LCI-HEM-MYE-KRdD-001: Phase II Study of Daratumumab Combined With Carfilzomib, Lenalidomide and Dexamethasone in Newly Diagnosed Multiple Myeloma
Phase: PHASE2
Conditions: Multiple Myeloma
Sponsor: Wake Forest University Health Sciences

 
 
 
Divya Upadhyay, 
Study Manager |  
BMS Investigator Sponsored Research Program 
GDO Late Development 
bms.com 
Divya.Upadhyay@bms.com(She/Her) 
Dr. Manisha Bhutani 
LEVINE CANCER INSTITUTE C, 
1021 MOREHEAD MEDICAL DR 
 
 
Dear Dr. Manisha Bhutani, 
 
 
This is an update to the letter that was dated Nov 6th regarding Direct to Patient 
(DtP) shipments. BMS has decided to discontinue the “Direct to Patient” (DtP) 
service provided by McKesson, which was implemented in response to COVID-19.  
This service allowed Sponsor ISR sites to request McKesson to ship Clinical 
supplies directly to patients.  McKesson will resume shipping Clinical supplies to 
sites only, for applicable hCelgene ISRs that include any of the following IMiDs: 
Lenalidomide, Revlimid, Pomalidomide.  
 
All services provided by McKesson before the pandemic will remain 
unchanged.  
 
Additionally, please disregard the statement in the previous letter that 
investigational sites will no longer be able to use their own courier to transfer 
IMP from site to the patient’s home. This statement should not have been 
included as the letter was intended to only address BMS/McKesson closing the 
COVID emergency response Direct to Patient (DtP) shipment arrangement for 
clinical supply of IMiDs only.   
 
Please be reminded that as the Sponsor of the study, you hold responsibility to 
follow applicable guidance, the protocol and be in alignment with its defined 
evaluations for safety, pregnancy, and overall patient assessments for any 
patient requested shipments. This change should be implemented as soon as 
possible, as no further McKesson direct to patient shipments of Clinical supplies 
will be authorized as of January 1, 2024. If you have any questions/concerns, 
please feel free to reach out to me. 
 
Sincerely, 
Divya Upadhyay 
Study Manager 
November 30, 2023 
Direct to Patient (DtP) 
shipments 
Protocol Number: RV-CL-
MM-PI-12836 

 
 
Divya Upadhyay, 
Study Manager |  
BMS Investigator Sponsored 
Research Program 
GDO Late Development 
bms.com 
divya.Upadhyay@bms.com(She/Her)
Dr. Manisha Bhutani 
LEVINE CANCER INSTITUTE C, 
1021 MOREHEAD MEDICAL DR 
 
Dear Dr. Manisha Bhutani 
 
 
BMS has taken the decision to close the “Direct to Patient” (DtP) service 
provided by McKesson. This service allowed the transfer of Investigational 
Medicinal Product (IMP) to the patient’s home as part of the BMS emergency 
response to the global COVID-19 pandemic.  
 
Due to the end of the COVID-19 emergency response, this service will no longer 
be an option. 
 
Additionally, investigational sites will no longer be able to use their own courier 
to transfer IMP from site to the patient’s home.  These changes will take effect 
immediately. 
 
If you have any questions/concerns, please reach out to your BMS Global Trial 
Manager/Trial Manager contact, contact information below in footer. 
 
Sincerely, 
Divya Upadhyay 
Study Manager 
November 6, 2023 
Direct to Patient (DtP) 
shipments 

Protocol: LCI-HEM-MYE-KRdD-001 
Version 8:   04/03/2023 
 
 
 
Protocol #: LCI-HEM-MYE-KRdD-001 
TITLE: Phase II Study of Daratumumab Combined with Carfilzomib, Lenalidomide and 
Dexamethasone in Newly Diagnosed Multiple Myeloma  
 
Coordinating Center: 
Levine Cancer Institute 
1021 Morehead Medical Drive 
Charlotte NC, 28204 
 
Sponsor-Investigator: 
Manisha Bhutani, MD 
Levine Cancer Institute 
1021 Morehead Medical Drive 
Charlotte NC, 28204 
Email: Manisha.Bhutani@atriumhealth.org 
 
Statistician: 
James Symanowski, PhD 
Levine Cancer Institute 
Email: James.Symanowski@atriumhealth.org 
 
Immune Monitoring Core Laboratory:  
David Foureau, PhD  
Levine Cancer Institute 
Telephone: 980-442-2828 
Email: David.Foureau@atriumhealth.org 
 
Trial Supported by: 
Janssen Scientific Affairs, Inc., Amgen Inc. and Celgene Corporation 
 
Investigational New Drug (IND) # 144160 
___________________________________________________________________________ 
The study will be conducted in compliance with the protocol, ICH/GCP and any applicable 
regulatory requirements. 
 
 
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed. 
Hence, the appearance of product names without these symbols does not imply that these names 
are not proprietary. 
 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the 
guidance of the clinical investigation. Reproduction or disclosure of this document - whether in part 
or in full - to parties not associated with the clinical investigation, or its use for any other purpose, 
without the prior written consent of the Sponsor-Investigator is not permitted. 

Protocol: LCI-HEM-MYE-KRdD-001 
Version 8:   04/03/2023 
 
 
 
 
PROTOCOL SIGNATURE PAGE 
Phase II Study of Daratumumab Combined with Carfilzomib, Lenalidomide and 
Dexamethasone in Newly Diagnosed Multiple Myeloma 
 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
 
 
 
 
___________________________________  
 
_____________________ 
 
 
Signature of Sponsor-Investigator 
 
 
 
Date 
 
 
Manisha Bhutani, M.D 
 
 
 

Protocol: LCI-HEM-MYE-KRdD-001 
Version 8:  04/03/2023 
 
I 
 
SYNOPSIS 
TITLE 
Phase II Study of Daratumumab Combined with Carfilzomib, 
Lenalidomide and Dexamethasone in Newly Diagnosed Multiple 
Myeloma  
STUDY POPULATION 
Newly Diagnosed Multiple Myeloma (NDMM) 
PHASE  
II 
SUMMARY OF STUDY 
RATIONALE 
Daratumumab is a first-in-class, human IgG1 monoclonal antibody that 
binds CD38-expressing malignant plasma cells with high affinity and 
induces tumor cell death through diverse mechanisms and is approved for 
the treatment of relapsed/refractory MM. The regimen of carfilzomib, 
lenalidomide and dexamethasone (KRd) is a highly active regimen used in 
the treatment of NDMM. The immunomodulatory effects of KRd have a 
strong potential for synergy with those of daratumumab, and preliminary 
data from a Phase I trial of KRd+daratumumab support the safety of this 
combination. Post induction, the treatment course for NDMM varies. 
While assessment of minimal residual disease (MRD) status post 
treatment is increasingly common, data on its utility as a tool to select the 
optimal post-induction therapy are not yet available. 
STUDY DESIGN  
This single arm, two-stage, open-label Phase II study is designed with the 
primary objective of evaluating the efficacy of induction therapy 
comprised of 8 cycles of carfilzomib, lenalidomide, dexamethasone and 
daratumumab (KRd+daratumumab) in terms of complete response or 
better (≥ CR) in subjects with NDMM and comparing to relevant 
historical controls (see Schema 1). Post induction, all subjects will 
undergo disease evaluation, including assessment of minimal residual 
disease (MRD). Post-induction disease evaluation will be followed by an 
MRD-based treatment algorithm (see Schema 2). This trial will allow us 
to gather preliminary data on use of MRD status to direct post-induction 
therapy. 
OBJECTIVES 
Primary Objective:  
• The primary objective is to evaluate the efficacy of daratumumab 
when combined with KRd as induction chemotherapy, in terms of 
complete response or better, in subjects with newly diagnosed 
multiple myeloma. 
 
Secondary Objectives: 
• Evaluation of daratumumab when combined with KRd by 
estimating Progression-free survival (PFS), Overall survival (OS), 
Time to disease progression (TTP), Overall response rate (ORR), 
Duration of response (DoR), Time to next treatment (TTNT).  

Protocol: LCI-HEM-MYE-KRdD-001 
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II
KEY INCLUSION 
CRITERIA  
• Newly diagnosed multiple myeloma (NDMM) as per the IMWG 
2014 criteria  
• No more than 1 prior cycle of systemic therapy (to accommodate 
subjects who needed emergent treatment at diagnosis) 
• Age ≥ 18 years 
• ECOG ≤ 2 
• Measurable disease: 
o Serum M-protein ≥1 g/dL (> 0.5 g/dL for IgA or IgM) OR 
o Urine M-protein ≥200 mg/24 h OR  
o Involved free light chain (FLC) level ≥10 mg/dL provided 
serum FLC ratio is abnormal  
• Adequate organ and bone marrow function 
• Negative serum pregnancy test in females of childbearing potential 
(FCBP) 
• Willingness to use required birth control as applicable 
 
STATISTICAL 
CONSIDERATIONS 
 
The primary objective is to evaluate the efficacy of daratumumab when 
combined with KRd, in terms of complete response or better, in subjects 
with newly diagnosed multiple myeloma, and compare to relevant 
historical controls.  For the NDMM patient population, 8 cycles of KRd 
induction provides a complete response or better rate of approximately 
50%.  For this population of patients treated with KRd+daratumumab, the 
aim is to achieve a rate of CR or better of 70%.  A minimax 2-stage 
design will be used to test the hypothesis that the CR or better rate is less 
than or equal to 50%.  Twenty-three (23) subjects will be enrolled in the 
first stage, and if at least 12 of the 23 subjects have a complete response 
or better after induction therapy, an additional 16 subjects will be enrolled 
(a total of 39 patients).  If at least 24 of 39 subjects have a complete 
response or better, the null hypothesis will be rejected.  Based on a one-
sided alpha = 0.10 significance level, this sample size will provide 90% 
power to reject the null hypothesis, assuming the true complete response 
or better rate is 70%. 
TOTAL  
NUMBER OF 
SUBJECTS 
Up to 39 
 
 
 

Protocol: LCI-HEM-MYE-KRdD-001 
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III
SCHEMA 1: STUDY OVERVIEW 
 
 
 
Note: MRD testing will only be performed in subjects with VGPR or better; subjects with less than 
VGPR will be considered MRD+ without performing the test 
 
Note: For subjects who completed a pre-study cycle of induction chemotherapy, only 7 cycles of KRdD 
Induction should be given. 
 

Protocol: LCI-HEM-MYE-KRdD-001 
Version 8:  04/03/2023 
 
IV
SCHEMA 2: POST-INDUCTION MRD BASED TREATMENT 
ALGORITHM 
 
After induction, all subjects will undergo disease evaluation. Those who experience ≥VGPR will undergo 
an assessment of minimal residual disease (MRD) and will be classified as MRD (+) or MRD (-). Those 
with <VGPR will be considered to have MRD (+) disease and will follow MRD (+) algorithm.  
 
Subjects who do not have an adequate baseline NGS MRD sample (for whatever reason) will be 
considered MRD unevaluable and will receive treatment as though MRD + for all subsequent MRD time-
points and will not have subsequent protocol directed NGS MRD samples collected.  
 
NOTE: MRD will be evaluated via flow cytometry and DNA sequencing.  Based on MRD results 
evaluated via DNA sequencing, subjects will be divided into 3 separate treatment groups. All subjects in 
each group will be followed until relapse or progression. 
 
 
 
Note: The 10-⁵ MRD result from the NGS MRD test will be used for treatment decisions 
If a subject does not have an NGS test report available (for whatever reason), the subject will be assumed 
to be MRD + and will receive treatment as though MRD+ per the algorithm. 
 

Protocol: LCI-HEM-MYE-KRdD-001 
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V 
LIST OF ABBREVIATIONS 
Abbreviation 
Spelled out abbreviation 
ADCC 
Antibody-dependent cell-mediated cytotoxicity 
AE 
Adverse event 
AESI 
Adverse event of special interest 
Anti-HBc 
Hepatitis B core antibody 
Anti-HBs 
Hepatitis B surface antibody 
AML 
Acute myeloid leukemia 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ARDS 
Acute respiratory distress syndrome 
ASCO 
American Society of Clinical Oncology 
ASCT 
Autologous stem cell transplant 
AST 
Aspartate aminotransferase 
BCR 
B cell receptor 
BM 
Bone marrow 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CBCD 
Complete blood count with differential and platelets 
CDC 
Compliment-dependent cytotoxicity 
CFR 
Code of Federal Regulations 
COPD 
Chronic obstructive pulmonary disease 
CR 
Complete response 
CRAB 
features 
Calcium elevation, renal failure, anemia, lytic bone lesions 
CrCl 
Creatinine clearance 
CTCAE 
Common terminology criteria for adverse events 
CTMS 
Clinical Trial Management System 

Protocol: LCI-HEM-MYE-KRdD-001 
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VI
Dara-SC 
Daratumumab Subcutaneous 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
DSMC 
Data and Safety Monitoring Committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
ESA 
Erythropoietic stimulation agents 
ESI 
Event of special interest 
F-FDG PET 
F-fluorodeoxyglucose PET 
FCM 
Flow cytometry 
FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FLC 
Free light chain 
FCBP 
Females of child bearing potential 
GCP 
Good clinical practice 
GMP 
Good manufacturing practice 
HBV 
Hepatitis B Virus 
HBsAg 
Hepatitis B surface antigen 
HSCT 
Haploidentical stem cell transplant 
HDC 
High dose chemotherapy 
Hgb 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s brochure 
ICSR 
Individual case safety report 
ICH 
International Council on Harmonisation 

Protocol: LCI-HEM-MYE-KRdD-001 
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VII
IFE 
Immunofixation 
IMiD 
Immunomodulatory agent 
IMP 
Investigational Medicinal Product 
IMWG 
International Myeloma Working Group 
IPM 
Initial primary malignancy 
IRB 
Institutional Review Board 
IRR 
Infusion related reactions 
IV 
Intravenously 
Kd 
Carfilzomib plus dexamethasone 
KRd 
Carfilzomib, lenalidomide and dexamethasone 
LCI 
Levine Cancer Institute 
LDH 
Lactate dehydrogenase 
LTD 
Last tolerated dose 
LVEF 
Left ventricular ejection fraction 
MDS 
Myelodysplastic syndrome 
MFS 
Multiparameter flow cytometry 
MM 
Multiple myeloma 
MPD 
Maximum planned dose 
MRD 
Minimal residual disease 
MTD 
Maximum tolerated dose 
MUGA 
Multi gated acquisition scan 
NCI 
National Cancer Institute 
NDMM 
Newly Diagnosed Multiple Myeloma 
NGF 
Next generation flow 
NGS 
Next generation sequencing 
NIH 
National Institutes of Health 
NK 
Natural killer 

Protocol: LCI-HEM-MYE-KRdD-001 
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VIII 
NYHA 
New York Heart Association 
ORR 
Overall response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 
PET/CT 
Positron emission tomography/computed tomography 
PFS 
Progression free survival 
PML 
Progressive multifocal leukoencephalopathy 
PO 
By mouth 
POEMS 
Polyneuropathy organomegaly endocrinopathy monoclonal gammopathy and 
skin changes 
PQC 
Product quality complaints 
PRES 
Posterior reversible encephalopathy syndrome 
QIg 
Quantitative immunoglobulins 
RBC 
Red blood cells 
Rd 
Lenalidomide/dexamethasone 
REMS 
Risk evaluation and mitigation strategy 
SADR 
Serious adverse drug reaction 
SAR 
Suspected adverse reaction 
SC 
Subcutaneous 
sCR 
Stringent complete response 
SAE 
Serious adverse event 
SJS 
Stevens-Johnson Syndrome 
SPD 
Sum of the products of the maximal perpendicular diameters of measured 
lesions 
SPM 
Secondary primary malignancy 
SOP 
Standard operating procedures 

Protocol: LCI-HEM-MYE-KRdD-001 
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IX
SPEP 
Serum protein electrophoresis 
SUSAR 
Suspected unexpected serious adverse reaction 
SUVmax 
Maximum standardized uptake value 
SVR 
Sustained virologic response 
TCR 
T cell receptor 
TEAEs 
Treatment emergent adverse events 
TEN 
Toxic epidermal necrolysis 
TH1 
Type 1 T helper 
TLS 
Tumor lysis syndrome 
TMA 
Thrombotic microangiopathy  
TTNT 
Time to next treatment 
TTP 
Time to progression 
TTP/HUS 
Thrombotic thrombocytopenic purpura/Hemolytic uremic syndrome 
UAP 
Unanticipated problem 
ULN 
Upper limit of normal 
UPEP 
Urine protein electrophoresis 
Vd 
Bortezomib plus dexamethasone 
VGPR 
Very good partial response 
WB-MRI 
Whole body magnetic resonance imaging 
WBC 
White blood cell 
 
 

Protocol: LCI-HEM-MYE-KRdD-001 
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X 
TABLE OF CONTENTS 
SYNOPSIS ...................................................................................................................................... I 
SCHEMA 1: STUDY OVERVIEW .......................................................................................... III 
SCHEMA 2: POST-INDUCTION MRD BASED TREATMENT ALGORITHM .............. IV 
LIST OF ABBREVIATIONS ..................................................................................................... V 
1. 
BACKGROUND AND RATIONALE ............................................................................. 1 
1.1 
Multiple Myeloma (MM) ..................................................................................................... 1 
1.2 
Carfilzomib (Kyprolis®), Lenalidomide (Revlimid®), Dexamethasone (KRd) in MM ..... 1 
1.3 
Daratumumab and Daratumumab+ Hyaluronidase-fihj ...................................................... 3 
1.4 
Study Rationale and Design ................................................................................................. 7 
2. 
OBJECTIVES .................................................................................................................... 9 
2.1 
Primary Objective ................................................................................................................ 9 
2.2 
Secondary Objectives........................................................................................................... 9 
2.3 
Safety Objectives ............................................................................................................... 10 
2.4 
Exploratory Objectives ...................................................................................................... 10 
3. 
SUBJECT SELECTION ................................................................................................. 10 
3.1 
Subject Recruitment ........................................................................................................... 10 
3.2 
Inclusion Criteria ............................................................................................................... 10 
3.3 
Exclusion Criteria .............................................................................................................. 13 
3.4 
Screen Failures ................................................................................................................... 15 
4. 
REGISTRATION ............................................................................................................ 15 
5. 
STUDY PLAN .................................................................................................................. 16 
5.1 
KRd+Daratumumab Induction Regimen ........................................................................... 16 
5.2 
Stem Cell Mobilization and Collection.............................................................................. 17 
5.3 
MRD Based Treatment Algorithm..................................................................................... 18 
5.4 
ASCT for Group B ............................................................................................................. 19 
5.5 
KRd Regimen for Consolidation (Groups B and C) .......................................................... 19 
5.6 
Lenalidomide Maintenance ................................................................................................ 20 
6. 
TREATMENT DETAILS AND DOSE MODIFICATIONS/DELAYS ...................... 20 
6.1 
Carfilzomib ........................................................................................................................ 21 
6.2 
Daratumumab ..................................................................................................................... 25 
6.3 
Lenalidomide ..................................................................................................................... 30 
6.4 
Dexamethasone .................................................................................................................. 32 
6.5 
Supportive Care ................................................................................................................. 34 
6.6 
Concomitant Medication .................................................................................................... 34 
7. 
STUDY CALENDARS .................................................................................................... 37 
7.1 
INDUCTION CALENDAR (28-day cycles) ..................................................................... 38 
7.2 
POST-INDUCTION CALENDAR: GROUP A (28-day cycles) ...................................... 42 
7.3 
POST-INDUCTION CALENDAR: GROUP B (28-day cycles) ...................................... 45 
7.4 
POST-INDUCTION CALENDAR: GROUP C (28-day cycles) ...................................... 49 
8. 
DETAILS ON STUDY PROCEDURES ........................................................................ 53 

Protocol: LCI-HEM-MYE-KRdD-001 
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XI
8.1 
Screening Procedures ......................................................................................................... 53 
8.2 
Induction Procedures ......................................................................................................... 54 
8.3 
Post-Induction Procedures ................................................................................................. 57 
8.4 
Safety Follow-up Visit ....................................................................................................... 61 
8.5 
Follow-up ........................................................................................................................... 62 
8.6 
Biospecimen Correlative Studies ....................................................................................... 62 
9. 
DISCONTINUATION FROM TREATMENT AND STUDY WITHDRAWAL ...... 64 
9.1 
Treatment Discontinuation Criteria ................................................................................... 64 
9.2 
Off Study ............................................................................................................................ 64 
10. 
DRUG INFORMATION ................................................................................................. 65 
10.1 Daratumumab ..................................................................................................................... 65 
10.2 Carfilzomib ........................................................................................................................ 67 
10.3 Lenalidomide ..................................................................................................................... 70 
10.4 Dexamethasone .................................................................................................................. 73 
11. 
DATA AND SAFETY MONITORING PLANS ........................................................... 73 
12. 
ADVERSE EVENTS AND UNANTICIPATED PROBLEMS.................................... 74 
12.1 Definitions.......................................................................................................................... 74 
12.2 Attribution .......................................................................................................................... 79 
12.3 Timing and Reporting ........................................................................................................ 80 
13. 
DISEASE EVALUATION .............................................................................................. 87 
13.1 IMWG 2016 Response Criteria ......................................................................................... 87 
14. 
STATISTICAL CONSIDERATIONS ........................................................................... 90 
14.1 Milestones .......................................................................................................................... 90 
14.2 Sample Size Determination................................................................................................ 91 
14.3 Endpoint Definitions .......................................................................................................... 91 
14.4 Analysis Populations .......................................................................................................... 93 
14.5 Analysis Methods............................................................................................................... 93 
15. 
STUDY COMPLETION OR TERMINATION ............................................................ 96 
15.1 Completion ......................................................................................................................... 96 
15.2 Termination ........................................................................................................................ 97 
16. 
STUDY MANAGEMENT ............................................................................................... 97 
16.1 IRB Approval ..................................................................................................................... 97 
16.2 Informed Consent............................................................................................................... 97 
16.3 Protocol Adherence ............................................................................................................ 97 
16.4 Changes to the Protocol and/or Informed Consent ............................................................ 98 
16.5 Other Protocol Deviations.................................................................................................. 98 
16.6 Retention of Records.......................................................................................................... 98 
16.7 Ethical and Legal Conduct of the Study ............................................................................ 98 
16.8 Confidentiality of Records ................................................................................................. 99 
16.9 Compliance with ClinicalTrials.gov .................................................................................. 99 
17. 
REFERENCES ............................................................................................................... 100 
18. 
APPENDICES ................................................................................................................ 104 

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XII
18.1 Appendix A: ECOG Performance Status ......................................................................... 104 
18.2 Appendix B: Cockcroft-Gault Equation .......................................................................... 105 
18.3 Appendix C: NYHA Classification ................................................................................. 106 
18.4 Appendix D: 2014 IMWG Diagnostic Criteria for MM .................................................. 107 
18.5 Appendix E: Assessment of Asthma Severity ................................................................. 108 
18.6 Appendix F: Assessment of Asthma Control................................................................... 109 

Protocol: LCI-HEM-MYE-KRdD-001 
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1
1. BACKGROUND AND RATIONALE 
1.1 
Multiple Myeloma (MM) 
Multiple myeloma (MM) is a neoplasm of plasma cells that is characterized by osteolytic bone 
lesions and organ damage, such as hypercalcemia, anemia, and renal insufficiency.  Despite 
major advances in therapy, MM is still considered an incurable malignancy.  The introduction of 
immunomodulatory agents (IMiDs; e.g., lenalidomide) and proteasome inhibitors (e.g., 
bortezomib, carfilzomib), coupled with advances in autologous stem cell transplant (ASCT) have 
improved progression free survival (PFS) and overall survival (OS) for MM patients.  
Unfortunately, the majority of patients still suffer relapses with progressively shorter disease-free 
intervals with each relapse.  
 
Relapse in MM, including in those who achieve a complete response (CR) post treatment, is 
likely due to the presence of minimal residual disease (MRD) undetectable by standard disease 
evaluation methods (i.e., assessment of monoclonal proteins in serum and urine and evaluation of 
bone marrow). Regardless of how MRD is measured, studies have consistently shown that MRD 
negative (-) disease is associated with better long-term outcomes in patients who achieve a 
complete response [1]. The International Myeloma Working Group (IMWG) defines MRD (-) as 
absence of clonal plasma cells either by flow cytometry (flow) or next-generation sequencing 
(NGS) provided the validated assay used has a minimum sensitivity of 1 per 105 nucleated cells 
[1]. This assay was recently approved by the FDA, on September 28th, 2018. The results are 
indicated to be interpreted by qualified healthcare professionals in accordance with professional 
guidelines for clinical decision-making in conjunction with other clinicopathological features.  
 Increasingly, MRD is being assessed at the time of response evaluation (within and outside of 
clinical trials) to help further refine the depth of response achieved, and to potentially identify 
those patients who may (or may not) need additional therapy.  
 
Currently, the typical treatment algorithm for good performance status patients with active MM 
includes induction chemotherapy typically comprised of 3 drugs. Post induction newly diagnosed 
(ND) MM patients may proceed to observation, maintenance therapy with single agent 
lenalidomide, or consolidation. Consolidation includes either high dose chemotherapy and ASCT 
in transplant eligible patients, or continuation of the same regimen used for induction. 
Consolidation may be followed by maintenance therapy, usually lenalidomide as a single agent 
continued until relapse or progression [31]. 
 
Common triplet induction regimens that can be used in transplant and non-transplant candidates 
include bortezomib/lenalidomide/dexamethasone, and carfilzomib/lenalidomide/dexamethasone 
[31].  
1.2 
Carfilzomib (Kyprolis®), Lenalidomide (Revlimid®), Dexamethasone (KRd) in MM 
Carfilzomib is an epoxomicin derivative with the ability to irreversibly inhibit proteosomes. It 
has been shown in preclinical and early clinical studies to have activity in MM [2]. In addition, 
when measured against a broad panel of proteases including metallo, aspartyl, and serine 
proteases, carfilzomib demonstrated less reactivity against non-proteasomal proteases when 
compared to bortezomib [3]. Pre/post carfilzomib in vivo pharmacogenomics gene expression 

Protocol: LCI-HEM-MYE-KRdD-001 
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2
profiling data from the University of Arkansas Car-505 protocol (unpublished data) suggests that 
the use of carfilzomib may impact the more proliferative and high risk MM sub-clone in a given 
patient, whereas this effect was not seen with the proteasome inhibitor bortezomib [4].  
1.2.1 Relapsed/Refractory 
The combination of carfilzomib (Kyprolis®) with lenalidomide (Revlimid®) and 
dexamethasone (a regimen termed “KRd”) initially exhibited excellent clinical activity in a 
phase Ib/II clinical trial in relapsed/refractory MM patients. In the dose escalation portion of the 
study (n=40), no maximally tolerated dose (MTD) was identified, and the maximum planned 
dose (MPD; 27mg/m2 of carfilzomib) was recommended for the phase II portion (with an initial 
dose of 20mg/m2 on days 1 and 2 of cycle 1, with the overall dosing regimen defined as 20/27 
mg/m2). The overall response rate (ORR) across the dose escalating cohorts was 62.5% [5]. In 
the phase II portion, 52 patients were enrolled and treated with the combination at the MPD for 
carfilzomib. The ORR in this cohort was 76.9%, and the median PFS was 15.4 months [6]. This 
trial was followed by the open-label phase 3 trial (ASPIRE) trial, wherein KRd was compared to 
Rd in patients with relapsed MM.  Median PFS was significantly improved with the triplet (26.3 
months compared to 17.6 months, p=0.0001). Median OS was not yet reached at the time of the 
analysis, but the OS rate at 24 months favored the triplet (73.3% versus 65%, p=0.04). Notably, 
patients in the KRd arm reported better quality of life as compared to the Rd arm [7]. 
1.2.2 KRd in NDMM Without ASCT 
KRd has also demonstrated unprecedented depth of response in NDMM in several clinical trials. 
In a phase I/II study of KRd in NDMM patients, 53 subjects received up to 24 monthly cycles of 
KRd, with lenalidomide recommended as maintenance therapy off protocol. Grade ≥ 3 AEs 
included hypophosphatemia (25%), hyperglycemia (23%), anemia (21%), thrombocytopenia 
(17%) and neutropenia (17%). 
 
Across all dose cohorts and after 8 cycles of KRd (n=44), the percent who achieved a complete 
response (CR) and stringent CR (sCR) was 34% and 30% respectively. The corresponding 
numbers after 18 cycles were 59% and 51%, respectively.  The 2-year PFS was 92% [8,9]. The 
MPD of carfilzomib (20/36mg/m2) was achieved and administered to 36 of the 53 subjects. Of 
the 36 who received this dose of carfilzomib, the rate of sCR after 8 cycles was 43% (reported in 
supplemental Table 1 from reference 8).   
 
Korde and colleagues evaluated 8 cycles of KRd as induction (at a carfilzomib dose of 20/36 
mg/m2) in 45 patients with NDMM, followed by 24 cycles of lenalidomide in subjects who 
achieved at least stable disease post induction. The most common ≥ Grade 3 adverse events 
(AEs) reported in the NDMM group included hematologic toxicities: lymphopenia (76%), 
thrombocytopenia (24%), leukopenia (20%), anemia (27%), neutropenia (33%), and non-
hematologic toxicities: electrolyte or metabolism disorders (36%). 
 
After 8 cycles of KRd, 90% (38 of 42 evaluable patients) had at least a very good partial 
response (VGPR), with 28 (43%) achieving ≥ CR. The rate of MRD (-) was 100% among the 28 
patients who achieved at least a CR, and as measured via flow; of the 21 who had MRD 
evaluated via NGS, 67% were MRD (-) [10].  MRD status was significantly associated with 
outcome; 12-month PFS for MRD (-) by NGS was 100% versus 95%, p=0.02.   

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1.2.3 KRd in NDMM with ASCT 
To evaluate the effect of incorporating ASCT into the KRd regimen, 72 NDMM patients eligible 
for transplant received 4 monthly cycles of KRd at a dose of 20/36mg/m2 followed by high dose 
chemotherapy and ASCT, 4 cycles of KRd as consolidation, and up to 10 additional cycles of 
KRd as maintenance. Lenalidomide monotherapy was recommended for maintenance therapy off 
protocol after the last cycle of KRd. As of January 2016, and at the end of KRd consolidation 
(i.e., after 8 cycles), CR was achieved in 73% and sCR was achieved in 69% (n=66) which 
increased to 82% at the end of KRd maintenance (n=44). At the end of KRd consolidation, 82% 
(of 33 patients evaluated) and 66% (of 29 evaluated) were MRD (-) after flow and NGS, 
respectively.  After a median follow-up of 17.5 months, the 2-year PFS was 97% for all 76 
patients [11]. Of the MRD (-) group (by NGS and/or flow) at the end of KRd consolidation, the 
2-year PFS was 100%. 
 
