratory aim 
 
 
3 
STUDY DESIGN  
 
3.1 OVERALL DESIGN 
 
This is a single site, open label phase II response adapted clinical trial. In this response adapted 
approach, older adults with newly diagnosed symptomatic multiple myeloma will receive daratumumab 
and dexamethasone for 2 months. Patients who achieve a partial response or better will continue on 
daratumumab. Patients who achieve less than a partial response will have lenalidomide or bortezomib 
added to their therapy. Patients who experience progressive disease on daratumumab after the initial 2 
months of monotherapy or on the combination of daratumumab and either lenalidomide or bortezomib will 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 24  
come off study. Because of the design, 3 arms may be defined (Arm A: daratumumab dexamethasone, 
Arm B: daratumumab lenalidomide and dexamethasone, and Arm C: daratumumab bortezomib and 
dexamethasone).  
 
3.2 END OF STUDY DEFINITION 
 
In general, patients will continue on study until progressive disease or unacceptable toxicity. Specifically, 
patients will continue to receive therapy on study until one of the following has been met: 
1- Progressive disease 
2- Unacceptable toxicity which in the assessment of the investigator alters the risk / benefit 
assessment for the patients 
3- A change in the medical condition of the patient which alters the risk / benefit assessment for the 
patient 
4- Noncompliance and nonadherence of the patient with the study assessments that could result 
impact patient safety  
5- Patient preference  
 
Patients who discontinue study therapy will be followed for reasons other than progressive disease will be 
followed every 3 months or until another therapy is initiated to assess for progression. This can be done 
by telephone and review of records.   
 
 
4 
STUDY POPULATION 
 
4.1 INCLUSION CRITERIA 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study: 
1. Understand and voluntarily sign an informed consent form. 
2. Age  65 years and presence of coexisting conditions which in the opinion of the treating physician 
are likely to result in the development of unacceptable side effects associated with high-dose 
chemotherapy with stem-cell transplantation 
3. Able to adhere to the study visit schedule and other protocol requirements. 
4. Diagnosed with multiple myeloma and be considered to have active disease with either CRAB criteria 
(hypercalcemia, renal failure, anemia, or bone lesions) or myeloma defining events (bone marrow ≥ 
60% plasma cells, sFLC ratio≥ 100 or MRI or PET defined lesions) (Appendix C). Patients must not 
have received an active chemotherapy regimen. Patients may have received palliative radiotherapy at 
least 2 weeks prior to the study start. Dexamethasone up to 160 mg total dose is allowed prior to 
participation 
5. Measurable myeloma paraprotein levels in serum (≥ 0.5 g/dL), urine (≥ 0.2 g excreted in a 24-hour 
urine collection sample) or by serum free light chains (involved free light chain greater than 100mg/L) 
6. Eastern Cooperative Group (ECOG) Performance Status of 0 - 2. 
7. Serum bilirubin levels 1.5 times the upper limit of the normal range for the laboratory (ULN).  
8. Serum AST or serum ALT] levels 2 x ULN 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 25  
9. Must have adequate bone marrow function:   
a. Absolute neutrophil count > 1,000 cells/mm3 (1.0 x 109/L).  
b. Platelets  75,000 /mm3.  
10. Hemoglobin > 8 g/dL (transfusions are allowed) 
11. Calculated creatinine clearance ≥ 30ml/min by Cockcroft-Gault formula.   
12. Men must agree to use a latex condom during sexual contact with a female of child bearing potential 
even if they have had a successful vasectomy.  See Appendix C: Risks of Fetal Exposure, Pregnancy 
Testing Guidelines and Acceptable Birth Control Methods. 
4.2 EXCLUSION CRITERIA 
 
The presence of any of the following will exclude a subject from study enrollment:  
1. Ongoing severe infection requiring intravenous antibiotic treatment. 
2. Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in-situ 
cervical cancer, or other cancer from which the subject has been disease-free for at least 2 years. 
3. Solitary bone or solitary extramedullary plasmacytoma as the only evidence of plasma cell dyscrasia. 
4. Patients with known COPD with a forced expiratory volume in 1 second (FEV1) <50% of predicted 
normal and , moderate or severe persistent asthma within the past 2 years or uncontrolled asthma. 
Patients with a history of COPD will have pulmonary function testing to include FEV1  
5. Uncontrolled medical problems such as diabetes mellitus, congestive heart failure, coronary artery 
disease, hypertension, unstable angina, arrhythmias), pulmonary, hepatic and renal diseases unless 
renal insufficiency is felt to be secondary to multiple myeloma.  
6. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the 
subject from signing the informed consent form. 
7. Pregnant or lactating females. 
8. Any condition, including the presence of laboratory abnormalities, which places the subject at 
unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data 
from the study.   
9. Concurrent use of other anti-cancer agents or treatments with the exception for hormonal therapy 
which is allowed. 
10. Known allergy or hypersensititvity or intolerance to any of the study drugs, hyaluronidase, mAbs, 
human proteins, or their excipients (refer to daratumumab IB), or known sensitivity to mammalian-
derived products 
11. Seropositive for human immunodeficiency virus (HIV) 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 26  
12. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). 
Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to 
hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must 
be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus 
(HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with 
serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) 
AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR. 
13. 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). 
 
4.3 SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently assigned to the study intervention. A minimal set of screen failure information is required 
to ensure transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demographics, screen failure details, eligibility criteria, and any 
serious adverse event (SAE). 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a 
modifiable factor may be rescreened (for example laboratory assessment). Rescreened participants 
should be assigned the same participant number as for the initial screening. 
 
4.4 STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Patients will be identified by a myeloma physician in the outpatient clinic of the departments of Malignant 
Hematology or Blood and Marrow and Cellular Immunotherapy at H. Lee Moffitt Cancer Center and 
Research Institute. We anticipate the median age of patients enrolled to be approximately 75 years and 
about half the patients to be male based on a prior study for this patient population conducted at our 
center.  
 
5 
STUDY INTERVENTION 
 
5.1 DARATUMUMAB  
5.1.1 DARATUMUMAB 
Daratumumab is approved by the U.S. FDA for the treatment of newly diagnosed as well as relapsed 
myeloma. Importantly it is approved as monotherapy as well as in combination with lenalidomide, or 
bortezomib or pomalidomide. SC daratumumab (DARZALEX FASPRO) was FDA approved for use in 
various combination for multiple myeloma patients in May 2020. The study will transition to commercial 
DARZALEX FASPRO supplied by Janssen for this study.  
5.1.2 DARATUMUMAB DOSING AND ADMINISTRATION 
Patient will receive daratumumab (1800 mg in 15 ml) premixed with recombinant human hyaluronidase 
enzyme (rHuPH20 30,000 units) to be administered by manual subcutaneous injections over 3-5 minutes 
on the following schedule: weekly for the first 8 weeks, every other week for the next 16 weeks and every 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 27  
4 weeks after. Injections will be using a 23G or 25G (5/8 inch or 1 inch) needle in the subcutaneous tissue 
in the abdomen. Injections sites will be rotated between individual doses.  
No dose reduction for daratumumab will be planned.  Only if any of the following criteria are met and 
the event cannot be ascribed to lenalidomide, bortezomib, dexamethasone, or underlying multiple 
myeloma, the daratumumab injection 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 infection, of any grade 
 
Grade 3 or higher non-hematologic toxicities with the following exceptions: 
o 
Grade 3 nausea or Grade 3 vomiting that responds to antiemetic treatment 
o 
Grade 3 diarrhea that responds to antidiarrheal treatment 
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. Administration may resume at the 
next planned dosing date 
The following premedication will be administered prior to daratumumab: 
 
Acetaminophen 650-1,000 mg PO once 
 
Cetirizine 10 mg PO once, or equivalent dose of another antihistamine, either PO or IV 
 
Dexamethasone 20 mg PO once (unless dose reduced) 
 
Montelukast 10 mg PO once. Montelukast may be omitted for any daratumumab dose after the 
second injection if the subject has no respiratory symptoms. 
All patients treated with SC daratumumab should be observed for at least 6 hours after the end of the SC 
injection on C1D1 and if deemed necessary by the investigator / treating physician, after subsequent 
injections. Vital signs (Heart rate, blood pressure, respiratory rate,  temperature) should be monitored 
before, at the end of the SC injection, 30 and 60 min after the SC injection for the first injection only. For 
all other administrations, vital signs should be measured before the start of injection and at the end of the 
injection. If the subject experiences any significant medical event, then the investigator should assess 
whether the subject should stay overnight for observation. 
 
5.1.2.1 MANAGEMENT OF INFUSION‐RELATED REACTIONS 
Subjects should be carefully observed during daratumumab injections. Trained study staff at the clinic 
should be prepared to intervene in case of any infusion reactions occurring, and resources necessary for 
resuscitation (eg, agents such as epinephrine and aerosolized bronchodilator, also medical equipment 
such as oxygen tanks, tracheostomy equipment, and a defibrillator) must be available at bedside. 
Attention to staffing should be considered when multiple subjects will be dosed at the same time. 
If an IRR develops, then the infusion should be temporarily interrupted. Subjects who experience adverse 
events during the infusion must be treated according to the investigator’s judgment and best clinical 
practice. The following guidelines apply: 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 28  
 
Subjects should be treated with acetaminophen, antihistamine, or corticosteroids as needed. 
Intravenous saline may be indicated. For bronchospasm, urticaria, or dyspnea, subjects may 
require antihistamines, oxygen, corticosteroids, and/or bronchodilators. For hypotension, subjects 
may require vasopressors. 
 
In the event of a life-threatening IRR (which may include pulmonary or cardiac events) or 
anaphylactic reaction, daratumumab should be discontinued and no additional daratumumab 
should be administered to the subject. Aggressive symptomatic treatment should be applied. 
Cases of severe reaction should be discussed with the Principal Investigator / Sponsor 
 
For IRR adverse events (other than laryngeal edema or bronchospasm) that are Grade 3, the 
daratumumab administration must be stopped and the participant must be observed carefully until 
resolution of the adverse event or until the intensity of the event decreases to Grade 1, at which 
point the daratumumab administration may be restarted at the investigator’s discretion. If the 
intensity of the adverse event returns to Grade 3 after restart of the daratumumab administration, 
then the participant must be withdrawn / permanently discontinued from daratumumab treatment. 
 
5.1.3 DARATUMUMAB HANDLING / STORAGE AND ACCOUNTABILITY 
5.1.3.1 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
The final daratumumab SC product for oncology/hematology is daratumumab at a target concentration of 
120 mg/mL co-formulated with rHuPH20 in a 25R vial at a nominal fill of 15 mL. 
 
 
5.1.3.2 PRODUCT STORAGE AND STABILITY 
The daratumumab SC vials should be stored in the original carton in a refrigerator at 2ºC to 8ºC and must 
not be utilized after the expiry date printed on the label. The product must be protected from light and 
must not be frozen. Any unused portion remaining in a daratumumab IV or SC vial must be discarded 
since daratumumab IV or SC does not contain preservatives. 
 
 
5.2 DEXAMETHASONE 
5.2.1 DEXAMETHASONE 
Commercial dexamethasone will be used in this study 
5.2.2 DEXAMETHASONE DOSING AND ADMINISTRATION 
The dexamethasone starting dose will be 20 mg PO once a week. Commercial dexamethasone will be 
used. Dexamethasone is often supplied in 4 mg tablets. Accordingly, patients will take 5 (4 mg tablets) 
one day of the week prior to the administration of daratumumab if this corresponds to a daratumumab 
dosing days. In non daratumumab dosing days, dexamethasone will be taken by the patient at home, 
usually in the morning with breakfast.   
5.2.3 DEXAMETHASONE PREPARATION / HANDLING / STORAGE AND ACCOUNTABILITY 
Commercial dexamethasone will be used and will be handled and stored per package insert.  
5.2.4 DEXAMETHASONE DOSE REDUCTION 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 29  
The following dose reduction schedule for dexamethasone will be used 
DL1: Dexamethasone 20 mg PO D1,8,15,22 of a 28 days cycle 
DL-1: Dexamethasone 10 mg PO D1,8,15,22 of a 28 days cycle 
DL-2: Dexamethasone 4 mg PO D1,8,15,22 of a 28 days cycle 
DL-3: Discontinue dexamethasone  
The following table will be used for dexamethasone dose modification although the treating physician has 
the discretion to reduce dexamethasone dose for a lower grade AE if clinically indicated.  
CTCAE 
CATEGORY 
ADVERSE 
EVENT 
ADVERSE EVENT 
TREATMENT ADJUSTMENT 
Gastrointestinal 
Dyspepsia, gastric or duodenal 
ulcer, gastritis  
Grade 1-2 
 
It is recommended patient receive proton 
pump inhibitors (PPI), such as omeprazole as 
prevention. However if the patients is not on 
PPI, start PPI.  If symptoms persist despite 
above measures, decrease dexamethasone 
dose by 1 dose level 
 
> Grade 3 
 
 
Hold corticosteroids until symptoms are 
adequately controlled. Reduce by 2 dose 
levels along with concurrent therapy with PPI 
or other. If symptoms persist despite above 
measures, discontinue corticosteroids and do 
not resume. 
 