In a similar trial conducted in France, 46 patients were enrolled in a phase II study that included 
4 cycles of KRd induction followed by high dose chemotherapy and ASCT. After hematologic 
recovery, 4 additional cycles of KRd were administered as consolidation followed by 1 year of 
lenalidomide maintenance. Post consolidation, 27 of 42 evaluable patients were in sCR (~64%) 
[12].  
 
The data on KRd in NDMM while preliminary, are promising, particularly when combined with 
an ASCT as part of induction therapy. Despite the promising rates of sCR, however, there is still 
significant room for improvement in the treatment of NDMM. 
1.3 
Daratumumab and Daratumumab+ Hyaluronidase-fihj 
Daratumumab is a first-in-class, human IgG1 monoclonal antibody that binds CD38-expressing 
malignant plasma cells with high affinity and induces tumor cell death through diverse 
mechanisms, including complement-dependent cytotoxicity (CDC), antibody-dependent cell-
mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis, and induction of 
apoptosis.   
 
Daratumumab IV  is currently approved by the Food and Drug Administration (FDA) as 
monotherapy in patients with MM who have received at least three prior lines of therapy 
including a proteasome inhibitor (PI) and an IMiD, or who are double refractory to both these 
classes of drugs, and in combination with lenalidomide and dexamethasone (D-Rd), or 
bortezomib and dexamethasone, for the treatment of patients with MM who have received at 
least one prior therapy[41]. Daratumumab is approved with the combination of carfilzomib and 
dexamethasone (D-Kd) in patients who have received one to three prior lines of therapy, and in 
combination with pomalidomide and dexamethasone (D-Pd) in patients who have received at 
least two prior lines of therapy including lenalidomide and a proteasome inhibitor [42]. 
Daratumumab is also approved for use in combination with bortezomib, melphalan and 
prednisone (D-VMP), for patients who are newly diagnosed but cannot receive an autologous 
stem cell transplant, as well as the combination of bortezomib, thalidomide, and dexamethasone 
(D-VTd) for patients who are newly diagnosed and eligible to receive an autologous stem cell 
transplant [42].  
 

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Daratumumab +hyaluronidase-fihj injection (DARZALEX FASPRO™) is given subcutaneously 
into the abdomen, and was recently approved by the Food and Drug Administration (FDA) in 
2020 [41]. It was developed with the goal of decreasing administration times and rates of IRRs in 
MM patients [40]. Daratumumab SC is currently approved as monotherapy in patients with MM 
who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and 
an IMiD, or who are double refractory to both these classes of drugs. Daratumumab 
+hyaluronidase-fihj is also indicated for newly diagnosed MM in combination with lenalidomide 
and dexamethasone  (D-Rd), or bortezomib and dexamethasone (D-Vd), for the treatment of 
patients with MM who have received at least one prior therapy. It is also approved in 
combination with bortezomib, melphalan and prednisone (D-VMP) in newly diagnosed patients 
who are ineligible for an autologous stem cell transplant [41]. 
 
For the most comprehensive nonclinical and clinical information regarding daratumumab or 
daratumumab+ hyaluronidase, refer to the latest versions of the Investigator’s Brochures. Also 
refer to the latest version of the prescribing information for daratumumab and 
daratumumab+hyaluronidase, and to Section 10.1. 
1.3.1 Daratumumab Pharmacokinetics 
The clinical pharmacology assessment of daratumumab SC monotherapy data are available from 
daratumumab SC-dosed subjects in a Phase 1/1b study MMY1004 [Part 2]) and Phase 3 study 
(MMY3012), Phase 2 combination therapy study MMY2040 and population pharmacokinetics 
and exposure-response analyses. In MMY1004, the 1800 mg dose achieved maximum Ctrough 
(Cycle 3 Day 1 predose) values that were similar or greater than the maximum Ctrough observed 
for the approved 16 mg/kg IV dose following the same dose schedule. The PK data from Part 2 
supported the daratumumab SC 1800 mg dose selection for the Phase 3 study. The PK data from 
MMY3012 study demonstrated that daratumumab SC 1800 mg is non-inferior to daratumumab 
IV 16 mg/kg in terms of maximum Ctrough (Cycle 3 Day 1 predose), with the lower bound of 
the 90% CI for the geometric means ratio for daratumumab SC versus daratumumab IV for 
maximum Ctrough (Cycle 3 Day 1 predose) exceeding 80%, thereby meeting the predefined 
non-inferiority criterion.  
 
Additionally, daratumumab SC 1800 mg monotherapy consistently produced lower peak-to-
trough fluctuations, similar or slightly higher trough levels over time, and lower peak 
concentrations compared with daratumumab IV 16 mg/kg monotherapy. Overall, consistent 
daratumumab concentrations were observed across the body weight ranges. As expected, slightly 
higher concentrations were observed for subjects with lower body weights. There was no 
apparent relationship between exposure and safety endpoints (SAEs, Grade 3 or higher TEAEs 
and neutropenia). 
 
The simulated trough concentrations following 6 weekly doses of daratumumab SC 1800 mg for 
combination therapy (daratumumab SC, bortezomib, melphalan, and prednisone [D-VMP], 
daratumumab SC, lenalidomide, and dexamethasone [D-Rd], daratumumab SC, bortezomib, 
lenalidomide, and dexamethasone [D-VRd]) were similar to monotherapy. 
 
Overall, daratumumab SC was well-tolerated with manageable side effects and a significantly 
reduced incidence of IRRs relative to daratumumab IV. The safety profile of daratumumab 

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administered subcutaneously at a flat dose of 1800 mg continued to be generally comparable to 
that of the 16 mg/kg IV formulation [43]. 
 
1.3.2 Daratumumab Nonclinical Studies 
DARZALEX FASPRO™ for subcutaneous injection contains daratumumab and hyaluronidase. 
Mice that were genetically modified to eliminate all CD38 expression (CD38 knockout mice) 
had reduced bone density at birth that recovered by 5 months of age. Data from studies using 
CD38 knockout animal models also suggest the involvement of CD38 in the regulation of 
humoral immune responses (mice), feto-maternal immune tolerance (mice), and early embryonic 
development (frogs). No systemic exposure of hyaluronidase was detected in monkeys given 
22,000 U/kg subcutaneously (12 times higher than the human dose) and there were no effects on 
embryo-fetal development in pregnant mice given 330,000 U/kg hyaluronidase subcutaneously 
daily during organogenesis, which is 45 times higher than the human dose. There were no effects 
on pre- and post-natal development through sexual maturity in offspring of mice treated daily 
from implantation through lactation with 990,000 U/kg hyaluronidase subcutaneously, which is 
134 times higher than the human doses [41].  
 
1.3.3 Daratumumab Clinical Studies  
The approval of daratumumab-SC was based on findings from the COLUMBA (MMY3012) 
study, a phase 3, non-inferiority, randomized, multicenter, open-label clinical trial which showed 
that the maximum Ctrough (Cycle 3 Day 1 predose) and overall response rate to SC 
daratumumab were non-inferior to IV daratumumab in subjects with relapsed or refractory 
multiple myeloma with considerably lower IRRs and reduced administration [40].   
 
1.3.3.1 Daratumumab Monotherapy 
The safety of DARZALEX FASPRO as monotherapy was evaluated in COLUMBA [see 
Clinical Trials (14.2)]. Patients received DARZALEX FASPRO 1,800 mg/30,000 units 
administered subcutaneously or daratumumab 16 mg/kg administered intravenously; each 
administered once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once 
every 4 weeks starting with week 25 until disease progression or unacceptable toxicity. Among 
patients receiving DARZALEX FASPRO, 37% were exposed for 6 months or longer and 1% 
were exposed for greater than one year.  
 
Serious adverse reactions occurred in 26% of patients who received DARZALEX FASPRO. 
Fatal adverse reactions occurred in 5% of patients. Fatal adverse reactions occurring in more 
than 1 patient were general physical health deterioration, septic shock, and respiratory failure.  
Permanent discontinuation due to an adverse reaction occurred in 10% of patients who received 
DARZALEX FASPRO. Adverse reactions resulting in permanent discontinuation of 
DARZALEX FASPRO in more than 2 patients were thrombocytopenia and hypercalcemia.  
Dosage interruptions due to an adverse reaction occurred in 26% of patients who received 
DARZALEX FASPRO. Adverse reactions requiring dosage interruption in >5% of patients 
included thrombocytopenia.  
 

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The most common adverse reaction (≥20%) was upper respiratory tract infection [41].  
 
1.3.3.2 FDA Approved Daratumumab Combinations 
The FDA approval of daratumumab in combination regimens for the treatment of MM was based 
on safety and efficacy data from two randomized phase 3 trials. The primary endpoint in both 
trials was PFS.   
 
Daratumumab + Lenalidomide and Dexamethasone 
The POLLUX trial (also known as MMY3003), randomized 569 patients who had received ≥ 1 
prior line of therapy to lenalidomide and dexamethasone alone or in combination with 
daratumumab [16]. Based on a protocol-specified interim analysis, PFS at 12 months was 
significantly improved in the daratumumab group (83.2%) compared to the control group 
(60.1%) after >7 cycles of therapy. Both the ORR and the rate of ≥CR were also significantly 
higher in the daratumumab group (92.9% versus 76.4%, p<0.001 and 43.1% versus 19.2%, 
p<0.001). In the daratumumab group, 22.4% of patients were MRD (-) as compared with 4.6% in 
the control group (p<0.001); MRD (-) disease was also associated with longer PFS.  
 
The most frequently reported TEAEs (≥20%) in the daratumumab group were neutropenia 
(59.4%), infusion reactions (47.7%), diarrhea (42.8%), fatigue (35.3%), upper respiratory tract 
infection (31.8%), anemia (31.1%), constipation (29.3%), cough (29%), thrombocytopenia 
(26.9%), muscle spasms (25.8%), nasopharyngitis (24%), nausea (24%) and pyrexia (20.1%). 
The most common (≥10%) ≥ Grade 3 TEAEs in the daratumumab arm were neutropenia 
(51.9%), thrombocytopenia (12.7%) and anemia (12.4%). The rates of AEs that led to treatment 
discontinuation were similar between the two arms of this trial. 
 
Daratumumab + Bortezomib and Dexamethasone 
Similar results were observed in the CASTOR trial (also known as MMY3004), which compared 
the combination of daratumumab, bortezomib, and dexamethasone with bortezomib and 
dexamethasone in 498 patients who had received ≥ 1 prior line of therapy [17]. Based on a 
protocol-specified interim analysis, PFS at 12 months after up to 12 cycles of therapy was 
significantly improved in the daratumumab group (60.7%) compared to the control group 
(26.9%). Patients in the daratumumab group experienced significantly better rates of ORR 
(82.9% versus 63.2%, p<0.001), ≥VGPR (59.2% versus 29.1%, p<0.001), and ≥CR (19.2% 
versus 9%, p<0.001).  
 
The most frequently reported TEAEs (≥20%) in the daratumumab group were thrombocytopenia 
(58.8%), IRRs (45.3%), peripheral sensory neuropathy (47.3%), diarrhea (31.7%), anemia 
(26.3%), upper respiratory tract infection (24.7 %), fatigue (21.4%) and cough (23.9%). The 
most common (≥10%) ≥ Grade 3 TEAEs in the daratumumab arm were thrombocytopenia 
(45.3%), anemia (14.4%) and neutropenia (12.8%).  Of note, the rates of ≥Grade 3 infections as 
well as the rates of AEs that led to treatment discontinuation were similar between the two arms 
of this trial. 
 
See section 1.3 for information of other FDA approved combinations of daratumumab in 
NDMM: dara-VTd, dara-VMP, dara-PD, and dara-Kd.  

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Section 1.3 notes information of FDA approved combinations of daratumumab-SC: dara-VMP 
and dara-Rd, and daratumumab with bortezomib + dexamethasone. 
 
1.3.3.3 KRd+Daratumumab in NDMM 
A multi-arm phase I trial of daratumumab in combination with various regimens commonly used 
in NDMM is ongoing (NCT01998971).  As of March 2017, 22 subjects accrued have been 
accrued to the KRd+daratumumab arm. The data was presented at the American Society of 
Clinical Oncology (ASCO) in June 2017. Based on unpublished/embargoed data available to the 
Sponsor-Investigator, no new safety signals have been observed to date. 
1.3.4 Daratumumab Infusion-Related Reactions 
 
Systemic reactions may occur with Dara-SC infusion. Approximately 1 in 10 patients 
experienced an injection related reaction. Most occurred following the first injection and were 
mild. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, 
throat irritation, as well as chills, vomiting and nausea. Less common symptoms were wheezing, 
runny nose, fever, chest discomfort, severe itching of the skin, and hypotension.  
 
1.3.5 Injection-Site Reactions 
 
Localized reactions may occur at the Dara-SC injection site (injection-site reactions). In 
approximately 7 out of 100 patients receiving Dara-SC monotherapy, mild pain or a burning 
sensation was reported at the site of injection in the abdominal wall. Redness and hardening of 
the skin at the injection site was observed and usually disappeared within a few hours after the 
infusion. In general, Dara-SC infusions in the abdominal wall were well tolerated. 
 
Injection-site reactions, all grade 1 and grade 2, were seen in (7%) patients receiving 
subcutaneous Daratumumab + hyaluronidase, with no treatment discontinuations. The only 
injection-site reaction was erythema (2%) [39]   
 
1.4 
Study Rationale and Design 
Daratumumab has demonstrated clinical efficacy in relapsed and relapsed/refractory MM as 
monotherapy as well as in combination with dexamethasone plus either bortezomib or 
lenalidomide. Of note, with the exception of infusion-related reactions, neutropenia and 
thrombocytopenia, the safety profiles of daratumumab in combination with either 
bortezomib/dexamethasone or lenalidomide/dexamethasone is similar to those of the background 
regimens. This suggests that an anti-CD38 monoclonal antibody strategy may add to the efficacy 
of a given novel agent regimen without adding to its toxicity profile. There are a number of 
studies of daratumumab in combination with various regimens other than KRd ongoing in the 
NDMM population (see clinicaltrials.gov, and the daratumumab Investigator’s Brochure). 
Further, the immunomodulatory effects of KRd have a strong potential for synergy with those of 
daratumumab (see Section 1.4.1). 

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Given the clinical activity and safety profile of daratumumab, the standard use of KRd as an 
induction regimen for NDMM, and the preliminary safety data from the phase I trial of 
KRd+daratumumab (see Section 1.3.3.3), we propose a phase II trial designed to evaluate the 
efficacy (rate of ≥ CR) after 8 cycles of KRd+daratumumab as induction therapy in NDMM 
patients (see Schema 1). The rate of ≥ CR will be compared to a historical control rate of 50% 
based on the studies referenced in Section 1.2.2 [8,10], with the aim of improving the rate to 
70% with the addition of daratumumab. This rate would be similar to that achieved with 8 cycles 
of KRd+ASCT (see Section 1.2.3) [11,12]. We have incorporated identical doses of carfilzomib 
and lenalidomide as were used in previous trials of KRd as induction [37,38], and have 
maintained the weekly dose of dexamethasone as 40mg throughout induction. In the Phase I dose 
of KRd+daratumumab, the dose of carfilzomib was higher, at 70mg/m2, yet no new safety 
signals have been reported to date (see Section 1.3.3.3).  Daratumumab subcutaneously will be 
given at 1800mg weekly the first two cycles of induction, twice monthly cycles 3-6, and monthly 
cycles 7-8. 
 
As outlined in Section 1.1, the typical post induction treatment course for NDMM may involve 
continuation of primary (induction) therapy, high dose chemotherapy +ASCT, maintenance 
therapy, or observation. The chosen course depends on a number of factors including response to 
induction, eligibility for transplant, performance status, patient preference etc. While assessment 
of MRD status post treatment is increasingly evaluated in clinical practice and incorporated into 
clinical trials, published data on its utility as a tool to select the optimal post-induction therapy 
are not yet available. Therefore, this trial will also allow us to gather preliminary data on use of 
MRD status to direct post-induction therapy. Specifically, induction will be followed by an 
MRD-based treatment algorithm (see Schema 2), with subjects divided into 3 separate groups: 
 
• Group A: Subjects who are MRD (-) via DNA sequencing post induction will receive 
lenalidomide maintenance or no further treatment, at the discretion of the investigator.  
• Group B: Subjects who remain MRD (+) via DNA sequencing post induction and are 
eligible for transplant will undergo ASCT. Post ASCT, those who remain MRD (+) will 
receive up to 12 cycles of KRd.*  
• Group C: Subjects who remain MRD (+) via DNA sequencing post induction who are 
not eligible for transplant (or defer transplant) will receive up to 12 additional cycles of 
KRd.* 
 
*For subjects in Group B or C, the number of cycles of KRd consolidation (maximum of 12) will 
depend on the MRD status during treatment. MRD status will be evaluated after completion of 
cycles 4, 8 and 12.  Those who convert to MRD (-) via DNA sequencing after cycles 4, 8 or 12 
will permanently discontinue KRd and may receive lenalidomide maintenance or no further 
treatment, at the discretion of the investigator. Those subjects who remain MRD (+) via DNA 
sequencing after 12 cycles of KRd will receive lenalidomide maintenance. When lenalidomide 
maintenance is prescribed for any subject, treatment will continue until relapse, progression, 
intolerance, or consent withdrawal.  
 
All subjects will be followed until relapse or progression. Secondary endpoints in this trial 
include ORR, duration of response (DoR), PFS, time to disease progression (TTP), time to next 

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treatment (TTNT) and OS. Safety endpoints include toxicities related to daratumumab 
administration, other treatment associated AEs, SAEs including deaths on study treatment. A 
number of exploratory objectives will also be evaluated as outlined in Section 2.4, and using 
serial blood and bone marrow samples collected from study subjects as outlined in the Study 
Calendars (Section 7). 
1.4.1 Correlatives 
Beyond a direct anti-MM plasma cell activity, proteasome inhibitor/IMiD drug combinations 
such as KRd have a potent effect on immune effector cells and overall inflammation. 
Carfilzomib and lenalidomide in particular can activate natural killer (NK) cells and enhance NK 
cell-mediated lysis [18]. Bortezomib and lenalidomide have also been shown to promote Type 1 
T helper (TH1) inflammation triggering T helper and cytotoxic T cells expansion [19]. 
Noticeably, dexamethasone can potentiate these strong pro-inflammatory stimuli by altering NK 
cell activating receptor expression [20] and sensitize T cells to anergy signaling [21].  
 
The aforementioned pro-inflammatory pathways triggered by KRd present strong potential 
synergy with daratumumab’s MM-killing mechanism and immune-modulatory effect. Antibody-
dependent cellular cytotoxicity (ADCC) against CD38-positive MM cell lines has been shown 
after incubation with daratumumab and peripheral blood mononuclear cells (PBMCs) enriched 
with NK cells [22]. In addition, depletion of CD38+ regulatory cells promotes TH1 
immunological events (T-helper cells and cytotoxic T-cells expansion and functionality) [23].  
 
In the present study, in order to correlate KRd+daratumumab synergistic activity on antitumor 
immune function with clinical response status (MRD, ORR, PFS or OS) comprehensive 
peripheral immune profiling techniques will be employed throughout each line of therapy (i.e., 
induction, ASCT, consolidation and maintenance). These are outlined in Section 8.6. 
 
Furthermore, changes in bone marrow microenvironment and bone marrow plasma cells (from 
bone marrow biopsies/aspirates performed after each line of therapy) will be investigated at the 
cellular and molecular level. These are also outlined in Section 8.6.2.  
2. OBJECTIVES 
2.1 
Primary Objective 
The primary objective is to evaluate the efficacy of daratumumab when combined with KRd as 
induction chemotherapy, in terms of complete response or better, in subjects with newly 
diagnosed multiple myeloma.   
2.2 
Secondary Objectives 
Secondary objectives include evaluation of daratumumab in combination with KRd by 
estimating Progression-free survival (PFS), Overall survival (OS), Time to disease progression 
(TTP), Overall response rate (ORR), Duration of response (DoR) and Time to next treatment 
(TTNT).  

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2.3 
Safety Objectives 
The safety objectives will include evaluation of study drug administration, adverse events 
assessed by NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.03, serious 
adverse events including deaths on study treatment.  
2.4 
Exploratory Objectives 
• Explore PET/CT response as an imaging correlate endpoint. 
• Explore stem cell yield after KRd-dara induction 
• Explore minimal residual disease (MRD) by: 
o Euro-flow criteria 
o DNA-PCR (Adaptive Technologies) 
• Explore correlation of systemic immune profiling with measurements of clinical response 
such as MRD, ORR, PFS and OS by performing: 
o Cytokine profiling by multiplex protein assay 
o Blood immunotyping [including NK, NK-T and T cell subsets distribution and 
activation analyses] by flow cytometry 
• Explore correlation of circulating T cell receptor (TCR) repertoire immuno-sequencing 
by NGS with parameters of clinical response such as MRD, ORR, PFS and OS. 
• Examine changes in biology of BM and BM plasma cells before and after treatment(s) by 
B cell receptor (BCR) sequencing and global gene expression profiling 
• Evaluate efficacy outcomes and safety data as a function of post-induction MRD status 
3. SUBJECT SELECTION 
3.1 
Subject Recruitment 
Subjects will be recruited at Levine Cancer Institute (LCI) locations and possibly at other 
participating sites. 
 
Because no dosing or adverse event data are currently available on the use of daratumumab in 
combination with KRd in subjects <18 years of age, children are excluded from this study. In 
addition, MM is not a disease typically diagnosed in those <18 years of age. 
3.2 
Inclusion Criteria 
Subject must meet all of the following applicable inclusion criteria to participate in this study: 
 
1. Written informed consent and HIPAA authorization for release of personal health 
information signed by the subject or his/her legally authorized representative. NOTE:  
HIPAA authorization may be included in the informed consent or obtained separately. 
 
2. Age ≥ 18 years at the time of consent.  
 
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 (see Appendix 
A, Section 18.1) within 28 days prior to day 1 of treatment. 
 

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4. Confirmation of newly diagnosed multiple myeloma (NDMM) as per the IMWG 2014 
criteria (see Appendix D, Section 18.4). Newly diagnosed MM patients who may have 
deferred transplant are also allowed. 
 
5. Measurable disease present at baseline assessments. Baseline disease assessments are 
defined as disease assessments collected within 28 days of initiation of the first pre-study  
induction chemotherapy cycle (subjects who received prior therapy) or within 28 days 
prior to day 1 of study treatment (subjects with no prior therapy). Measurable disease is 
defined as: 
a. Serum M-protein ≥1 g/dL (> 0.5 g/dL for IgA or IgM) OR   
b. Urine M-protein ≥200 mg/24 h OR  
c. Involved free light chain (FLC) level ≥10 mg/dL provided serum FLC ratio is 
abnormal   
 
6. No more than one prior cycle of systemic chemotherapy for MM (to accommodate 
subjects who needed emergent therapy at diagnosis); any prior radiotherapy must be 
completed at least 14 days prior to day 1 of study treatment. No more than 6 weeks 
should occur between completing the pre-study cycle of systemic chemotherapy and 
C1D1 of study treatment. It is acceptable for subjects to receive the pre-study cycle 
during study screening as long as subjects have recovered from treatment-induced 
toxicities to ≤grade 1 or baseline prior to C1D1.  
 
7. Demonstrate adequate organ function within 1 week of day 1 of treatment as defined in 
the table below:  
System 
Laboratory Value 
Hematological 
White Blood Cell (WBC)  
≥ 2,000/mm3 
Absolute Neutrophil Count (ANC) 
≥ 1,000/mm3 without growth factors 
within 1 week of day 1 of treatment 
Hemoglobin (Hgb) 
≥ 8 g/dL 
Platelet count  
≥ 70,000/mm3 if bone marrow 
plasmacytosis of <50%; otherwise ≥ 
50,000/mm3 
Renal 
Creatinine clearance  
 creatinine clearance≥ 30 mL/min as 
measured by a 24-hour urine collection, 
or estimated by the Cockcroft – Gault 
formula1 
Hepatic 
Bilirubin 
≤2 × ULN; < 3.0 for subjects with 
Gilbert’s Syndrome  
Aspartate aminotransferase (AST) 
≤ 3× ULN 
Alanine aminotransferase (ALT) 
≤ 3 × ULN 
1See formula in Appendix B, Section 18.2  
 

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8. Adequate cardiac function as defined by ≥45% Left Ventricular Ejection Fraction (LVEF) 
by ECHO or MUGA  
 
9. Females of childbearing potential (FCBP) must have a negative serum pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to day 1 of 
treatment and be willing to undergo serial serum or urine pregnancy testing. NOTE: Females 
are considered of child bearing potential unless they are surgically sterile (have undergone a 
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are postmenopausal (at 
least 12 consecutive months with no menses without an alternative medical cause). 
 
10. FCBP must be willing to use a highly effective contraceptive method (i.e., achieves a 
failure rate of <1% per year when used consistently and correctly) plus a second 
contraceptive method (considered acceptable [failure rate of >1% per year] or highly 
effective) from the time of informed consent until 3 months after the last protocol 
prescribed therapy (which also includes FCBP on carfilzomib) has been discontinued. 
NOTE: estrogens may further increase the risk of thrombosis (beyond that 
associated with lenalidomide) and their use should be based on a benefit-risk 
decision. For the highly effective contraceptive method, a method with low user 
dependency is preferable but not required (see tables, adapted from: 
2020_09_HMA_CTFG_Contraception_guidance_Version_1.1_updated.pdf 
 
 
Highly Effective Birth Control Methods  
• combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation 
o oral 
o intravaginal 
o transdermal 
• progestogen-only hormonal contraception associated with inhibition of ovulation 
o oral 
o injectable 
o implantable2 
• intrauterine device (IUD) 2 
• intrauterine hormone-releasing system (IUS) 2 
• 
vasectomised partner 2,3 
• sexual abstinence 4 
1 Hormonal contraception may be susceptible to interaction with the investigational medicinal 
product (IMP), which may reduce the efficacy of the contraception method  
2 Contraception methods that in the context of this guidance are considered to have low user 
dependency.  
3 Vasectomised partner is a highly effective birth control method provided that partner is the 
sole sexual partner of the WOCBP trial participant and that the vasectomised partner has 
received medical assessment of the surgical success.  
4 In the context of this guidance sexual abstinence is considered a highly effective method only 
if defined as refraining from heterosexual intercourse during the entire period of risk associated 
with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the clinical trial and the preferred and usual lifestyle of the subject. 

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Acceptable Birth Control Methods  
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not 
the primary mode of action 
• Male or female condom with or without spermicide1 
• 
Cap, diaphragm or sponge with spermicide1 
1A combination of male condom with either cap, diaphragm or sponge with spermicide (double 
barrier methods) are also considered acceptable, but not highly effective, birth control methods. 
 
 
11. Male subjects (even those who have had a vasectomy) who are sexually active with a 
FCBP must be willing to use latex or synthetic condoms from initiation of study 
treatment until 3 months after the last protocol prescribed therapy has been discontinued. 
They must also refrain from donating sperm for at least 90 days after the last dose of 
carfilzomib and at least 90 days from the last dose of daratumumab. The FCBP partner 
should also consider contraception recommendations (see inclusion #10). 
 
12. As determined by the enrolling physician, ability of the subject to understand and comply 
with study procedures for the entire length of the study. 
3.3 
Exclusion Criteria 
Subjects meeting any of the criteria below may not participate in the study: 
 
1. Any infection requiring systemic therapy (i.e. involving IV antibiotics) (NOTE: at 
discretion of investigator, subjects with uncomplicated urinary tract infections may be 
eligible). 
 
2. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the 
mother is being treated on study, and any female subject must agree not to donate eggs 
during the study and for 3 months after the last protocol prescribed therapy has been 
discontinued). 
 
3. Known previous or concurrent malignancies in the last two years other than multiple 
myeloma are excluded. The only allowed exceptions are:  
• Adequately treated non-invasive bladder cancer that is considered cured 
• Adequately treated skin cancer (non-melanoma or melanoma) that is considered cured 
• Adequately treated non-invasive cervical cancer that is considered cured 
• Adequately treated localized prostate cancer considered to have a very low risk of 
recurrence 
• Adequately treated lobular carcinoma in situ, ductal carcinoma in situ, or localized 
breast cancer considered to have a very low risk of recurrence 
• Other malignancy that is considered cured with minimal risk of recurrence from 
which the patient has been disease free for at least 2 years 
• The participant must not be receiving active therapy, other than hormonal therapy for 
other malignancy  
 

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4. Non-secretory MM. 
 
5. Active involvement of the central nervous system by MM. 
 
6. Prior cardiovascular cerebrovascular accident with persistent neurological deficit. 
 
7. Has chronic obstructive pulmonary disease with a forced expiratory volume in 1 second 
(FEV1) < 50% of predicted normal.  FEV1 is required for subjects suspected of having 
chronic obstructive pulmonary disease and are not eligible if FEV1 is < 50% of predicted 
normal. 
 
8. Has had moderate or severe persistent asthma within the past 2 years from enrollment 
and/or has currently uncontrolled asthma of any classification, as defined by the National 
Asthma Education and Prevention Program/NIH (see Appendix 18.5 and 18.6). Note that 
participants who currently have controlled intermittent asthma or controlled mild 
persistent asthma are allowed to participate. 
 
9. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, 
endocrinopathy, monoclonal protein, and skin changes). 
 
10. Had major surgery within 2 weeks prior to day 1 of treatment. Kyphoplasty is not 
considered major surgery. 
 
11. Exposure to any investigational drug (including investigational vaccine) or invasive 
investigational medical device within 4 weeks or 5 pharmacokinetic half-lives prior to 
day 1 of treatment, whichever is longer. 
 
12. Uncontrolled clinically significant illness including, but not limited to, uncontrolled 
hypertension (as per the most updated Joint National Committee for the Management of 
Hypertension definitions), symptomatic congestive heart failure (as per New York Heart 
Association [NYHA] class III or IV [see Appendix C, Section 18.3], uncontrolled angina 
pectoris, myocardial infarction within the past 6 months from consent, known or 
suspected amyloidosis, uncontrolled cardiac arrhythmia, psychiatric illness/social 
situations that would limit compliance with study requirements as determined by the 
investigator, or any other condition (including laboratory abnormalities) that would, in 
the opinion of the investigator, place the subject at unacceptable risk if he/she were to 
participate in the study. 
 
13. Known allergies, hypersensitivity or intolerance to monoclonal antibodies or human 
proteins, daratumumab+hyaluronidase or its excipients or known sensitivity to 
mammalian-derived products, carfilzomib or its excipients, lenalidomide or its excipients, 
or dexamethasone or its excipients. 
 
14. Is seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen 
[HBsAg]). Subjects with resolved infection (i.e. subjects who are HBsAg negative but 
positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to 

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15
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 HBV vaccination, do not need to be tested for HBV DNA by PCR.  
 
15. Is known to be 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). Subject is not required to have hepatitis C testing at screening. 
 
16. Is known to be seropositive for human immunodeficiency virus. 
 
17. Transplant ineligible subjects > 70 years old only: Defined frail, per IMWG criteria of 
‘frailty’ [32]. Frailty assessment does not need to be performed unless the subject is 
transplant ineligible and > 70 years old. “Frail” is defined as a frailty score of ≥ 2.  
 