Acute pancreatitis 
Discontinue corticosteroids and do not 
resume 
Cardiovascular 
Edema 
> Grade 2 
Diuretics as needed, and decrease 
corticosteroids dose by 1 dose level; if edema 
persists despite above measures decrease 
dose by 2 dose levels from the initial dose; 
discontinue corticosteroids and do not 
resume if symptoms persist despite reduction. 
Neurology 
Confusion or Mood alteration 
> Grade 2 (interfering with 
function 
+/- interfering with activities of 
daily living) 
Hold corticosteroids until symptoms resolve to 
< grade1. Reduce dose by 2 dose levels from 
current dose. 
If symptoms persist despite above measures, 
discontinue corticosteroids and do not 
resume. 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 30  
Musculoskeletal 
Muscle weakness 
> Grade 2 (symptomatic and 
interfering with function +/- 
interfering with activities of daily 
living) 
Decrease corticosteroids dose by 1 dose 
level; If weakness persists despite above 
measures decrease dose by 2 dose levels 
from the initial dose. Discontinue 
corticosteroids and do not resume if 
symptoms persist despite reduction. 
Metabolic 
Hyperglycemia 
> Grade 3 or higher 
Treatment with insulin or oral hypoglycemics 
as needed. If uncontrolled despite above 
measures, decrease dose by 1 dose level 
decrements until levels are satisfactory 
  
 
5.3 LENALIDOMIDE 
5.3.1 LENALIDOMIDE 
Commercial supply of lenalidomide will be used.  
5.3.2 LENALIDOMIDE DOSING AND ADMINISTRATION 
Lenalidomide will be given orally on days 1-21 of a 28 days cycle. The starting dose of lenalidomide will 
be based on the patient creatinine clearance and age.  
The starting dose of lenalidomide will be 10 mg if the creatinine clearance is < 50 ml/min or the patient is 
over 80 years of age, 15 mg if the patient is 75 years of age or older and the creatinine clearance is >50 
ml/min; and 25 mg if the patient is <75 years and with a creatinine clearance of 50 ml/min. Patients with a 
creatinine clearance < 30 ml/min are not eligible but patients who experience a deterioration in the renal 
function during screening or treatment may continue on lenalidomide therapy as long as the risk / benefit 
profile is deemed acceptable, that study therapy is in the best interest of the patient and after discussion 
with the study principal investigator / sponsor.   
Given lenalidomide supply is commercial, it is possible that at times, the lenalidomide monthly supply is 
not available on the first day of a cyle. If lenalidomide is not anticipated to be available for at least 7 days 
after D1 of the cycle, the dosing of all study drugs (dexamethasone / daratumumab) will be delayed until 
lenalidomide is available again in an attempt to stay on schedule with all study drugs. On the other hand, 
if lenalidomide delays are anticipated to be less than 7 days, it is ok to proceed with daratumumab and 
dexamethasone and lenalidomide would be started when it is obtained but missed doses will not be 
replaced and patients will stop lenalidomide on D21 of the cycle.  
If a patient skips or forgets a lenalidomide dose, the dose will not be made up.  
5.3.3 LENALIDOMIDE PREPARATION / HANDLING / STORAGE AND ACCOUNTABILITY 
Commercial Lenalidomide will be used for this study. It will be stored, handled per the package insert 
requirement. In addition, a dosing diary will be provided to patients for drug accountability. 
5.3.4 LENALIDOMIDE DOSE REDUCTION 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 31  
The following dose levels of Lenalidomide will be used: 
Dose level 1: 25 mg PO D1-21 of a 28 days cycle 
Dose level -1: 15 mg PO D1-21 of a 28 days cycle 
Dose level -2: 10 mg PO D1-21 of a 28 days cycle 
Dose level -3: 5 mg PO D1-21 of a 28 days cycle 
Dose level -4: 2.5 mg PO D1-21 of a 28 days cycle 
Dose level -5: discontinue lenalidomide 
The table below will review guidelines for lenalidomide dose reduction although the treating physician has 
the discretion to reduce the lenalidomide dose for a lower grade AE if clinically indicated. 
CTCAE CATEGORY 
ADVERSE EVENT 
CTCAE 
GRADE 
TREATMENT ADJUSTMENT  
Maintenance Phase 
Neutropenia 
Grade 3 with 
fever   
or 
Grade 4 
Hold lenalidomide for remainder of cycle if the toxicity occurs 
in the latter 2 weeks of the cycle and resume the next cycle at 
the dose detailed below. Alternatively if the toxicity occurred 
during the first 2 weeks of the cycle, then hold lenalidomide 
until the toxicity improves to ≤ grade 2 and resume 
lenalidomide as detailed below.  
First occurrence: when resolved to ≤ grade 2 begin next cycle 
with one dose level reduction of lenalidomide  
Second occurrence: when resolved to ≤ grade 2 begin next 
cycle with one level dose reduction of lenalidomide  
Subsequent dose reductions of lenalidomide are permitted at 
the investigators discretion. 
Thrombocytopenia  
Grade 4 
Hold lenalidomide for remainder of cycle if the toxicity occurs 
in the latter 2 weeks of the cycle and resume the next cycle 
with one dose level reduction in lenalidomide. Alternatively if 
the toxicity occurred during the first 2 weeks of the cycle, then 
hold lenalidomide until the toxicity improves to ≤ grade 2 and 
resume lenalidomide with one dose level reduction.  
Cardiac toxicity  
Arrhythmia 
> grade 2 
Hold lenalidomide until resolved to < grade 1.  Resume at one 
dose level reduction of lenalidomide. 
Arrhythmia 
> grade 3 
Discontinue lenalidomide at the investigators discretion. 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 32  
Congestive 
heart failure 
> grade 2 
Discontinue lenalidomide at the investigators discretion. 
Hyperthyroidism/ 
Hypothyroidism  
Any grade 
Hold lenalidomide and evaluate patient for other causes.  May 
resume therapy at the same dose once patient is stable at 
investigators discretion.   
Non desquamating 
rash  
Grade 2 
Hold lenalidomide for remainder of cycle if the toxicity occurs 
in the latter 2 weeks of the cycle and resume the next cycle 
with one dose level reduction in lenalidomide if the toxicity 
resolves to less than grade 2. Alternatively if the toxicity 
occurred during the first 2 weeks of the cycle, then hold 
lenalidomide until the toxicity improves to < grade 2 and 
resume lenalidomide with one dose level reduction. 
Grade 3 or 4 
Discontinue protocol therapy. 
Desquamating rash 
or Erythema 
Multiforme 
Any grade 
Discontinue protocol therapy. 
Allergic reaction or 
hypersensitivity  
Grade 2 or 3 
Hold lenalidomide for remainder of cycle if the toxicity occurs 
in the latter 2 weeks of the cycle and resume the next cycle 
with one dose level reduction in lenalidomide if the toxicity 
improves to less than grade 2. Alternatively if the toxicity 
occurred during the first 2 weeks of the cycle, then hold 
lenalidomide until the toxicity improves to less than grade 2 
and resume lenalidomide with one dose level reduction.   
Grade 4 
Discontinue lenalidomide  
Venous 
thrombosis/embolism  
 
≥ Grade 3 
Hold (interrupt) dose, therapeutic anticoagulation as 
appropriate; restart at investigator’s discretion (maintain dose 
level) 
Other non-
hematologic toxicity 
except those events 
specifically attributed 
to dexamethasone 
as outlined in table 
4.  
Grade 3 / 4  
Hold lenalidomide for remainder of cycle if the toxicity occurs 
in the latter 2 weeks of the cycle and resume the next cycle 
with one dose level reduction in lenalidomide. Alternatively if 
the toxicity occurred during the first 2 weeks of the cycle, then 
hold lenalidomide until the toxicity improves to ≤ grade 2 and 
resume lenalidomide with one dose level reduction.  
 
5.4 BORTEZOMIB 
5.4.1 BORTEZOMIB 
Commercial supply of bortezomib will be used in this study 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 33  
5.4.2 BORTEZOMIB DOSING AND ADMINISTRATION 
Bortezomib will be given weekly subcutaneously in an effort to decrease the toxicity of the therapy. 
Specifically patients will receive a starting dose of bortezomib of 1.3 mg/m2 SC D1,8,15 of  a 28 day 
cycle. Bortezomib will be administered per standard of care procedures. After 8 cycles of bortezomib 
based therapy (cycle 10 of the trial), patients may receive a less frequent maintenance dose of 
bortezomib (dose reduction to bortezomib on days 1 and 15 every 28 days or discontinue bortezomib but 
continue on daratumumab) at the discretion of the treating physician. 
5.4.3 BORTEZOMIB PREPARATION / HANDLING / STORAGE AND ACCOUNTABILITY 
Bortezomib will prepare, handled and stored per standard of care procedures outlined in the package 
insert.   
5.4.4 BORTEZOMIB DOSE REDUCTION 
The following dose levels of bortezomib will be considered in this study: 
Dose level 1: bortezomib 1.3 mg/m2 SC D1,8,15 of a 28 days cycle 
Dose level -1: 1mg/m2 SC D1,8,15 of a 28 days cycle 
Dose level -2: 0.7 mg/m2 SC D1,18,15 of a 28 days cycle 
Dose level -3: discontinue bortezomib 
Guidelines for bortezomib dose reduction are shown below: 
Dose adjustments should be based on the highest grade of toxicity that is ascribed to bortezomib. 
Bortezomib therapy should be withheld at the onset of any Grade 3 or Grade 4 
non-hematological or Grade 4 hematological toxicities excluding neuropathy. In addition, the treating 
physician has the discretion to reduce bortezomib dose for a lower grade AE if clinically indicated. 
Once the symptoms of the toxicity have resolved, bortezomib therapy may be reinitiated at a reduced 
dose level.  
 
The following table outlines bortezomib dose reductions for neuropathy: 
 
CTCAE 
CATEGORY 
ADVERSE EVENT 
CTCAE 
GRADE 
TREATMENT 
ADJUSTMENT  
 
Neuropathy 
Grade 1 (asymptomatic, loss of deep tendon 
reflexes or paresthesias) without pain or loss 
of function 
No action 
 
Grade 1 with pain or  
Reduce bortezomib by 1 dose 
level  

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 34  
Grade 2 (moderate symptoms, limiting 
instrumental ADL) 
 
Grade 2 with pain or 
Grade 3 or 4 (severe symptoms, limiting self-
care ADL) 
Discontinue bortezomib  
Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, 
managing money etc. 
 
Self-care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
 
5.5 STUDY INTERVENTION COMPLIANCE 
 
Daratumumab will be administered in the cancer center and compliance will be easily monitored with 
review of the electronic health record. It is anticipated that SC daratumumab would be associated with 
better compliance than IV daratumumab given quicker infusion times and possibly a lower rate of IRR.  
Bortezomib will be administered in the cancer center and compliance will be monitored with review of the 
electronic health record.  
Dexamethasone and lenalidomide are orally given on non treatment days and a diary will be provided for 
patients.  
 
5.6 CONCOMITANT THERAPY 
 
Concomitant medication is defined as any prescription or over-the-counter preparation, including vitamins 
and supplements. Patients will receive concomitant medications to treat symptoms, adverse events and 
intercurrent illnesses that are medically necessary as standard care. Medications to treat concomitant 
diseases like diabetes, hypertension, etc. are allowed. 
1. Use of blood products and growth factors 
Patients may receive red blood cell (RBC) or platelet transfusions, if clinically indicated, per institutional 
guidelines. Appropriate anti-coagulation is allowed during the study (eg: LMW heparin, direct factor Xa 
inhibitors, etc). Patients may receive supportive care with erythropoietin, darbepoetin, G-CSF or GM-CSF 
in accordance with clinical practice or institutional guidelines prior to entry and throughout the study. 
2. Glucocorticoid therapy 
Patients must receive corticosteroid therapy as part of the treatment regimen. Additional corticosteroid 
are allowed for the treatment of non-malignant conditions (inflammatory disorders or adrenal 
insufficiency) provided the dose does not exceed the equivalent of 20 mg of prednisone daily 
3. Radiation Treatment 
The need for radiation therapy is generally considered to be a treatment failure. However, an exception 
(that is patients allowed to remain in the treatment phase of the study) is made for radiation therapy to a 
pathological fracture site to enhance bone healing or to treat post-fracture pain that is refractory to 
narcotic analgesics because pathologic bone fractures do not by themselves fulfill a criterion for disease 
progression  
4. Proton pump inhibitors 
The use of proton pump inhibitors (for example omeprazole) will be recommended for the prevention of 
dexamethasone toxicity as is clinical practice 
5. Bisphosphonate 
The use of bisphosphonates or denosumab for the prevention of skeletal related events due to myeloma 
is allowed per routine clinical care.  