18. Prior or current exposure to daratumumab or other anti-CD-38 therapies.  
• Prior or current exposure to daratumumab will be allowed if administered with a pre-
study cycle of induction chemotherapy that consists of carfilzomib, lenalidomide and 
dexamethasone OR bortezomib, lenalidomide and dexamethasone. 
• Prior or current exposure to daratumumab must be in accordance with Section 3.2, 
Inclusion #6: No more than one prior cycle of systemic therapy (completed within 6 
weeks of consent) for MM (to accommodate subjects who needed emergent therapy 
at diagnosis); any prior radiotherapy must be completed at least 14 days prior to day 1 
of treatment. Subject must have recovered from treatment-induced toxicities to 
≤grade 1 or baseline. 
 
19. Focal radiation therapy within 14 days prior to C1D1 with the exception of palliative 
radiotherapy for symptomatic management but not on measurable extramedullary 
plasmacytoma.  
 
3.4 
Screen Failures 
A subject who, for any reason (e.g. failure to satisfy the selection criteria or withdraws consent), 
terminates his/her study participation before receiving the first dose of study treatment is 
regarded as a “screen failure.” All screen failures will be tracked.  Reason (e.g. specific 
inclusion/exclusion criteria) for screen failure will be recorded in the CTMS. Enrollment will 
continue until the targeted sample size in the evaluable population (Section 14.4) is achieved. 
4. REGISTRATION  
Following informed consent, subjects will be registered by the Coordinating Center and assigned 
a Sequence Number.  A subject is considered registered when they are assigned a Sequence 
Number.  

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5. STUDY PLAN  
See Schema 1 and Schema 2. 
 
This single arm, two-stage, open-label Phase II study is designed with the primary objective of 
evaluating the efficacy of induction therapy comprised of 8 cycles of carfilzomib, lenalidomide, 
dexamethasone and daratumumab (KRd+daratumumab) in terms of complete response or better 
in subjects with NDMM and comparing to relevant historical controls. After induction, all 
subjects will undergo disease evaluation. Those who experience ≥VGPR will undergo an 
assessment of minimal residual disease (MRD) and will be classified as MRD (+) or MRD (-) as 
determined by MRD via DNA sequencing. (NOTE: MRD will be evaluated via flow cytometry 
and DNA sequencing. If MRD via DNA sequencing detects MRD, the subject will be classified 
as MRD (+)).  Those with <VGPR will be considered to have MRD (+) disease and will follow 
MRD (+) algorithm. Based on MRD DNA sequencing results, subjects will be divided into 3 
separate treatment groups (see Schema 2). All treatment decisions will be based from MRD via 
DNA sequencing results. Subsequent MRD assessments (as outlined in Schema 2) will follow 
the same paradigm described above for the post-induction disease assessment. All subjects in 
each group will be followed until relapse or progression. 
 
For subjects who completed a pre-study cycle of induction chemotherapy containing 
daratumumab and/or carfilzomib, only 7 cycles of KRdD Induction should be given. 
 
All subjects considered eligible for transplant (as per institutional standards based on age, 
medical history, overall health, co-morbid conditions, physical examination and laboratory 
studies) will undergo stem cell mobilization and collection any time after Cycle 3 of induction. 
Given difficulties with stem cell mobilization later during KRD-dara induction, initial attempt at 
stem cell collection is preferred after C3 or C4 of induction. (per investigator discretion; see 
Section 5.2 and Induction Calendar Section 7.1).  
 
This study will initially open as a single center study at LCI and additional investigational site(s) 
may be added following activation at the coordinating center. We anticipate subjects will be 
accrued over 24 months. 
5.1 
KRd+Daratumumab Induction Regimen  
All subjects enrolled will receive KRd+daratumumab induction. See Section 6 for details on drug 
administration and dose modifications/delays. 
 
 
 
 
 
 
 
 
 

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5.1.1 Table 1: Overview of KRd+Daratumumab Induction Regimen (Daratumumab SC) 
 
Drug 
Dose 
Route 
Schedule 
4-Week (28D) 
Cycle 
Carfilzomiba,b 
20 mg/m2  
IV 
D1 
Cycle 1▲ 
Carfilzomiba,b 
56 mg/m2 
IV 
D 8, 15  
Cycle 1▲ 
Carfilzomiba,b 
56 mg/m2 
IV 
D1, 8, 15  
Cycles 2-8* 
Lenalidomidec  
25 mg 
Oral 
Once a day on D1-21 
Cycles 1-8* 
Dexamethasoned  
40 mg 
Oral/IV  
Once weekly on D1, 8, 15, 22 
Cycles 1-8* 
Daratumumab 
1800 mg 
SC  
D1, 8, 15, 22 
Cycles 1-2▲  
Daratumumab 
1800 mg 
SC  
Twice Monthly on D1, D15 
Cycles 3-6▲ 
Daratumumab 
1800 mg 
SC  
Once monthly on D1 
Cycles 7-8*▲ 
a Calculate the dose using the subject’s actual body surface area (BSA) at baseline (the most recent weight collected prior to 
study treatment on C1D1). For subjects with a BSA >2.2m2, calculate the dose based upon a BSA of 2.2m2. NOTE: Use the 
subject’s actual (not ideal) body weight for dosing as per the American Society of Clinical Oncology (ASCO) guidelines on 
dosing of obese adult subjects.  If a subject’s weight changes by more than 20% from cycle 1 day 1 the dose of carfilzomib 
should be recalculated. 
b NOTE: In subjects who enroll with a bilirubin and/or AST >1 x ULN, the starting dose of carfilzomib should be reduced by 
25% to 42 mg/m2 (maintain the first dose of 20mg/m2). The dose may be escalated to 56mg/m2 if both bilirubin and AST 
resolve to ≤ ULN. 
c For subjects who enroll with a CrCl between 30-50 mL/min, the starting dose of lenalidomide may be reduced to 10mg 
d At discretion of the investigator, dexamethasone may be given as 20mg over 2 consecutive days each week. Additionally, 
dexamethasone may be given at 20 mg once weekly for subjects >75 years old, diabetic subjects, and underweight subjects. 
 
▲For subjects who received daratumumab and/or carfilzomib as part of a cycle of pre-study 
induction chemotherapy, this should be considered Cycle 1 of daratumumab and /or carfilzomib, 
and they should enter the study as Cycle 1, but receiving the standard Cycle 2 schedule of 
daratumumab and/or carfilzomib.  
(For example: 
• 
If subject receives daratumumab without carfilzomib in a pre-study cycle, the subject will enter the study on 
Cycle 1 with the Cycle 2 schedule of daratumumab dosing and will receive carfilzomib with Cycle 1 schedule of 
carfilzomib dosing during their on-study Cycle 1.  
• 
If a subject receives carfilzomib without daratumumab in a pre-study cycle, the subject will enter the study on 
Cycle 1 with the Cycle 2 schedule of carfilzomib dosing and will receive daratumumab with the Cycle 1 
schedule of daratumumab dosing during their on-study Cycle 1.  
• 
If a subject received both daratumumab and carfilzomib in a pre-study cycle, the subject will enter the study 
on Cycle 1 with the Cycle 2 schedule of dosing for both daratumumab and carfilzomib during their on-study 
Cycle 1.) 
 
*NOTE: For subjects who completed a pre-study cycle of induction chemotherapy, only 7 cycles of 
KRdD Induction should be given. 
 
 
5.2 
Stem Cell Mobilization and Collection 
All subjects who are considered eligible for transplant at the discretion of the investigator (and as 
per institutional standards based on age, medical history, overall health, co-morbid conditions, 
physical examination and laboratory studies) will undergo stem cell mobilization and collection, 

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18
any time after Cycle 3 of induction. Given difficulties with stem cell mobilization later during 
KRD-dara induction, initial attempt at stem cell collection is preferred after C3 or C4 of 
induction. This will be completed with the hematopoietic growth factor G-CSF (filgrastim or 
equivalent) with or without the chemokine receptor type 4 (CXCR4) antagonist plerixafor, as per 
institutional standards. Collection and freezing of stem cells should be performed as per 
institutional standards. For subjects who fail collection of adequate stem cells during induction or 
post-induction, re-attempts at mobilization and stem cell collection are acceptable during 
maintenance therapy per investigator discretion. Treatment can be held during mobilization/ 
collection per investigator discretion, and it will not be considered a protocol deviation. 
 
AEs related to mobilization do not need to be reported. However, any AEs considered related to 
induction (i.e., either daratumumab, carfilzomib, lenalidomide and/or dexamethasone) should 
continue to be reported.   
5.3 
MRD Based Treatment Algorithm  
After completion of 8 cycles of induction, those subjects who experience ≥VGPR will undergo 
an assessment of MRD by flow cytometry and DNA sequencing and will be classified as MRD 
(+) or MRD (-) as determined by MRD via DNA sequencing. Those with <VGPR will be 
considered to have MRD (+) disease. Results of MRD testing via DNA sequencing will be used 
to separate subjects into Group A [MRD (-)], Group B [MRD (+) and eligible for transplant] 
and Group C [MRD (+) and NOT eligible (or defer) for transplant]. If a subject does not have an 
NGS MRD test report available (for whatever reason), the subject will be assumed to be MRD 
+ and will receive treatment as though MRD+ per the algorithm. Subjects who do not have an 
adequate baseline NGS MRD sample (for whatever reason) will be considered MRD 
unevaluable and will receive treatment as though MRD + for all subsequent MRD time-points. 
Also, all subsequent protocol directed NGS MRD samples do not need to be collected for these 
subjects. NOTE: The 10-⁵ MRD result from the NGS MRD test will be used for treatment 
decisions. 
5.3.1 Group A 
Subjects who are MRD (-) post induction via DNA sequencing may receive lenalidomide 
maintenance (as per Section 5.6) until relapse or progression or no further treatment, at the 
discretion of the investigator.  If prescribed in transplant eligible subjects, lenalidomide 
maintenance therapy may begin after recovery from stem cell mobilization and collection. 
5.3.2 Group B 
Subjects who are MRD (+) via DNA sequencing and eligible for transplant will undergo high 
dose chemotherapy (HDC) and ASCT (as per Section 5.4), followed by a second MRD 
evaluation. Results of the second MRD testing via DNA sequencing will be used to determine 
subsequent treatment: any Group B subject who converts to MRD (-) disease via DNA 
sequencing after ASCT may receive lenalidomide maintenance (as per Section 5.6) until relapse 
or progression or no further treatment, at the discretion of the investigator; any Group B subject 
who is MRD (+) via DNA sequencing after ASCT will receive up to 12 cycles of KRd 
consolidation (as per Section 5.5). The number of cycles will depend on the MRD status via 
DNA sequencing during treatment. MRD status will be evaluated after completion of cycles 4, 8 
and 12.  Any subject who converts to MRD (-) via DNA sequencing disease after 4, 8 or 12 

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cycles of KRd consolidation will permanently discontinue KRd and may receive lenalidomide 
maintenance (as per Section 5.6) until relapse or progression or no further treatment, at the 
discretion of the investigator. Those who have MRD (+) disease via DNA sequencing after 12 
cycles of KRd consolidation will receive lenalidomide maintenance until relapse or progression 
(as per Section 5.6). 
5.3.3 Group C 
Subjects who are MRD (+) via DNA sequencing and NOT eligible for or defer transplant will 
receive up to 12 cycles of KRd consolidation (as per Section 5.5). The number of cycles will 
depend on the MRD status via DNA sequencing during treatment. MRD status will be evaluated 
after completion of cycles 4, 8 and 12.  
 
Any subject who converts to MRD (-) disease via DNA sequencing after 4, 8 or 12 cycles of 
KRd consolidation will permanently discontinue KRd and may receive lenalidomide 
maintenance (as per Section 5.6) until relapse or progression or no further treatment, at the 
discretion of the investigator. Those who have MRD (+) disease via DNA sequencing after 12 
cycles of KRd consolidation will receive lenalidomide maintenance until relapse or progression 
(as per Section 5.6). 
5.4 
ASCT for Group B 
After recovery from stem cell mobilization and collection, HDT (melphalan) should be 
administered followed by ASCT, as per institutional standards, including any necessary 
prophylactic antibiotics, hematopoietic growth factors, and other supportive care during and post 
ASCT. AEs related to HDC and ASCT do not need to be reported. However, any AEs 
considered related to induction (i.e., either daratumumab, carfilzomib, lenalidomide and/or 
dexamethasone) should continue to be reported.   
 
Disease evaluation after ASCT will take place after engraftment is complete, as defined per 
institutional standards. Subsequent treatment can be initiated at the discretion of the investigator 
after disease evaluation and recovery from ASCT (~60-100 days post ASCT). 
5.5 
KRd Regimen for Consolidation (Groups B and C)  
 
Table 2: Overview of KRd Regimen for Consolidation  
 
Drug 
Dose 
Route 
Schedule 
4-Week 
(28D) Cycle 
Carfilzomiba 
56 mg/m2 or LTDb 
 
IV over 
approximately 
30 minutes 
On days D1, 8, 15 
Cycles 1-12d 
Lenalidomide  
10-15 mgc 
Oral 
Once a day on D1-21 
Cycles 1-12d 
Dexamethasone  
20 mg or LTDb 
Oral/IV 
Once every 2 weeks on 
D1,15 
Cycles 1-12d 

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aCalculate the dose using the subject’s actual body surface area (BSA) at baseline (baseline weight in consolidation is defined 
as the most recent weight prior to initiation of C1D1 of consolidation). For subjects with a BSA >2.2m2, calculate the dose 
based upon a BSA of 2.2m2. If a subject’s weight changes by more than 20% from cycle 1 day 1 of consolidation the dose of 
carfilzomib should be recalculated. NOTE: Use the subject’s actual (not ideal) body weight for dosing as per the American 
Society of Clinical Oncology (ASCO) guidelines on dosing of obese adult subjects. 
bLTD= last tolerated dose from end of induction 
c10 or 15 mg orally at discretion of investigator 
d Subjects will receive up to 12 cycles, depending on MRD status via DNA sequencing during treatment, see Sections 5.3.2 
and 5.3.3. 
 
5.6 
Lenalidomide Maintenance  
Revlimid is currently FDA approved for maintenance in patients following a stem cell transplant 
until disease progression and in patients who do not receive a stem cell transplant irrespective of 
depth of response.  The role of stopping treatment for MRD negative patients is investigational. 
 
Table 3: Lenalidomide Maintenance 
 
Drug 
Dose 
Route 
Schedule 
4-Week (28D) Cycle 
Lenalidomide  
10 mg or LTDa 
Oral 
Once a day on D1-21 
Until relapse or 
progression 
aLTD= last tolerated dose (if <10 mg) 
 
For subjects receiving lenalidomide for maintenance, creatinine clearance should be reviewed, 
and dosing followed per Section 6.3.2.2. 
 
6. TREATMENT DETAILS AND DOSE MODIFICATIONS/DELAYS 
Any subject who receives treatment on this protocol will be evaluable for toxicity.  Each subject 
will be assessed periodically for the development of any toxicity according to the Study 
Calendars.  Toxicity will be assessed according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), v4.03. Dose adjustments should be made 
according to the system showing the greatest degree of toxicity.  
 
In the event of a possible drug-related toxicity, the investigator should, to the best of his/her 
ability, assess its relationship to each of the drugs within the regimen when KRd + daratumumab, 
or KRd are prescribed, or to the combination to the extent possible. Actions outlined in the 
sections below should be instituted for the agent(s) considered likely to be involved. Dose 
modifications different from those stated in the protocol should only be made in consultation 
with the Sponsor-Investigator; unless required for immediate subject safety. NOTE: if any 
agent(s) in the regimen is discontinued, treatment should continue with the remaining agent(s). 
 
If dosing is delayed during a cycle (for any reason), any doses not administered will not be made 
up (i.e., the length of the cycle should be maintained). 

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6.1 
Carfilzomib  
6.1.1 Administration 
If a subject’s weight changes by more than 20% from induction C1D1 (or KRd consolidation 
C1D1), the subject’s BSA and carfilzomib dose should be recalculated. Carfilzomib should be 
administered only after the dose is diluted in 5% Dextrose Injection, USP. 
 
Pre-medications for carfilzomib should be included per investigator discretion. Subjects will 
receive carfilzomib as an intravenous (IV) infusion over approximately 30 minutes as per the 
dose and schedule outlined in Table 1 for induction, and/or in Table 2 for consolidation. If the 
subject has a dedicated line for carfilzomib administration, the line must be flushed with a 
minimum of 20 mL of normal saline prior to and after drug administration. The dose must be 
administered at a facility capable of managing IRRs.  
 
On the days both carfilzomib and daratumumab are due to be administered, carfilzomib will be 
administered first.  
6.1.2 Pre- and Post-Dose Hydration and Monitoring for Carfilzomib 
 
IV hydration will be given immediately prior to carfilzomib per investigator discretion.  This will 
consist of normal saline or other appropriate IV fluid, the volume to be determined per 
investigator discretion.   Subject should remain in clinic for at least 1 hour observation period for 
the first dose on study, and per investigator discretion for subsequent doses. During this period, 
post dose IV hydration (normal saline or other appropriate IV fluid formulation) will be given, 
per investigator discretion.  Subjects should be monitored periodically during this period for 
evidence of fluid overload.  
 
If lactate dehydrogenase (LDH) or uric acid is elevated (and/or in subjects considered still at risk 
for TLS) after the second dose in Cycle 1 of induction, then the recommended IV hydration 
should be given additionally before each remaining dose per investigator discretion.  The goal of 
the hydration program is to maintain robust urine output (e.g. ≥ 2 L/day).  Subjects should be 
monitored periodically during this period for evidence of fluid overload.  
6.1.3 First Dose Effect for Carfilzomib during Induction 
A “first dose effect” has been seen with carfilzomib, which is notable for fever, chills, rigors, 
and/or dyspnea occurring during the evening following the first day of infusion and an increase 
in creatinine on Day 2, which may be the clinical sequelae of rapid tumor lysis and/or cytokine 
release.   Should a “first dose” effect occur at any point during Cycle 1 or 2 of induction, 
treatment with high dose glucocorticoids (e.g. methylprednisolone 50–100 mg) is recommended.  
In addition, intravenous fluids, vasopressors, oxygen, bronchodilators, and acetaminophen 
should be available and instituted, as medically indicated.  
6.1.4 Dose Modifications for Carfilzomib-Related Toxicities 
If a dose of carfilzomib is missed, the subject should not be administered an additional dose, but 
should be given the next usual prescribed dose.  
 

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22
Refer to the following table for carfilzomib dose levels when dose reductions are required during 
induction: 
 
Table 4: Dose Levels for Carfilzomib during Induction 
 
Dose Level 
Dose 
Schedule 
0* 
56 mg/m2  
 
D1, 8, 15 
- 1 
45 mg/m2  
 
D1, 8, 15 
- 2 
36 mg/m2  
 
D1, 8, 15 
- 3 
27 mg/m2  
D1, 8, 15 
-4 
20 mg/m2 
D1, 8, 15 
 
* Dose level 0 refers to the starting dose for carfilzomib during Induction   
Refer to the following table for carfilzomib dose levels when dose reductions are required during 
consolidation: 
 
Table 5: Dose Levels for Carfilzomib during Consolidation 
 
Dose Level 
Dose 
Schedule 
0* 
56 mg/m2  
 
D1, 8, 15 
- 1 
45 mg/m2  
 
D1, 8, 15 
- 2 
36 mg/m2  
 
D1, 8, 15 
-3 
27 mg/m2 
D1, 8, 15 
-4 
20 mg/m2 
D1, 8, 15 
 
* Dose level 0 refers to the starting dose for carfilzomib during Consolidation   
If dose reductions of carfilzomib beyond those levels listed in Tables 4 and 5, this agent should 
be permanently discontinued. 
6.1.4.1 Carfilzomib Hematologic Toxicities 
NOTE: Thrombocytopenia has been transient and typically resolves during the week between 
treatments. 
 
 
 
 
 

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Table 6: Carfilzomib Dose Modifications for Hematologic Toxicities 
 
Toxicity 
Recommended Action 
ANC < 500/mm3 
• For first occurrence: hold dose; resume at same 
dose level once ANC recovers to ≥ 500/mm3  
• For subsequent occurrence(s), hold dose; resume 
with dose reduced by 1 level once ANC recovers to 
≥ 500/mm3  
ANC < 500/mm3 and 
temperature >38.5ºC or 2 
consecutive readings of >38.0ºC 
for 2 hours  
• Hold dose; resume at same dose level once ANC 
returns to baseline and fever resolves 
 
Platelets < 10,000/mm3 or 
evidence of bleeding with 
thrombocytopenia 
• First occurrence: hold dose; resume at same dose 
level once platelets recover to ≥ 10,000/mm3 and/or 
bleeding is controlled 
• For subsequent occurrence(s), hold dose; resume 
with dose reduced by 1 level once platelets recover 
to ≥ 10,000/mm3 and/or bleeding is controlled 
6.1.4.2 Carfilzomib Non-Hematologic Toxicities 
Creatinine clearance (CrCl) changes associated with carfilzomib are mostly transient, reversible, 
and non-cumulative. Renal function must be monitored closely during treatment with 
carfilzomib.  Serum chemistry values, including creatinine, must be obtained and reviewed prior 
to each dose of carfilzomib on Day 1, 8, and 15 of Cycles 1 and 2 during induction, and on Day 1 
and 15 of Cycles 3-8 of induction and all consolidation cycles. Creatinine clearance should be 
calculated on Day 1 of each cycle.  
 
Carfilzomib treatment can cause nausea, vomiting, diarrhea, or constipation sometimes requiring 
the use of antiemetics or antidiarrheals.  Fluid and electrolyte replacement should be 
administered as clinically indicated to prevent dehydration.   
 
Subjects with active or suspected infection of any kind that require systemic treatment should not 
be dosed with carfilzomib until the infection has resolved and if being treated with an anti-
infective(s), the course of antibiotics has been completed.  
 
Subjects with a history of HBV should be closely monitored for signs and symptoms of active 
HBV infection throughout treatment with carfilzomib, including the 30-day safety monitoring 
follow-up period. 
 
Subjects receiving carfilzomib should be monitored for any new or worsening neurologic, 
cognitive or behavioral signs and symptoms that may be suggestive of Progressive Multifocal 
Leukoencephalopathy (PML) as part of the differential diagnosis of central nervous system 
disorders. If PML is suspected, carfilzomib should be held and subjects referred to a specialist 
and appropriate diagnostic testing should be initiated. If a PML diagnosis is confirmed, 
carfilzomib should be permanently discontinued. 
 

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24
 
Table 7: Carfilzomib Dose Modifications for Non-Hematologic Toxicities 
Toxicity 
Recommended Action 
Serum creatinine ≥ 2 X baseline or 
CrCl < 15mL/min, or CrCl 
decreases to ≤ 50% of baseline, or 
need for hemodialysis 
(Creatinine clearance only 
applicable for Day 1 of each cycle) 
• 
Hold dose and continue monitoring renal function  
• 
If attributable to carfilzomib, resume with dose reduced 
by 1 level once renal function has recovered to within 
25% of baseline 
• 
If not attributable to carfilzomib, dosing may be 
resumed at discretion of investigator 
• 
If on hemodialysis, administer the dose after the 
hemodialysis procedure 
 
 
 Grade 2 elevation in total bilirubin 
or AST and/or ALT  
• 
Reduce 1 dose level 
• 
Dose may be re-escalated if LFT return to normal or 
baseline level and DILI* is excluded 
 
Grade ≥ 3 elevation in total 
bilirubin or AST and/or ALT 
• 
Hold dose; resume with dose reduced by 1 level once 
LFT return to normal or baseline level and DILI* is 
excluded 
 
DILI* attributed to carfilzomib 
 
*DILI: clinician has reviewed case and 1) 
established that event is not transient 
elevation of transaminases (there is 
evidence of hepatic synthetic dysfunction 
e.g. coagulopathy) and 2) clinician has 
considered a differential diagnosis, 
investigated for other potential causes (e.g. 
reactivation of viral hepatitis, sepsis, auto-
immune, or other common drug causes) 
and, has concluded that there has been a 
liver injury and that carfilzomib was the 
cause 
 
• 
Discontinue carfilzomib 
 
 
If Posterior Reversible 
Encephalopathy Syndrome (PRES) 
is suspected  
• 
Hold dose; consider evaluation with neuroradiological 
imaging, specifically MRI, for onset of visual or 
neurological symptoms suggestive of PRES. 
• 
If confirmed, permanently discontinue carfilzomib 
• 
If the diagnosis of PRES is excluded and if clinically 
appropriate, restart dose administration 
• 
If PRES recurs, permanently discontinue carfilzomib   
If thrombotic microangiopathy 
(TMA) (TTP/HUS) is suspected 
• 
Hold dose; and manage per standard of care including 
plasma exchange as clinically appropriate 
• 
If TMA is confirmed and related to carfilzomib, 
permanently discontinue 
• 
If diagnosis is excluded, carfilzomib can be re started at 
the previous dose 
• 
If the condition recurs, permanently discontinue 
carfilzomib   

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Hypertensive Urgency/emergency 
(defined as sustained or persistent 
SBO ≥ 180 mmHg or DBP ≥ 
110mmHg) 
 
• 
Hold dose until resolution to baseline and restart at 1 
dose decrement  
If Progressive Multifocal 
Leukoencephalopathy (PML) is 
suspected 
• 
HOLD carfilzomib administration and refer to a 
specialist; appropriate diagnostic testing should be 
initiated 
• 
If the diagnosis of PML is confirmed, permanently 
discontinue carfilzomib 
Active HBV reactivation 
• 
Withhold carfilzomib until the infection is adequately 
controlled. If the benefits outweigh the risks, 
carfilzomib may be resumed with concomitant 
prophylaxis as per local standard of care. Consult a liver 
disease specialist as clinically indicated. 
Active or suspected infection of any 
kind that requires systemic 
treatment 
• 
Hold carfilzomib until the infection has resolved and the 
course of antibiotics has been completed, if being 
treated with an anti-infective(s) 
≥ Grade 3 non-hematologic 
toxicitya 
• 
Hold dose; resume with dose reduced by 1 level once 
resolved or returned to baseline 
aOther than nausea, vomiting or diarrhea that responds to supportive care within 7 days, or Grade 3 fatigue or 
asthenia that lasts <7 days  
 
6.2 
Daratumumab  
6.2.1 Administration 
For Cycle 1 Day 1 of induction, daratumumab dose should be administered only after the 
observation period post carfilzomib is complete. Daratumumab will be administered by 
subcutaneous (SC) injection. See Study Calendar for Induction regarding “blood type and 
screen” requirements of all subjects prior to the first dose.  
 
Daratumumab-SC will be provided as a fixed-dose (1800 mg), combination drug product 
containing rHuPH20 drug substance (2000 U/mL) and daratumumab drug substance (120 
mg/mL) in a single vial.  
 
See Sections 1.3.4 and 10.1.7, and the most up to date prescribing information and Investigator’s 
Brochure for details on IRRs from daratumumab. To reduce the risk of reactions during the 
infusion, subjects should be pre-medicated as outlined in Section 6.2.2. Each daratumumab dose 
must be administered at a facility capable of managing infusion-related reactions. See section 
6.2.5 for management of any daratumumab infusion-related reaction. 
 
Daratumumab (1800 mg) will be administered by SC injection by manual push over 
approximately 3 – 5 minutes in the abdominal subcutaneous tissues in the left/right locations, 
alternating between individual doses. The volume of the SC solution will be 15 mL for the 1800 
mg dose. If the subject experiences pain during the administration, the injection should be paused 

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or slowed. If pausing or slowing the delivery rate does not alleviate the pain, a second injection 
site may be chosen on the opposite side of the abdomen to deliver the remainder of the dose.  
 
Subject should remain in clinic for at least 1 hour observation period for the first dose on study, 
and per investigator discretion for subsequent doses.  Reasons for continued observation on 
subsequent daratumumab infusion may include but are not limited to the following: subjects with 
a higher risk of respiratory complications (e.g., subjects with mild asthma or subjects with COPD 
who have an FEV1 < 80% at screening or developed FEV1 < 80% during the study without any 
medical history), subjects who experience infusion-related reactions with the first injection of 
study drug, subject with decreased condition on day of dosing compared to prior dosing day. The 
dose of daratumumab will remain constant throughout the study. 
 
Vital signs should be measured during Induction per institutional standards but at a minimum 
before the start of injection for all doses. Measurement of vital signs at the end of the injection is 
only required for C1D1 and C1D8 and thereafter per investigator discretion. If the subject 
experiences any significant medical event, then the investigator should assess whether the 
subject should stay overnight for observation. If the subject has not experienced a significant 
medical event but is hospitalized overnight only for observation, then the hospitalization should 
not be reported as an SAE.  
 
6.2.2 Pre-Daratumumab Medications 
 
Cycle 1 of Induction 
On Cycle 1 Day 1 dexamethasone administered as protocol-directed therapy per Section 6.4 will 
be administered at a dose of 40 mg or as 20 mg over 2 doses per investigator discretion and will 
also serve as daratumumab pre-medication given 1-3 hours prior to the daratumumab dose.  
 
All cycles 
All pre- and post- dosing medications to be administered per institutional standards. 
Dexamethasone administered as protocol-directed therapy per Section 6.4 will also serve as 
daratumumab pre-medication given oral/IV 1-3 hours prior to daratumumab dose. 
 
NOTE: Subjects with a history of chronic obstructive pulmonary disease (COPD) may require 
additional post-infusion medications to manage respiratory complications. Consider prescribing 
short- and long-acting bronchodilators and inhaled corticosteroids for subjects with COPD. 
 
The following are recommended guidelines for prevention and management of infusion 
reactions, but can be adjusted per investigator:  
All participants will receive the following medications 1 to 3 hours prior to each study drug 
administration:  
• An antipyretic: paracetamol (acetaminophen) 650-1000 mg IV or PO 
• An antihistamine: diphenhydramine 25-50 mg IV or PO or equivalent. Avoid IV use of 
promethazine.  

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27
o After Cycle 6, if a participant has not developed an infusion-related reaction and 
is intolerant to antihistamines, modifications are acceptable as per investigator 
discretion. 
• Corticosteroids (Long-acting or intermediate-acting):  
o Monotherapy: Methylprednisolone 100 mg, or equivalent, administered 
intravenously. Following the second infusion, the dose of corticosteroid may be 
reduced (oral or intravenous methylprednisolone 60 mg or equivalent).  
o Combination therapy:  
 Administer 20 mg dexamethasone (or equivalent) prior to every 
daratumumab infusion. When dexamethasone is the background regimen 
specific corticosteroid, the dexamethasone treatment dose will instead 
serve as pre-medication on daratumumab infusion days.  
 Dexamethasone is given orally or intravenously prior to the first 
daratumumab infusion and oral administration may be considered prior to 
subsequent infusions.  
o If the subject does not experience a major systemic administration-related reaction 
after the first 3 doses, consider discontinuing the administration of corticosteroids 
(excluding any background regimen-specific corticosteroid). 
 