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 35  
6. IVIG 
The use of intravenous immunoglobulins for the prevention of recurrent infections in patients with 
hypogammaglobulinemia is allowed per routine clinical practice  
7. Antiviral prophylaxis 
Prophylaxis for varicella zoster reactivation will be required for all patients. Examples of appropriate 
prophylaxis is acyclovir.  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. 
8. Venous thromboembolic event prophylaxis 
Prophylaxis for venous thromboembolic events will be required for all patients receiving lenalidomide. The 
prophylactic strategy will be at the discretion of the treating physician. In general, aspirin 81 mg PO daily 
is recommended for patients at low risk for thromboembolic event whereas low molecular weight heparin 
or other anticoagulants are recommended for patients at high risk for venous thromboembolic events.  
Prohibited Medications 
Concurrent therapy with an approved or investigative anticancer therapeutic, other than glucocorticoids 
and therapy defined per the protocol is not allowed.  
Use of any immunosuppressive agents during the study is not allowed   
Other investigational agents should not be used during the study. 
 
6 
CORRELATIVE STUDIES 
6.1 EMMA 
Within the context of this trial, we aim to pursue a personalized treatment schema that best allocates the 
use of either Bortezomib or Lenalidomide in patients who do not achieve at least a partial response to 
subcutaneous datatumumab and dex after 8 weekly doses.  Carry this out, we have developed a 
platform, EMMA (ex vivo mathematical malignancy advisor), consisting of patient-specific mathematical 
models parameterized by an ex vivo assay that reverse engineers the intensity and heterogeneity of 
sensitivity of primary cells from patients to up to 31 drugs simultaneously. This unique in silico platform 
predicts months of therapeutic response in patients within a clinically actionable time frame (5 days) using 
fresh tissue, ex vivo response/resistance data, mathematical models and drug-specific pharmacokinetics, 
with a high predictive accuracy, to multiple classes of drugs(Figure)12, 13. EMMA’s accuracy, 
reproducibility, short turnaround time and high-throughput potential demonstrate promise as (i) a patient 
specific decision-support system for therapeutic management, (ii)  in silico clinical trials, wherein a single 
cohort of patients is simultaneously tested against multiple drugs and regimens and (iii) when paired with 
high fidelity molecular sequencing, a predictive biomarker discovery tool. Collectively, EMMA has great 
potential to augment clinical decision 
making for oncologists and our 
patients. Within this clinical trial, we 
focus on advancing this novel 
predictive in silico modeling 
approach to accelerate utilization of 
clinical decision support tools for the 
delivery of personalized therapies. 
Further, EMMA’s capabilities also 
extend to agents in early clinical and 
preclinical development highlighting 
the potential for improved clinical 
trial matching and accelerated drug 
discovery 
We respectfully submit that our ex vivo system is highly innovative platform for personalized therapy. 
First, EMMA is a phenomenological mathematical model based on ex vivo drug response, measured 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 36  
directly in patient-derived MM cells, to predict longer-term response to therapy. This unique methodology 
for personalized oncology does not make the assumption that targeting a specific pathway (or gene) 
using genetic profiling of the bulk tumor will result in durable responses. Instead, we use empirical data 
(1,920 data points per drug) from a patient’s cancer cells to obtain information on drug 
sensitivity/resistance. This is essential in view of findings that as of today genomic mutations are a poor 
indicator of drug efficacy, even in targeted therapy. As such, phenomenological models based on 
methods to monitor individual cells have the potential to be more reliable because they are based on 
actual measurements from the data, as opposed to network-diagram based models, which are based on 
intuition or literature, and are then “molded” into the data. Second, unlike similar efforts that cultivate 
patient cells and test drugs using cell death as readout, we use validated mathematical models to predict 
how drugs will perform clinically based on ex vivo cell death kinetics, accounting for in vivo 
pharmacokinetics (PK), tumor heterogeneity and TME. Thus, EMMA accounts for critical components of 
tumor drug sensitivity/resistance not previously accounted in ex vivo modeling. Third, EMMA’s 
characteristics represent significant advantages over historical colony formation assays (CFA) and 
contemporary patient derived xenograft (PDX) drug sensitivity models in terms of clinical translation. 
Forth, EMMA is high throughput.  It can be used for personalized testing of up to 127 drugs or drug 
combinations simultaneously (including immunobiologics) on as few as 1 million patient cells. To this end, 
each patient is “enrolled” on up to 127 in silico clinical trials simultaneously. Recall, this means that each 
patient samples tested on this trial will also be test 127 drugs/regimens simultaneously.  Fifth, EMMA is 
scalable. We recognize that additional aspects of MM tumor biology, patient biology and the TME 
(immune and supportive) contribute to drug response and the evolution of drug resistance. Critically, we 
will test the incorporation additional representative data elements in predictive accuracy within the 
exploratory aims of this trial. Sixth, EMMA samples are uniquely paired with both whole exome 
sequencing (WES) and RNA sequencing (RNAseq). Thus, we have an ex vivo high throughput platform 
for investigation of molecular profiles and mechanisms of response to single agents and combinations to 
improve predictive modeling of EMMA, discover tumor vulnerabilities and identify critical molecular 
signatures of response for molecular-based trial matching. Finally, we anticipate that EMMA affords a 
radical change in the allocation of therapeutic regimens to patients, moving beyond current “one-size-fits-
all” management system, where a regimen is assigned to a group of patients according to shared 
observable characteristics, irrespective of inter-patient and intra-tumoral heterogeneity. EMMA is a 
platform to assist clinicians in assigning the right patient the right drugs at the right time.  
Preliminary Data and Current State of Technology: With EMMA we propose a radical change in the 
way therapeutic regimens are assigned to patients, moving away from a “boxing” classification system 
wherein the same regimen is assigned to a group of patients according to inclusion criteria based on 
shared observable characteristics (genetic, epigenetic, clinical history) irrespective of unobservable traits 
(inter-patient and intra-tumoral heterogeneity). To provide a more personalized approach for the 
allocation of therapy, we have developed a system consisting of patient-specific mathematical models 
parameterized by an ex vivo assay that reverse engineers the intensity and heterogeneity of drug 
sensitivity of primary cells from MM patients to up to 31 drugs simultaneously. This unique in silico 
platform was specifically designed to translate 4 days of ex vivo response/resistance data, mathematical 
models, and drug-specific PK data, into months of clinical response . Our recent data demonstrates that 
EMMA has high predictive accuracy with patients treated with multiple classes of drugs, in addition to 
high reproducibility, short turnaround time and high-throughput potential.  
EMMA represents a platform for truly personalized therapy by proactively estimating clinical benefit and 
providing a means to minimize use of ineffective agents with potential avoidable toxicity and financial 
burden. This transformative potential stems from the nature of EMMA’s end product: trajectories of 
predicted clinical response validated in real time by surrogates of clinical response (paraprotein in MM, 
lymphadenopathy, malignant cells in peripheral blood in MCL and other HEME). As such, EMMA stands 
out from current prognostic biomarkers and companion biomarkers. Current prognostic tools only indicate 
risk of shorter survival, but do not suggest a preferred therapy. Similarly, companion biomarkers are 
tailored to a particular drug or regimen and are more often a tool to discard the use of therapies rather 
than to actually dictate treatment. Lastly, EMMA can predict clinical outcomes for off-label drugs and used 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 37  
to estimate clinical response to drug combinations or schedules for which they have not been trained.  To 
this end, we anticipate that EMMA represents a “novel predictive ex vivo and/or in silico modeling 
approach to accelerate preclinical research and development of personalized therapies.”  
Accuracy and reproducibility of EMMA’s clinical predictions: From a cohort of 52 MM patients, 
EMMA correctly classified 96% as responders/non-responders and correctly classified 79% according to 
IMWG stratification of level of response. The strictest validation of this model is the direct correlation of 
the tumor burden predictions with all available tumor burden measurements. The regression line between 
in silico model predictions and clinical response, shown flanked by the 95% confidence interval, had a 
slope of 0.83 and Pearson correlation coefficient r=0.5658 (P<0.0001). Furthermore, we have 
demonstrated excellent concordance in inter-day, inter-laboratory and intra-plate reproducibility. It is also 
important to note that most of the dispersion observed stems from non-responders, whose clinical 
outcome is not driven by chemosensitivity but rather by tumor growth rate.  
Wide range of agents: EMMA is able to assess up to 31 drugs simultaneously. We have published 
successful and accurate results of EMMA on all therapeutics evaluated, including proteasome inhibitors, 
immunomodulatory drugs (IMIDs), steroids, DNA damaging agents, acetylase inhibitors, nuclear export 
inhibitors, protein kinase inhibitors (PKI) among others.  We have also demonstrated activity of 
monoclonal antibodies (critically, daratumumab) recapitulating both drug-induced and immune-mediated 
cell death. This is, in part, due to the organotypic nature of EMMA, where each well is a re-construction of 
the bone marrow microenvironment, including patient-derived soluble factors and bone marrow stroma.  
While the simultaneous testing of 31 drugs in a patient encompasses a relatively wide range of agents, 
we are currently expanding this capability to 127 drugs in 1,536 well plates to capture a larger number of 
relevant compounds and combinations.   
Exploratory Objectives.  
Validate EMMA’s ability to predicted response to daratumuamb and characterize patient specific 
immune TME. Consistent with known mechanism of action, antibody dependent cellular phagocytosis 
(ADCP), our preliminary studies with daratumumab (Dara) has shown MM-specific cell death due to 
ADCP after at least 3-4 days of exposure to daratumumab. EMMA’s preliminary clinical predictions of 11 
MM patients to single agent daratumumab agree with patient status (no response in 3 Dara-refractory 
patients and estimated response in 4 of 8 Dara-naïve patients). Although very promising, we need to 
confirm that this sensitivity readout translates to accurate predictions of clinical response. Technical 
Validation: The same accuracy metrics will be applied as previously published14 will be applied to the 
patients enrolled in this clinical trial. Should this direct method of prediction fail (<96% accuracy 
responders/no-responders14), we will determine if the order of sensitivity determined by ex vivo LD50 or 
AUC correlates with actual clinical sensitivity, suggesting a means to estimate clinical efficacy of mAbs by 
comparison to previously tested patients). Additional/alternative plans. Additional relevant questions also 
being addressed: (a) cell of origin of the phagocytes, (b) dependency of ex vivo responses on density of 
these MM phagocytic cells, (c) physiological cell density and malignant-to-phagocyte ratio, and (d) 
EMMA’s current PK model adequacy for this drug-to immune cell-MM cell interaction accounting for 
indirect activities of these immunologic agents.  
Incorporate clinical parameters and early dynamics of monoclonal paraprotein response to 
therapy to extend EMMA’s capacity to include longer term predictions of patient outcome. While 
response predictions have the potential for immediate impact on patient care, response rates represent 
an indirect measure of clinical success in MM, thus here we incorporate additional parameters to extend 
EMMA’s predictive capabilities to time to progression (TTP).  
6.2 IMMUNE PROFILING 
The immune Tumor MicroEnvironment (TME) is defined by both cellular and soluble extracellular elements, 
necessitating a multi-modality approach to achieve a comprehensive characterization of these components. 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 38  
Gene expression profiling (GEP) affords a powerful global assessment and the nCounter™ 
PanCancer  Immune Profiling Panel (NanoString Technologies) provides a robust platform for simultaneous 
assessment of 770 immune-related genes. Purified mRNA isolated from marrow aspirate samples will be 
processed for GEP in the Moffitt Molecular Genomics Core Facility according to protocol specifications. 
Raw data will be analyzed using the nSolver™ proprietary software (NanoString) and with the assistance 
from the Moffitt Cancer Informatics Core. Multiparameter flow cytometry, utilizing 4 comprehensive, high-
parameter panels detailed in Table 2, offers high resolution detail at the single-cell level.  
 The myeloid panel incorporates a broad assortment of cell surface markers to allow for in-depth 
characterization of the myeloid populations including dendritic cells, macrophage, neutrophils, and myeloid-
derived suppressor cells. Three lymphoid panels are designed to resolve T cell and NK cell populations, 
with extensive classification of T cells in 
particular, measuring maturation state 
(naïve, central memory, effector memory, 
effector and memory stem cells), subset 
composition (eg. TH1, TH2, TH17, TREG, and 
CD8+ 
counterpart 
populations, 
and 
activation/exhaustion status (eg. PD-1, 
CTLA-4, TIM-3, Lag3, BTLA, CD27, 2B4 
expression). Once prepared for analysis, 
data acquisition will be performed on a 
FACSymphony cytometer housed and 
maintained in the Moffitt Flow Cytometry 
Core Facility. Data analysis will be 
performed on FlowJo software using both 
classic phenotype-defined and computer-based non-supervised principal component approaches which will 
be merged to provide additional analytic insight. Soluble factor concentrations in the extracellular marrow 
environment will be analyzed by bead-capture-based assay using the Lunaris™ system (Ayoxxa 
Biosystems) offering an efficient multiplex strategy for cytokine and chemokine quantification (Table 3). 
APRIL (A PRoliferation-Inducing Ligand) and BAFF (B cell Activation Factor) concentrations will continue 
to be assessed via ELISA assay 
(Invitrogen), analyzed on a Cytation3 
Imaging Reader (BioTek). Collectively, 
these 
measures 
of 
immune 
populations 
and 
the 
cytokine 
communication networks will provide 
informative insights into the dynamic 
immunologic interactions in the TME. 
Comprehensive 
gene 
expression 
profiling will provide population-level perspective while unifying the more granular details provided by the 
high-resolution analysis of cellular and soluble factor elements.  
6.3 GERIATRIC ASSESSMENT 
It is well recognized that elderly patients are a heterogeneous population with varying physiological 
reserves and comorbidities that affect treatment outcomes. Geriatric assessment is an effective way to 
identify frailty in elderly cancer patients, and help predict for risk of toxicity from treatment in this 
population. Geriatric assessment involves systematic evaluation of various domains of functioning in the 
elderly, including ADLs/IADLs, medical comorbidities, cognition, nutrition and psychological state.  There 
have been numerous validated models developed to evaluate frailty in older adults, particularly the 
International Myeloma Working group (IMWG) frailty score, which was shown to predict mortality and 
toxicity in elderly myeloma patients1. To our knowledge, the prognostic and predictive value of geriatric 
assessment has not been evaluated with elderly patients who are treated with daratumumab.  