Pre-dose administration of a leukotriene inhibitor (montelukast 10 mg PO or equivalent) is 
optional in Cycle 1 Day 1 and can be administered up to 24 hours before infusion as per 
investigator discretion.  
 
If necessary, all PO pre-infusion medications may be administered out of the clinic on the day of 
the infusion, provided they are taken within 3 hours before the infusion.  
 
6.2.3 Post-Daratumumab Medications 
 
Cycle 1 of Induction 
Cycle 1 (D1 and D8 only), the subject should take 4mg of dexamethasone orally 24 and 48 hours 
post daratumumab. NOTE: if the 40 mg dose of dexamethasone as part of the KRd regimen is 
given as 20mg over 2 days, the 24-hour 4 mg dose of dexamethasone can be omitted. 
 
The following are recommended guidelines to reduce the risk of delayed infusion related 
reactions, but can be adjusted per investigator:  
• Monotherapy studies: 
o In an effort to prevent delayed infusion-related reactions, all participants will 
receive long- or intermediate-acting corticosteroid orally (20 mg 
methylprednisolone or equivalent in accordance with local standards) on the 2 
days following all daratumumab infusions (beginning the day after the infusion).  
o In the absence of infusion related AEs after the first 3 infusions, post-infusion 
corticosteroids should be administered per investigator discretion.  
• Combination therapy:  
o Consider administering low-dose methylprednisolone (≤ 20 mg) or equivalent, the 
day after the infusion. However, if a background regimen-specific corticosteroid 

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(e.g. dexamethasone) is administered the day after the infusion, additional post-
infusion steroids are not required, but may be considered by the investigator.  
 
All cycles 
Per investigator’s discretion, if high risk participants are not hospitalized for monitoring, a 
follow-up telephone call should be made to monitor their condition within 48 hours (no later than 
72 hours) after all drug administrations. If the participant has not experienced a significant 
medical event but is hospitalized overnight only for observation, then the hospitalization should 
not be reported as a serious adverse event. Investigators may prescribe bronchodilators, H1-
antihistamines, and corticosteroids that are deemed necessary to provide adequate supportive 
care in the event a bronchospasm occurs after participants are released from the hospital/clinic. If 
an at-risk participant experiences no major infusion-related reactions, then these post-
administration medications may be waived after 4 doses at the investigator’s discretion.  
 
6.2.4 Dose Delay for Daratumumab-Related Toxicities  
Dose modification (increase or decrease) of daratumumab is not permitted. Dose delay is the 
primary method for managing daratumumab-related toxicities, as outlined in Sections 6.2.5 and 
6.2.6.  
 
Unless otherwise noted below, daratumumab treatment may be delayed ≤ 4 weeks from the 
expected day of the next treatment for any reason.  If treatment is delayed for > 4 weeks, 
daratumumab will be permanently discontinued.   
 
6.2.5 Infusion-Related Reaction (IRR) for Daratumumab SC 
 
Infusion-related reactions (IRRs) are systemic reactions related to daratumumab administration. 
Participants should be observed carefully during daratumumab administrations. Trained study 
staff at the clinic should be prepared to intervene in case of any IRRs, and resources necessary 
for resuscitation (e.g., agents such as epinephrine and aerosolized bronchodilator, medical 
equipment such as oxygen tanks, tracheostomy equipment, and a defibrillator) must be available 
at the bedside. Attention to staffing should be considered when multiple participants will be 
dosed at the same time. If an IRR develops during Dara SC administration, then the 
administration should be temporarily interrupted. Participants who experience AEs during Dara-
SC administration must be treated for their symptoms. Participants should be treated with 
paracetamol (acetaminophen), antihistamine, or corticosteroids, as needed. Intravenous saline 
may be indicated. For bronchospasm, urticaria, or dyspnea, participants may require 
antihistamines, oxygen, corticosteroids, or bronchodilators. For hypotension, participants may 
require vasopressors. In the event of a life-threatening IRR (which may include pulmonary or 
cardiac events) or an anaphylactic reaction, Dara-SC should be discontinued. 
 
Infusion-related Reactions <Grade 3:  
If the investigator assesses an IRR less than (<) Grade 3 to be related to administration of study 
intervention, then the Dara-SC administration should be interrupted. When the participant's 
condition is stable, Dara-SC administration may be restarted at the investigator's discretion.  

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If the participant experiences a Grade 2 or higher event of laryngeal edema, or a Grade 2 or 
higher event of bronchospasm that does not respond to systemic therapy and does not resolve 
within 6 hours from onset, then the participant must be permanently discontinued from Dara-SC 
treatment. 
 
Infusion-related Reactions Grade 3 or Higher:  
For IRR AEs (other than laryngeal edema or bronchospasm) that are Grade 3, the Dara-SC 
administration must be stopped, and the participant must be observed carefully until resolution of 
the AE or until the intensity of the event decreases to Grade 1, at which point the Dara-SC 
administration may be restarted at the investigator’s discretion.  
If the intensity of the AE returns to Grade 3 after restart of the Dara-SC administration, then the 
participant must be permanently discontinued from Dara-SC treatment.  
For IRR AEs that are Grade 4, the Dara-SC administration must be stopped, and the participant 
permanently discontinued from Dara-SC treatment. 
 
Recurrent Infusion-related Reactions:  
If a Grade 3 IRR (or Grade 2 or higher event of laryngeal edema, or a Grade 2 or higher event of 
bronchospasm) recurs during or within 24 hours after a subsequent Dara-SC administration, the 
participant must be permanently discontinued from Dara-SC treatment. 
 
Injection Site Reactions:  
In clinical studies, SC administration of daratumumab was associated with local injection site 
reactions, such as induration and erythema, in some subjects. The reactions usually resolved 
within 60 minutes. Local injection-site reactions should be managed per institutional standards. 
 
6.2.6 Other Daratumumab Toxicities 
Hold daratumumab for the following hematologic toxicities, regardless of relationship to 
daratumumab: 
• Grade 4 neutropenia 
• ≥Grade 3 or higher thrombocytopenia with bleeding 
• ≥ Grade 3 febrile neutropenia or neutropenia with infection  
 
For other ≥ Grade 3 non-hematologic toxicities, hold daratumumab only if specifically related to 
daratumumab with the following exceptions: 
– Grade 3 nausea that responds to antiemetic treatment within 7 days 
– Grade 3 vomiting that responds to antiemetic treatment within 7 days 
– Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days 
– Grade 3 fatigue or asthenia that lasts for <7 days after the last administration 
of daratumumab 
 
Daratumumab treatment should be resumed when the toxicity has resolved to ≤ Grade 2. If the 
daratumumab administration does not commence within the pre-specified window (Table 8) of 
the scheduled administration date, then the dose will be considered a missed dose.  
 

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Administration may resume at the next planned dosing date. A missed dose will not be made up. 
If the daratumumab is administered within the pre-specified window, the schedule of subsequent 
doses of daratumumab does NOT need to be adjusted. 
 
Table 8:  Allowed Delays of Daratumumab Based on Schedule 
 
Cycles 
Frequency 
If Dose Delay: 
Dosing Resumption 
1-2  
Weekly 
>3 days, miss dose 
next planned weekly dosing 
date  
3-6  
Every 2 weeks  
>14 days, miss dose 
next planned dosing date  
7-8 
Every 4 weeks  
>21 days, miss dose 
next planned dosing date  
 
6.3 
Lenalidomide  
6.3.1 Administration 
Lenalidomide is self-administered and should be taken orally at about the same time each day 
with water. It may be taken on a full or empty stomach. Subjects should not break, chew or open 
capsules. Missed doses of lenalidomide will not be made up. If dosing with lenalidomide is 
delayed due to an extenuating circumstance (e.g., needing a new prescription due to dose 
reduction), a delay of up to 5 days will not be considered a deviation. 
6.3.2 Dose Modification for Lenalidomide-Related Toxicities 
If a dose of lenalidomide is missed, the subject should not take an additional dose, but should 
take the next usual prescribed dose.  
 
Refer to the following table for lenalidomide dose levels when dose reductions are required 
during induction, consolidation or maintenance: 
 
Table 9: Dose Levels for Lenalidomide1 
 
Dose Level 
Dose 
Schedule 
02 
25 mg  
 
D1-21 
- 1 
15mg  
 
D1-21 
- 2 
10mg  
 
D1-21 
- 3 
5mg  
 
D1-21 
- 4 
2.5mg  
D1-21 
- 5 
2.5mg  
 
Every other day during D1-21 
 
1If dose reduction required due to renal dysfunction, see Section 6.3.2.2, Table 11. 

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2 Dose level 0 refers to the starting dose of lenalidomide during Induction 
 
6.3.2.1 Lenalidomide Hematologic Toxicities 
 
Table 10a: Lenalidomide Dose Modifications for Hematologic Toxicities 
 
Toxicity 
Recommended Action 
ANC < 1000/mm3 
• Interrupt lenalidomide 
• Resume at same dose level once ANC recovers to ≥ 
1000/mm3  
• For any recurrence, interrupt lenalidomide; resume 
with dose reduced by 1 level once ANC recovers to 
≥ 1000/mm3  
Platelets < 30,000/mm3 or 
evidence of bleeding with 
thrombocytopenia 
• Interrupt lenalidomide 
• Resume with dose reduced by 1 level once platelet 
count recovers to ≥ 30,000/mm3  
• For any recurrence, interrupt lenalidomide; resume 
with dose reduced by 1 level once platelets recover 
to ≥ 30,000/mm3 
 
Table 10b: Lenalidomide Dose Modifications for Hematologic Toxicities (post auto-HSCT) 
 
Toxicity 
Recommended Action 
ANC < 500/mm3 
• Interrupt lenalidomide, follow CBC weekly 
• Resume at next lower dose continuously for Days 
1-28 of repeated 28-day cycle once ANC recovers 
to ≥ 500/mm3  
• For any recurrence, interrupt lenalidomide; do not 
dose below 5mg daily. Resume at 5 mg daily. 
Platelets < 30,000/mm3 or 
evidence of bleeding with 
thrombocytopenia 
• Interrupt lenalidomide, follow CBC weekly 
• Resume at next lower dose continuously for Days 
1-28 of repeated 28-day cycle once platelet count 
recovers to ≥ 30,000/mm3  
• For any recurrence, interrupt lenalidomide; do not 
dose below 5mg. Resume at 5 mg daily. 
 
6.3.2.2 Lenalidomide Dosing in Renal Impairment 
Because lenalidomide is primarily excreted unchanged by the kidney, adjustments to the dose of 
lenalidomide are recommended in subjects with renal impairment. The recommended doses for 
subjects with multiple myeloma and renal impairment are shown in the table below.  
 
 
 

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Table 11: Lenalidomide Dose Modifications for Renal Impairment 
 
Dose modifications related to creatinine clearance only apply to Day 1 of each cycle. 
 
Renal Function in MM 
Dose 
Frequency 
CrCl >60 mL/min 
10 mg 
Once Daily 
CrCl 30-60 mL/min 
5 mg 
Once Daily 
CrCl <30 mL/min (not 
requiring dialysis) 
2.5 mg 
Once Daily 
CrCl <30 mL/min (requiring 
dialysis) 
2.5 mg 
Once Daily. On dialysis days, 
administer the dose following 
dialysis 
 
6.3.2.3 Lenalidomide: Other Non-specified Non-Hematologic Toxicities 
 
Table 12: Lenalidomide Dose Modifications for Non-Hematologic Toxicities 
 
Toxicity 
Recommended Action 
Other ≥ Grade 3 non-hematologic 
toxicitya 
• Hold dose; resume with dose reduced by 1 level 
once resolved to ≤ Grade 2 
aOther than nausea, vomiting or diarrhea that responds to supportive care within 7 days, or Grade 3 fatigue or 
asthenia that lasts <7 days  
6.4 
Dexamethasone  
6.4.1 Administration 
For induction, the dexamethasone total dose of 40 mg may be taken weekly, or at discretion of 
investigator, as a split dose of 20 mg over 2 consecutive days weekly during the 8 cycles of 
induction. On days when daratumumab is administered, the dexamethasone will serve as 
premedication given 1 to 3 hours prior to each daratumumab infusion (see Section 6.2.2). Note: 
If the dexamethasone split dose of 20 mg is given with daratumumab, the first 20 mg dose will 
be given on the first day of daratumumab.  
 
For KRd consolidation, dexamethasone 20mg (or LTD from end of induction) is to be taken 
every 2 weeks (D1 and D15). 
 
Refer to the following table for dexamethasone dose levels when dose reductions are required 
during induction: 
 
 
 
 
 
 

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Table 13: Dose Levels for Dexamethasone during Induction 
 
Dose Level 
Dose 
Schedule 
0* 
40mg1  
 
D1, 8, 15, 22 
- 1 
20mg  
 
D1, 8, 15, 22 
- 2 
12mg  
 
D1, 8, 15, 22 
 
* Dose level 0 refers to the starting dose of dexamethasone during Induction 
1 At discretion of the investigator, dexamethasone may be administered as a split dose of 20 mg 
over 2 consecutive days weekly during the 8 cycles of induction. 
 
Refer to the following table for dexamethasone dose levels when dose reductions are required 
during consolidation: 
 
Table 14: Dose Levels for Dexamethasone during Consolidation 
 
Dose Level 
Dose 
Schedule 
0* 
20mg  
 
D1, 15 
- 1 
12mg  
 
D1, 15 
- 2 
8mg  
 
D1, 15 
 
* Dose level 0 refers to the starting dose of dexamethasone during Consolidation 
 
If dose reductions of dexamethasone beyond those levels listed in Tables 13 and 14, this agent 
should be permanently discontinued. 
6.4.2 Dose Modifications for Dexamethasone-Related Toxicities 
If a dose of dexamethasone is missed, the subject should not take an additional dose, but should 
take the next usual prescribed dose.  
 
Table 15: Dexamethasone Dose Modifications for Non-Hematologic Toxicities 
 
Toxicity 
Recommendation Action 
Dyspepsia, gastric or duodenal ulcer, 
gastritis  
 
Grade 1-2 (requiring medical 
management) 
 
 
 
Treat with H2 blockers, sucralfate, or 
omeprazole. If symptoms persist despite above 
measures, decrease dexamethasone dose by 1 
dose level. 

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>Grade 3 (requiring hospitalization or 
surgery 
 
Hold dexamethasone until symptoms adequately 
controlled. Restart dexamethasone reduced by 1 
dose level; consider concurrent therapy with H2 
blockers, sucralfate, or omeprazole. If symptoms 
persist despite above measures, discontinue 
dexamethasone permanently. 
Acute pancreatitis 
Discontinue dexamethasone permanently. 
Edema > Grade 3 (limiting function and 
unresponsive to therapy or anasarca) 
Diuretics as needed, and restart dexamethasone 
reduced by 1 dose level; if edema persists 
despite 
above measures, decrease dose another level. 
Discontinue dexamethasone permanently if 
symptoms persist despite second reduction. 
Confusion or mood alteration > Grade 2 
(interfering with function +/– interfering 
with activities of daily living) 
Hold dexamethasone until symptoms resolve. 
Restart dexamethasone reduced by 1 dose level. 
If symptoms persist despite above measures, 
reduce by another dose level. 
Muscle weakness > Grade 2 (symptomatic 
and interfering with function +/– 
interfering with activities of daily living) 
Decrease dexamethasone by 1 dose level. If 
weakness persists, decrease dose by 1 more dose 
level. Discontinue dexamethasone permanently 
if symptoms persist. 
Hyperglycemia ≥ Grade 3 
Treatment with insulin or other hypoglycemic 
agents as needed. If uncontrolled despite above 
measures, decrease dose by 1 dose level until 
levels are satisfactory. 
Other non-hematologic toxicity ≥ Grade 3 
felt related to dexamethasonea 
Hold dexamethasone dose. Resume 
dexamethasone reduced by 1 dose level when 
toxicity has resolved to 
≤Grade 2 or to baseline. If toxicity recurs, 
discontinue dexamethasone permanently. 
aOther than nausea, vomiting or diarrhea that responds to supportive care within 7 days, or 
Grade 3 fatigue or asthenia that was present at baseline or that lasts <7 days 
6.5 
Supportive Care 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Subjects may receive palliative radiation at the discretion of the Sponsor-
Investigator. 
6.6 
Concomitant Medication 
6.6.1 Recommended Medications 
6.6.1.1 Bisphosphonates 
For subjects who have not previously received bisphosphonates, bisphosphonates are 

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35
recommended for all subjects. Bisphosphonate therapy is recommended to be continued per 
treatment guidelines. In addition, denosumab use is also permitted. 
6.6.1.2 Allopurinol 
It is recommended that subjects at high risk for TLS (i.e., those with a high tumor burden, high 
LDH and/or high uric acid level before the start of treatment) be treated prophylactically in 
accordance with local standards including allopurinol 300 mg daily. 
6.6.1.3 Anti-Viral 
Acyclovir or equivalent antiviral should be given to all subjects to decrease the risk of herpes 
zoster reactivation, per institutional prophylaxis guidelines, unless contraindicated. In those 
subjects with a history of herpes zoster infection, antiviral prophylaxis should begin within 1 
week after the initiation of daratumumab and continue until 3 months after daratumumab is 
discontinued. 
 
Primary antiviral prophylaxis is permitted as per local standard of care for management of 
hepatitis B virus reactivation. HBV DNA testing is mandatory for subjects at risk for HBV 
reactivation. Refer to Section 7 for further details. For subjects 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 
prophylaxis as per local standard of care. Consult a liver disease specialist as clinically indicated. 
6.6.1.4 Thromboprophylaxis 
Thromboprophylaxis is recommended for all subjects receiving the combination of carfilzomib, 
lenalidomide and dexamethasone. The regimen of thromboprophylaxis should be based on an 
assessment of the subjects’ underlying risks. Instruct subjects to report immediately any signs 
and symptoms suggestive of thrombotic events.  
6.6.2 Prohibited Medications 
Concomitant administration of investigational agents, other than those mandated by the protocol, 
are prohibited.  
 
No investigational or commercial agents or therapies other than those described may be 
administered with the intent to treat the subject’s malignancy. 
6.6.3 Permitted Medications 
Subjects may receive antiemetics and antidiarrheal agents as necessary. Myeloid growth factors 
may be used if neutropenia occurs but should not be given prophylactically. Subjects may 
receive platelet transfusions if clinically indicated in accordance with institutional guidelines 
Subjects should have anemia treated in accordance with the institutional guidelines (however, 
see Section 6.6.3.1).  
 
All other treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. 

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6.6.3.1 Precautionary Medications 
If an erythropoietic stimulating agents (ESAs) is given for anemia, keep in mind that there is an 
increased risk of thrombosis with lenalidomide and carfilzomib. Include all concomitant 
medications that are not specifically prohibited but require additional monitoring during study 
treatment.

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7. STUDY CALENDARS 
Use the Induction Calendar for all enrolled subjects. Based on disease evaluation after induction, subjects will be divided into 3 separate treatment 
groups (see Schema 2). There is a separate Post-Induction Calendar for each group (Group A, Group B and Group C). After the post-induction 
disease evaluation, use the appropriate Post-Induction Calendar for a given subject. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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7.1 
INDUCTION CALENDAR (28-day cycles) 
 
Study Procedures 
Screening1 
Induction Cycles 1-
22 
Induction Cycles 
3-62 
Induction Cycles 7-
82, 23 
Post-
Induction 
Disease 
Evaluation4 
(only for subjects 
who complete 
induction) 
Safety 
Follow-up24 
(only subjects who 
permanently 
discontinue induction 
early and do not have 
a Post-Induction 
visit) 
Follow-up25 
(only subjects who 
permanently 
discontinue induction 
early and do not have a 
Post-Induction visit) 
Go to appropriate post-induction calendar (A, B or C) based on the MRD based 
treatment algorithm (see Schema 2) 
 
Study Day 
 
1 
8 
15 
22 
1 
8 15 
223 
1 
8 
15 
223 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam5 
X 
Symptom-directed physical exam only 
 
Weight6 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
ECOG Performance 
status 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Vital signs7 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
ECG 
X26 
X1 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
ECHO or MUGA 
  X26 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Forced expiratory 
volume test (subjects 
with COPD) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B (HBV) virus 
serology20 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV DNA testing21 
X 
Every 12 weeks up to 6 months after last dose of Dara 
 
Blood type and screen8 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistries9 
X9 
X1 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
CBCD10, 30 
X 
X1 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Pregnancy test11  
  X11 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
 
AEs & concomitant 
meds 
X 
Monitor continuously (see Section 12.3 for timing of AE/SAE collection) 
 
 
Serum beta2-
microglobulin19 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood and urine for 
disease evaluation12, 19 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
Daratumumab 
Interference Testing 
 
At suspected CR; subjects with IgG Kappa MM only 
Bone marrow aspirate 
and biopsy for disease 
assessment and MRD13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X27 
  
 
Skeletal Survey14 
X 
As clinically indicated 
 
 

Protocol: LCI-HEM-MYE-KRdD-001 
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39
 
Key to Footnotes for Induction  
1 Within 28 days prior to induction cycle 1 day 1 (C1D1) unless otherwise noted; if screening hematology and serum chemistries were performed within 7 days of 
induction C1D1, these do not need to be repeated C1D1; if screening ECG was performed within 14 days of induction C1D1, an ECG does not need to be repeated 
C1D1.  
2 A window of +/- 2 days will be applied to all induction treatment study visits except for blood and urine disease evaluation on Day1 of each cycle. Day 1 blood 
and urine disease evaluation must be done within 7 days prior to Cycle 1 Day 1 (starting with cycle 2, urine disease evaluation can be ±7 days of Day 1 of each 
cycle, blood disease evaluation must remain within 7 days prior to Day 1).  This includes study treatment and required protocol procedures prior to dosing. Every 
effort should be made to maintain consecutive dosing days.  
3 There is no study visit required on D22 of induction cycles 3-8; however, weekly oral dexamethasone schedule includes D22 
4 The primary endpoint (CR or better post induction) will be assessed at the post-induction disease evaluation.  
5 Complete physical exam, including height and neurologic exam to detect peripheral neuropathy, at screening. Thereafter symptom-directed physical exam only. 
During the COVID-19 pandemic, virtual visits may be performed starting with Cycle 2 of induction per investigator discretion. 
6 If a subject’s weight changes by more than 20% from induction C1D1, the dose of carfilzomib should be re-calculated.  
7 Vital signs to include temperature, pulse rate, blood pressure and respiratory rate. Measure at the following time points: For all daratumumab injections, vital 
signs will be measured per institutional standards but at a minimum prior to the start of injection for all doses. Vital signs at the end of the injection only required 
for C1D1 and C1D8 and thereafter per investigator discretion. Subject should remain in clinic for at least 1 hour observation period for the first dose of 
daratumumab and the first of carfilzomib on study, and per investigator discretion for subsequent doses.  
8 ABO and Rh blood typing and indirect antiglobulin test (also known as indirect Coombs test) to be performed any time between screening and initiation of study 
treatment. It is recommended that the subject carry a card with the blood antigen profile at all times during the study. 
Assess extramedullary 
plasmacytomas15 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Carfilzomib16 
 
X 
X 
X 
 
X 
X X 
 
X 
X 
X 
 
 
 
 
Lenalidomide29 
 
Days 1-21 
(oral) 
 
Days 1-21 
(oral) 
 
Days 1-21 
(oral) 
 
 
 
 
Dexamethasone17 
 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
 
 
 
Daratumumab22 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
Blood sample for 
correlatives18 
 
Collect D1 of cycles 1, 3, 5 and 7 
X 
 
 
Stem cell 
mobilization/collection28 
 
May be done any time after Cycle 3 of induction per investigator discretion 
 
 
  Documentation of 
survival and occurrence 
of secondary 
malignancies 
 
X 
Disease Evaluation 
Confirmation Data 
Capture31 
 
X 
 

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40
9 Serum chemistries: BUN, creatinine (with calculated creatinine clearance at Screening and on Day 1 of each cycle), glucose, uric acid, calcium, chloride, 
phosphorus, potassium, sodium, LDH, albumin, total protein, magnesium, total bilirubin, alkaline phosphatase, AST and ALT. NOTE: calcium should also be 
corrected for albumin.  
10 CBCD: complete blood count with differential and platelets 
11 Serum or urine B-HCG in FCBP within 24 hours prior to induction C1D1. Pregnancy testing (serum or urine) must be repeated once a week (D1, 8, 15, 22) in 
induction cycle 1, and then monthly (D1 of each cycle) for subsequent cycles in FCBP. 
12 Tests to include: serum quantitative immunoglobulins (QIg; including IgA, IgM, IgG, IgD**, IgE**), serum protein electrophoresis (SPEP), urine protein 
electrophoresis (UPEP; 24-hr urine sample required), serum and urine immunofixation, and serum free light chain (FLC). If screening tests were performed within 
14 days of induction C1D1, these do not need to be repeated C1D1. Day 1 blood and urine disease evaluation must be done within 7 days prior to Cycle 1 Day 1 
(starting with cycle 2, urine disease evaluation can be ±7 days of Day 1 of each cycle, blood disease evaluation must remain within 7 days prior to Day 1). 
**Testing for IgD and IgE will only be performed for subjects with IgD and IgE-type myeloma. Serum FLC to be performed on D1 of each cycle for subjects with 
light chain only disease only. After screening assessments, subjects without measurable urine M-Protein at baseline will not be required to have UPEP or urine 
immunofixation repeated at subsequent disease assessment time-points, unless clinically indicated. At the post-induction disease evaluation, serum FLC to be 
performed in subjects with light chain only disease and in subjects where at least a CR is suspected or are maintaining at least a CR. 
13 Bone marrow aspirate and biopsy collected for disease assessment and MRD* analyses/correlatives (see Section 8.6.2). If a fresh biopsy is not collected at 
screening, may use non-decalcified diagnostic tissue (i.e., bone marrow aspirate slides or FFPE tissue) if collected within 6 months of enrollment. Please see 
laboratory guidelines for details. *At post-induction disease evaluation, only those subjects who experience ≥VGPR will undergo an assessment of MRD. All other 
subjects will be considered MRD (+).  NOTE: MRD will be evaluated via flow cytometry and DNA sequencing. The MRD result evaluated via DNA sequencing 
will be used to determine treatment decisions. If a subject has disease progression/relapse and a bone marrow aspirate is performed as part of clinical care, bone 
marrow samples will be collected for correlatives as described in Section 8.6.2 and the laboratory guidelines. Bone marrow samples taken for disease evaluation 
purposes where MRD is not required to be assessed should still be collected for banking and should include up to 12 ml whenever possible. 
14 Acceptable for screening if performed as part of standard of care within 42 days prior to day 1 of study treatment. For subjects who received prior therapy, 
skeletal survey must have been performed no earlier than 42 days prior to initiation of the pre-study induction cycle. If a skeletal survey was not performed prior to 
initiation of the pre-study induction cycle, it is acceptable if skeletal survey is performed after initiation of the pre-study induction cycle as long as it is performed 
prior to initiation of study treatment. 
15 Assess extramedullary plasmacytomas using PET/CT and/or Whole Body (WB)-MRI. Acceptable for screening if performed as part of standard of care within 
42 days prior to initiation of the pre-study induction cycle (subjects who received prior therapy) or within 42 days of day 1 of study treatment (subjects with no 
prior therapy). For subjects who received prior therapy, the skeletal survey or CT will be acceptable and PET/CT/Whole Body MRI is not required.  
16 See Section 6.1 for required hydration and additional information regarding cycle 1 dosing 
17 See Section 6.4 for dosing instructions. On days when daratumumab is administered, protocol-directed dexamethasone will serve as premedication given 1 to 3 
hours prior to each daratumumab infusion (see Section 6.2).  
18Approximately 30 mL of blood will be collected pre-treatment D1 of cycles 1, 3, 5 and 7, and at the post-induction disease evaluation. See Section 8.6.1 for 
detailed information on blood sample acquisition.  
19 Unless otherwise noted, all baseline disease assessments must be completed within 28 days of initiation of the first pre-study induction cycle (subjects who 
received prior therapy) or within 28 days of day 1 of study treatment (subjects with no prior therapy). Subjects who received a cycle of prior therapy: If a UPEP 
and/or urine IFE was not collected prior to initiation of pre-study induction, this will not be considered a deviation as long as the subject has evidence of 
measurable disease by another assessment (SPEP, FLC, etc). If a serum beta-2 microglobulin was not collected prior to initiation of pre-study induction, this will 
not be considered a deviation. Collection of serum beta-2 microglobulin at screening is not required if previously collected prior to initiating pre-study induction. 
20 Local testing for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (Anti-HBs), and hepatitis B core antibody (Anti-HBc). 

Protocol: LCI-HEM-MYE-KRdD-001 
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41
21 For subjects with serologic evidence of resolved HBV infection (i.e. positive anti-HBs or positive anti-HBc) at Screening. HBV DNA testing must be performed 
locally. 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. During and following study treatment, subjects who have a history of HBV infection will be closely monitored 
for clinical and laboratory signs of reactivation of HBV as specified in the study calendar. Results of HBV testing may be reported to the local health authorities. 
22  Per Investigator’s discretion, for subjects at higher risk for pulmonary complications that are not hospitalized for monitoring after daratumumab infusion , a 
follow-up telephone call should be made and documented to monitor their condition within 48 hours (no later than 72 hours) after all daratumumab infusions. 
23 For subjects who completed a pre-study cycle of induction chemotherapy, only 7 cycles of KRdD Induction should be given. 
24 This visit should occur in subjects 30 days (+/-10 days) after study treatment stops for whatever reason.   
25 Only for subjects who permanently discontinue induction prior to completion of 8 cycles. PFS (progression-free survival) Follow-up: Subjects who have not 
progressed and permanently discontinued treatment for reasons per Section 9.2 will go into PFS Follow Up. Subjects in PFS Follow-up should continue to have 
disease evaluations per standard of care until confirmed disease progression, start of new anti-cancer treatment, or meet the off study criteria in Section 9.2,  
whichever occurs first. Survival Follow-up: Subjects who have permanently discontinued study treatment and have confirmed progression or initiated new anti-
cancer treatment will go into Survival Follow-up every 6 months (+/- 30 days) from the date of disease progression or initiation of subsequent anti-cancer 
treatment until off study criteria in Section 9.2 are met. Survival Follow-up may be conducted via telephone. Any second primary malignancies discovered during  
the subject’s participation in the study will be documented.   
26 Subjects who received a cycle of pre-study induction: Echo or MUGA and/or ECG does not need to be repeated during screening if previously performed 
prior to initiation or during cycle of pre-study induction. 
27 If a subject has disease progression/relapse and a bone marrow aspirate is performed as part of clinical care, bone marrow samples will be collected for disease 
evaluation and correlatives as described in Section 8.6.2 and the laboratory guidelines. 
28 Per Investigator discretion for transplant eligible subjects, induction treatment may be delayed for stem cell mobilization/collection and held until subjects have 
recovered.  This will not be considered a deviation. Given difficulties with stem cell mobilization later during KRD-dara induction, initial attempt at stem cell 
collection is preferred after C3 or C4 of induction (see Section 5.2). 
29 If dosing with lenalidomide is delayed due to an extenuating circumstance (e.g., needing a new prescription due to dose reduction), a delay of up to 5 days will 
not be considered a deviation. 
30 CBCD only required in C1 and C2 on days subject is coming on-site to receive study treatment (i.e., receiving C3 dosing in C2 due to receiving a pre-study 
cycle of induction).  
31 For disease evaluation, please refer to footnotes * and II in the IMWG criteria, see Section 13. All response categories require two consecutive assessments, 
which should be captured in the dataset. Each category, except for stable disease, will be considered unconfirmed until the confirmatory test is performed. The 
confirmatory scan data should be entered into the database. 
 