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 39  
The original Balducci frailty score was among the first systems developed to identify frailty in oncology 
patients15. This score classified patients as being fit, vulnerable, or frail, based on a geriatric assessment 
that included age, ability to perform ADLs, comorbidity, and the presence of geriatric syndromes. A 
modified version of this score has been proposed which takes into account a patient’s independence in 
ADLs, IADLs, comorbidities, and presence of geriatric syndromes. Notably, this does not include age as a 
criterion, but rather focuses on functional age rather than chronological age.  
The International Myeloma Working group (IMWG) frailty score has been shown to predict mortality and 
toxicity in elderly myeloma patients1. Similar to the Balducci score, the IMWG frailty score is calculated 
using age, the Charlson comorbidity index, and ability to perform ADLs/IADLs. In patients classified as 
“fit,” 3 yr overall survival was 84%, compared to 57% in patients classified as “frail”.  
The IMWG frailty score as well as a modified Balducci frailty score will be administered during screening 
and during cycle 2 day 22.  These assessments will be used to stratify patients into fit, intermediate-
fitness, and frail categories.  
Geriatric assessment will be correlated with the following: Grade 3 or greater non hematologic adverse 
events, grade 3 or greater hematologic adverse events, discontinuation of the trial, dose reduction of 
lenalidomide or bortezomib and finally progression free survival.  
Biomarkers may also predict for frailty and adverse outcomes in older patients. For example, the C-
reactive protein (CRP) rise with increasing age and are associated with decreased walking speed and 
grip strength. Other molecular markers that have been found to be associated with clinical signs of frailty 
include D-dimer levels. These biomarkers will be obtained at screening and C2D22.     
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 DISCONTINUATION OF STUDY INTERVENTION 
 
Patients can continue on treatment as part of this trial as long as they are benefiting from therapy or 
unacceptable toxicities. Patients with progressive disease on daratumumab during the first 2 months of 
therapy, will be allowed to receive the addition of lenalidomide or bortezomib. Progression beyond the 
first two months of therapy will result in the patients discontinuing treatment on the trial.  
 
Patients who discontinue therapy on the trial for reasons other than progressive disease will continue to 
be monitored for progression until progressive disease or the start of another myeloma therapy. This can 
be performed via phone interview and review of records at least every 3 months.  
 
The data to be collected at the time of treatment discontinuation will include the following: 
 
IMWG response assessment 
 
Assessment of adverse events  
 
7.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
 
Pregnancy 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 40  
 
Significant study intervention non-compliance which in the opinion of the investigator places the 
patient at increased risk   
 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
 
Disease progression which requires discontinuation of the study intervention (except during the 
first 2 months of therapy where the addition of lenalidomide or bortezomib would be allowed on 
the trial) 
 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
 
Participant unable to receive trial therapy for greater than 8 weeks. 
 
The reason for participant discontinuation or withdrawal from the study will be recorded within the 
patient’s medical record and OnCore and/or the Clinical Trial Management System (CTMS). Subjects who 
sign the informed consent form but do not receive the study intervention may be replaced. Subjects who 
sign the informed consent form, receive the study intervention, and subsequently withdraw, or are 
withdrawn or discontinued from the study; may not be replaced and are considered treatment failure per 
intent to treat. 
 
7.3 LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for 2 consecutive scheduled 
visits and is unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
 
The site will attempt to contact the participant and reschedule the missed visit within 2 weeks and 
counsel the participant on the importance of maintaining the assigned visit schedule and 
ascertain if the participant wishes to and/or should continue in the study. 
 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, a 
certified letter to the participant’s last known mailing address or local equivalent methods). These 
contact attempts should be documented in the participant’s medical record or study file.  
 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 EFFICACY ASSESSMENTS  
 
The primary endpoint of this trial is overall response rate as assessed by the uniform response criteria of 
the international myeloma working group (appendix A) 
 
 
At screening, and day 1 of every cycle (except cycle 3) and cycle 2 day 22 and at the end of 
treatment,  patients will have a serum protein electrophoresis with immunofixation, a 24h urine 
protein electrophoresis with immunofixation, as well as serum free light chain testing. These will 
be used for response assessments on these time points. If a 24 h urine protein electrophoresis is 
obtained within 7 days prior to cycle 1 day 1, it will not need to be repeated on cycle 1 day 1 and 
the screening value will be used for baseline.  
 
Compliance with 24h urine protein electrophoresis is a concern for many multiple myeloma trials 
due to the fact that obtaining 24h urine collection is a burden on patients. In addition, considering 
many patients enrolled on this study will be / are elderly and some may have incontinence or 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 41  
other mobility issues that may make such a collection a difficulty; we anticipate some patients will 
not be able to obtain monthly 24h urine testing for protein electrophoresis. Patients will be 
reminded to collect a 24h urine for protein elctrophoresis prior to the appointment date by the trial 
coordinator. If despite these reminders, the patients was not able or did not provide a 24h urine 
collection for testing, the missing labortatory test will not be considered a deviation from the 
protocol.   
 
A serum b2microglobulin and LDH will be obtained at screening for risk stratification.  
 
A bone marrow biopsy and aspirate will be performed on screening, cycle 2 day 22, and end of 
treatment. EMMA testing will be performed using the bone marrow aspirates from these time 
points. The screening bone marrow assessment will include metaphase cytogenetics as well as 
standard myeloma FISH testing. In addition, patients who achieve a VGPR (if the remainder m 
spike is consistent with daratumumab interference) or CR at any point or better will undergo a 
bone marrow biopsy for histology (confirmation of CR) and MRD testing using NGS and by flow 
cytometry.  
 
A skeletal survey or FDG PET/CT will be performed on screening and at the end of treatment in 
the event of progressive disease. If PET CT or bone survery has been performed within 28 days 
of cycle 1 day 1 but prior to screening (per standard of care), it would not need to be repeated 
during screening 
 
Geriatric assessments will be performed on screening and cycle 2 day 22. This will be captured 
on the MM frailty eCRF  
 
Immune profiling will be performed on screening and cycle 2 day 22.  
 
8.2 SAFETY AND OTHER ASSESSMENTS 
The following assessments will be performed to evaluate the safety of this strategy 
 
 
Physical examination, weight and ECOG performance status: These are assessments are 
performed on screening, day 1 of every cycle and end of treatment. Height will only be measured 
on screening. Note that only baseline/screening height, weight, and performance status will be 
captured in the eCRF.  
 
Review of the medical history: This trial will focus on collecting notable comorbidities and 
geriatric syndromes (e.g. falls, incontinence, cognitive impairment) especially considering the 
geriatric / frailty assessment is dependent on this assessment  
 
Vital signs (e.g., temperature, pulse, respirations, blood pressure). Vitals are to be obtained on 
screening, day 1 of every cycle and end of treatment. Vitals signs will not be captured in the 
eCRF unless an adverse event is noted which would be captured in the AE log 
 
Laboratory evaluations. A complete blood count with differential, a complete metabolic profile 
and LDH will be obtained on screening, weekly during the first 2 cycles and every 2 weeks during 
cycles 3-6 and monthly after cycle 7. At screening,  a type and screen will also be performed per 
standard of care for patients receiving daratumumab. Only the screening hematology and 
chemistry will be captured in the eCRF unless there is an adverse event which will be captured in 
the AE log   
 
Assessment of adverse events. Adverse event review and evaluation will be an ongoing 
process during the treatment phase of the trial. Patients will be followed for AE and SAE for 30 
days after the discontinuation from the treatment phase of trial unless there is a treatment related 
AE which has not recovered to grade 1 or less.   
 
Review of concomitant medications : this will be an ongoing process and will concomitant 
medications will only be recorded in the eCRF if they are associated with an AE. Concomitant 
medications will only be reviewed at the time of clinic appointments for D1 of each cycle but not 
during laboratory appointments in between cycles.  
 
 
8.3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 42  
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a). 
 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
An adverse event or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes:  
 
death,  
 
a life-threatening adverse event,  
 
inpatient hospitalization or prolongation of existing hospitalization,  
 
a persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or  
 
a congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require hospitalization may 
be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient 
or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
  
All AEs will be graded using the CTCAE 5.0 criteria.  
For AEs not included in the protocol-defined grading system, the following guidelines will be used to 
describe severity. 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or incapacitating. 
Of note, the term “severe” does not necessarily equate to “serious”. 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
For all collected AEs, the clinician who examines and evaluates the participant will determine the 
AE’s causality based on temporal relationship and his/her clinical judgment. The degree of certainty 
about causality will be graded using the categories below. 
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to drug administration and cannot 
be explained by concurrent disease or other drugs or chemicals. The response to withdrawal of 
the drug (dechallenge) should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, with use of a satisfactory rechallenge procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of 
other factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs 
within a reasonable time after administration of the drug, is unlikely to be attributed to 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 43  
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response 
on withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition. 
• 
Possibly Related – There is some evidence to suggest a causal relationship (eg, the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (eg, the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, 
it can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related,” as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to drug administration makes a causal relationship improbable (eg, the 
event did not occur within a reasonable time after administration of the trial medication) and in 
which other drugs or chemicals or underlying disease provides plausible explanations (eg, the 
participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study drug administration, and/or evidence 
exists that the event is definitely related to another etiology. There must be an alternative, 
definitive etiology documented by the clinician. 
 
8.3.3.3 EXPECTEDNESS  
 
The PI will be responsible for determining whether an AE is expected or unexpected. An AE will be 
considered unexpected if the nature, severity, or frequency of the event is not consistent with the risk 
information previously described for the study agent. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND 
FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
Adverse events can be spontaneously reported or elicited during open-ended questioning, examination, 
or evaluation of a patient. 
 
All AEs, including local and systemic reactions not meeting the criteria for SAEs, will be captured on the 
appropriate case report form (CRF). Information to be collected will include event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any time 
during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode when grade 3 or greater. All other intermittent AE will be reported as 
one episode using the highest grade.  
 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 44  
All events beginning with start of study intervention until 30 days after the last day of study intervention 
will be reported. At each study visit, the investigator will inquire about the occurrence of AE/SAEs since 
the last visit. Events will be followed for outcome information until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
 
All adverse events will be recorded through 30 days following cessation of treatment and at each 
examination on the Adverse Event case report forms/worksheets. 
 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
The study clinician will immediately report to the sponsor any serious adverse event, whether or not 
considered study intervention related, including those listed in the protocol or investigator brochure and 
must include an assessment of whether there is a reasonable possibility that the study intervention 
caused the event. Such reporting will be within 24 hours of knowledge of the event. Study endpoints that 
are serious adverse events (e.g., all-cause mortality) must be reported in accordance with the protocol 
unless there is evidence suggesting a causal relationship between the study intervention and the event 
(e.g., death from anaphylaxis). In that case, the investigator must immediately report the event to the 
sponsor. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site investigator 
deems the event to be chronic or the participant is stable.  
 
It is the responsibility of the PI and the research team to ensure that serious adverse events are reported 
according to the Code of Federal Regulations, Good Clinical Practices, the protocol guidelines, the 
sponsor’s guidelines, and Institutional Review Board policy. 
 
All adverse experience reports must include the patient number, age, sex, weight, severity of reaction 
(mild, moderate, severe), relationship to study drug (probably related, unknown relationship, definitely not 
related), date and time of administration of test medications, all concomitant medications, and medical 
treatment provided. The PI is responsible for evaluating all adverse events to determine whether criteria 
for “serious” as defined above are present. Adverse drug reactions that are serious, unlisted/unexpected, 
and at least possibly associated to the drug, and that have not previously been reported in the 
Investigator’s Brochure, or reference safety information document should be reported promptly to the 
Food and Drug Administration (FDA) in writing by each investigator/physician engaged in clinical 
research. A clear description of the suspected reaction should be provided along with an assessment as 
to whether the event is drug or disease related.  
 
The Principal Investigator or designee shall notify the FDA by telephone or by fax of any unexpected fatal 
or life threatening experience associated with the use of the drug, as soon as possible, but no later than 7 
calendar days after the sponsor’s initial receipt of the information. Each phone call or fax shall be 
transmitted to the FDA new drug review division in the Center for Drug Evaluation and Research or the 
product review division in the Center for Biologics Evaluation and Research that has responsibility for 
review of the IND if applicable. 
 