 
 
 

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42
 
 
7.2 
POST-INDUCTION CALENDAR: GROUP A (28-day cycles) 
 
Study 
Procedures 
Stem Cell  
Mobilization 
and Collection1 
Lenalidomide Maintenance  
Cycles 1-12 
Lenalidomide 
Maintenance 
Cycles 13+ 
Safety 
Follow-up 
Visit3 
PFS 
Follow 
Up4 
Survival  
Follow-
up15 
Study Day 
D12 
D1 every 
three cycles2 
per 
standard 
of care 
Q 6 
months 
+/- 30 
days 
Physical exam14 
Symptom-directed physical exam only 
 
ECOG 
Performance 
status 
X 
X 
 
 
Serum 
chemistries5 
X 
X 
 
 
CBCD6 
X 
X 
 
 
Pregnancy test7 
X7 
X7 
 
 
AEs & 
concomitant 
medications 
Monitor continuously until 30 days after the last dose of study treatment 
 
Blood and urine 
for disease 
evaluation8 
X 
X 
X 
 
Daratumumab 
Interference 
Testing 
At suspected CR; subjects with IgG Kappa MM only 
 
Bone marrow 
aspirate and 
biopsy for 
disease 
assessment and 
MRD9 
See footnote #9 
 
Skeletal Survey 
As clinically indicated 
Assess 
extramedullary 
plasmacytomas10 
See footnote #10 
Lenalidomide12 
Days 1-21 (oral) each cycle 
 
 

Protocol: LCI-HEM-MYE-KRdD-001 
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43
Blood sample for 
correlatives11 
See footnote #11 
 
 
Documentation 
of survival and 
occurrence of 
secondary 
malignancies 
X 
Disease 
Evaluation 
Confirmation 
Data Capture16 
X 
 
HBV DNA 
testing13 
Every 12 weeks up to 6 months after last dose of Dara 
 
 
Key to Footnotes for Post-Induction Group A  
 
1 Subjects who are considered eligible for transplant at the discretion of the investigator will undergo stem cell mobilization with the hematopoietic growth factor 
G-CSF (filgrastim or equivalent) with or without the CXCR4 antagonist plerixafor, as per institutional standards. For subjects who fail collection of adequate stem 
cells during induction or post-induction, re-attempts at mobilization and stem cell collection are acceptable during maintenance therapy per investigator discretion. 
Collection and freezing of stem cells should be performed as per institutional standards. AEs related to mobilization do not need to be reported. However, any AEs 
considered related to induction (i.e., either daratumumab, carfilzomib, lenalidomide and/or dexamethasone) should continue to be reported.  If prescribed, 
lenalidomide maintenance may begin after recovery from stem cell mobilization and collection. Treatment can be held during mobilization/ collection per 
investigator discretion and it will not be considered a protocol deviation. 
2 Lenalidomide maintenance is at the discretion of the investigator. For subjects on lenalidomide maintenance, study visits will occur once every 28 days for the 
first year (D1 of each cycle for cycles 1-12), and then every 12 weeks (3 cycles, i.e., D1 cycle 13, cycle 16, etc.) for subsequent years. A window of +/-7 days will 
be applied to all lenalidomide maintenance visits during the first year (cycles 1-12). A window of +/-15 days will be applied to all subsequent lenalidomide 
maintenance visits (cycles 13+). Windows include study treatment and required protocol procedures prior to dosing, except bone marrow biopsy which is not 
required prior to treatment. 
3 This visit should occur in subjects 30 days (+/-10 days) after study treatment stops for whatever reason (toxicity, progression, or at discretion of the investigator). 
For subjects who do not go on lenalidomide maintenance, this visit may occur the day of (but prior to) stem cell mobilization (if the subject is eligible for 
transplant) if stem cell mobilization is scheduled.  
NOTE: subjects who have ongoing Grade 4 AE or SAE at the time of the Safety Follow-up Visit will continue to be followed until the event is resolved or 
deemed irreversible by the investigator. 
4   PFS (progression-free survival) Follow-up: Subjects who do not receive lenalidomide maintenance or subjects who initiate lenalidomide maintenance but 
permanently discontinue study treatment for reasons in Section 9.2 except disease progression will go into PFS Follow Up. Subjects in PFS Follow-up should 
continue to have disease evaluations per standard of care until confirmed disease progression, start of new anti-cancer treatment, or meet the off study criteria in 
Section 9.2, whichever occurs first. . Any second primary malignancies discovered during the subject’s participation in the study will be documented. If confirmed 
PD occurs or new anti-cancer treatment is initiated, subjects will enter Survival Follow-up.  

Protocol: LCI-HEM-MYE-KRdD-001 
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44
5 Serum chemistries: BUN, creatinine (with calculated creatinine clearance on Day 1 of each cycle), glucose, uric acid, calcium, chloride, phosphorus, potassium, 
sodium, LDH, albumin, total protein, magnesium, total bilirubin, alkaline phosphatase, AST and ALT. NOTE: calcium should also be corrected for albumin. 
6 CBCD: complete blood count with differential and platelets 
7 Pregnancy testing (serum or urine) must be repeated monthly while on lenalidomide treatment (D1 of each cycle) in FCBP. Not required for subjects who are not 
receiving lenalidomide treatment. Pregnancy testing may be done at a local medical office at the discretion of the investigator. 
8 Tests to include: serum quantitative immunoglobulins (QIg; including IgA, IgM, IgG, IgD**, IgE**), serum protein electrophoresis (SPEP), urine protein 
electrophoresis (UPEP; 24-hr urine sample required), serum and urine immunofixation, and serum free light chain (FLC). **Testing for IgD and IgE will only be 
performed for subjects with IgD and IgE-type myeloma. Subjects without measurable urine M-Protein at baseline will not be required to have UPEP or urine 
immunofixation repeated at subsequent disease assessment time-points, unless clinically indicated. Serum FLC to be performed for subjects with light chain only 
disease and for subjects with a suspected CR or are maintaining at least a CR. Day 1 blood disease evaluation must be done within 7 days prior to Day 1. Urine 
disease evaluation may be done ±7 days of Day 1. 
9 For subjects on lenalidomide maintenance and PFS follow-up, bone marrow aspirate and biopsy should be performed for disease evaluation and 
MRD/correlatives at 6 and 12 months (each +/- 15 days) after the Post-Induction disease evaluation.  After the 12-month Post-Induction evaluation, bone marrow 
aspirate and biopsy should be performed annually (+/- 30 days)(see Section 8.6.2 and the laboratory guidelines for detailed information) until disease progression 
or initiation of new anti-cancer treatment. NOTE: MRD will be evaluated via flow cytometry and DNA sequencing only in subjects who experience ≥ VGPR. All 
other subjects will be considered MRD (+). If a subject has disease progression/relapse and a bone marrow aspirate is performed as part of clinical care, bone 
marrow samples will be collected for correlatives as described in Section 8.6.2 and the laboratory guidelines. Bone marrow samples taken for disease evaluation 
purposes where MRD is not required to be assessed should still be collected for banking and should include up to 12 mL whenever possible. 
10 For subjects with extramedullary plasmacytomas present at post-induction, PET/CT and/or WB-MRI every 12 weeks for the first year, and then once a year for 
subsequent years (or as clinically indicated). 
11 Approximately 30 mL of blood will be collected D1 of cycles 3, 5, 7, 9 and 11. An additional blood sample will be collected at progression. See Section 8.6.1 
and the laboratory guidelines for detailed information. 
12 Not required for subjects not receiving lenalidomide treatment. For subjects receiving lenalidomide for maintenance, creatinine clearance should be reviewed, 
and dosing followed per Section 6.3.2.2. If dosing with lenalidomide is delayed due to an extenuating circumstance (e.g., needing a new prescription due to dose 
reduction), a delay of up to 5 days will not be considered a deviation. 
13 For subjects with serologic evidence of resolved HBV infection (i.e. positive anti-HBs or positive anti-HBc) at Screening. HBV DNA testing must be performed 
locally. 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. During and following study treatment, subjects who have a history of HBV infection will be  
closely monitored for clinical and laboratory signs of reactivation of HBV as specified in the study calendar. Results of HBV testing may be reported to the local 
health authorities. 
14 During the COVID-19 pandemic, virtual visits may be performed per investigator discretion. 
15 Subjects who have permanently discontinued study treatment and have confirmed progression or initiated new anti-cancer treatment will go into Survival 
Follow-up every 6 months (+/- 30 days) from the date of disease progression or initiation of subsequent anti-cancer treatment until off study criteria in Section 9.2 
are met. Survival Follow-up may be conducted via telephone. Any second primary malignancies discovered during the subject’s participation in the study will be 
documented.   
16 For disease evaluation, please refer to footnotes * and II in the IMWG criteria, see Section 13. All response categories require two consecutive assessments, 
which should be captured in the database. Each category, except for stable disease, will be considered unconfirmed until the confirmatory test is performed. The 
confirmatory scan data should be entered into the database. 
 
 

Protocol: LCI-HEM-MYE-KRdD-001 
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45
7.3 
POST-INDUCTION CALENDAR: GROUP B (28-day cycles) 
 
Study 
Procedures 
ASCT 1 
Post-ASCT Disease 
Evaluation2 
KRd Consolidation 
Cycles 1-123  
 
Post-
Consolidation 
Disease 
Evaluation5 
 
Lenalidomide 
Maintenance 
Cycles 1-12 
Lenalidomide 
Maintenance 
Cycles 13+ 
Safety 
Follow-
up 
Visit7 
 
PFS 
Follow-
up8 
Survival  
Follow-
up21 
Study Day 
D14 
D8 
D154 
D16 
D1 every 
three cycles6 
Per 
standard 
of care 
Q 6 
months 
+/- 30 
days 
Physical exam20 
Symptom-directed physical exam only 
 
 
Weight9 
 
X9 
 
 
 
 
 
 
 
 
ECOG 
Performance 
status 
X 
X 
 
 
X 
X 
X 
X 
 
 
ECG10 
 
X 
 
 
X 
 
 
 
 
 
Serum 
chemistries11 
X 
X 
 
X 
X 
X 
X 
X 
 
 
CBCD12 
X 
X 
 
X 
X 
X 
X 
X 
 
 
Pregnancy test13 
 
X 
 
 
 
X18 
X18 
 
 
 
AEs & 
concomitant 
medications 
Monitor continuously until 30 days after the last dose of study treatment 
 
 
Blood and urine 
for disease 
evaluation14 
X 
X 
 
 
X 
X 
X 
 
X 
 
Daratumumab 
Interference 
Testing 
At suspected CR; subjects with IgG Kappa MM only 
 
 
Bone marrow 
aspirate and 
biopsy for 
disease 
assessment and 
MRD15 
X 
X3 
 
 
X 
See footnote #15 
 
 
Skeletal Survey 
As clinically indicated 
 
 
Assess 
extramedullary 
plasmacytomas16 
See footnote #16 
 
 
Carfilzomib 
 
X 
X 
X 
 
 
 
 
 
 
Lenalidomide18 
 
Days 1-21 (oral)18 
 
Days 1-21 (oral) each cycle18 
 
 
Dexamethasone 
 
X 
 
X 
 
 
 
 
 
 

Protocol: LCI-HEM-MYE-KRdD-001 
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46
Blood sample for 
correlatives17 
See footnote #17 
 
 
 
HBV DNA 
testing19 
Every 12 weeks up to 6 months after last dose of Dara 
 
 
Documentation 
of survival and 
occurrence of 
secondary 
malignancies 
 
X 
Disease 
Evaluation 
Confirmation 
Data Capture22 
 
X 
 
 
Key to Footnotes for Post-Induction Group B 
 
1 Subjects will undergo stem cell mobilization with the hematopoietic growth factor G-CSF (filgrastim or equivalent) with or without the CXCR4 antagonist 
plerixafor, as per institutional standards, if not done during induction per investigator discretion. Collection and freezing of stem cells should be performed as per 
institutional standards. After recovery from stem cell mobilization and collection, high dose melphalan should be administered followed by ASCT, as per 
institutional standards, including any necessary prophylactic antibiotics, hematopoietic growth factors, and other supportive care during and post ASCT. AEs 
related to mobilization, HDC and ASCT do not need to be reported. However, any AEs considered related to induction (i.e., either daratumumab, carfilzomib, 
lenalidomide and/or dexamethasone) should continue to be reported.   
2 Disease evaluation after ASCT will take place after engraftment is complete, as defined per institutional standards. Any subject who converts to MRD (-) disease 
via DNA sequencing after ASCT may receive lenalidomide maintenance until relapse or progression or no further treatment (skip to lenalidomide maintenance 
section of the calendar), at the discretion of the investigator. Any subject who is MRD (+) via DNA sequencing after ASCT will receive up to 12 cycles of KRd 
consolidation (see footnote #3). Lenalidomide maintenance or KRd consolidation can be initiated at the discretion of the investigator after disease evaluation and 
recovery from ASCT (~60-100 days post ASCT).  
3 The number of cycles of KRd will depend on the MRD status (based on MRD result evaluated via DNA sequencing) during treatment. A bone marrow aspirate 
and biopsy will be performed after completion of cycle 4 and cycle 8 of KRd (if applicable) for disease evaluation and to assess MRD/correlatives only in subjects 
with ≥VGPR based on blood and urine evaluation [all other subjects will be considered MRD (+)]. The MRD result evaluated via DNA sequencing will be used to 
determine treatment decisions. There may be a delay in initiating C5D1 and C9D1 (if applicable) of KRd consolidation until disease assessment and MRD via 
DNA sequencing (if applicable) results are available. Those who convert to MRD (-) via DNA sequencing after cycle 4 or cycle 8 will permanently discontinue 
KRd and may receive lenalidomide maintenance until relapse or progression or no further treatment, at the discretion of the investigator (skip to lenalidomide 
maintenance section of the calendar). For those subjects, this disease evaluation may serve as their post-consolidation disease evaluation. NOTE: MRD will be 
evaluated via flow cytometry and DNA sequencing (see Section 8.6.2).   
4 A window of +/-2 days will be applied to all KRd consolidation study visits except for blood and urine disease evaluation on Day1 of each cycle.  Day 1 blood 
disease evaluation must be done within 7 days prior to Day 1. Urine disease evaluation may be done ±7 days of Day 1. This includes study treatment and required 
protocol procedures prior to dosing. 
5 Any subject who converts to MRD (-) disease via DNA sequencing during or after KRd consolidation may receive lenalidomide maintenance until relapse or 
progression or no further treatment, at the discretion of the investigator. For those subjects who convert to MRD (-) disease and permanently discontinue KRd prior 

Protocol: LCI-HEM-MYE-KRdD-001 
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47
to completing 12 cycles, the C1D1 Lenalidomide Maintenance visit may serve as the Post-Consolidation disease evaluation visit at the investigator’s discretion. 
The EKG required at the Post-Consolidation visit should be done at the C1D1 Lenalidomide Maintenance timepoint. Those who have MRD (+) disease via DNA 
sequencing after 12 cycles of KRd consolidation will receive lenalidomide maintenance until relapse or progression.  
Note: If MRD results have been positive at previous timepoints, and physician plans to continue lenalidomide regardless of Post-Consolidation MRD 
results, then the C1D1 Maintenance visit may serve as the Post-Consolidation disease evaluation visit. For these same subjects, they may also begin 
lenalidomide on C1D1 Maintenance visit per investigator discretion.  
6 For subjects on lenalidomide maintenance, study visits will occur once every 28 days for the first year (D1 of each cycle for cycles 1-12), and then every 12 
weeks (3 cycles, i.e., D1 cycle 13, cycle 16, etc.) for subsequent years. A window of +/-7 days will be applied to all lenalidomide maintenance visits during the 
first year (cycles 1-12). A window of +/- 15 days will be applied to all subsequent lenalidomide maintenance visits (cycles 13+). This window includes study 
treatment and required procedures prior to dosing, except bone marrow biopsy which is not required prior to treatment. 
7 This visit should occur in subjects 30 days (+/-10 days) after treatment stops for whatever reason (toxicity, progression, or at discretion of the investigator). For 
subjects who do not go on lenalidomide maintenance after ASCT, this visit may occur the day of Post-ASCT Disease Evaluation. NOTE: subjects who have 
ongoing Grade 4 AE or SAE at the time of the Safety Follow-up Visit will continue to be followed until the event is resolved or deemed irreversible by the 
investigator. 
8 PFS (progression-free survival) Follow-up: Subjects who permanently discontinue study treatment for reasons other than disease progression as per Section 9.2, 
will go into PFS Follow Up. Subjects in PFS Follow-up should continue to have disease evaluations per standard of care until confirmed disease progression, start 
of new anti-cancer treatment, or meet the off study criteria in Section 9.2, whichever occurs first.  Any second primary malignancies discovered during the 
subject’s participation in the study will be documented.  If confirmed PD occurs or new anti-cancer treatment is initiated, subjects will enter Survival Follow-up.  
9 If a subject’s weight changes by more than 20% from KRd consolidation C1D1, the dose of carfilzomib should be recalculated. 
10 An ECG should be performed D1 of KRd consolidation cycles 1, 4 and, if applicable, cycles 7 and 11, and then at the post-consolidation disease evaluation.  
11 Serum chemistries: BUN, creatinine (with calculated creatinine clearance on Day 1 of each cycle), glucose, uric acid, calcium, chloride, phosphorus, potassium, 
sodium, LDH, albumin, total protein, magnesium, total bilirubin, alkaline phosphatase, AST and ALT. NOTE: calcium should also be corrected for albumin. 
12 CBCD: complete blood count with differential and platelets 
13 Pregnancy testing (serum or urine) must be repeated monthly while on lenalidomide treatment (D1 of each cycle of KRd or lenalidomide) in FCBP. Not required 
for subjects not receiving lenalidomide treatment. Pregnancy testing may be done at a local medical office at the discretion of the investigator. 
14 Tests to include: serum quantitative immunoglobulins (QIg; including IgA, IgM, IgG, IgD**, IgE**), serum protein electrophoresis (SPEP), urine protein 
electrophoresis (UPEP; 24-hr urine sample required), serum and urine immunofixation, and serum free light chain (FLC). **Testing for IgD and IgE will only be 
performed for subjects with IgD and IgE-type myeloma. Subjects without measurable urine M-Protein at baseline will not be required to have UPEP or urine 
immunofixation repeated at subsequent disease assessment time-points, unless clinically indicated. Serum FLC to be performed for subjects with light chain only 
disease and for subjects with a suspected CR or who are maintaining at least a CR. Day 1 blood disease evaluation must be done within 7 days prior to Day 1. 
Urine disease evaluation may be done ±7 days of Day 1. 
15 Bone marrow aspirate and biopsy collected at the following time-points for disease evaluation and MRD analyses/correlatives (see Section 8.6.2 and laboratory 
guidelines for detailed information): Post-ASCT visit, during KRd consolidation as referenced above in Footnote #3, and the Post-Consolidation visit. During 
maintenance and PFS follow up: Bone marrow aspirate and biopsy should be performed for disease evaluation and MRD/correlatives at 6, and 12 months (each +/- 
15 days) after the Post-Consolidation disease evaluation, and then annually (+/- 30 days) until disease progression or initiation of new anti-cancer treatment. For 
subjects who convert to MRD (-) after ASCT and do not receive consolidation, bone marrow aspirate and biopsy for disease evaluation and MRD 
analysis/correlatives should be evaluated at 6 and 12 months (each +/- 15 days) after transplant.  NOTE: MRD will be evaluated via flow cytometry and DNA 
sequencing only in subjects who experience ≥ VGPR. All other subjects will be considered MRD (+). If a subject has disease progression/relapse and a bone 
marrow aspirate is performed as part of clinical care, bone marrow samples will be collected for correlatives as described in Section 8.6.2 and the laboratory 

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guidelines. Bone marrow samples taken for disease evaluation purposes where MRD is not required to be assessed should still be collected for banking and should 
include up to 12mL whenever possible. 
16 For subjects with extramedullary plasmacytomas present at the post-induction assessment, PET/CT and/or WB-MRI every 12 weeks during KRd consolidation 
and for the first year of lenalidomide maintenance, and then once a year for subsequent years (or as clinically indicated). 
17 Approximately 30 mL of blood will be collected at the post-ASCT disease evaluation,  pre-treatment every 4 cycles during KRd consolidation (C5D1 and 
C9D1), and D1 of lenalidomide maintenance (if applicable) cycles 1, 3, 5, 7, 9 and 11. An additional blood sample will be collected at progression. See Section 
8.6.1 and the laboratory guidelines for detailed information.  
18 Not required for subjects not receiving lenalidomide treatment. For subjects receiving lenalidomide for maintenance, creatinine clearance should be reviewed, 
and dosing followed per Section 6.3.2.2. If dosing with lenalidomide is delayed due to an extenuating circumstance (e.g., needing a new prescription due to dose 
reduction), a delay of up to 5 days will not be considered a deviation. 
19 For subjects with serologic evidence of resolved HBV infection (i.e. positive anti-HBs or positive anti-HBc) at Screening. HBV DNA testing must be performed 
locally. 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. During and following study treatment, subjects who have a history of HBV infection will be closely monitored 
for clinical and laboratory signs of reactivation of HBV as specified in the study calendar. Results of HBV testing may be reported to the local health authorities. 
20 During the COVID-19 pandemic, virtual visits may be performed per investigator discretion. 
21 Subjects who have permanently discontinued study treatment and have confirmed progression or initiated new anti-cancer treatment will go into Survival 
Follow-up every 6 months (+/- 30 days) from the date of disease progression or initiation of subsequent anti-cancer treatment until off study criteria in Section 9.2 
are met. Survival Follow-up may be conducted via telephone. Any second primary malignancies discovered during the subject’s participation in the study will be 
documented.  
22 For disease evaluation, please refer to footnotes * and II in the IMWG criteria, see Section 13. All response categories require two consecutive assessments, 
which should be captured in the dataset. Each category, except for stable disease, will be considered unconfirmed until the confirmatory test is performed. The 
confirmatory scan data should be entered into the dataset. 
 
 
 
 
 

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7.4 
POST-INDUCTION CALENDAR: GROUP C (28-day cycles) 
 
Study 
Procedures 
KRd Consolidation Cycles 1-121 
 
 
Post-
Consolidation 
Disease 
Evaluation3 
 
Lenalidomide 
Maintenance 
Cycles 1-12 
Lenalidomide 
Maintenance 
Cycles 13+ 
Safety 
Follow-up 
Visit5 
PFS Follow 
Up6 
 Follow-
up19 
Study Day 
D12 
D8 
D152 
D14 
D1 every three 
cycles4 
Per standard 
of care 
Q 6 months 
+/- 30 days 
Physical exam18 
Symptom-directed physical exam only  
 
 
Weight7 
X 
 
 
 
 
 
 
 
 
ECOG 
Performance 
status 
X 
 
 
X 
X 
X 
X 
 
 
ECG8 
X 
 
 
X 
 
 
 
 
 
Serum 
chemistries9 
X 
 
X 
X 
X 
X 
X 
 
 
CBCD10 
X 
 
X 
X 
X 
X 
X 
 
 
Pregnancy test11 
X 
 
 
 
X16 
X16 
 
 
 
AEs & 
concomitant 
medications 
Monitor continuously until 30 days after the last dose of study treatment 
 
 
Blood and urine 
for disease 
evaluation12 
X 
 
 
X 
X 
X 
 
X 
 
Daratumumab 
Interference 
Testing 
At suspected CR; subjects with IgG Kappa MM only 
 
 
Bone marrow 
aspirate and 
biopsy for 
disease 
assessment and 
MRD13 
X1 
 
 
X 
See footnote #13 
 
Skeletal Survey 
As clinically indicated 
 
 
Assess 
extramedullary 
plasmacytomas14 
See footnote #14 
 
 
 
Carfilzomib 
X 
X 
X 
 
 
 
 
 
 
Lenalidomide16 
Days 1-21 (oral)16 
 
Days 1-21 (oral) each cycle16 
 
 
 
Dexamethasone 
X 
 
X 
 
 
 
 
 
 

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Blood sample for 
correlatives15 
See footnote #15 
 
 
 
HBV DNA 
testing17 
Every 12 weeks up to 6 months after last dose of Dara 
 
 
Documentation 
of survival and 
occurrence of 
secondary 
malignancies 
X 
Disease 
Evaluation 
Confirmation 
Data Capture20 
X 
 
 
 
Key to Footnotes for Post-Induction Group C 
 
1 The number of cycles of KRd will depend on the MRD status (based on MRD results evaluated via DNA sequencing) during treatment. A bone marrow aspirate 
and biopsy will be performed after completion of cycle 4 and cycle 8 of KRd (if applicable) for disease evaluation and to assess MRD/correlatives in subjects with 
≥VGPR based on blood and urine evaluation [all other subjects will be considered MRD ([+)]. The MRD result evaluated via DNA sequencing will be used to 
determine treatment decisions. There may be a delay in initiating C5D1 and C9D1 (if applicable) of KRd consolidation until disease assessment and MRD via 
DNA sequencing (if applicable) results are available. Those who convert to MRD (-) after cycle 4 or cycle 8 will permanently discontinue KRd and may receive 
lenalidomide maintenance until relapse or progression or no further treatment, at the discretion of the investigator (skip to lenalidomide maintenance section of the 
calendar). For those subjects, this disease evaluation may serve as their post-consolidation disease evaluation. NOTE: MRD will be evaluated via flow cytometry 
and DNA sequencing (see Section 8.6.2).  
2 A window of +/- 2 days will be applied to all KRd consolidation study visits except for blood and urine disease evaluation on Day1 of each cycle. Day 1 blood 
disease evaluation must be done within 7 days prior to Day 1. Urine disease evaluation may be done ±7 days of Day 1. This includes study treatment and required 
protocol procedures prior to dosing. 
3 Any subject who converts to MRD (-) disease after 12 cycles of KRd consolidation may receive lenalidomide maintenance until relapse or progression or no 
further treatment, at the discretion of the investigator. For those subjects who convert to MRD (-) disease and permanently discontinue KRd prior to completing 12 
cycles, the C1D1 Lenalidomide Maintenance visit may serve as the Post-Consolidation disease evaluation visit at the investigator’s discretion. The EKG required 
at the Post-Consolidation visit should be done at the C1D1 Lenalidomide Maintenance timepoint. Those who have MRD (+) disease via DNA sequencing after 
KRd consolidation will receive lenalidomide maintenance until relapse or progression.  
Note: If MRD results have been positive at previous timepoints, and physician plans to continue lenalidomide regardless of Post-Consolidation MRD results, then 
the C1D1 Maintenance visit may serve as the Post-Consolidation disease evaluation visit. For these same subjects, they may also begin lenalidomide on C1D1 
Maintenance visit per investigator discretion. 
4 For subjects on lenalidomide maintenance, study visits will occur once every 28 days for the first year (D1 of each cycle for cycles 1-12), and then every 12 
weeks (3 cycles, i.e., D1 cycle 13, cycle 16, etc.) for subsequent years. A window of +/- 7 days will be applied to all lenalidomide maintenance visits during the 
first year (cycles 1-12). A window of +/- 15 days will be applied to all subsequent lenalidomide maintenance visits (cycles 13+). This window includes study 
treatment and required procedures prior to dosing, except bone marrow biopsy which is not required prior to treatment. 

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5 This visit should occur in subjects 30 days (+/-10 days) after treatment stops for whatever reason (toxicity, progression, or at discretion of the investigator). For 
subjects who do not initiate lenalidomide maintenance after Post-Consolidation, this visit may occur the day of Post-Consolidation Disease evaluation. NOTE: 
subjects who have ongoing Grade 4 AE or SAE at the time of the Safety Follow-up Visit will continue to be followed until the event is resolved or deemed 
irreversible by the investigator. 
6 PFS (progression-free survival) Follow-up: Subjects who permanently discontinue study treatment for reasons other than disease progression as per Section 9.2 
will go into PFS follow up. Subjects in PFS Follow-up should continue to have disease evaluations per standard of care until confirmed disease progression, start 
of new anti-cancer treatment, or meet the off study criteria in Section 9.2, whichever occurs first. Any second primary malignancies discovered during the 
subject’s participation in the study will be documented. If confirmed PD occurs or new anti-cancer treatment is initiated, subjects will enter Survival Follow-up.     
7 If a subject’s weight changes by more than 20% from KRd consolidation C1D1, the dose of carfilzomib should be recalculated. 
8 An ECG should be performed D1 of KRd consolidation cycles 1, 4, and, if applicable, cycles 7 and 11, and then at the post-consolidation disease evaluation.  
9 Serum chemistries: BUN, creatinine (with calculated creatinine clearance on Day 1 of each cycle), glucose, uric acid, calcium, chloride, phosphorus, potassium, 
sodium, LDH, albumin, total protein, magnesium, total bilirubin, alkaline phosphatase, AST and ALT. NOTE: calcium should also be corrected for albumin. 
10 CBCD: complete blood count with differential and platelets 
11 Pregnancy testing (serum or urine) must be repeated monthly while on lenalidomide treatment (D1 of each cycle of KRd or lenalidomide) in FCBP. Not required 
for subjects on observation. Pregnancy testing may be done at a local medical office at the discretion of the investigator. 
12 Tests to include: serum quantitative immunoglobulins (QIg; including IgA, IgM, IgG, IgD**, IgE**), serum protein electrophoresis (SPEP), urine protein 
electrophoresis (UPEP; 24-hr urine sample required), serum and urine immunofixation, and serum free light chain (FLC). **Testing for IgD and IgE will only be 
performed for subjects with IgD and IgE-type myeloma. Subjects without measurable urine M-Protein at baseline will not be required to have UPEP or urine 
immunofixation repeated at subsequent disease assessment time-points, unless clinically indicated. Serum FLC to be performed for subjects with light chain only 
disease and for subjects with a suspected CR or who are maintaining at least a CR. Day 1 blood disease evaluation must be done within 7 days prior to Day 1. 
Urine disease evaluation may be done ±7 days of Day 1. 
13 Bone marrow aspirate and biopsy collected at the following time-points for disease assessment and MRD analyses/correlatives (see Section 8.6.2 and the 
laboratory guidelines for detailed information): During KRd consolidation as referenced above in Footnote #1, and the Post-consolidation visit. During 
maintenance/ PFS follow up: bone marrow aspirate and biopsy should be performed for disease evaluation and MRD at 6 and 12 months (each +/- 15 days) from 
the Post-Consolidation disease evaluation, and then annually (+/- 30 days) until disease progression or initiation of new anti-cancer treatment. NOTE: MRD will 
be evaluated via flow cytometry and DNA sequencing only in subjects who experience ≥ VGPR. All other subjects will be considered MRD (+). If a subject has 
disease progression/relapse and a bone marrow aspirate is performed as part of clinical care, bone marrow samples will be collected for correlatives as described in 
Section 8.6.2 and the laboratory guidelines. Bone marrow samples taken for disease evaluation purposes where MRD is not required to be assessed should still be 
collected for banking and should include up to 12mL whenever possible. 
14 For subjects with extramedullary plasmacytomas present at the post-induction assessment, PET/CT and/or WB-MRI every 12 weeks during KRd consolidation 
and for the first year of lenalidomide maintenance, and then once a year for subsequent years (or as clinically indicated). 
15 Approximately 30mL of blood will be collected pre-treatment of every 4 cycles of KRd consolidation ( C5D1and C9D1) and D1 of lenalidomide maintenance (if 
applicable) cycles 1, 3, 5, 7, 9 and 11. An additional blood sample will be collected at progression. See Section 8.6.1 and the laboratory guidelines for detailed 
information.  
16 Not required for subjects not receiving lenalidomide treatment. For subjects receiving lenalidomide for maintenance, creatinine clearance should be reviewed, 
and dosing followed per Section 6.3.2.2. If dosing with lenalidomide is delayed due to an extenuating circumstance (e.g., needing a new prescription due to dose 
reduction), a delay of up to 5 days will not be considered a deviation. 
17 For subjects with serologic evidence of resolved HBV infection (i.e. positive anti-HBs or positive anti-HBc) at Screening. HBV DNA testing must be performed 
locally. Subjects with serologic findings suggestive of HBV vaccination (Anti-HBs positivity as the only serologic marker) and a known history of prior HBV 

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vaccination do not need to be tested for HBV DNA. During and following study treatment, subjects who have a history of HBV infection will be closely monitored 
for clinical and laboratory signs of reactivation of HBV as specified in the study calendar. Results of HBV testing may be reported to the local health authorities. 
18 During the COVID-19 pandemic, virtual visits may be performed per investigator discretion. 
19 Subjects who have permanently discontinued study treatment and have confirmed progression or initiated new anti-cancer treatment will go into Survival 
Follow-up every 6 months (+/- 30 days) from the date of disease progression or initiation of subsequent anti-cancer treatment until off study criteria in Section 9.2 
are met. Survival Follow-up may be conducted via telephone. Any second primary malignancies discovered during the subject’s participation in the study will be 
documented.   
20 For disease evaluation, please refer to footnotes * and II in the IMWG criteria, see Section 13. All response categories require two consecutive assessments, 
which should be captured in the dataset. Each category, except for stable disease, will be considered unconfirmed until the confirmatory test is performed. The 
confirmatory scan data should be entered into the dataset. 
 
 
 
 

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8. DETAILS ON STUDY PROCEDURES 
Please also refer to the Study Calendars in Section 7.  
8.1 
Screening Procedures 
• Informed Consent: No protocol-related assessments may be performed prior to 
obtaining informed consent.  
• Medical History: A complete relevant medical history should be obtained, including 
documentation of any clinically significant pre-existing conditions.  
• Physical Examination and Weight: Evaluation by body system, including height, 
weight and neurologic exam to detect peripheral neuropathy.  
• Performance Status: ECOG performance status 
• Vital Signs: Vital signs should include temperature, pulse rate, blood pressure and 
respiratory rate  
• Cardiac Evaluation: ECG and MUGA or ECHO  
• Forced Expiratory Volume Test: Subjects with COPD only 
• Laboratory Assessments 
o Serum chemistries: BUN, creatinine (and calculated creatinine clearance), 
glucose, uric acid, calcium, chloride, phosphorus, potassium, sodium, LDH, 
albumin, total protein, magnesium, total bilirubin, alkaline phosphatase, AST and 
ALT. NOTE: calcium should also be corrected for albumin. 
o CBCD: complete blood count with differential and platelets 
o Serum or urine pregnancy test for FCBP 
o HBV Serology: hepatitis B surface antigen (HBsAg), hepatitis B surface antibody 
(Anti-HBs), and hepatitis B core antibody. 
o HBV DNA testing: only for subjects positive for Anti-HBc or Anti-HBs  
o Blood type and screen: ABO and Rh blood typing and indirect antiglobulin test 
to be performed once any time between screening and initiation of study treatment 
 
• Baseline Symptoms and Toxicities: Document pre-existing symptoms and any toxicities 
present (per NCI CTCAEv4.03) at the time of informed consent and prior to the first dose 
of study treatment 
• Concomitant Medications: Document any concomitant medications; concomitant 
medications include but are not limited to over the counter medications, supplements, and 
vitamins. 
• Disease Evaluation: 
o Serum beta2-microglobulin 
o Blood and urine tests: Serum QIg (including IgA, IgM, IgG, IgD**, IgE**), SPEP, 
UPEP (24-hr urine sample required), serum and urine immunofixation, and serum 
FLC. **Testing for IgD and IgE will only be performed for subjects with IgD and 
IgE-type myeloma.  
o Bone marrow aspirate and biopsy (including MRD analysis/correlatives): If a 
fresh biopsy is not collected at screening, may use non-decalcified diagnostic 
tissue (i.e., bone marrow aspirate slides or FFPE tissue) if collected within 6 
months of enrollment; see Section 8.6.2. 

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o Skeletal Survey 
o Assess extramedullary plasmacytomas: PET/CT and/or Whole Body (WB)-MRI 
 Note: For subjects who received prior therapy, the skeletal survey or CT will 
be acceptable and PET/CT/Whole Body MRI is not required  
 
8.2 
Induction Procedures 
NOTE: The sections below are focused on study procedures, and not drug administration; 
however, please note that for subjects who completed a pre-study cycle of induction 
chemotherapy, only 7 cycles of KRdD Induction should be given.  
Section 8.2.1 covers the non-laboratory assessments that are to be performed at each study visit. 
NOTE: serum or urine pregnancy testing is required weekly only during cycle 1 of induction in 
FCBP. Thereafter it is required on day 1 of each cycle. 
8.2.1 Throughout the Induction Period 
• Physical Exam: Symptom-directed physical exam only  
• AEs: Record all AEs per the NCI CTCAEv4.03.   
• Concomitant Medications: Record any changes in concomitant medications. 
Concomitant medications include but are not limited to over the counter medications, 
supplements, and vitamins. 
• Laboratory Assessments 
o HBV DNA testing: every 12 weeks for up to 6 months after last dose of 
daratumumab only for subjects positive for Anti-HBc or Anti-HBs at Screening.  
• Disease Evaluation: 
o Skeletal Survey only if clinically indicated 
o Daratumumab Interference Testing at suspected CR (subjects with IgG Kappa 
MM only) 
8.2.2 Day 1 Cycles 1-8 (unless otherwise noted) 
• Weight: If a subject’s weight changes by more than 20% from induction C1D1, the dose 
of carfilzomib should be re-calculated.   
• Performance Status: ECOG performance status 
o Vital Signs: Vital signs should include temperature, pulse rate, blood pressure 
and respiratory rate. For all daratumumab injections, vital signs will be measured 
per institutional standards but at a minimum prior to the start of injection for all 
doses. Vital signs at the end of the injection only required for C1D1 and C1D8 
and thereafter per Investigator discretion. Subject should remain in clinic for at 
least 1 hour observation period for the first dose of daratumumab and the first of 
carfilzomib on study, and per investigator discretion for subsequent doses. 
• Cardiac Evaluation: ECG   
• Blood type and screen: ABO and Rh blood typing and indirect antiglobulin test to be 
performed once any time between screening and initiation of study treatment 
• Laboratory Assessments 
o Serum chemistries: BUN, creatinine (with calculated creatinine clearance), 
glucose, uric acid, calcium, chloride, phosphorus, potassium, sodium, LDH, 

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albumin, total protein, magnesium, total bilirubin, alkaline phosphatase, AST and 
ALT. NOTE: calcium should also be corrected for albumin. 
o CBCD: complete blood count with differential and platelets 
o Pregnancy test (serum or urine) in FCBP 
• Disease Evaluation: 
o Blood and urine tests: Serum QIg (including IgA, IgM, IgG, IgD**, IgE**), SPEP, 
UPEP (24-hr urine sample required), serum and urine immunofixation, and serum 
FLC. **Testing for IgD and IgE will only be performed for subjects with IgD and 
IgE-type myeloma. Serum FLC to be performed for subjects with light chain only 
disease only and in subjects where at least a CR is suspected or who are 
maintaining at least a CR. Subjects without measurable urine M-Protein at 
baseline will not be required to have UPEP or urine immunofixation repeated at 
subsequent disease assessment time-points, unless clinically indicated. 
• Blood sample for correlatives: See Study Calendar and Section 8.6.1. 
• Per Investigator’s discretion, for subjects at higher risk for pulmonary complications that 
are not hospitalized for monitoring after daratumumab infusion, a follow-up telephone 
call should be made and documented to monitor their condition within 48 hours (no later 
than 72 hours) after all daratumumab infusions.  
8.2.3 Day 8 Cycles 1-2 Only (unless otherwise noted) 
• Vital Signs: Vital signs should include temperature, pulse rate, blood pressure and 
respiratory rate and will be measured per institutional standards but at a minimum prior to 
the daratumumab injection for all doses. Vital signs at the end of the injection only 
required on C1D1 and C1D8 and thereafter per Investigator discretion. Subject should 
remain in clinic for at least 1 hour observation period for the first dose of daratumumab 
and the first of carfilzomib on study, and per investigator discretion for subsequent doses. 
• Laboratory Assessments 
o Serum chemistries: BUN, creatinine, glucose, uric acid, calcium, chloride, 
phosphorus, potassium, sodium, LDH, albumin, total protein, magnesium, total 
bilirubin, alkaline phosphatase, AST and ALT. NOTE: calcium should also be 
corrected for albumin. 
o CBCD: complete blood count with differential and platelets 
o Pregnancy test (serum or urine) in FCBP: Cycle 1 only 
• Per Investigator’s discretion, for subjects at higher risk for pulmonary complications that 
are not hospitalized for monitoring after daratumumab infusion, a follow-up telephone 
call should be made and documented to monitor their condition within 48 hours (no later 
than 72 hours) after all daratumumab infusions.  
8.2.4 Day 15 Cycles 1-8 (unless otherwise noted) 
• Observation: Observe subject for one hour post daratumumab injection per investigator 
discretion.  
• Laboratory Assessments 
o Serum chemistries: BUN, creatinine, glucose, uric acid, calcium, chloride, 
phosphorus, potassium, sodium, LDH, albumin, total protein, magnesium, total 
bilirubin, alkaline phosphatase, AST and ALT. NOTE: calcium should also be 
corrected for albumin. 

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o CBCD: complete blood count with differential and platelets 
o Pregnancy test (serum or urine) in FCBP: Cycle 1 only 
• Per Investigator’s discretion, for subjects at higher risk for pulmonary complications that 
are not hospitalized for monitoring after daratumumab infusion , a follow-up telephone 
call should be made and documented to monitor their condition within 48 hours (no later 
than 72 hours) after all daratumumab infusions. 
 
8.2.5 Day 22 Cycles 1-2 Only (unless otherwise noted) 
• Observation: Observe subject for one hour post daratumumab injection per investigator 
discretion. 
• Laboratory Assessments 
o CBCD: complete blood count with differential and platelets 
o Pregnancy test (serum or urine) in FCBP: Cycle 1 only 
• Per Investigator’s discretion, for subjects at higher risk for pulmonary complications that 
are not hospitalized for monitoring after daratumumab infusion, a follow-up telephone 
call should be made and documented to monitor their condition within 48 hours (no later 
than 72 hours) after all daratumumab infusions. 
 
8.2.6 Post-Induction Disease Evaluation 
• Performance Status: ECOG performance status 
• Cardiac Evaluation: ECG  
• Laboratory Assessments 
o Serum chemistries: BUN, creatinine, glucose, uric acid, calcium, chloride, 
phosphorus, potassium, sodium, LDH, albumin, total protein, magnesium, total 
bilirubin, alkaline phosphatase, AST and ALT. NOTE: calcium should also be 
corrected for albumin. 
o CBCD: complete blood count with differential and platelets 
o HBV DNA testing: only for subjects positive for Anti-HBc or Anti-HBs at 
Screening. 
• Disease Evaluation: 
o Blood and urine tests: Serum QIg (including IgA, IgM, IgG, IgD**, IgE**), SPEP, 
UPEP (24-hr urine sample required), serum and urine immunofixation, and serum 
FLC. **Testing for IgD and IgE will only be performed for subjects with IgD and 
IgE-type myeloma. Serum FLC to be performed in subjects with light chain only 
disease and in subjects where at least a CR is suspected or who are maintaining at 
least a CR. Subjects without measurable urine M-Protein at baseline will not be 
required to have UPEP or urine immunofixation repeated at subsequent disease 
assessment time-points, unless clinically indicated. 
o Bone marrow aspirate and biopsy for disease evaluation (including MRD 
analysis/correlatives); see Section 8.6.2 *only those subjects who experience 
≥VGPR will undergo an assessment of MRD. 
o Assess extramedullary plasmacytomas: PET/CT and/or WB-MRI 
o Daratumumab Interference Testing at suspected CR (subjects with IgG Kappa 
MM only) 

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• Blood sample for correlatives: See Study Calendar and Section 8.6.1  
8.3 
Post-Induction Procedures 
Based on disease evaluation after induction, subjects will be divided into 3 separate treatment 
groups (see Schema 2). The specific post-induction treatments for a given subject differ based on 
Group, MRD results (based on DNA sequencing) and investigator discretion, but may include: 
ASCT, KRd consolidation, lenalidomide maintenance and/or observation. Procedures for each 
category are included in the sections below. 
8.3.1 Throughout the Post-Induction Period 
• Physical Exam: Symptom-directed physical exam only  
• AEs: Record all AEs per the NCI CTCAEv4.03.   
• Concomitant Medications: Record any changes in concomitant medications. 
Concomitant medications include but are not limited to over the counter medications, 
supplements, and vitamins. 
• Laboratory Assessments 
o HBV DNA testing: every 12 weeks for up to 6 months after last dose of 
daratumumab only for subjects positive for Anti-HBc or Anti-HBs at Screening. 
• Disease Evaluation: 
o Skeletal Survey only if clinically indicated 
o Daratumumab Interference Testing at suspected CR (subjects with IgG Kappa 
MM only) 
8.3.2 ASCT Procedures 
8.3.2.1 Stem Cell Mobilization and Collection 
All subjects in Group B and subjects in Group A who are transplant eligible will undergo stem 
cell mobilization and collection (see Section 5.2).  
 
• AEs: AEs related to mobilization do not need to be reported. However, any AEs 
considered related to induction (i.e., either daratumumab, carfilzomib, lenalidomide 
and/or dexamethasone) should continue to be reported.   
8.3.2.2 ASCT  
All subjects in Group B will undergo ASCT (see Section 5.4).  
 
• AEs: AEs related to HDC and ASCT do not need to be reported. However, any AEs 
considered related to induction (i.e., either daratumumab, carfilzomib, lenalidomide 
and/or dexamethasone) should continue to be reported. 
8.3.2.3 Post-ASCT Disease Evaluation 
• Performance Status: ECOG performance status 
• Laboratory Assessments 
o Serum chemistries: BUN, creatinine, glucose, uric acid, calcium, chloride, 
phosphorus, potassium, sodium, LDH, albumin, total protein, magnesium, total 

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bilirubin, alkaline phosphatase, AST and ALT. NOTE: calcium should also be 
corrected for albumin. 
o CBCD: complete blood count with differential and platelets 
• Disease Evaluation: 
o Blood and urine tests: Serum QIg (including IgA, IgM, IgG, IgD**, IgE**), SPEP, 
UPEP (24-hr urine sample required), serum and urine immunofixation, and serum 
FLC. **Testing for IgD and IgE will only be performed for subjects with IgD and 
IgE-type myeloma. Serum FLC to be performed for subjects with light chain only 
disease and for subjects with a suspected CR or who are maintaining at least a 
CR. Subjects without measurable urine M-Protein at baseline will not be required 
to have UPEP or urine immunofixation repeated at subsequent disease assessment 
time-points, unless clinically indicated. 
o Bone marrow aspirate and biopsy for disease evaluation (including MRD 
analysis/correlatives); see Section 8.6.2; *only those subjects who experience 
≥VGPR will undergo an assessment of MRD. 
o Assess extramedullary plasmacytomas: PET/CT and/or WB-MRI every 12 weeks 
from the Post-Induction disease evaluation (only subjects with extramedullary 
plasmacytomas present at the post-induction assessment) 
o Daratumumab Interference Testing at suspected CR (subjects with IgG Kappa 
MM only) 
• Blood sample for correlatives: See Study Calendar and Section 8.6.1. 
8.3.3 KRd Consolidation Procedures 
8.3.3.1 Day 1 Cycles 1-12 (unless otherwise noted) 
• Weight: If a subject’s weight changes by more than 20% from KRd consolidation C1D1, 
the dose of carfilzomib should be re-calculated.   
• Performance Status: ECOG performance status 
• Cardiac Evaluation: ECG; Cycles 1, 4, and, if applicable, 7 and 11 (see Disease 
Evaluation below)   
• Laboratory Assessments 
o Serum chemistries: BUN, creatinine (with calculated creatinine clearance), 
glucose, uric acid, calcium, chloride, phosphorus, potassium, sodium, LDH, 
albumin, total protein, magnesium, total bilirubin, alkaline phosphatase, AST and 
ALT. NOTE: calcium should also be corrected for albumin. 
o CBCD: complete blood count with differential and platelets 
o Pregnancy test (serum or urine) in FCBP 
• Disease Evaluation: 
o Blood and urine tests: Serum QIg (including IgA, IgM, IgG, IgD**, IgE**), SPEP, 
UPEP (24-hr urine sample required), serum and urine immunofixation, and serum 
FLC. **Testing for IgD and IgE will only be performed for subjects with IgD and 
IgE-type myeloma. Serum FLC to be performed for subjects with light chain only 
disease and for subjects with a suspected CR or who are maintaining at least a 
CR. Subjects without measurable urine M-Protein at baseline will not be required 
to have UPEP or urine immunofixation repeated at subsequent disease assessment 
time-points, unless clinically indicated. 

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o In subjects with ≥VGPR based on blood and urine evaluation, bone marrow 
aspirate and biopsy; after completion of cycles 4 and 8 only (see Section 8.6.2): A 
bone marrow aspirate and biopsy will be performed for disease evaluation and to 
assess MRD/correlatives. Those who convert to MRD (-) per DNA sequencing 
after cycles 4 or 8 will permanently discontinue KRd. NOTE: For those subjects 
who convert to MRD (-), this evaluation will serve as their post-consolidation 
disease evaluation (see Section 8.3.3.3). 
o Subjects with extramedullary plasmacytomas present at the post-induction 
assessment: Assess extramedullary plasmacytomas: PET/CT and/or WB-MRI 
every 12 weeks for a year, then once a year for subsequent years 
o Daratumumab Interference Testing at suspected CR (subjects with IgG Kappa 
MM only) 
 
• Blood sample for correlatives: See Study Calendar and Section 8.6.1. 
8.3.3.2 Day 15 Cycles 1-12 
• Laboratory Assessments 
o Serum chemistries: BUN, creatinine, glucose, uric acid, calcium, chloride, 
phosphorus, potassium, sodium, LDH, albumin, total protein, magnesium, total 
bilirubin, alkaline phosphatase, AST and ALT. NOTE: calcium should also be 
corrected for albumin. 
o CBCD: complete blood count with differential and platelets 
8.3.3.3 Post-Consolidation Disease Evaluation 
• Performance Status: ECOG performance status 
• Cardiac Evaluation: ECG  
• Laboratory Assessments 
o Serum chemistries: BUN, creatinine, glucose, uric acid, calcium, chloride, 
phosphorus, potassium, sodium, LDH, albumin, total protein, magnesium, total 
bilirubin, alkaline phosphatase, AST and ALT. NOTE: calcium should also be 
corrected for albumin. 
o CBCD: complete blood count with differential and platelets 
• Disease Evaluation: 
Note: For those subjects who permanently discontinue KRd due to conversion to MRD (-
) disease via DNA sequencing after completion of cycle 4 or cycle 8, this evaluation will 
serve as their post-consolidation disease evaluation (see Section 8.3.3.3) 
o Blood and urine tests: Serum QIg (including IgA, IgM, IgG, IgD**, IgE**), SPEP, 
UPEP (24-hr urine sample required), serum and urine immunofixation, and serum 
FLC. **Testing for IgD and IgE will only be performed for subjects with IgD and 
IgE-type myeloma. Serum FLC to be performed for subjects with light chain only 
disease and for subjects with a suspected CR or who are maintaining at least a 
CR. Subjects without measurable urine M-Protein at baseline will not be required 
to have UPEP or urine immunofixation repeated at subsequent disease assessment 
time-points, unless clinically indicated. 

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o Bone marrow aspirate and biopsy for disease evaluation (including MRD 
analysis/correlatives); see Section 8.6.2; *only those subjects who experience 
≥VGPR will undergo an assessment of MRD. 
o Subjects with extramedullary plasmacytomas present at the post-induction 
assessment: Assess extramedullary plasmacytomas: PET/CT and/or WB-MRI 
every 12 weeks for a year, then once a year for subsequent years 
o Daratumumab Interference Testing at suspected CR (subjects with IgG Kappa 
MM only) 
8.3.4 Lenalidomide Maintenance Procedures 
8.3.4.1 Day 1 Cycles 1-12 (unless otherwise noted) 
• Performance Status: ECOG performance status 
• Laboratory Assessments 
o Serum chemistries: BUN, creatinine (with calculated creatinine clearance), 
glucose, uric acid, calcium, chloride, phosphorus, potassium, sodium, LDH, 
albumin, total protein, magnesium, total bilirubin, alkaline phosphatase, AST and 
ALT. NOTE: calcium should also be corrected for albumin. 
o CBCD: complete blood count with differential and platelets 
o Pregnancy test (serum or urine) in FCBP 
• Disease Evaluation: 
o Blood and urine tests: Serum QIg (including IgA, IgM, IgG, IgD**, IgE**), SPEP, 
UPEP (24-hr urine sample required), serum and urine immunofixation, and serum 
FLC. **Testing for IgD and IgE will only be performed for subjects with IgD and 
IgE-type myeloma. Serum FLC to be performed for subjects with light chain only 
disease and for subjects with a suspected CR or who are maintaining at least a 
CR. Subjects without measurable urine M-Protein at baseline will not be required 
to have UPEP or urine immunofixation repeated at subsequent disease assessment 
time-points, unless clinically indicated. 
o Subjects with extramedullary plasmacytomas present at the post-induction 
assessment: Assess extramedullary plasmacytomas: PET/CT and/or WB-MRI 
every 12 weeks for a year, then once a year for subsequent years 
o Daratumumab Interference Testing at suspected CR (subjects with IgG Kappa 
MM only) 
• Blood sample for correlatives: See Study Calendar and Section 8.6.1. 
8.3.4.2 At6and 12 months after post-induction (Group A) or post-consolidation (Groups B 
and C) and then annually (+/- 30 days) until disease progression or initiation of new 
anti-cancer treatment:  
: 
o Bone marrow aspirate and biopsy for disease evaluation and MRD 
analysis/correlatives; see Section 8.6.2; *only those subjects who experience 
≥VGPR will undergo an assessment of MRD. 
o For subjects in Group B who convert to MRD (-) after ASCT and do not receive 
consolidation, bone marrow aspirate and biopsy for disease evaluation and MRD 
analysis/correlatives should be evaluated at 6 and 12 months after transplant. 

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8.3.4.3 Day 1 every 3 Cycles for Cycles 13+ (unless otherwise noted) 
• Performance Status: ECOG performance status 
• Laboratory Assessments 
o Serum chemistries: BUN, creatinine (with calculated creatinine clearance), 
glucose, uric acid, calcium, chloride, phosphorus, potassium, sodium, LDH, 
albumin, total protein, magnesium, total bilirubin, alkaline phosphatase, AST and 
ALT. NOTE: calcium should also be corrected for albumin. 
o CBCD: complete blood count with differential and platelets 
o Pregnancy test (serum or urine) in FCBP: D1 of every cycle. 
• Disease Evaluation: 
o Blood and urine tests: Serum QIg (including IgA, IgM, IgG, IgD**, IgE**), SPEP, 
UPEP (24-hr urine sample required), serum and urine immunofixation, and serum 
FLC. **Testing for IgD and IgE will only be performed for subjects with IgD and 
IgE-type myeloma. Serum FLC to be performed for subjects with light chain only 
disease and for subjects with a suspected CR or who are maintaining at least a 
CR. Subjects without measurable urine M-Protein at baseline will not be required 
to have UPEP or urine immunofixation repeated at subsequent disease assessment 
time-points, unless clinically indicated. 
o Subjects with extramedullary plasmacytomas present at the post-induction 
assessment: Assess extramedullary plasmacytomas: PET/CT and/or WB-MRI 
every 12 weeks for a year, then once a year for subsequent years 
o Daratumumab Interference Testing at suspected CR (subjects with IgG Kappa 
MM only) 
8.4 
Safety Follow-up Visit 
This visit should occur in subjects 30 days (+/-10 days) after study treatment stops for whatever 
reason (toxicity, progression, or at discretion of the investigator). NOTE: this 30-day time period 
applies even if the subject is taken off study treatment and begins new anti-cancer treatment 
during this time period. 
 
For subjects in Group A who do not go on lenalidomide maintenance, this visit may occur the 
day of (but prior to) stem cell mobilization (if the subject is eligible for transplant). For subjects 
in Group B who do not go on lenalidomide maintenance after ASCT, this visit may occur the day 
of the post-ASCT disease evaluation. 
 
• Performance Status: ECOG performance status 
• Laboratory Assessments 
o Serum chemistries: BUN, creatinine, glucose, uric acid, calcium, chloride, 
phosphorus, potassium, sodium, LDH, albumin, total protein, magnesium, total 
bilirubin, alkaline phosphatase, AST and ALT. NOTE: calcium should also be 
corrected for albumin. 
o Hematology: complete blood count with differential and platelets 
• AEs: Record all AEs; subjects who have ongoing Grade 4 AE or SAE at the time of 
discontinuation from treatment, and those who come off treatment prematurely for safety 

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reasons will continue to be followed until the event is resolved or deemed irreversible by 
the investigator.  
• Concomitant Medications: Record any changes in concomitant medications. 
Concomitant medications include but are not limited to over the counter medications, 
supplements, and vitamins. 
8.5 
Follow-up  
Any second primary malignancies discovered during long-term follow-up will be documented. 
 
PFS Follow-up: For subjects who permanently discontinue study treatment before relapse or  
PD (including subjects who do not go on lenalidomide maintenance), disease evaluations should 
continue to be performed per standard of care until relapse or confirmed PD, start of a new 
anticancer treatment, or the subject meets the criteria for Off Study as defined in Section 9.2, 
whichever occurs first.  
 
Survival Follow-up: For subjects who have had confirmed disease progression or started new 
anticancer treatment, long-term follow-up contact will occur every 6 months (+/- 30 days) from 
the date of confirmed disease progression or initiation of new anti-cancer treatment until the 
subject meets the criteria for Off Study as defined in Section 9.2 and may be conducted via 
telephone. Follow-up clinical information may also be obtained through chart reviews or other 
data sources (e.g. death registries).   
 
The investigator is responsible for following the subject during the required follow-up period 
even if the subject lives elsewhere or has been released from his or her care and is being treated 
at another institution. 
 
If the subject cannot be contacted following three attempted telephone calls over a period of 10 
business days, the subject will be contacted in writing. Lost to follow-up is defined as four 
consecutive unsuccessful documented attempts (telephone and written) to contact the subject. 
 
NOTE: in the event the criteria for the final analysis are met, and there are subjects who have 
not yet been permanently discontinued from study treatment, subjects in follow-up will continue 
to be followed until all subjects have permanently discontinued study treatment and completed 
the Safety Follow-up Visit (see above). 
 
8.6 
Biospecimen Correlative Studies 
8.6.1 Blood Samples  
Correlatives: Approximately 30 mL of blood will be collected at each time-point for 
correlatives as outlined in the Study Calendars in Section 7. The blood will be used for 
peripheral blood phenotyping by flow cytometry, and for PBMC isolation (T cell receptor 
sequencing) and plasma collection (cytokine profiling). Comprehensive peripheral immune 
profiling techniques will be employed including: 
• Soluble immune analytes measurements combining cytokine, chemokine and growth 
factor profiling [15 cytokines (IL-1b. IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-12p70, 

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IL-13, IL-15, IL-17, IL-22, TNFa, INFg); 5 chemokines (IL-8, MIP1a, MIP1b, MCP1, 
IP10); and 5 growth factors (VEGF, FGF, PDGF, EGF, HGF) together with 3 markers of 
hypoxia and bone remodeling (IGF-1, HIF, RANK-L)]. 
• Flow cytometry-based enumeration and characterization of circulating effector and 
functional memory T cell mobilization (T helper and cytotoxic T cell subsets) [24] as 
well as γδ T cells, NK cells, and inducible NK-T activation [24,25] 
• Circulating T cells (αβ and γδ subsets) clonal expansion assessment TCR-VD(J) 
rearrangement sequencing. 
 
8.6.2 Bone Marrow Samples 
In addition to the bone marrow samples required for routine clinical disease evaluation, bone 
marrow samples from aspirates and biopsies performed after each phase of treatment as 
applicable (induction, ASCT, consolidation with KRd, maintenance) will also be evaluated for: 
• 
Flow cytometry-based tumor microenvironment analysis: MRD status will be assessed 
for this study in part using a flow cytometry-based MM MRD assay developed by the 
Euroflow consortium (https://www.ncbi.nlm.nih.gov/pubmed/28104919)  utilizing 10 
markers (CD138, CD38, CD45, CD19 CD56, CD27, CD117, CD81, κ / λ free light 
chains) to identify plasma cells, differentiate normal from MM-PC and well as PC 
clonality. Using alternative gating strategy, this flow cytometry panel will also allow 
identification and characterization of NK, T, B and myeloid cell subsets. MRD flow will 
not be required at screening. 
• MRD assessment by NGS: MRD will be assessed via NGS which utilizes MM cell DNA 
from bone marrow samples. 
• Micro-array / global gene expression analysis of isolated plasma cells.  
• Clonal evolution of PC (and MM-PC subpopulation) IgG VJ rearrangement sequencing. 
 