 
8.3.7 EVENTS OF SPECIAL INTEREST  
 
Adverse events of special interest are events that Janssen Scientific Affairs, LLC is actively monitoring as 
a result of a previously identified signal (even if non-serious). These adverse events are: 
 
Infusion reactions: ≥ grade 3 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 45  
 
Infections: ≥ grade 4  
 
Cytopenias: ≥ grade 4  
 
Tumor lysis syndrome 
 
Other malignancies 
 
Intravascular hemolysis – all grades 
 
Any Adverse Event of Special Interest that is to be reported to the COMPANY should be recorded on a 
Serious Adverse Event Report Form and be reported to the COMPANY within 24 hours of 
knowledge of the event. 
 
8.3.8 SPECIAL REPORTING SITUATIONS 
 
Although female participants in this study are of non-child bearing age (given requisite age > 65 years), a 
pregnancy in a female partner of male participant is a possibility. Pregnancy, although not itself a serious 
adverse event, should also be reported on a serious adverse event form or pregnancy form and be 
followed up to determine outcome, including spontaneous or voluntary termination, details of birth, and 
the presence or absence of any birth defects or congenital abnormalities. 
Safety events of interest for a Janssen medicinal product that require expediting reporting and/or safety 
evaluation include, but are not limited to: 
 
Drug exposure during pregnancy (maternal and paternal) 
 
Overdose of a Janssen medicinal product  
 
Exposure to a Janssen medicinal product from breastfeeding  
 
Suspected abuse/misuse of a Janssen medicinal product 
 
Inadvertent or accidental exposure to a Janssen medicinal product  
 
Any failure of expected pharmacological action (i.e., lack of effect) of a Janssen 
medicinal product 
 
Medication error involving a Janssen medicinal product (with or without patient 
exposure to the Janssen medicinal product, e.g., name confusion) 
 
Suspected transmission of any infectious agent via administration of a 
medicinal product 
 
 Unexpected therapeutic or clinical benefit from use of a Janssen medicinal 
product 
 
 
 
8.4 UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 46  
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB). The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:  
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the DCC/study 
sponsor in accordance with Moffitt policy.  
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor in accordance with Moffitt 
policy  
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP) in accordance with Moffitt policy.  
 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Unanticipated problems that impact the risk, benefits of the participation in the clinical trial will be reported 
to the patients and the decision to continue or discontinue trial therapy will be made by the patient and 
their treating physician. Patients who will continue on treatment will need to be re-consented with an 
informed consent that has the updated risk / unanticipated problem discussed.    
 
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 
 
 
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 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 47  
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, a photograph should be obtained. 
 
All initial PQCs involving a Janssen medicinal product under study must be reported to Janssen Scientific 
Affairs, LLC by the 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 Janssen medicinal product under study is combined with either a serious adverse event 
or non-serious adverse event, the PRINCIPAL INVESTIGATOR must report the PQC to Janssen 
Scientific Affairs, LLC according to the serious adverse event reporting timelines.  A sample of the 
suspected product should be maintained for further investigation if requested by Janssen Scientific 
Affairs, LLC. 
 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 STATISTICAL HYPOTHESES 
 
 
Primary Efficacy Endpoint(s):  
 
Overall response rate (partial response and better) of the response adapted strategy using the uniform 
response criteria of the IMWG 
 
 
Secondary Efficacy Endpoint(s): 
 
The proportion of patients who progression free at 1 and 2  years 
 
Overall response rate (partial response or better) after 2 cycles of daratumumab 
Proportion of patients who continue on daratumumab monotherapy after 2 cycles.  
Proportion of patients who are without minimal residual disease (MRD-) using Next Generation 
sequencing (NGS) 
The 2 year overall survival of this response adapted approach 
Safety profile of subcutaneous daratumumab based therapy in older adults newly diagnosed multiple 
myeloma 
Agreement between actual responses and responses as predicted by an Ex Vivo Mathematical Myeloma 
Advisor (EMMA) 
 
 
9.2 SAMPLE SIZE DETERMINATION 
 
The primary goal of the study is to evaluate the efficacy of daratumumab alone or in combination with 
lenalidomide or bortezomib. The primary endpoint is overall response rate (partial response and better) of 
the response adapted strategy using the uniform response criteria of the IMWG in older patients with 
newly diagnosed multiple myeloma. A patient who withdraws prior to the completion of cycle 2 at any 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 48  
reasons other than the progression of disease or death is considered “non-evaluable” for efficacy and will 
be replaced. The overall response rate in these patients is 70%. From this historical data, we will consider 
overall response rate of ≤70% as not warranting further study. We will use overall response rate of ≥90% 
as a promising result to pursue further study. Simon’s minimax two-stage design 1618181818with 5% type I 
error rate and 10% type II error rate will be used17. Eighteen evaluable patients will be enrolled in the first 
stage. If 14 or more PR or better responses are noted as the best response to the response adapted 
therapy, additional 14 evaluable patients will be enrolled. If 27 or more patients achieve a PR or better 
among 32 evaluable subjects, the combination is deemed promising. If the regimen is actually not 
effective, there is a 5% probability of concluding that it is. If the regimen is actually effective, there is a 
9.9% probability of concluding that it is not. The probability of early termination is 66.7% and 2.8% if the 
true overall response rate is 70% and 90%, respectively. 
 
9.3 POPULATIONS FOR ANALYSES 
 
 
Safety Analysis Population: Patients who took at least one dose of daratumumab. This population 
will be used for the evaluation of safety of the study agent. 
 
 
Per-Protocol (PP) Population: A patient who withdraws prior to the completion of cycle 2 at any 
reasons rather than the progression of disease or death is considered “non-evaluable” for 
efficacy. PP population includes all evaluable patients and will be used for efficacy evaluation of 
daratumumab alone or in combination with lenalidomide or bortezomib. 
 
9.4 STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
Patient demographic and clinical characteristics will be summarized using descriptive statistics (frequency 
and proportion for categorical variables and mean, standard deviation, median and range for continuous 
variables). All toxicities will be listed for each patient and summarized per Safety Analysis Population. 
Data transformation may be considered to apply parametric analytic methods.  
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
For the primary endpoint, the overall response rate of the response adapted strategy is estimated and is 
compared with historical efficacy data in old patients with newly diagnosed multiple myeloma. The overall 
response rate and its confidence interval will be calculated by using the Atkinson and Brown method182020. 
This confidence interval takes into account the nature of Simon’s two-stage design17. 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINTS 
 
 
Progression-Free Survival (PFS): Time from start of the treatment to death of any cause, 
disease progression or relapse, or the date of last follow-up, whichever comes first. The PFS will 
be estimated by the Kaplan-Meier method and 95% confidence interval (CI) will be computed by 
complementary log-log transformation. The 1 and 2 year PFS and 95% CIs will be reported. 
 
 
Overall Survival (OS): Time from start of the treatment to death of any cause or the date of last 
follow-up, whichever comes first. The OS will be estimated by the Kaplan-Meier method and 95% 
confidence interval will be computed by complementary log-log transformation. The 2 year OS 
and 95% CI will be reported. 
 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 49  
 
Overall response rate after 2 cycle of daratumumab will be estimated and the 95% confidence 
interval will be computed by the Clopper-Pearson method. 
 
 
Proportion of patients who are without minimal residual disease using Next Generation 
Sequencing (NGS) will be estimated and the 95% confidence interval will be computed by the 
Clopper-Pearson method. 
 
 
The performance of EMMA will be evaluated by estimating the sensitivity, specificity, positive 
predictive value (PPV), negative predictive value (NPV), and the area under the receiver 
operating characteristic (AUC) curve. The accuracy of the EMMA will be reported and 95% CI will 
be computed by the Clopper-Pearson method. 
 
 
Correlation between the grade 3 and greater non hematologic and hematolgic adverse events 
and frailty assessment.   
 
9.4.4 SAFETY ANALYSES 
 
All toxicities will be listed for each patient and summarized for each study arm (daratumumab alone + 
dexamethasone (Arm A), daratumumab + dexamethasone + lenalidomide (Arm B), daratumumab + 
dexamethasone + bortezomib (Arm C)). 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
Patient demographic and clinical characteristics will be summarized using descriptive statistics (frequency 
and proportion for categorical variables and mean, standard deviation, median and range for continuous 
variables). 
 
9.4.6 PLANNED INTERIM ANALYSES  
 
Eighteen evaluable patients will be enrolled in the first stage. The study will be early terminated for futility 
if ≤13 patients achieve a PR or better response. If 14 or more PR or better responses are noted, 
additional 14 evaluable patients will be enrolled. The interim analysis will occur after 18 patients have 
received at least 4 cycles of therapy. if the requisite number of response has already been met, prior to 
the completion of 4 cycles by all 18 evaluable patients, enrollment would continue. However if it is felt that 
the requisite number of response is not met (13 or less responders), the enrollment would be halted until 
all 18 evluables patients have received 4 cycles of therapy.  
 
9.4.7 SUB-GROUP ANALYSES 
 
The overall response rate, OS, and PFS will be estimated for each study arm (daratumumab alone + 
dexamethasone (Arm A), daratumumab + dexamethasone + lenalidomide (Arm B), daratumumab + 
dexamethasone + bortezomib (Arm C)). However, no formal comparisons between arms will be made. 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 50  
10.1.1.1 
CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS 
PROVIDED TO PARTICIPANTS  
 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.  
 
10.1.1.2 
CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
and continues throughout the individual’s study participation. Consent forms will be Institutional Review 
Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may arise. A 
verbal explanation will be provided in terms suited to the participant’s comprehension of the purposes, 
procedures, and potential risks of the study and of their rights as research participants. Participants will 
have the opportunity to carefully review the written consent form and ask questions prior to signing. The 
participants should have the opportunity to discuss the study with their family or surrogates or think about 
it prior to agreeing to participate. The participant will sign the informed consent document prior to any 
procedures being done specifically for the study. Participants must be informed that participation is 
voluntary and that they may withdraw from the study at any time, without prejudice. A copy of the 
informed consent document will be given to the participants for their records. The informed consent 
process will be conducted and documented in the source document (including the date), and the form 
signed, before the participant undergoes any study-specific procedures. The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their medical care will not be 
adversely affected if they decline to participate in this study. 
 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to study participants, investigator, funding agency, the 
Investigational New Drug (IND) or Investigational Device Exemption (IDE) sponsor and regulatory 
authorities. If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 
promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will provide the 
reason(s) for the termination or suspension. Study participants will be contacted, as applicable, and be 
informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
 
Determination of unexpected, significant, or unacceptable risk to participants 
 
Demonstration of efficacy that would warrant stopping   
 
Insufficient compliance to protocol requirements 
 
Data that are not sufficiently complete and/or evaluable 
 
Determination that the primary endpoint has been met 
 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
 
10.1.3 FUTURE USE OF STORED SPECIMENS AND DATA  
 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 51  
Data collected for this study will be analyzed and stored at Moffitt cancer center.  
 
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to biosample 
storage may not be possible after the study is completed.  
 
 
10.1.4 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Rachid Baz, MD 
H. Lee Moffitt Cancer Center & Research Institute  
12902 Magnolia Drive, FOB3, Tampa, Fl 33612 
8137458212 
Email Rachid.Baz@moffitt.org 
 
10.1.5 SAFETY OVERSIGHT 
 
Serious Adverse Events: Serious Adverse Events (SAEs) from this protocol will be reported concurrently 
to the IRB and the study sponsor. The Protocol Monitoring Committee (PMC) will review these SAEs in 
accordance with the protocol-specific DSMP. The data and safety plan will define dose limiting toxicities, 
rules for escalation of dose, and criteria for stopping the trial and defining the Maximum Tolerated Dose 
(MTD) according to rules set forth by this protocol. This trial will be continuously monitored by the PI and 
the research team and reviewed at biweekly Myeloma Research Group meetings. Safety and monitoring 
reports will be submitted to the PMC after completing each odd numbered dose level (ie, 1, 3, 5, etc.) or 
more frequently if requested by the PMC. A final safety and monitoring report will be submitted to the 
PMC within three months of defining the MTD. This protocol will be subject to periodic internal audits 
based on risk or as recommended by the PMC. 
 
10.1.6 CLINICAL MONITORING 
Moffitt’s Internal Monitors will periodically monitor regulatory documents and case report forms according 
to the protocol specific clinical monitoring plan.  Monitoring will include review of data for accuracy, 
completeness, and source verification, reporting of SAEs, and adherence to the protocol, Good Clinical 
Practice (GCP) guidelines, and applicable regulatory requirements. 
 
10.1.7 QUALITY ASSURANCE AND QUALITY CONTROL 
 
Each clinical site will perform internal quality management of study conduct, data and biological specimen 
collection, documentation and completion. An individualized quality management plan will be developed 
to describe a site’s quality management. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is 
conducted and data are generated and biological specimens are collected, documented (recorded), and 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 52  
reported in compliance with the protocol, International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), 
Good Manufacturing Practices (GMP)).  
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory 
authorities. 
 
10.1.8 DATA HANDLING AND RECORD KEEPING  
 
10.1.8.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data will be captured in OnCore and/or Moffitt’s electronic Clinical Trials Management System. For each 
subject enrolled, the electronic CRF must be completed by the assigned data manager or other 
authorized study staff. Any paper forms should be typed or filled out indelible ink and must be legible. 
Errors should be crossed out but not obliterated, the correction inserted, and the change initialed and 
dated by the investigator or his/her authorized delegate. This also applies to records for those subjects 
who fail to complete the study. If a subject stops dosing or terminates from the study, the dates 64 and 
reasons must be noted on the CRF. If a subject terminates from the study because of a DLT, thorough 
efforts should be made to clearly document the outcome. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into <specify name of data capture system>, a 21 CFR 
Part 11-compliant data capture system provided by the <specify Data Coordinating Center>. The data 
system includes password protection and internal quality checks, such as automatic range checks, to 
identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from 
the source documents. 
 
 
10.1.8.2 
STUDY RECORDS RETENTION  
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an International Conference on Harminosation (ICH) region and until there are no pending 
or contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study intervention. These documents should be 
retained for a longer period, however, if required by local regulations. No records will be destroyed 
without the written consent of the sponsor, if applicable. It is the responsibility of the sponsor to inform the 
investigator when these documents no longer need to be retained. 
 
10.1.9 PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 53  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report deviations. 
All deviations must be addressed in study source documents, reported to the Protocol Monitoring 
Committee. Protocol deviations must be sent to the reviewing Institutional Review Board (IRB) per their 
policies. The site investigator is responsible for knowing and adhering to the reviewing IRB requirements. 
Further details about the handling of protocol deviations will be included in the MOP. Deviations must be 
entered into the Clinical Trials Management System (CTMS). 
 
 
10.1.10 
PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed 
journals. Data from this study may be requested from other researchers 5 years after the completion of 
the primary endpoint by contacting Rachid Baz, MD  
 
In addition, this study will comply with the NIH Genomic Data Sharing Policy, which applies to all NIH-
funded research that generates large-scale human or non-human genomic data, as well as the use of these 
data for subsequent research. Large-scale data include genome-wide association studies (GWAS), single 
nucleotide polymorphisms (SNP) arrays, and genome sequence, transcriptomic, epigenomic, and gene 
expression data. 
 
 
10.1.11 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial. The study leadership in 
conjunction with the Center (IC) has established policies and procedures for all study group members to 
disclose all conflicts of interest and will establish a mechanism for the management of all reported 
dualities of interest. 
 
 
 
 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 54  
10.2 ABBREVIATIONS 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Science 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
CMS 
Centers for Medicare and Medicaid Services 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRP 
C reactive protein 
CTMS 
Clinical Trial Management System 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Forms 
EMMA 
Ex Vivo Mathematical Myeloma Advisor 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
ICH E6 
International Conference on Harmonisation Guidance for Industry, Good Clinical Practice: 
Consolidated Guidance 
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Investigational Review Board 
ISO 
International Organization for Standardization 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NIH 
National Institutes of Health 
NIH IC 
NIH Institute & Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 55  
 
10.3 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, 
including a description of the change and rationale. A Summary of Changes table for the current 
amendment is located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
5.0 
08/12/2019 
Title Page: tracked from version 4 
to 5 
Header : Tracked to version 5 dated 
08/12/2019  
Appendix C:  
Section 4.1:  age of inclusion 
changed from 70 to 65  
Page 3:   #12 already shows 
Appendix C: Risks of Fetal 
Exposure, Pregnancy Testing 
Guidelines and Acceptable Birth 
Control Methods added; all 
references in Protocol amended to 
Appendix C  
 
 
6.0 
9/9/2019 
Title Page: tracked from version 5 
to 6 
Header : Tracked to version 6 dated 
9/9/2019  
Addition of section 13.4 and 13.5, 
Senior Adult Supplement Screening 
Questionnaire, The Mini Cog 
Evaluation 
Added language in Appendix C 
 
 
7.0 
12/19/2019 
Title Page: tracked from version 6 
to 7 
 
Eligibility of Patients : ECOG 
Performance status- typo updated 
from “0 or 2” to “0 – 2  
 
Inclusion Criteria : Inclusion # 6 – 
ECOG Performance status-typo 
updated from “0 or 2” to “0 – 2  
 
Added a 7 day window for cycle 3 
day 1  
 
Added NTC Number 
 
8.0 
1/29/2021 
Title page tracked from version 7 to 
8 
 
Updated header 
 
 
 
 
 
 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 56  
Added Appendix D for definition of 
myeloma defining event 
 
Allow bortezomib maintenance after 
8 cycles of bortezomib based 
therapy per treating physician 
discretion. Allow holding bortezomib 
for some grade 2 adverse event per 
treating physician recommendations 
 
Allow hormonal therapy inclusion as 
concomitant therapy 
 
Updated visit windows for cycle 3 
and beyond 
 
Allowed use of pre-screening 
standard of care PET CT or skeletal 
survey if done within 28 days of 
starting therapy 
 
Allowed avoiding to repeat a 24h 
urine protein electrophoresis for 
cycle 1 day 1 if performed withing 7 
days during screening  
 
Clarified the time when a bone 
marrow biopsy to confirm CR is 
needed for patients in VGPR in 
case of suspected daratumumab 
interference with immunofixation 
 
Added type and screen on 
screening  
 
Omitted phosphorus form routine 
chemistry labs to be performed 
 
 
Updated wording on FDA approval 
of SC daratumumab in the protocol 
and use of commercial “DARZALEX 
FASPRO” supplied by Janssen 
 
Updated senior adult oncology 
questionnaire form version number 
 
Corrected various typos 
 
 
This was recommended at 
monitoring visit 
 
This is to confirm with standard 
practice as bortezomib for 
bortezomib maintenance and 
therapy 
 
 
 
This is not expected to 
interfere with myeloma therapy 
 
For patient convenience 
 
 
PET CT or skeletal survey 
often performed as part of 
standard of care do not need 
to be repeated within 28 days 
 
24h urine collection is an 
inconvenient test for patients 
and a repeat within 7 days is 
not clinically needed 
 
This is per standard of care 
 
 
 
 
 
This is per standard of care 
 
 
This is not needed for the 
study and can be ordered if 
clinically indicated 
 
Daratumumab SC was 
approved in 5/2020 and 
Janssen will be providing 
DARZALEX FASPRO 
 