For Group A subjects on lenalidomide maintenance or  PFS follow up ,bone marrow aspirate and 
biopsy will be performed post-induction  at the time-points indicated in the Study Calendar.  For 
Group B and C subjects with ≥VGPR based on blood and urine evaluation, bone marrow aspirate 
and biopsy will also be performed after completion of cycle 4 and cycle 8 (if applicable) of KRd 
consolidation for disease evaluation and MRD status via flow cytometry and NGS. In addition, 
bone marrow aspirate will be collected for banking/correlatives at disease progression/relapse as 
indicated below if a bone marrow aspirate is performed as part of clinical care. 
 
In addition to the volumes required for routine clinical evaluation, a minimum of 15mL of bone 
marrow aspirate (1st pull or 1st technical pull after needle repositioning) will be required for 
MRD assessment by flow cytometry and NGS and banking. See laboratory guidelines for details. 
In the event difficulty arises while marrow specimens are collected preventing collection of all 
5x3ml of bone marrow aspirate, the sample should be prioritized as follows: 
1) MRD NGS (Adaptive):3ml  
2) MRD flow (Immune Monitoring Core Lab): 6ml  
3) Banking (Hematology Oncology Translational Lab): 6ml. Optional: If possible, an 
additional 6ml of bone marrow aspirate can be collected at baseline and upon 
progression/relapse for banking [i.e. CD138+ plasma cell isolation (B cell receptor 
sequencing)]. Note: if a bone marrow biopsy/aspirate is done for disease evaluation 

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purposes where MRD is not required to be assessed due to disease response, bone 
marrow should still be collected for banking and should include up to 12ml whenever 
possible. 
9. DISCONTINUATION FROM TREATMENT AND STUDY 
WITHDRAWAL 
9.1 
Treatment Discontinuation Criteria 
Study treatment will continue until one of the following criteria applies: 
• Disease relapse or progression 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable adverse event(s) 
• Subject decides to withdraw study consent  
• General or specific changes in the subject’s condition render the subject unacceptable for 
further treatment in the judgment of the investigator 
• Study subject becomes pregnant 
• Completion of protocol-directed therapy per Investigator-discretion (e.g. MRD negative 
subjects entering observation per Investigator) 
 
 
NOTE: In the event the criteria for the final analysis are met, and there are subjects who have 
not yet been permanently discontinued from study treatment, they will continue to receive 
treatment until one of the above criteria applies. 
9.2 
Off Study 
Subjects will remain on study until the criteria for the final analysis are met (Section 14.5.1).  
Reasons a subject may be removed from study early include, but are not limited to: 
• Subject non-compliance with study participation, in the opinion of the investigator 
• The subject or legal representative (such as a parent or legal guardian) withdraws study 
consent 
• The subject is lost to follow-up 
• Study completion 
• Investigator’s decision to withdraw the subject 
• Subject death 
• Early study termination 
 
When subjects are removed from the study, the reason for study removal and date the subject 
was removed should be documented.  
 
Subjects that are Off Study will not participate in any study related procedures, including data 
collection. 

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10. DRUG INFORMATION 
10.1 Daratumumab 
For complete information, please refer to the latest version of the daratumumab IB, provided as a 
document separate from this protocol. Please also refer to the latest version of the prescribing 
information for daratumumab, which can be found at http://www.janssenlabels.com/package-
insert/product-monograph/prescribing-information/DARZALEX+Faspro-pi.pdf  
 
Daratumumab is a CD38-directed cytolytic antibody approved by the FDA in combination with 
lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of 
patients with multiple myeloma who have received at least one prior therapy. It is also approved 
as monotherapy for the treatment of patients with multiple myeloma who have received at least 
three prior lines of therapy including a proteasome inhibitor and an IMiD agent or who are 
double refractory to both of these classes of drugs. 
10.1.1 Supplier/How Supplied?  
Daratumumab will be supplied free of charge to study subjects by Janssen Biotech, Inc., the 
manufacturer of daratumumab.  
 
For SC injections, Daratumumab will be provided as a fixed-dose (1800 mg), combination drug 
product containing rHuPH20 drug substance (2000 U/mL) and daratumumab drug substance 
(120 mg/mL) in a single vial.  
 
10.1.2 Preparation  
NOTE: See latest version of the daratumumab prescribing information which can be found at 
http://www.janssenlabels.com/package-insert/product-monograph/prescribing-
information/DARZALEX+Faspro-pi.pdf for the most up to date information on preparation of 
daratumumab for administration. 
10.1.3 Storage and Stability 
All investigational study drugs will be stored at the investigational site in accordance with Good 
Clinical Practice (GCP) and Good Manufacturing Practices (GMP) requirements and will be 
inaccessible to unauthorized personnel. 
 
Store Daratumumab for subcutaneous injection vials in a refrigerator at 2°C to 8°C (36°F to 
46°F) in the original carton to protect from light. Do not freeze or shake.  
Daratumumab prepared for SC administration should be used immediately. If not used 
immediately, store solution for up to 4 hours at ambient temperature and ambient light. Discard 
after 4 hours, if not used. 
 
10.1.4 Handling  
Daratumumab should be handled using standard precautions for the safe handling of 
antineoplastic agents. Personal protection equipment is recommended. It must be dispensed only 
from official study sites by authorized personnel according to local regulations and stored in a 

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secure area according to local regulations.  It is the responsibility of the investigator to ensure 
that study drug is only dispensed to eligible study subjects. 
10.1.5 Accountability  
An adequate record of receipt, distribution, destruction, or return of this agent must be kept in the 
form of a Drug Accountability Form. The investigator, or responsible party designated by the 
investigator, will maintain a careful record of the inventory using the Drug Accountability Form. 
The investigational drug for this clinical trial shall only be dispensed by authorized personnel to 
subjects enrolled in this clinical trial. 
10.1.6 Destruction 
The investigator or designee is responsible for keeping accurate records of the clinical supplies 
received from Janssen Biotech Inc., including the amount remaining at the conclusion of the 
trial. Upon completion or termination of the study, all unused product will be destroyed at the 
site according to site pharmacy policies or as dictated by the manufacturer. Any vials that are 
used during dose preparation may be destroyed immediately after preparation. It is the 
investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
10.1.7 Adverse Events Associated with Daratumumab SC 
The most frequently reported adverse reactions in clinical trials were: infusion related reactions, 
upper respiratory tract infection, bronchitis, pneumonia, thrombocytopenia, anemia, neutropenia, 
anorexia, peripheral sensory neuropathy, headache, hypertension, cough, dyspnea, constipation, 
diarrhea, nausea, vomiting, muscle spasms, peripheral edema, asthenia, pyrexia, back pain, 
insomnia, and arthralgia.  Also common were: urinary tract infection, flu like symptoms, herpes 
zoster, sepsis, hyperglycemia, hypocalcemia, dehydration, arrhythmia, chills, low oxygen 
saturation, pharyngitis, pulmonary edema, dizziness, pancreatitis, rash, pruritis, muscular chest 
pain.  
 
The most commonly reported adverse events from recombinant human hyaluronidase (rHuPH20, 
enzyme included in daratumumab SC) 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. Mild to moderate headache have also been reported. Some 
patients who receive rHuPH20 may develop antibodies directed to the PH20 hyaluronidase; 
approximately 5% of the general population has these antibodies even without ever having been 
exposed to rHuPH20. 
 
See Section 1.3 and the daratumumab Investigator’s Brochure for additional information. See 
Section 1.3.3.3 for safety information when daratumumab was evaluated in combination with 
carfilzomib, lenalidomide and dexamethasone.  
 
The following warnings are associated with the use of daratumumab SC (from the current 
prescribing information): 
 

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• Hypersensitivity and Other Administration Reactions: Both systemic administration-
related reactions, including severe or life-threatening reactions, and local injection-site 
reactions can occur with DARZALEX FASPRO.  SYSTEMIC REACTIONS: In a 
pooled safety population of 490 patients who received DARZALEX FASPRO as 
monotherapy or in combination, 11% of patients experienced a systemic administration-
related reaction (Grade 2: 3.9%, Grade 3: 1.4%). Systemic administration-related 
reactions occurred in 10% of patients with the first injection, 0.2% with the second 
injection, and cumulatively 0.8% with subsequent injections. The median time to onset 
was 3.7 hours (range: 9 minutes to 3.5 days). Of the 84 systemic administration-related 
reactions that occurred in 52 patients, 73 (87%) occurred on the day of DARZALEX 
FASPRO administration. Delayed systemic administration-related reactions have 
occurred in less than 1% of the patients. Severe reactions included hypoxia, dyspnea, 
hypertension,tachycardia, choroidal effusion, acute myopia, and acute angle closure 
glaucoma. Other signs and symptoms of systemic administration-related reactions may 
include respiratory symptoms, such as bronchospasm, nasal congestion, cough, throat 
irritation, allergic rhinitis, and wheezing, as well as anaphylactic reaction, pyrexia, chest 
pain, pruritis, chills, vomiting, nausea, and hypotension.  LOCAL REACTIONS: In this 
pooled safety population, injection-site reactions occurred in 8% of patients, including 
Grade 2 reactions in 0.6%. The most frequent (>1%) injection-site reaction was injection 
site erythema. These local reactions occurred a median of 7 minutes (range: 0 minutes to 
4.7 days) after starting administration of DARZALEX FASPRO. 
• Neutropenia: Daratumumab may increase neutropenia induced by background therapy.  
• Thrombocytopenia: Daratumumab may increase thrombocytopenia induced by 
background therapy.   
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise pregnant women of the potential 
risk to a fetus and advise females of reproductive potential to use effective contraception. 
• Interference with cross-matching and red blood cell antibody screening.  
 
 
10.2 Carfilzomib 
For complete information, please refer to the latest version of the prescribing information for 
carfilzomib, which can be found at www.kyprolis.com. 
 
Carfilzomib is proteasome inhibitor approved by the FDA in combination with lenalidomide and 
dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who 
have received one to three prior lines of therapy, or as monotherapy in patients with relapsed or 
refractory multiple myeloma who have received one or more lines of therapy. 
10.2.1 Supplier/How Supplied  
Carfilzomib will be supplied free of charge to study subjects by Amgen, the manufacturer of 
carfilzomib. The vial size it will be provided in is 60 mg and will be labeled “Carfilzomib for 
injection 60mg/vial in 4x carton”. Carfilzomib will be provided as a lyophilized powder which, 
when reconstituted, contains a 2 mg/mL isotonic solution of carfilzomib.  

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10.2.2 Reconstitution and Preparation  
Refer to the latest version of the prescribing information for carfilzomib, which can be found at 
www.kyprolis.com, for instructions on reconstitution and preparation of carfilzomib. 
10.2.3 Storage and Stability 
Refer to the latest version of the prescribing information for carfilzomib, which can be found at 
www.kyprolis.com, for details on stability of unopened vials of carfilzomib, and on stability of 
carfilzomib once it is reconstituted. 
10.2.4 Handling  
Carfilzomib should be handled using standard precautions for the safe handling of antineoplastic 
agents. Personal protection equipment is recommended. It must be dispensed only from official 
study sites by authorized personnel according to local regulations and stored in a secure area 
according to local regulations.  It is the responsibility of the investigator to ensure that study drug 
is only dispensed to eligible study subjects. 
10.2.5 Accountability  
An adequate record of receipt, distribution, destruction, or return of this agent must be kept in the 
form of a Drug Accountability Form. The investigator, or responsible party designated by the 
investigator, will maintain a careful record of the inventory using the Drug Accountability Form. 
The investigational drug for this clinical trial shall only be dispensed by authorized personnel to 
subjects enrolled in this clinical trial. 
10.2.6 Destruction 
The investigator or designee is responsible for keeping accurate records of the clinical supplies 
received from Amgen Inc., including the amount remaining at the conclusion of the trial. Upon 
completion or termination of the study, all unused product will be destroyed at the site according 
to site pharmacy policies or as dictated by the manufacturer. Any vials that are used during dose 
preparation may be destroyed immediately after preparation. It is the investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal have 
been established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 
10.2.7 Adverse Events Associated with Carfilzomib 
For complete information on safety, please refer to the latest version of the prescribing 
information for carfilzomib, which can be found at www.kyprolis.com. 
 
See Section 1.3.3.3 for safety information when carfilzomib was evaluated in combination with 
daratumumab, lenalidomide and dexamethasone.  
 
The safety of carfilzomib in combination with lenalidomide and dexamethasone (KRd) was 
evaluated in an open-label randomized study in patients with relapsed multiple myeloma. 
Adverse Reactions that occurred at a rate of ≥10% in the KRd arm (n=392) during the first 12 
cycles of therapy are in the table below. 
 
 

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KRd Arm 
n (%) 
Adverse Reaction 
Any Grade 
≥ Grade 3 
Anemia 
138 (35) 
53 (14) 
Asthenia 
53 (14) 
11 (3) 
Bronchitis 
54 (14) 
5 (1) 
Constipation 
68 (17) 
0 
Cough 
91 (23) 
2 (1) 
Diarrhea 
115 (29) 
7 (2) 
Dyspnea 
70 (18) 
9 (2) 
Fatigue 
109 (28) 
21 (5) 
Hyperglycemia 
43 (11) 
18 (5) 
Hypertension 
41 (11) 
12 (3) 
Hypocalcemia 
55 (14) 
10 (3) 
Hypokalemia 
78 (20) 
22 (6) 
Insomnia 
63 (16) 
6 (2) 
Muscle spasms 
88 (22) 
3 (1) 
Nasopharyngitis 
63 (16) 
0 
Nausea 
60 (15) 
1 (0) 
Neutropenia 
124 (32) 
104 (27) 
Peripheral edema 
63 (16) 
2 (1) 
Peripheral neuropathies 
43 (11) 
7 (2) 
Pneumonia 
54 (14) 
35 (9) 
Pyrexia 
93 (24) 
5 (1) 
Rash 
45 (12) 
5 (1) 
Thrombocytopenia 
100 (26) 
58 (15) 
Upper Respiratory Tract Infection 
85 (22) 
7 (2) 
Venous Embolic and Thrombotic Events 
49 (13) 
16 (4) 
 
 
Laboratory abnormalities ≥ Grade 3 reported at a rate of ≥ 10% in the KRd arm included 
decreases in the following (% of patients): lymphocytes (46%), ANC (39%), phosphorus (31%), 
platelets (26%), total WBC (25%), hemoglobin (15%) and potassium (11%). 
 
The following warnings are associated with the use of carfilzomib (from the August 2020 
prescribing information): 
 
The most common adverse reactions occurring in at least 20% of patients treated with Kyprolis 
in the combination therapy trials: anemia, diarrhea, fatigue, hypertension, pyrexia, upper 
respiratory tract infection, thrombocytopenia, cough, dyspnea, and insomnia. 
 
Other risks of special concern include: cardiac toxicities, acute renal failure, Tumor Lysis 
Syndrome (TLS), pulmonary toxicity including (acute respiratory distress syndrome, acute 
respiratory failure, acute diffuse infiltrative pulmonary disease), pulmonary hypertension, 
dyspnea, hypertension including hypertensive crisis, venous thrombosis, infusion-related 

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reactions, hemorrhage, thrombocytopenia, hepatic toxicity and hepatic failure, Hepatitis B 
reactivation, thrombotic microangiopathy, Posterior Reversible Encephalopathy Syndrome 
(PRES), Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone 
in Newly Diagnosed Transplant-Ineligible Patients and embryo-fetal toxicity.  
 
Cases of Progressive Multifocal Leukoencephalopathy (PML) have been reported in patients 
treated with carfilzomib who have had prior or concurrent immunosuppressive therapy. The 
causal relationship with carfilzomib is unknown. Patients should be monitored for any new or 
worsening neurologic, cognitive or behavioral signs, or symptoms that may be suggestive of 
PML as part of the differential diagnosis of CNS disorders. If PML is suspected, Carfilzomib 
should be HELD and patients promptly referred to a specialist with appropriate diagnostic testing 
initiated. Discontinue carfilzomib if PML diagnosis is confirmed. 
 
10.3 Lenalidomide 
For complete information, please refer to the latest version of the prescribing information for 
lenalidomide, which can be found at www.revlimid.com. 
 
Lenalidomide is a thalidomide analogue approved by the FDA in combination with 
dexamethasone for the treatment of patients with MM, and for use as maintenance therapy post 
ASCT. 
10.3.1 Supplier/How Supplied  
Lenalidomide will be supplied free of charge to study subjects by Celgene Corporation, the 
manufacturer of lenalidomide, through a contract pharmacy. Subjects in the U.S. must be 
enrolled into the REVLIMID Risk Evaluation and Mitigation Strategy (REMS)™ program for 
the procurement of lenalidomide.  Lenalidomide is formulated in hard capsules containing 2.5 
mg, 5 mg, 10 mg, 15 mg, or 25 mg active drug for PO administration only.  
 
Per standard Revlimid REMS® program requirements, all physicians who prescribe 
lenalidomide for research subjects enrolled into this trial, and all research subjects enrolled into 
this trial, must be registered in, and must comply with, all requirements of the Revlimid REMS® 
program.   
 
Further information about the Revlimid REMS® program is available at 
www.celgeneriskmanagement.com. 
10.3.2 Storage and Stability 
Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F). 
10.3.3 Handling  
Lenalidomide should be handled using standard precautions for the safe handling of 
antineoplastic agents. Personal protection equipment is recommended. Lenalidomide capsules 
should not be opened or broken. It is the responsibility of the investigator to ensure that study 
drug is only dispensed to eligible study subjects. 

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10.3.4 Administration Compliance 
For subjects due for another cycle of lenalidomide and have a visit scheduled at the research site, 
lenalidomide will be dispensed to subjects, and the study drug pill bottles returned to site 
research staff. Local pharmacy staff will report the number of capsules in the study drug bottles 
returned to site research staff. The number of capsules taken by the subject per cycle will be 
derived from these capsule counts rather than reported by the subjects on a pill diary. Subjects 
will be asked to return used study drug bottles at designated time-points.  
For subjects due for another cycle of lenalidomide and do not have a visit scheduled at the 
research site, lenalidomide may be shipped to the subject’s home after approval of the sponsor. 
Administration will be documented using a diary or other source documentation of lenalidomide 
administration at home rather than a pill count. Pill bottles will not be returned to the site 
research staff.   
 
Compliance with study treatment will be assessed at the end of each cycle. Subject compliance 
with the treatment and protocol includes willingness to comply with all aspects of the protocol. 
At the discretion of the investigator, a subject may be permanently discontinued from the 
protocol for non-compliance with study drug. 
10.3.5 Accountability  
An adequate record of receipt, distribution, destruction, or return of this agent must be kept in the 
form of a Drug Accountability Form. The investigator, or responsible party designated by the 
investigator, will maintain a careful record of the inventory using the Drug Accountability Form. 
The investigational drug for this clinical trial shall only be dispensed by authorized personnel to 
subjects enrolled in this clinical trial. 
10.3.6 Destruction 
The investigator or designee is responsible for keeping accurate records of the clinical supplies 
received from Celgene Corporation, including the amount remaining at the conclusion of the 
trial. Upon completion or termination of the study, all unused product will be destroyed (after the 
appropriate steps have been taken to count and document the number of units returned) at the site 
according to site pharmacy policies or as dictated by the manufacturer. It is the investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for proper 
disposal have been established according to applicable federal, state, local and institutional 
guidelines and procedures, and provided that appropriate records of disposal are kept. 
10.3.7 Adverse Events Associated with Lenalidomide 
For complete information on safety, please refer to the latest version of the prescribing 
information for lenalidomide, which can be found at www.revlimid.com. The most common 
adverse reactions (≥20%) when lenalidomide is used in MM include diarrhea, fatigue, anemia, 
constipation, neutropenia, leukopenia, peripheral edema, insomnia, muscle cramp/spasms, 
abdominal pain, back pain, nausea, asthenia, pyrexia, upper respiratory tract infection, bronchitis, 
nasopharyngitis, gastroenteritis, cough, rash, dyspnea, dizziness, decreased appetite, 
thrombocytopenia and tremor. 
 
See Section 1.3.3.3 for safety information when lenalidomide was evaluated in combination with 
daratumumab, carfilzomib and dexamethasone when used as maintenance. 

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The following warnings are associated with the use of lenalidomide in MM (from the October 
2019 prescribing information; Black Box Warnings are noted as such): 
 
• BLACK BOX WARNING: Embryo-fetal Toxicity: 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. Because of this, lenalidomide is only 
available through a restricted distribution program called the REVLIMID REMS™ 
program.  
• BLACK BOX WARNING: Hematologic Toxicity: Lenalidomide can cause significant 
neutropenia and thrombocytopenia. 
• BLACK BOX WARNING: Venous and Arterial Thromboembolism: 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 MM receiving lenalidomide in 
combination with dexamethasone. Anti-thrombotic prophylaxis is recommended. Second 
Primary Malignancies: In clinical trials in patients with MM receiving lenalidomide an 
increase of invasive second primary malignancies notably AML and MDS have been 
observed. The increase of cases of AML and MDS occurred predominantly in NDMM 
patients receiving lenalidomide in combination with oral melphalan (frequency of 5.3%) 
or immediately following high dose intravenous melphalan and ASCT (frequency of up 
to 5.2%).  
• Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated 
with lenalidomide in combination with dexamethasone. In clinical trials, 15% of patients 
experienced hepatotoxicity (with hepatocellular, cholestatic and mixed characteristics); 
2% of patients with MM and 1% of patients with myelodysplasia had serious 
hepatotoxicity events. The mechanism of drug-induced hepatotoxicity is unknown. Pre-
existing viral liver disease, elevated baseline liver enzymes, and concomitant medications 
may be risk factors.). 
• Allergic Reactions, including fatalities: Angioedema and serious dermatologic reactions 
including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have 
been reported. These events can be fatal. 
• Tumor Lysis Syndrome: Fatal instances of TLS have been reported during treatment 
with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to 
treatment.  
• Impaired Stem Cell mobilization: A decrease in the number of CD34+ cells collected 
after treatment (> 4 cycles) with lenalidomide has been reported. 
 
The most common adverse reactions include: leukopenia, neutropenia, febrile neutropenia, 
granulocytopenia, lymphopenia, anemia, thrombocytopenia, vision blurred, diarrhea, abdominal 
pain, constipation, dyspepsia, nausea, vomiting, asthenia, fatigue, edema, peripheral edema, 
pyrexia, chills, pneumonia, influenza, bronchitis, upper respiratory tract infection, sinusitis, 
urinary tract infection, gastroenteritis, renal failure, nasopharyngitis, pharyngitis rhinitis, weight 
loss, decreased appetite, hyperglycemia, hypokalemia, hypocalcemia, alanine aminotransferase 
increased, gamma-glutamyltransferase increased, arthralgia, back pain, bone pain, muscle 

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spasms, myalgia, tumor flare dizziness, dysgeusia, headache, cataract, paresthesia, hypoesthesia, 
neuropathy, peripheral neuropathy, tremor, cough, dyspnea, epistaxis, pulmonary embolism, 
deep vein thrombosis, pruritus, rash, depression, insomnia.  
10.4 Dexamethasone 
Dexamethasone is a synthetic adrenoglucocorticoid. It is commercially available as a generic in 
tablet form for oral administration. It is indicated for a variety of medical conditions, including 
cancer. Commercial supplies of dexamethasone will be used for this study and charged to study 
subjects or their insurance company. 
10.4.1 Storage  
Dexamethasone is to be stored at controlled room temperature 20 to 25°C (68 to 77°F). 
Consult the package insert of the respective product for additional storage and usage instructions. 
10.4.2 Summary of Adverse Events Associated with Dexamethasone  
See Reference [27] for a more complete summary. Also see Section 6.4.2, Table 15. 
 
The side effects from systemic glucocorticoids are usually dose and duration dependent and can 
impact virtually all body systems. Common side effects include thinning of the skin, purpura, 
Cushingoid appearance, weight gain, sleep disturbance and mood changes. Hyperglycemia is 
common if these agents are used in patients with pre-existing diabetes or those at risk of diabetes 
for other reasons. Cataracts are also common with prolonged (>1 year) of glucocorticoids. Other 
risks of concern with glucocorticoids include an increased risk of cardiovascular disease and 
hypertension (particularly when glucocorticoids are prescribed in patients with pre-existing 
cardiac or renal disease), increased risk of peptic ulcer disease and gastritis (especially when 
patients are also taking nonsteroidal anti-inflammatory agents), osteoporosis, increased fracture 
risk, osteonecrosis, myopathy, edema, and immunosuppression with an increased risk of 
infection. With the exception of cataracts and some of the cardiac and bone toxicities, adverse 
effects from glucocorticoids are at least partially reversible upon discontinuation. 
11. DATA AND SAFETY MONITORING PLANS 
 
Data will be collected in electronic case report forms (eCRFs). Study personnel will be trained 
on data entry by the sponsor and provided protocol-specific eCRF guidelines. 
 
This protocol will be monitored according to the processes in effect for all LCI investigator-
initiated studies, the protocol-specific monitoring plan, and will abide by applicable regulations 
and guidelines (e.g. Good Clinical Practice [GCP]).  It is the responsibility of the Sponsor-
Investigator to monitor the safety data for this study.  The Sponsor-Investigator and other 
sponsor-level team members will meet regularly to monitor subject consents, enrollment and 
retention, safety data, and timeliness/validity/integrity of the data. Documentation of these 
meetings will be kept with study records. The Sponsor-Investigator will submit reports to the 
LCI Data and Safety Monitoring Committee according to the institutional Data and Safety 
Monitoring Plan. 
 

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This study will be monitored to ensure the study is conducted in compliance with the study 
protocol, SOPs of the LCI and Atrium Health Office of Clinical and Translational Research 
(and/or other participating institutional SOPs), the FDA, and other applicable regulations and 
guidelines (e.g. GCP).  
 
12. ADVERSE EVENTS AND UNANTICIPATED PROBLEMS 
12.1 Definitions 
12.1.1 Adverse Event 
An adverse event is any untoward medical occurrence in a study subject who is administered any 
drug that does not necessarily have a causal relationship with this treatment.  An adverse event 
can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product.  Pre-existing conditions that increase in 
frequency or severity or change in nature during or as a consequence of use of a drug in human 
clinical trials are also considered adverse events.  Adverse events may also include pre or post-
treatment complications that occur as a result of protocol mandated procedures (e.g., invasive 
procedures such as biopsies). 
 
An increase in grade to a pre-existing CTCAE toxicity grade present at the time of study 
treatment initiation will be recorded as an AE. Changes in vital signs, ECG, physical 
examination and laboratory test results will be recorded as an AE if they are judged clinically 
significant by the investigator and/or require a medical intervention or dose modification. 
 
Any continuing medical condition or clinically significant laboratory abnormality with an onset 
date before the first date of study treatment administration should be considered pre-existing and 
should be documented. 
 
An AE does not include: 
• relapse or progression of the underlying malignant disease;  
• medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion); 
NOTE: the condition that leads to the procedure may be an adverse event; 
• situations where an untoward medical occurrence has not occurred (e.g., hospitalization 
for elective surgery, social and/or convenience admissions); 
• overdose of either study drug or concomitant medication without any signs or symptoms 
unless the subject is hospitalized for observation 
 
The severity of adverse events should be classified and recorded according to the CTCAE 
version 4.03. 
12.1.2 Adverse Event of Special Interest (AESI)  
Adverse Events of Special Interest (AESI) that require expedited reporting to Janssen Scientific 
Affairs, LLC for subjects exposed to daratumumab include: 
 

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• Infusion Reactions ≥ Grade 3 
• Infections ≥ Grade 4 
• Cytopenias ≥Grade 4 
• HBV Reactivation 
• Other malignancies 
 
12.1.3 Special Reporting Situations for Daratumumab 
Safety events of interest for daratumumab that requires expedited reporting and/or safety 
evaluating include, but are not limited to: 
 
• Drug exposure during pregnancy (maternal and paternal) 
• Overdose of daratumumab  
• Exposure to daratumumab from breastfeeding  
• Suspected abuse/misuse of daratumumab 
• Inadvertent or accidental exposure to daratumumab 
• Any failure of expected pharmacological action (i.e., lack of effect) of daratumumab 
• Medication error involving daratumumab (with or without subject exposure 
daratumumab, e.g., name confusion) 
• Suspected transmission of any infectious agent via administration of daratumumab 
• Unexpected therapeutic or clinical benefit from use of daratumumab 
• Any failure of expected pharmacological action (i.e., lack of effect) of daratumumab 
 
                                                                                                                                                                                    
These safety events may not meet the definition of an adverse event; however, from a Janssen 
Scientific Affairs, LLC perspective, they are treated in the same manner as AEs.  
 
12.1.4 Special Reporting Situations for Lenalidomide 
Important safety information to be reported for lenalidomide, includes, for example: 
 
• any SAE, pregnancy or secondary primary malignancies not previously reported as 
referenced in Section 12.3 
• Adverse Events occurring during breastfeeding 
• lack of therapeutic efficacy for lenalidomide* 
• suspected transmission of infectious agents 
• medication errors 
• overdose 
• abuse 
• misuse 
• off-label use which is not in conformity with the Protocol 
• occupational exposure 
• any public health emergency 
• any major safety finding arising from an audit or a Regulatory Authority inspection and  

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• any issue which may affect the conduct of the Study, the safety of Study subjects or the 
risk/benefit ratio of lenalidomide  
 
* “Lack of therapeutic efficacy” is defined as a significant failure of lenalidomide to achieve an 
expected pharmacologic or therapeutic outcome for an indication approved under the marketing 
authorization. 
 
Overdose 
 
Overdose for lenalidomide, as defined for this protocol, refers to lenalidomide dosing only.   
 
On a per dose basis, an overdose is defined as the following amount over the protocol-specified 
dose of lenalidomide assigned to a given subject, regardless of any associated adverse events or 
sequelae. 
 
PO  
any amount over the protocol-specified dose 
 
IV 
10% over the protocol-specified dose  
 
SC 
10% over the protocol-specified dose 
 
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol required schedule or frequency.   
 
Celgene Drug Safety Contact Information: 
 
Celgene Corporation      
Global Drug Safety and Risk Management    
86 Morris Avenue     
Summit, NJ  07901        
Fax: (908) 673-9115 
E-mail: drugsafety@celgene.com 
 
12.1.5 Suspected Adverse Reaction (SAR) 
A suspected adverse reaction (SAR) is any AE for which there is a reasonable possibility that the 
drug is the cause. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the drug and the AE.  A suspected adverse reaction implies a lesser degree 
of certainty about causality than adverse reaction, which means any adverse event caused by a 
drug.   
 