A new version is available. No 
change in content 
 
 
 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 57  
11 REFERENCES  
 
1. 
Palumbo A, Bringhen S, Mateos M‐V, Larocca A, Facon T, Kumar SK, Offidani M, McCarthy P, Evangelista A, 
Lonial S, Zweegman S, Musto P, Terpos E, Belch A, Hajek R, Ludwig H, Stewart AK, Moreau P, Anderson K, 
Einsele H, Durie BGM, Dimopoulos MA, Landgren O, San Miguel JF, Richardson P, Sonneveld P, Rajkumar 
SV. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: An international 
myeloma working group report. Blood. 2015;125:2068‐2074 
2. 
Wildes TM, Tuchman SA, Klepin HD, Mikhael J, Trinkaus K, Stockerl‐Goldstein K, Vij R, Colditz G. Geriatric 
assessment in older adults with multiple myeloma. J Am Geriatr Soc. 2018 
3. 
Zweegman S, Engelhardt M, Larocca A, Aging ESo, Hematology. Elderly patients with multiple myeloma: 
Towards a frailty approach? Curr Opin Oncol. 2017;29:315‐321 
4. 
Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, Pinto A, Weisel K, Ludwig H, 
Bahlis N, Banos A, Tiab M, Delforge M, Cavenagh J, Geraldes C, Lee J‐J, Chen C, Oriol A, de la Rubia J, Qiu L, 
White DJ, Binder D, Anderson K, Fermand J‐P, Moreau P, Attal M, Knight R, Chen G, Van Oostendorp J, 
Jacques C, Ervin‐Haynes A, Avet‐Loiseau H, Hulin C, Facon T, Team FT, Forsyth C, Presgrave P, Szer J, 
Durrant S, Campbell P, Mollee P, Coghlan D, Wellwood J, Cannell P, Prince M, Eek R, Horvath N, Harrison 
S, Renwick W, Thaler J, Petzer A, Kasparu H, Bauernhofer T, Meran J, Fridrik M, Balcke P, Gisslinger H, 
Greil R, Doyen C, Meuleman N, Pierre P, Vekemans M, Demuynck H, Wu K, Van Droogenbroeck J, Schots 
R, Offner F, Van de Velde A, Leblanc R, Tosikyan A, Shustik C, Song K, Lemieux B, Minuk L, Lalancette M, 
Cheung M, Noble M, Vanderjagt R, Desjardins P, Aucoin N, Dueck G, Yee A, Reiman A, Kouroukis T, 
Assouline S, Al‐Tourah A, Lu J, Chen W, Liu T, Shen Z, Alexis M, Assouline D, Audhuy B, Azais I, Belhadj K, 
Benramdane R, Tempescul A, Boue F, Rose C, Bourhis J, Bouscary D, Caillot D, Casassus P, De Renzis B, 
Genet P, De Revel T, Dib M, Dorvaux V, Etienne G, Gabriel E, Eisenmann J, Fitoussi O, Garderet L, Gaspard 
M, Sebban C, Glaisner S, Griffoul I, Decaux O, Herbrecht R, Jaccard A, Jardel H, Kaphan R, Kolb B, Barbe 
ME, Laribi K, Lenain P, Macro M, Maisonneuve H, Pavy S, Marit G, Michallet M, Allangbam O, Mosser L, 
Pegourie B, Rigaudeau S, Rodon P, Rossi J, Royer B, Eschard J, Stoppa A, Suc E, Thyss A, Salles G, Vilque J, 
Voillat L, Voog E, Wetterwald M, Zarnitsky C, Junghanss C, Duhrsen U, Fenk R, Rummel M, Derigs HG, Zeis 
M, Mugge L, Ottmann O, Ostermann H, Kropff M, Niederwieser D, Langer C, Rollig C, Panagiotidis P, Corso 
A, Di Renzo N, Foa R, Fragasso A, Canepa L, Martinelli G, Gamberi B, Musso M, Petrini M, Pisani F, Quarta 
G, Sacchi S, Tassone P, Lazzaro A, Ciceri F, Browett P, Romeril K, Butler A, Parreira J, Martins A, Herlander 
M, Goncalves C, Lee JH, Yoon S, Eom H, Jo D, Kwak J, Ryoo H, Lee J, Kim SJ, Min CK, Suh C, Kim K, Lee W, 
Mun Y, Kim HJ, Lahuerta‐Palacios JJ, Lleonart JB, Gonzalez MS, Bermudez‐Rodriguez A, de la Fuente FDA, 
Mateo‐Morales M, Gonzalez‐Montes Y, Hernandez‐Maraver D, Clapes V, Prosper‐Cardoso F, Ramirez G, 
Casasus AT, Granell M, Giraldo‐Castellano P, Echeveste‐Gutierrez A, Palomera‐Bernal L, Nahi H, Gruber A, 
Sjoo F, Leyvraz S, Pabst T, Heim D, Bargetzi M, Cathomas R, Huang S, Yeh S, Chiou T, Ezaydi Y, Littlewood 
T, Knechtli C, McQuaker G, Fegan C, Mehta A, Bird J, Ashcroft J, Kazmi M, Hunter H, Cook M, Crawley C, 
Basu S, Hall R, Seale J, Bensinger W, Coutre S, Priego V, Martin T, Kaplan H, Tirumali N, Dakhil S, Gupta M, 
Jacobson R, Vogl D, Moezi M, Gravenor D, Yunus F, Guthrie T, Reu F, Catchatourian R, Gabrail N, Nieva J, 
De la Puerta M, Ryan H. Lenalidomide and dexamethasone in transplant‐ineligible patients with myeloma. 
N Engl J Med. 2014;371:906‐917 
5. 
Niesvizky R, Flinn IW, Rifkin R, Gabrail N, Charu V, Clowney B, Essell J, Gaffar Y, Warr T, Neuwirth R, Zhu Y, 
Elliott J, Esseltine D‐L, Niculescu L, Reeves J. Community‐based phase iiib trial of three upfront 
bortezomib‐based myeloma regimens. J Clin Oncol. 2015;33:3921‐3929 
6. 
Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, Belch A, Krishnan A, Vescio RA, Mateos MV, 
Mazumder A, Orlowski RZ, Sutherland HJ, Blade J, Scott EC, Oriol A, Berdeja J, Gharibo M, Stevens DA, 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 58  
LeBlanc R, Sebag M, Callander N, Jakubowiak A, White D, de la Rubia J, Richardson PG, Lisby S, Feng H, 
Uhlar CM, Khan I, Ahmadi T, Voorhees PM. Daratumumab monotherapy in patients with treatment‐
refractory multiple myeloma (sirius): An open‐label, randomised, phase 2 trial. Lancet. 2016;387:1551‐
1560 
7. 
Mateos M‐V, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Kaplan 
P, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon S‐S, Iosava G, 
Fujisaki T, Garg M, Chiu C, Wang J, Carson R, Crist W, Deraedt W, Nguyen H, Qi M, San‐Miguel J, 
Investigators AT, Fantl D, Bar D, Riveros DA, Jarchum G, Enrico AI, Pavlovsky A, Jaksic W, Szer J, Murphy N, 
Sadawarte S, Forsyth C, Blum R, Ho J, Mills A, Horvath N, Bries G, Van Eygen K, Wu KL, Deeren D, Van 
Steenweghen S, Berneman ZN, Offner F, Mineur P, Schots R, Hungria V, Maciel J, Maiolino A, Braga W, 
Barbosa S, Kaufman J, Barreto W, Oliveira L, Fogliatto L, Castro N, Farias D, Santucci R, Hamerschlak N, 
Duarte F, Hadjiev E, Radinoff A, Tzvetkov N, Gercheva‐Kyuchukova L, Mihaylov G, Yotov G, Raynov J, 
Sivcheva L, Goranov S, Kolonic SO, Skunca Z, Batinic J, Pejsa V, Spicka I, Gregora E, Scudla V, Maisnar V, 
Hajek R, Jungova A, Zodelava M, Gaprindashvili E, Fuhrmann S, Schleicher J, Jakob C, Dickinson JP, Hindahl 
H, Jacobs G, Chaidos A, Crawley C, Al‐Rafaie F, Sahu S, Hamblin M, Makkuni S, Zhelyazkova A, Symeonidis 
A, Anagnostopoulos A, Pappa V, Anargyrou K, Zikos P, Illes A, Szomor A, Masszi T, Mikala G, Rosta A, Egyed 
M, Varga G, Rambaldi A, Boccadoro M, Palumbo A, Offidani M, Foa R, Rossi G, Cafro AM, Musto P, 
Fabbiano F, Corso A, di Raimondo F, Zambello R, Gobbi M, Nagafuji K, Iida S, Matsumoto M, Takezako N, 
Sunami K, Kosugi H, Ishikawa T, Izutsu K, Imada K, Kaneko H, Sugiura I, Shinagawa A, Onishi Y, Takamatsu 
H, Uchida T, Matsue K, Wake A, Aotsuka N, Lee WS, Eom HS, Kim KH, Kim S, Yoon DH, Lee J‐O, Kim JS, Lee 
JH, Min C‐k, Lee J, Stankovic S, Georgievski B, Chevreska L, Czyz J, Kloczko J, Jedrzejczak WW, Homenda W, 
Woszczyk D, Holojda J, Hus M, Hellmann A, Wrobel T, Walewski J, Martins J, Esteves G, Martins A, 
Gheorghita E, Borsaru G, Popov VM, Danaila CD, Lazaroiu M, Alekseev S, Samoilova O, Pristupa A, 
Udovitsa D, Rossiev V, Afanasyev B, Konstantinova T, Samarina I, Dunaev Y, Kaplanov K, Milanovic N, 
Marjanovic G, Marisavljevic D, Jovanovic D, Milojevic Z, Savic A, Hernandez Garcia MT, De La Rubia J, 
Couto Caro C, Perez de Oteyza J, Blade J, Gonzales Y, Oriol A, Rodriguez P, Martin Sanchez J, Sole M, de 
Arriba F, Sureda A, Martinez J, Alvarez Rivas MA, Gironella M, Casado Montero LF, Encinas C, Palomera L, 
Sastre Moral JL, Yagci M, Altuntas F, Ozet G, Ozsan GH, Vural F, Turgut M, Turgut B, Ferhanoglu B, 
Bolaman AZ, Besisik SK, Unal A, Beksac M, Pylypenko H, Samura B, Popovska T, Masliak Z, Glushko N, 
Rekhtman G, Moezi M, de Lima M, Ehsan M, Vaughn C, Roman E, Schiller G, Jhangiani H, Wallace O, 
Holden V, Snider J, Noga S, Haile D, Alraws A. Daratumumab plus bortezomib, melphalan, and prednisone 
for untreated myeloma. N Engl J Med. 2018;378:518‐528 
8. 
Dimopoulos MA, San‐Miguel J, Belch A, White D, Benboubker L, Cook G, Leiba M, Morton J, Ho PJ, Kim K, 
Takezako N, Moreau P, Kaufman JL, Sutherland HJ, Lalancette M, Magen H, Iida S, Kim JS, Prince HM, 
Cochrane T, Oriol A, Bahlis NJ, Chari A, O' Rourke L, Wu K, Schecter JM, Casneuf T, Chiu C, Soong D, Sasser 
AK, Khokhar NZ, Avet‐Loiseau H, Usmani SZ. Daratumumab plus lenalidomide and dexamethasone versus 
lenalidomide and dexamethasone in relapsed or refractory multiple myeloma: Updated analysis of pollux. 
Haematologica. 2018 
9. 
Palumbo A, Chanan‐Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, Spicka I, Hungria V, Munder M, 
Mateos MV, Mark TM, Qi M, Schecter J, Amin H, Qin X, Deraedt W, Ahmadi T, Spencer A, Sonneveld P, 
Investigators C, Spencer A, Estell J, Quach H, Horvath N, Murphy N, Augustson B, Lee C, Romeo M, de Lima 
V, Castro N, Hamerschlak N, Hungria V, Barreto W, Miguel CE, Capra M, Pour L, Maisnar V, Hajek R, Spicka 
I, Gregora E, Engelhardt M, Repp R, Teichmann M, Fenk R, Munder M, Langer C, Jung W, Binder M, 
Bassermann F, Weisel K, Vohringer M, Knop S, Schmidt‐Hieber M, Altai E, Nagy Z, Szomor A, Gasztonyi Z, 
Illes A, Masszi T, Carella AM, Palumbo A, Foa R, Musto P, Cavo M, Corradini P, Di Raimondo F, Bosi A, 
Corso A, Ferrara F, Cascavilla N, Rambaldi A, Min C, Shin H‐J, Kim B, Lee J, Park J, Mun YC, Yoon DH, Jo J‐C, 
Ovilla R, Gomez D, Te Boome L, Croockewit AJ, Bos G, Von Dem Borne PA, Vellenga E, Klein S, Levin M‐D, 
Westerman M, Grosicki S, Komarnicki M, Kyrcz‐Krzemien S, Jurczyszyn A, Walewski J, Warzocha K, 
Samoilova O, Khuazheva N, Pristupa A, Rossiev V, Melnichenko V, Chagorova T, Serduk O, Udovitsa D, 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 59  
Vladimirov V, Proydakov A, De la Rubia J, Jarque I, Mateos MV, Martinez J, Gimenez E, Casado F, 
Blanchard MJ, Rivas JAH, Lauri B, Forsberg K, Uggla B, Carlsson K, Hansson M, Ahlberg L, Strandberg M, 
Kragsbjerg P, Unal A, Beksac M, Kaya E, Hacihanefioglu A, Cagirgan S, Tuglular T, Besisik S, Pylypenko H, 
Samura B, Glushko N, Kaplan P, Masliak Z, Karamanesht E, Korenkova S, Skrypnyk I, Oliynyk H, Dyagil I, Bar 
M, Lentzsch S, Kyasa MJ, Lipe B, de Idiaquez D, Khan AC, Klein L, Bensinger W, Green DJ, Weiss B, Nooka A, 
Holland KH, Mark T, Voorhees PM, Winer E, Srkalovic G, Vescio R, Medvedova E, Cosgriff T, Laubach J. 
Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:754‐766 
10. 
Chari A, Mateos M‐V, van de Donk NW, Kaufman JL, Moreau P, Oriol A, Plesner T, Benboubker L, Nahi H, 
Tang J, Hellemans P, Tromp B, Clemens PL, Farnsworth A, San‐Miguel JF, Usmani SZ. Subcutaneous 
daratumumab in patients with relapsed or refractory multiple myeloma: Part 2 safety and efficacy update 
of the open‐label, multicenter, phase 1b study (pavo). Blood. 2018;132:1995‐1995 
11. 
Zonder JA, Crowley J, Hussein MA, Bolejack V, Moore DF, Sr., Whittenberger BF, Abidi MH, Durie BGM, 
Barlogie B. Lenalidomide and high‐dose dexamethasone compared with dexamethasone as initial therapy 
for multiple myeloma: A randomized southwest oncology group trial (s0232). Blood. 2010;116:5838‐5841 
12. 
Silva A, Silva MC, Sudalagunta P, Distler A, Jacobson T, Collins A, Nguyen T, Song J, Chen D‐T, Chen L, 
Cubitt C, Baz R, Perez L, Rebatchouk D, Dalton W, Greene J, Gatenby R, Gillies R, Sontag E, Meads MB, 
Shain KH. An ex vivo platform for the prediction of clinical response in multiple myeloma. Cancer Res. 
2017;77:3336‐3351 
13. 
Khin ZP, Ribeiro MLC, Jacobson T, Hazlehurst L, Perez L, Baz R, Shain K, Silva AS. A preclinical assay for 
chemosensitivity in multiple myeloma. Cancer Res. 2014;74:56‐67 
14. 
Silva AS, Silva MD, Sudalagunta P, Distler AI, Jacobson T, Collins A, Nguyen T, Song J, Chen D‐T, Chen L, 
Cubitt CL, Baz R, Perez L, Rebatchouk D, Dalton W, Greene J, Gatenby RA, Gillies RJ, Sontag E, Meads MB, 
Shain K. An ex vivo platform for the prediction of clinical response in multiple myeloma. Cancer Res. 2017 
15. 
Balducci L, Extermann M. Management of cancer in the older person: A practical approach. Oncologist. 
2000;5:224‐237 
16. 
Simon R. Optimal two‐stage designs for phase ii clinical trials. Control Clin Trials. 1989;10:1‐10 
17. 
Simon R. Optimal two‐stage designs for phase ii clinical trials. Control Clin Trials. 1989;10:1‐10 
18. 
Atkinson EN, Brown BW. Confidence limits for probability of response in multistage phase ii clinical trials. 
Biometrics. 1985;41:741‐744 
 
 
 
 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 60  
12 APPENDIX A: IMWG RESPONSE CRITERIA 
 
 
a. All response categories require two consecutive assessments made at any time before the 
institution of any new therapy; all categories also require no known evidence of progressive or 
new bone lesions if radiographic studies were performed. Radiographic studies are not required 
to satisfy these response requirements. 
b. Confirmation with repeat bone marrow biopsy not needed. 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 61  
c. Presence/absence of clonal cells is based upon the k/λ ratio. An abnormal k/λ ratio by 
immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for 
analysis. An abnormal ratio reflecting presence of an abnormal clone is k/λ of > 4:1 or < 1:2. 
d. Measurable disease is defined as meeting at least one of the following measurements:  
Serum M‐protein≥ 1 g/dL or  
Urine M‐protein ≥ 200 mg/24 hr or  
Serum FLC assay with an involved FLC level ≥ 10 mg/dL (≥ 100 mg/L) provided serum FLC ratio is 
abnormal  
e. Not recommended for use as an indicator of response; stability of disease is best described by 
providing the time to progression estimates. 
Notes:  
* Clarification 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 is defined as a normal FLC ratio of 0.26 – 1.65 in addition to CR criteria listed 
above. VGPR in such subjects is defined as a > 90% decrease in the difference between involved 
and uninvolved free light chain FLC levels. 
** Serum and urine M‐protein testing is required to fulfill requirements of VGPR and CR 
categories regardless of whether disease at baseline was measurable on serum, urine, both, or 
neither. 
† For those subjects with negative or low SPEP (≤0.2 g/dL) and suspected daratumumab 
interference, a reflex assay using anti‐idiotype antibody will be utilized to confirm daratumumab 
interference and rule out false positive immunofixation. Subjects who have confirmed 
daratumumab interference, but meet all other clinical criteria for CR or sCR, will be considered 
CR/sCR. Subjects with a non IgG kappa multiple myeloma who have an IgG kappa monoclonal 
protein on immunofixation will be assumed to have daratumumab interference in the absence 
of an assay.  
 
Progressive disease is defined as below: 
Increase of > 25% from lowest response value in any one or more of the following: 
 
Serum M‐component and/or (the absolute increase must be > 0.5 g/dL). For progressive disease, 
serum M‐component increases of >1 gm/dL are sufficient to define relapse if starting M‐
component is >5 g/dL. 
 
Urine M‐component and/or (the absolute increase must be > 200 mg/24 h) 
 
Only in patients without measurable serum and urine M‐protein levels; the difference between 
involved and uninvolved FLC levels. The absolute increase must be > 10 mg/dL 
 
Bone marrow plasma cell percentage; the absolute percentage must be > 10% 
 
Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in 
the size of existing bone lesions or soft tissue plasmacytomas 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 62  
 
Development of hypercalcaemia (corrected serum calcium > 11.5 mg/dL or 2.65 mmol/L) that 
can be attributed solely to the plasma cell proliferative disorder 
All responses must be confirmed by repeat testing within 6 weeks for the definition of a best response and 
progression.  
13 APPENDIX B: IMWG GERIATRIC ASSESSMENT 
13.1.1 ACTIVITIES OF DAILY LIVING (ADL) AND INTRUMENTAL ACTIVITY OF DAILY LIVING 
(IADL) 
 
The ADL scale includes six items (bathing, dressing, toileting, transferring, continence, and feeding), with 
a score for each item ranging from 0 (unable to perform the activity) to 1 (able to perform the activity). 
Total score ranges from 0 to 6 (0 = completely dependent; 6 = completely independent). The IADL scale 
includes eight items (ability to use the telephone, shopping, cooking, housekeeping, doing laundry, taking 
own medication, using transportation, and handling finances), with a score for each item of 0 (low 
function, dependent) or 1 (high function, independent). The total score ranges from 0 to 8 (0 = completely 
dependent; 8 = completely independent). 
 
13.1.2 CHARLSON COMORBIDITY INDEX (CCI) 
 
 
 
 
Score 
ADL 
 
IADL 
0-1 
Bathing 
Ability to use the phone 
0-1 
Dressing 
Shopping 
0-1 
Toiletting  
Food preparation 
0-1 
Transferring  
Housekeeping 
0-1 
Continence  
Laundry 
0-1 
Feeding 
Mode of transportation 
0-1 
 
Responsible for own medications 
0-1 
 
Responsible for own finances 
Assigned 
Weight 
Condition(s) 
1 
Myocardial infarction, congestive heart failure, peripheral arterial disease, 
cerebrovascular disease (includes transient ischemic attack), dementia, 
chronic pulmonary disease, connective tissue disease, peptic ulcer 
disease, mild liver disease (no portal hypertension), diabetes without end 
organ damage  
2 
Hemiplegia, moderate to severe renal disease, diabetes with organ 
damage, tumor without metastasis (within 5 years), leukemia, lymphoma 
3 
Moderate to severe liver disease 
6 
Metastatic solid tumor, Acquired Immunodeficiency Syndrome (AIDS) 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 63  
13.1.3 IMWG FRAILTY SCORING 
 
Condition 
Score 
Age  
75 or less 
76-80 
>80 
 
0 
1 
2 
ADL 
>4 
4 or less 
 
0 
1 
IADL 
>5 
5 or less 
 
0 
1 
CCI 
1 or less 
2 or more 
 
0 
1 
 
 
Score 
Frailty Category 
Estimated 3 years Overall Survival 
0 
Fit 
84% 
1 
Intermediate fitness 
(unfit) 
76% 
2 or more 
Frail  
57% 
 
13.1.4 TIMED UP AND GO (GAIT SPEED) 
Gait speed can be evaluated as previously described by Liu M, and others, where in brief: from a 
standing start, participants are asked to walk at a usual pace for 4 meters using distinct landmarks and 
with speed recorded in meters per second, using a stopwatch  (Liu M, et al. Blood 2019). This was found 
to be a useful marker of frailty.   
13.1.5 SENIOR ADULT ONCOLOGY CLINIC QUESTIONNAIRE  
We will employ the senior adult oncology clinic questionnaire as part of the geriatric assessment. The 
questionnaire is show below. 
  
 
 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 64  
SENIOR ADULT SUPPLEMENT SCREENING QUESTIONNAIRE (SAOP3) 
Form #16952‐1‐004 5/19  
1. If it was necessary, is there someone who could help take care of you   
[ ] Yes    [ ] No 
2. Do you feel sad more days than not   
 
 
 
     
[ ] Yes    [ ] No 
3. Have you lost interest in things you used to enjoy (hobbies, food, sex, being with friends / family) 
 
 
 
 
 
 
 
 
 
 
[ ] Yes    [ ] No  
4. On a scale of 1 to 10, rate your present quality of life (10 is the best, 1 is the worst) 
 
[ ] 1 
[ ] 2 
[ ] 3  
[ ] 4 
[ ] 5 
[ ] 6 
[ ] 7  
[ ] 8 
[ ] 9 
[ ] 10 
5. On a scale of 1 to 10, rate your present overall health (10 is the best, 1 is the worst).  
 
[ ] 1 
[ ] 2 
[ ] 3  
[ ] 4 
[ ] 5 
[ ] 6 
[ ] 7  
[ ] 8 
[ ] 9 
[ ] 10 
6. Activities of Daily Living / Instrumental Activities of Daily Living (ADL/IADL 
 
( please check one for each line ) 
a. Do you use a cane or a walker? 
[ ] Yes  
[ ] Occasionally 
[ ] No 
b. Do you need help to get out of bed / chair? 
[ ] Yes  
[ ] Occasionally 
[ ] No 
c. Have you tripped or fallen in the past year? 
[ ] Yes  
 
[ ] No 
d. Can you shower or bathe yourself completely? 
[ ] Yes  
[ ] Yes, but with help 
[ ] No 
e. Can you dress yourself completely? 
[ ] Yes  
[ ] Yes, but with help 
[ ] No 
f. 
Can you feed yourself? 
[ ] Yes  
[ ] Yes, but with help 
[ ] No 
g. Are you able to drive? 
[ ] Yes  
[ ] Have never 
driven 
[ ] No 
h. Are you able to prepare your own meals? 
[ ] Yes  
[ ] Yes, but with help 
[ ] No 
i. 
Are you able to go shopping? 
[ ] Yes  
[ ] Yes, but with help 
[ ] No 
j. 
Can you take care of your finances? 
[ ] Yes  
[ ] Yes, but with help 
[ ] No 
k. Can you use a telephone? 
[ ] Yes  
[ ] Yes, but with help 
[ ] No 
l. 
Do you remember to take your medicines? 
[ ] Yes  
[ ] Yes, but with help 
[ ] No 
m. Do you have problems holding your urine or stools 
(more than small leaks controlled with a pad)? 
[ ] Yes  
[ ] Occasionally 
[ ] No 
7. Have you lost 5 or more pounds in the past 6 months without dieting?   
[ ] Yes    [ ] No 
8. Has your appetite decreased in the last 3 months?  
 
 
 
[ ] Yes    [ ] No 
9. Has there been a change in the types of food you are able to eat?  
 
[ ] Yes    [ ] No 
10. Are you able to pay for your prescription medications?  
 
 
[ ] Yes    [ ] No 
11. Do you feel you are sleeping well? 
 
 
 
 
 
[ ] Yes    [ ] No 
  
 
 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 65  
 
 
 
 
 
The Mini Cog Evaluation ™ 
 
 
 
 
 
------------------------------------------------------------------------------------------------------------------ 
1. Insruct the patient to listen carefully and repeat the following words: [ ] Apple   [ ] Watch  [ ] Penny 
2. Instruct the patient to draw a clock and put in all the number where they go. then instruct the patient to 
place the hands of the clock to represent the time “forty five minutes past ten o’clock”  
3. Ask the patient to repeat the three words previously given: _______   _______   ________ 
Scoring: 
Number of correct items recalled : ______ (if 3, then normal. Stop. If 0, then cognitive impairement. Stop) 
If 1-2, is clock drawing abnormal?  [ ] Yes (cognitive impairement )  [ ] No (normal) 
Psychosocial items 1-3: if at least one Yes response, then consult Social Work 
ADL / IADL mobility items (6a-6c): if at least two Yes responses, then consult Outpatient Physical 
therapy 
ADL / IADL ietms 6c-6m: if at least one No response, then consult Outpatient Occupational therapy  
Quality of life (QOL) and self rate health items (4-5), if score less then 8, then consult Social Work 
Nutrition items (7-9): if at least two Yes responses, then consult Outpatient Nutrition  
Mini-Cog: MMSE <24 if cognitive impairement, then consult Outpatient Occupational therapy or 
Speech Path 
Number of Medications greater than 5, then consult Pharmacy  
If No to #10, refer to Social Work or Patient Financial Services 
If No to #11, administer Pittsburgh Sleep Quality Index (PSQI) for further referral  
Geriatric Depression Scale Score: ______, if Score greater than 5, the consult Behavioral Medicine 
Referral: [ ] Yes   [ ] No | To:  
 
 
 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 66  
14 APPENDIX C: RISKS OF FETAL EXPOSURE, PREGNANCY TESTING 
GUIDELINES AND ACCEPTABLE BIRTH CONTROL METHODS 
There are no human or animal data to assess the risk of daratumumab use during pregnancy. IgG1 
monoclonal antibodies are known to cross the placenta after the first trimester of pregnancy. Therefore, 
daratumumab should not be used during pregnancy unless the benefit of treatment to the woman is 
considered to outweigh the potential risks to the fetus. If the participant becomes pregnant while taking 
this drug, the participant should be informed of the potential risk to the fetus. 
To avoid exposure to the fetus, women of reproductive potential should use effective contraception during 
and for 3 months after cessation of daratumumab treatment. 
While this study will enroll participants over the age of 65 years, women who are enrolled on the study are 
not of childbearing potential. Female participants must agree not to become pregnant while enrolled in 
this study. In addition, pregnant or breastfeeding women are not allowed to participate. For men, the 
effect of daratumumab on sperm is unknown. 
Men must adhere to the following.  
 
Participants must agree to the use of independent highly effective methods of contraception 
during the study (including during dose interruptions), and for 4 weeks following discontinuation of 
lenalidomide, and if receiving daratumumab, for 3 months after the last dose 
 
A man, even if he has undergone a successful vasectomy, 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) 
 
A man who is sexually active with a woman who is pregnant must use a latex or synthetic 
condom. 
 
A man must agree not to donate sperm 
 
Because of the embryo-fetal risk of lenalidomide, all subjects who are receiving this agent, must adhere 
to the lenalidomide REMS program that can be accessed at http://www.revlimidrems.com/ 
 
 
 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 67  
15 APPENDIX C: INTERNATIONAL MYELOMA WORKING GROUP 
UPDATED CRITERIA FOR THE DIAGNOSIS OF MULTIPLE MYELOMA 
Definition of symptomatic multiple myeloma 
Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma* 
and any one or more of the following myeloma defining events:  
Myeloma defining events:  
 
Evidence of end organ damage that can be attributed to the underlying plasma cell 
proliferative disorder, specifically: 
 
Hypercalcaemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of 
normal or >2.75 mmol/L (>11 mg/dL) 
 
Renal insufficiency: creatinine clearance <40 mL per min† or serum creatinine >177 
μmol/L (>2 mg/dL) 
 
Anemia: haemoglobin value of >20 g/L below the lower limit of normal, or a haemoglobin 
value <100 g/L 
 
Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT‡  
Any one or more of the following biomarkers of malignancy: 
 
Clonal bone marrow plasma cell percentage* ≥60% 
 
Involved:uninvolved serum free light chain ratio§ ≥100  
 
>1 focal lesions on MRI studies¶ 
 PET-CT=¹⁸F-fluorodeoxyglucose PET with CT.  
*Clonality should be established by showing κ/λ-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. 
Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of a disparity between the 
aspirate and core biopsy, the highest value should be used.  
†Measured or estimated by validated equations.  
‡If bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with 
minimal marrow involvement.  
§These values are based on the serum Freelite assay (The Binding Site Group, Birmingham, UK). The involved free light chain must be ≥100 
mg/L. 
¶Each focal lesion must be 5 mm or more in size. 
 
Adapted from Rajkumar et al. Lancet Oncol. 2014 Nov;15(12):e538-48.  
 
 

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 68  
APPENDIX D: Worksheet for Revised International Staging System (R-ISS) and Classification of FISH 
Findings (Adapted from Palumbo et al J Clin Oncol; 2015; 33(26):2863-9) 
FISH (circle all that applies):  
Deletion 13 
 
YES 
 
NO 
Deletion 17  
 
YES 
 
NO 
Amp/ Gain 1q   
YES 
 
NO 
Deletion 1p  
 
YES 
 
NO 
T(11;14)  
 
YES 
 
NO 
T(4;14)   
 
YES 
 
NO 
T(14,16)  
 
YES 
 
NO 
Hyperdiploid  
 
YES 
 
NO 
CA by iFISH 
 
    High risk 
Presence of del(17p) and/or translocation t(4;14) and/or translocation t(14;16) 
    Standard risk No high-risk CA 
 
ISS: _________ 
B2microglobulin:_______ 
Albumin: _______ 
ISS stage  
    I Serum β2-microglobulin < 3.5 mg/L, serum albumin ≥ 3.5 g/dL 
    II Not ISS stage I or III 
    III Serum β2-microglobulin ≥ 5.5 mg/L 
 
LDH: ________ 
LDH 
 
    Normal Serum LDH < the upper limit of normal 
    High 
Serum LDH > the upper limit of normal 
 
R-ISS: ________ 
    R-ISS stage  

Phase II study of daratumumab based response adapted therapy for older  
adults with newly diagnosed multiple Myeloma 
Protocol 20130 
 
Version 9.0 
 
9/2/2022 
 
 Page | 69  
        I 
ISS stage I and standard-risk CA by iFISH and normal LDH 
        II 
Not R-ISS stage I or III 
        III ISS stage III and either high-risk CA by iFISH or high LDH