Causality assessment to a study drug is a medical judgment made in consideration of the 
following factors: temporal relationship of the AE to study drug exposure, known mechanism of 
action or side effect profile of study treatment, other recent or concomitant drug exposures, 
normal clinical course of the disease under investigation, and any other underlying or concurrent 
medical conditions.  Other factors to consider in considering drug as the cause of the AE: 
 

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• Single occurrence of an uncommon event known to be strongly associated with drug 
exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome) 
• One or more occurrences of an event not commonly associated with drug exposure, but 
otherwise uncommon in the population (e.g., tendon rupture); often more than once 
occurrence from one or multiple studies would be needed before the Sponsor-Investigator 
could determine that there is reasonable possibility that the drug caused the event.   
• An aggregate analysis of specific events observed in a clinical trial that indicates the 
events occur more frequently in the drug treatment group than in a concurrent or 
historical control group 
12.1.6 Adverse Reaction 
An adverse reaction means any adverse event caused by a drug. Adverse reactions are a subset of 
all suspected adverse reactions where there is reason to conclude that the drug caused the event. 
12.1.7 Serious AE or SAR 
An AE or SAR is to be considered serious if the investigator deems it as such and the event 
results in any of the following outcomes: 
 
• Death (fatal); 
• Life-threatening situation (subject is at immediate risk of death); 
• Persistent or significant disability/incapacity; 
• Requires or prolongs inpatient hospitalization*; 
• A congenital anomaly/birth defect in the offspring of a subject who received study drug;  
• Is a suspected transmission of any infectious agent via a medicinal product; 
• Based upon appropriate medical judgment, may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the afore listed outcomes from 
occurring (e.g. intensive treatment in an emergency room without hospitalization, blood 
dyscrasias or convulsions that do not result in hospitalization, development of drug 
dependency or drug abuse). 
 
NOTE: DEATH FOR ANY REASON SHOULD BE REPORTED AS A SERIOUS ADVERSE 
EVENT. 
 
Pregnancy and Lactation Exposure 
The following do not meet the criteria for seriousness per ICH definition but must be reported in 
the same manner as SAEs. Therefore, these events are considered serious for reporting purposes:  
 
• Lactation exposure within 90 days of the subject’s last dose of daratumumab and 30 days 
after last dose of all other study drugs. 
• Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of 
age or disease state) of a female subject occurring while the subject is on study treatment, 
or within 90 days after last dose of daratumumab and 30 days after last dose all other 
study drugs.  
o Pregnancies in partners of male subjects exposed to daratumumab. Informed 
consent of the pregnant partner will be required prior to reporting health 
information on a pregnant partner. 

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*Hospitalizations for study drug administration, protocol-related procedures, palliative or 
hospice care, or placement of an indwelling catheter, unless associated with other serious events, 
will not be recorded as SAEs. Other hospitalizations planned at the beginning of the trial also do 
not need to be reported as an SAE.  
12.1.7.1 Serious Adverse Drug Reaction (SADR) 
A serious adverse drug reaction is a serious adverse event (SAE) that is considered to at least 
have a reasonable possibility of a causal relationship, based on facts and evidence, between the 
study drug and the AE. 
12.1.7.2 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A suspected unexpected Serious Adverse Reaction (SUSAR) is a Serious Adverse Drug Reaction 
(SADR) that is unexpected (as defined in Section 12.1.8). 
12.1.7.3 Hospitalization 
For reports of hospitalization, it is the sign, symptom or diagnosis which led to the 
hospitalization that is the serious event for which details must be provided. 
 
Any event requiring hospitalization or prolongation of hospitalization that occurs during the 
study must be reported as a serious adverse event, except hospitalizations for the following: 
 
• Hospitalizations not intended to treat an acute illness or adverse event (e.g., social 
reasons such as pending placement in long-term care facility) 
• Surgery or procedure planned before entry into the study. [Note: Hospitalizations 
that were planned before the start of data collection and where the underlying 
condition for which the hospitalization was planned has not worsened will not be 
considered serious adverse events. Any adverse event that results in a 
prolongation of the originally planned hospitalization is to be reported as a new 
serious adverse event.] 
• [For convenience the investigator may choose to hospitalize the subject for the 
duration of the treatment period.]  
 
12.1.7.4 Life-Threatening Conditions 
Disease progression should not be recorded as an adverse event or serious adverse event term; 
instead, signs and symptoms of clinical sequelae resulting from disease progression/lack of 
efficacy will be reported if they fulfill the serious adverse event definition. 
12.1.8 Unexpected AE (AE or SAE) or SAR 
An AE or SAR (whether serious or not) is considered unexpected if the specificity or severity of 
it is not consistent with the applicable product information (e.g., IB for an unapproved 
investigational product or package insert/summary of product characteristics for an approved 
product).  Unexpected also refers to AEs or SARs that are mentioned in the IB as occurring with 
a class of drugs or as anticipated from the pharmacological properties of the drug but are not 
specifically mentioned as occurring with the particular drug under investigation.   

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http://www.janssenlabels.com/package-insert/product-monograph/prescribing-
information/DARZALEX+Faspro-pi.pdf  
 
For DARZALEX® (daratumumab), the expectedness of an adverse event will be determined by 
whether or not it is listed in the Investigator's Brochure. 
12.1.9 Product Quality Complaint (PQC) for Daratumumab 
A product quality compliant is defined as any suspicion of a daratumumab 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 
12.1.10 Unanticipated Problem (UAP) 
An UAP is any incidence, experience or outcome that is unexpected, given the information 
provided in research-related documentation (e.g., IB, informed consent) and the study population 
characteristics that is related or possibly related to participation in the research study and places 
the participant at an increased risk. By this definition, any event that meets the criteria defined in 
Section 12.1.8 would meet the criteria for a UAP. However other events may also meet the 
criteria for a UAP, e.g., a lost or stolen laptop computer that contains sensitive study information.  
 
12.2 Attribution 
The relationship to study treatment should be assessed using the following definitions: 
 
Definite 
The AE is clearly related to the drug(s) under investigation 
Probable 
The AE is likely related to the drug(s) under investigation 
Possible 
The AE possibly related to the drug(s) under investigation 
Unlikely 
The AE is doubtfully related to the drug(s) under investigation 
Unrelated 
The AE is clearly not related to the drug(s) under investigation 

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The investigator is responsible for verifying and providing source documentation for all AEs and 
assigning the attribution for each event for all subjects enrolled on the trial. 
12.3 Timing and Reporting  
12.3.1 Adverse Events 
All AEs, from the time of study treatment initiation until 30 days after last dose of study 
treatment (including event name, grade, start/stop date and attribution) will be documented. 
12.3.1.1 Reporting to Sponsor-Investigator 
After informed consent but prior to initiation of study medications, only SAEs caused by a 
protocol-mandated intervention will be collected (e.g. SAEs related to invasive procedures such 
as biopsies, medication washout). For any other experience or condition that meets the definition 
of an SAE, AESI, or Special Reporting Situation, recording of the event must begin from day 1 
of treatment and continue through 30 days after last dose of study treatment. All SAEs and 
AESIs (whether considered related or not, expected or not) must be reported to the Sponsor-
Investigator within 1 business day of awareness. Special Reporting Situations must be recorded 
in the eCRF with an email notification to the Sponsor-Investigator or designee within 1 business 
day of awareness. SAEs that are determined to be related to study treatment or procedures must 
be reported to the Sponsor-Investigator throughout the duration of the subject’s participation in 
the trial (from consent until off-study). 
 
When new significant information becomes available, a follow-up report must be reported to the 
Sponsor-Investigator within 1 business day of awareness. 
 
All serious adverse events must be followed until any of the following occurs: 
 
• The event resolves 
• The event stabilizes 
• The event returns to baseline, if a baseline value/status is available 
• The event can be attributed to agents other than the study drug or to factors unrelated to study 
conduct 
• It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of 
due diligence with follow-up efforts) 
 
It is the responsibility of the Sponsor-Investigator, investigators and the protocol team to ensure 
SAEs are reported according to the Code of Federal Regulations (CFR), GCP, the protocol 
guidelines, IRB, and FDA policy.  
12.3.1.2 Reporting to Janssen Scientific Affairs, LLC 
 
The following methods are acceptable for transmission of safety information to Janssen 
Scientific Affairs, LLC: 
 

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• Electronically via Janssen SECURE Email service (preferred) to IIS-BIO-VIRO-
GCO@its.jnj.com 
• For business continuity purposes, if SECURE Email is non-functional: 
o Facsimile (fax) to 866-651-0219, receipt of which is evidenced in a successful 
fax transmission report  
• Telephone to current Local Trial Manager (if fax is non-functional). 
 
 
12.3.1.2.1 
SAEs for Daratumumab 
From the time of initiation of study treatment, through 30 days after the last dose of study 
treatment, all SAEs (whether considered related or not, expected or not, and including any 
Special Reporting Situation or PQCs for daratumumab that meet the criteria of an SAE [see 
Sections 12.1.3]) excluding those from subjects not exposed to daratumumab must be reported to 
Janssen Scientific Affairs, LLC by the Sponsor-Investigator or designee within 24 hours of 
awareness of the event. 
 
12.3.1.2.2 
AESI for Daratumumab 
AESI for daratumumab (see Section 12.1.2) will be reported from the time of study treatment 
initiation to 30 days after last dose to Janssen Scientific Affairs, LLC by the Sponsor-Investigator 
or designee within 24 hours of Sponsor-Investigator awareness. 
12.3.1.2.3 
PQC for Daratumumab 
A PQC for daratumumab (see Section 12.1.9) 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 subjects, investigators, and Janssen Scientific Affairs, 
LLC, and are mandated by regulatory agencies worldwide. Janssen Scientific Affairs, LLC has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information. Lot and/or Batch #s shall be collected or any reports 
failure of expected pharmacological action (i.e., lack of effect). The product should be 
quarantined immediately and if possible, take a picture. 
 
All initial PQCs involving daratumumab must be reported to Janssen Scientific Affairs, LLC by 
the Sponsor-Investigator or designee within 24 hours after being made aware of the event. An 
email to this effect should be sent to IIS-BIO-VIRO-GCO@its.jnj.com and depending on the 
nature of the complaint 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 Sponsor-Investigator must report the 
PQC to Janssen Scientific Affairs, LLC according to the serious adverse event reporting 
timeline. A sample of the suspected product should be maintained for further investigation if 
requested by Janssen Scientific Affairs, LLC. 
 
If the defect for a Janssen medicinal product under study is combined with either a serious adverse 
event or non-serious adverse event, the Sponsor 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. 

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Reporting Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) for Non-
Janssen Medicinal Products  
For SAEs, special reporting situations and PQCs following exposure to a non-Janssen medicinal 
product under study, the Sponsor-Investigator should notify the appropriate regulatory/competent 
authority or the manufacturer of that medicinal product (in the absence of appropriate local 
legislation) as soon as possible. 
 
12.3.1.2.4 
Special Reporting Situations for Daratumumab 
Any Special Reporting Situation for daratumumab from the time of consent until 30 days after 
last dose of daratumumab will be documented.  
 
Any Special Reporting Situation for daratumumab (see Section12.1.3) will be reported to 
Janssen Scientific Affairs, LLC by the Sponsor-Investigator or designee within 24 hours of 
Sponsor-Investigator awareness. 
 
12.3.1.2.5 
Pregnancy 
All initial reports of pregnancy must be reported as an SAE to Janssen Scientific Affairs, LLC by 
the Sponsor-Investigator or designee within 24 hours of becoming aware of the event. Abnormal 
pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, congenital anomaly, ectopic 
pregnancy) are considered SAEs and must be reported as such.  
 
Any subject who becomes pregnant during study treatment must promptly discontinue further 
study treatment. 
 
Because the effect of daratumumab on sperm is unknown, pregnancies in partners of male subjects 
exposed to daratumumab will be reported by the Sponsor-Investigator or designee within 24 hours 
of becoming aware of the event as an SAE.  Depending on local legislation this may require prior 
consent of the partner. 
 
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required. 
 
12.3.1.2.6 
Individual Case Safety Report (ICSR) 
A valid ICSR must contain the four minimum criteria required to meet regulatory reporting 
requirements. 
• an identifiable subject (but not disclosing personal information such as the 
subject’s name, initials or address) 
• an identifiable reporter (investigational site) 
• a Janssen medicinal product 
• an adverse event, outcome, or certain special situations 
 
The minimum information required is: 
 
• suspected Janssen medicinal product (doses, indication) 

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• date of therapy (start and end date, if available) 
• batch or lot number, if available 
• subject details (subject ID and country) 
• gender 
• age at AE onset 
• reporter ID 
• adverse event detail (AE verbatim in English), onset date, relatedness, causality, 
action taken, outcome, (if available) 
• Janssen protocol ID 
 
Maintenance of Safety Information 
All safety data should be maintained in a clinical database in a retrievable format. The Sponsor-
Investigator will provide all adverse events, both serious and non-serious, in report format. 
However, in certain circumstances more frequent provision of safety data may be necessary, e.g. 
to fulfill a regulatory request, and as such the data shall be made available within a reasonable 
timeframe at Janssen Scientific Affairs, LLC’s request. 
12.3.1.3 Reporting to Amgen 
All SUSARs and Pregnancy and Lactation Exposure Reports generated from the Study will be 
reported on a MedWatch form. To avoid misinterpretation, all SUSARs reports provided must 
clearly indicate the reported AE terms, seriousness criterion, reported assessment of causality 
and Sponsor assessment of causality (if different).  
 
Sponsor will inform Amgen of any pregnancy occurring and/or existing during exposure to 
carfilzomib and potential infant exposure within 10 calendar days of Sponsor awareness. Amgen 
may in accordance with local data privacy laws request the subject’s physician’s contact 
information in order to follow-up the pregnancy until birth outcome. 
 
SUSARs will be submitted to Amgen on a MedWatch form within twenty-four (24) hours of 
submitting that report to the applicable regulatory authority.   
 
Additional information should be sought on initial and/or follow-up SAE reports and Pregnancy 
and Lactation Exposure Reports with incomplete information. The information obtained from the 
report source should be sufficient to provide a true and comprehensive description and medical 
confirmation of the SAE or pregnancy or lactation exposure as it is understood at the time of 
follow-up. If available, follow-up information should include a summary of the relevant critical 
data found in medical records (e.g., discharge summaries, lot numbers, relevant laboratory and 
scan data, and autopsy reports as applicable). 
 
Sponsor will be responsible for obtaining follow-up information for the SAEs occurring in this 
study (including attempts to obtain medical confirmation) and will demonstrate diligence in 
attempting to obtain such information by, among other things, maintaining written records of 
such attempts. 
 

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Sponsor will forward all follow-up information to Amgen within the same timeframes that it is 
required to provide initial reports. The notification of subsequent follow-up information on the 
same case should reflect the same Sponsor’s unique case number. 
 
MedWatch (or equivalent) forms will be used to communicate ICSRs.  
 
All transfer of safety information to Amgen will be made through the designated contact fax or 
email address listed below: 
 
Fax: 
 
888-814-8653 (toll-free, US) 
                        805-480-9205 (toll) 
 
E-mail: 
svc-ags-in-us@amgen.com 
 
12.3.1.3.1 
Individual Case Safety Report (ICSR) 
 
An ICSR includes Pregnancy Exposure Reports and Follow-up Reports (as those phrases are 
defined below). Each ICSR shall contain, at a minimum, the following information: 
 
• Event reference number; 
• Protocol name and number; 
• Sponsor-Investigator contact information; 
• Specific subject identifiers (e.g., initials, subject number, date of birth or age, or gender); 
• The name of the suspect study drug;  
• The date(s) and dosage(s) of exposure; 
• Event; 
• Date(s) of event; 
• Country of event; 
• "Serious" Criteria; 
• Relationship/causality of study drug; 
• Hospitalization history for the event; 
• Event status/outcome; 
• Relevant history (including diagnostics, laboratory values, radiographs, concomitant 
medications, and event treatment); and 
• Narrative summary. 
 
Every ninety (90) calendar days, ICSRs of all new and follow-up SAEs including Pregnancy 
Exposure Reports during the preceding 90-day period will be reported on a MedWatch form (or 
equivalent). Seriousness and causality assessments should be specified. For the avoidance of 
doubt, the reporting periods begins on the date the first subject enrolls in the study. 
12.3.1.4 Reporting to Celgene 
Safety events will be reported to Celgene by the Sponsor-Investigator or designee per the 
timeframes listed below: 

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Safety Event 
Timeframe for Reporting 
SUSARs 
Within 24 hours of submitting the report to 
the applicable regulatory authority 
SADRs 
Within 15 days of Sponsor-Investigator 
awareness 
All other SAEs not meeting definition of 
SUSAR or SADR (initial and follow-up 
reports) 
Every 90 calendar days, reporting period to 
begin with date of first subject enrollment. 
Special Reporting Situations for lenalidomide  Within 24 hours of Sponsor-Investigator 
awareness 
 
Any correspondence to the FDA or other Regulatory Authority regarding Adverse Events or 
other safety issues will be simultaneously copied via facsimile to Celgene. The MedWatch 
3500A form should be utilized to report Serious Adverse Events to Celgene, the FDA or other 
Regulatory Authority (The MedWatch 3500A form will be faxed with the Celgene reference 
number on the fax cover). 
 
The reporting periods will commence as the date the first subject enrolls in the study.  The 
reporting period ends thirty (30) days after discontinuation of dosing. In addition, any Serious 
Adverse Event that may occur after this time period which is believed to be certainly, probably 
or possibly related to the study drug must be reported to Celgene.  
 
12.3.1.4.1 
Pregnancy 
If a subject becomes pregnant while still being treated with the study drug the Sponsor-
Investigator will:  
 
• immediately discontinue at least the treatment with the Celgene study drug;   
• instruct the subject to return immediately any unused portion of the Celgene study drug; 
and 
• immediately refer the subject to an obstetrician-gynecologist experienced in reproductive 
toxicity for further evaluation and counseling. 
 
The Sponsor-Investigator will use reasonable efforts in order to ensure that: 
 
• any study-related pregnant person is advised to consult her general practitioner or 
gynecologist as soon as possible; and  
• the contact details of the healthcare provider who is following the pregnancy are provided 
to the Sponsor-Investigator. 
 

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The Sponsor-Investigator or designee will follow pregnant subjects until the end of the 
pregnancy and must notify Celgene’s Drug Safety Department at fax # 908-673-9115 about the 
outcome of the pregnancy (including false-positive pregnancy tests) immediately upon having 
knowledge of the event using the Celgene “Pregnancy Reporting Form” and the Celgene 
“Follow Up Pregnancy Reporting Form”. 
 
The Sponsor-Investigator or designee will report:  
 
• any outcome of a pregnancy which qualifies as a Serious Adverse Event (including 
spontaneous or therapeutic abortion, fetal and neonatal death or congenital anomaly); and 
• any death of an infant which occurs in connection with in utero exposure to the Study 
Drug within twenty-eight (28) days of birth. The Sponsor-Investigator or designee will 
also document any congenital anomaly detected in an aborted fetus. 
• The Sponsor-Investigator or designee will notify Celgene of any discontinuation of any 
subject for the reasons set forth in this section using a MedWatch 3500A form. 
 
The Sponsor-Investigator or designee will use their best efforts in order to require that male 
subjects inform it/him/her if their partners get pregnant while the subject is still treated with the 
Study Drug and to provide the Sponsor-Investigator or designee the contact details of the 
healthcare provider who follows the pregnancy in question. Informed consent of the pregnant 
partner will be required prior to reporting health information on a pregnant partner. Any 
information provided by the pregnant partner or medical professional following the pregnancy 
should be reported to Celgene’s Drug Safety Department using the Celgene Pregnancy Reporting 
Form. 
 
12.3.1.4.2 
SPM Reporting 
Secondary primary malignancy (SPM) is any malignancy which (i) is diagnosed in a study 
subject in the course of the study or during long-term follow-up, (ii) is different from the 
malignancy for which the study subject is treated in the context of the study (IPM – initial 
primary malignancy) and (iii) does not result from metastasis from the IPM. All SPM for the 
earlier of (x) the period for which the Sponsor and/or Sponsor-Investigator follows the study 
subjects for survival or (y) for three (3) years following the discontinuation of the study drug will 
be collected and reported. Such reporting will occur on a quarterly basis via facsimile to Celgene 
at fax # 908-673-9115 with the Celgene reference number on the fax cover. 
12.3.1.5 Reporting to the IRB 
All events occurring during the conduct of the protocol and meeting the definition of an SAE 
will be reported to the IRB per IRB reporting requirements.   
12.3.1.6 Reporting to the FDA 
According to CFR 312.32, unexpected fatal or life-threatening events possibly related with the 
use of the study drug (drugs) will be reported to the FDA by fax or by email as soon as possible, 
but in no event later than 7 calendar days after the initial receipt of the information regarding the 
event. A comprehensive written report will be submitted as an amendment to the IND within an 
additional 8 days (15 calendar days total).   
 

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All other serious unexpected events related to use of the study drug (i.e., serious SARs) will be 
reported to FDA as an amendment to the IND as soon as possible, but in no event later than 15 
calendar days after initial receipt of the information regarding the event.  
12.3.2 Reporting UAPs  
All UAPs occurring during the conduct of a protocol and meeting the definition of an UAP will 
be reported to the IRB per IRB reporting requirements.  
 
13. DISEASE EVALUATION 
13.1 IMWG 2016 Response Criteria 
Please refer to footnotes * and ||. All response categories require two consecutive assessments, 
which should be captured in the dataset. Each category, except for stable disease, will be 
considered unconfirmed until the confirmatory test is performed. The date of the initial test is 
considered as the date of response for evaluation of time dependent outcomes such as duration of 
response.  
 
 
IMWG MRD Criteria (Requires a complete response as defined below)  
Sustained MRD-
negative 
MRD negativity in the marrow (NGF or NGS, or both) and by imaging as defined below, 
confirmed minimum of 1 year apart. Subsequent evaluations can be used to further specify 
the duration of negativity (eg, MRD-negative at 5 years)† 
Flow MRD-negative 
Absence of phenotypically aberrant clonal plasma cells by NGF‡ on bone marrow aspirates 
using the EuroFlow standard operation procedure for MRD detection in multiple myeloma 
(or validated equivalent method) with a minimum sensitivity of 1 in 10⁵ nucleated cells or 
higher 
Sequencing MRD-
negative 
Absence of clonal plasma cells by NGS on bone marrow aspirate in which presence of a 
clone is defined as less than two identical sequencing reads obtained after DNA sequencing 
of bone marrow aspirates using the LymphoSIGHT platform (or validated equivalent 
method) with a minimum sensitivity of 1 in 10⁵ nucleated cells§ or higher 
Imaging-positive 
MRD-negative 
MRD negativity as defined by NGF or NGS plus disappearance of every area of increased 
tracer uptake found at baseline or a preceding PET/CT or decrease to less mediastinal blood 
pool SUV or decrease to less than that of surrounding normal tissue¶ 
Standard IMWG Response Criteria||; NOTE: see [1] for additional details 
Stringent Complete 
Response 
(sCR) 
• 
Complete response as defined below plus normal FLC ratio** and absence of clonal 
cells in bone marrow biopsy by immunohistochemistry (κ/λ ratio ≤4:1 or ≥1:2 for 
             κ and λ patients, respectively, after counting ≥100 plasma cells)†† 
Complete Response 
(CR) 
• 
Negative immunofixation on the serum and urine and disappearance of any soft 
tissue plasmacytomas and <5% plasma cells in bone marrow aspirates  

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Very Good Partial 
Response 
(VGPR) 
• 
Serum and urine M-protein detectable by immunofixation but not on electrophoresis 
or ≥90% reduction in serum M-protein plus urine M-protein level <100 mg 
per 24 h 
Partial Response 
(PR) 
• 
≥50% reduction of serum M-protein plus reduction in 24 h urinary M-protein by 
≥90% or to <200 mg per 24 h; 
• 
If the serum and urine M-protein are unmeasurable, a ≥50% decrease in the 
difference between involved and uninvolved FLC levels is required in place of the 
M-protein criteria; 
• 
If serum and urine M-protein are unmeasurable, and serum-free light assay is also 
unmeasurable, ≥50% reduction in plasma cells is required in place of M-protein, 
provided baseline bone marrow plasma-cell percentage was ≥30%. In addition to 
these criteria, if present at baseline, a ≥50% reduction in the size (SPD)§§ of soft 
tissue plasmacytomas is also required 
Minimal Response 
(MR) 
• 
≥25% but ≤49% reduction of serum M-protein and reduction in 24-h urine M-protein 
by 50–89%. In addition to the above listed criteria, if present at baseline, a ≥50% 
reduction in the size (SPD)§§ of soft tissue plasmacytomas is also required. 
Stable Disease (SD) 
• 
Not recommended for use as an indicator of response; stability of disease is best 
described by providing the time-to-progression estimates 
• 
Not meeting criteria for CR, VGPR, PR, MR or progressive disease 
Progressive disease 
(PD)¶¶, |||| 
Increase of > 25% from lowest response value in any one or more of the following: 
• 
Serum M-protein (absolute increase must be ≥0.5 g/dL); 
• 
Serum M-protein increase ≥1 g/dL, if the lowest M component was ≥5 g/dL; 
• 
Urine M-protein (absolute increase must be ≥200 mg/24 h); 
• 
In patients without measurable serum and urine M-protein levels, the difference 
between involved and uninvolved FLC levels (absolute increase must be >10 
mg/dL); 
• 
In patients without measurable serum and urine M-protein levels and without 
measurable involved FLC levels, bone marrow plasma-cell percentage irrespective of 
baseline status (absolute increase must be ≥10%); 
• 
Appearance of a new lesion(s), ≥50% increase from nadir in SPD§§ of >1 lesion, or 
≥50% increase in the longest diameter of a previous lesion >1 cm in short axis;  
• 
≥50% increase in circulating plasma cells (minimum of 200 cells per μL) if this is the 
only measure of disease 
Clinical Relapse 
Clinical relapse requires one or more of the following criteria: 
• 
Direct indicators of increasing disease and/or end organ dysfunction (CRAB 
features) related to the underlying clonal plasma-cell proliferative disorder. It is not 
used in calculation of TTP or PFS but is listed as something that can be reported 
optionally or for use in clinical practice; 
• 
Development of new soft tissue plasmacytomas or bone lesions (osteoporotic 
fractures do not constitute progression); 
• 
Definite increase in the size of existing plasmacytomas or bone lesions. A definite 
increase is defined as a 50% (and ≥1 cm) increase as measured serially by the 
SPD§§of the measurable lesion; 
• 
Hypercalcaemia (>11 mg/dL); 

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• 
Decrease in haemoglobin of ≥2 g/dL not related to therapy or other non-myeloma-
related conditions; 
• 
Rise in serum creatinine by 2 mg/dL or more from the start of the therapy and 
attributable to myeloma; 
• 
Hyperviscosity related to serum paraprotein 
For MRD assessment, the first bone marrow aspirate should be sent to MRD (not for morphology) and this 
sample should be taken in one draw with a volume of minimally 2 mL (to obtain sufficient cells), but 
maximally 4–5 mL to avoid haemodilution. IMWG=International Myeloma Working Group. MRD=minimal 
residual disease. NGF=next-generation flow. NGS=next-generation sequencing. FLC=freelight chain. M-
protein=myeloma protein. SPD=sum of the products of the maximal perpendicular diameters of measured 
lesions. CRAB features=calcium elevation, renal failure, anaemia, lytic bone lesions. FCM=flow cytometry. 
SUVmax=maximum standardised uptake value. MFC=multiparameter flow cytometry. 18F-FDG PET=18F-
fluorodeoxyglucose PET. ASCT=autologous stem cell transplantation. 
 
* All response categories require two consecutive assessments made any time before starting any new 
therapy; for MRD there is no need for two consecutive assessments, but information on MRD after each 
treatment stage is recommended (eg, after induction, high-dose therapy/ASCT, consolidation, maintenance). 
MRD tests should be initiated only at the time of suspected complete response. All categories of response 
and MRD require no known evidence of progressive or new bone lesions if radiographic studies were 
performed. However, radiographic studies are not required to satisfy these response requirements except for 
the requirement of FDG PET if imaging MRD-negative status is reported. †Sustained MRD negativity when 
reported should also annotate the method used (eg, sustained flow MRD-negative, sustained sequencing 
MRD-negative).  
 
‡ Bone marrow MFC should follow NGF guidelines.30 The reference NGF method is an eight-colour two-
tube approach, which has been extensively validated. The two-tube approach improves reliability, 
consistency, and sensitivity because of the acquisition of a greater number of cells. The eight-colour 
technology is widely available globally and the NGF method has already been adopted in many flow 
laboratories worldwide. The complete eight-colour method is most efficient using a lyophilised mixture of 
antibodies which reduces errors, time, and costs. 5 million cells should be assessed. The FCM method 
employed should have a sensitivity of detection of at least 1 in 10⁵ plasma cells.  
 
§ DNA sequencing assay on bone marrow aspirate should use a validated assay such as LymphoSIGHT 
(Sequenta).  
 
¶ Criteria used by Zamagni and colleagues,85 and expert panel (IMPetUs; Italian Myeloma criteria for PET 
Use).81,97 Baseline positive lesions were identified by presence of focal areas of increased uptake within 
bones, with or without any underlying lesion identified by CT and present on at least two consecutive slices. 
Alternatively, an SUVmax=2.5 within osteolytic CT areas >1 cm in size, or SUVmax=1.5 within osteolytic CT 
areas ≤1 cm in size were considered positive. Imaging should be performed once MRD negativity is 
determined by MFC or NGS.  
 
|| Derived from international uniform response criteria for multiple myeloma.11 Minor response definition 
and clarifications derived from Raj Kumar and colleagues.14 When the only method to measure disease is by 
serum FLC levels: complete response can be defined as a normal FLC ratio of 0.26 to 1.65 in addition to the 

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14. STATISTICAL CONSIDERATIONS 
14.1 Milestones 
14.1.1 Registration Date 
The date the subject signs the informed consent. 
14.1.2 Enrollment Date 
The date of initiation of study treatment on Cycle 1, Day 1. 
complete response criteria listed previously. Very good partial response in such patients requires a ≥90% 
decrease in the difference between involved and uninvolved FLC levels. 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 or extramedullary plasmacytomas if 
radiographic studies were performed. Radiographic studies are not required to satisfy these response 
requirements. Bone marrow assessments do not need to be confirmed. Each category, except for stable 
disease, will be considered unconfirmed until the confirmatory test is performed. The date of the initial test 
is considered as the date of response for evaluation of time dependent outcomes such as duration of 
response.  
 
** All recommendations regarding clinical uses relating to serum FLC levels or FLC ratio are based on 
results obtained with the validated Freelite test (Binding Site, Birmingham, UK).  
†† Presence/absence of clonal cells on immunohistochemistry is based upon the κ/λ/L ratio. An abnormal 
κ/λ ratio by immunohistochemistry requires a minimum of 100 plasma cells for analysis. An abnormal ratio 
reflecting presence of an abnormal clone is κ/λ of >4:1 or <1:2.  
 
‡‡ Special attention should be given to the emergence of a different monoclonal protein following treatment, 
especially in the setting of patients having achieved a conventional complete response, often related to 
oligoclonal reconstitution of the immune system. These bands typically disappear over time and in some 
studies have been associated with a better outcome. Also, appearance of monoclonal IgG κ in patients 
receiving monoclonal antibodies should be differentiated from the therapeutic antibody.  
 
§§ Plasmacytoma measurements should be taken from the CT portion of the PET/CT, or MRI scans, or 
dedicated CT scans where applicable. For patients with only skin involvement, skin lesions should be 
measured with a ruler. Measurement of tumour size will be determined by the SPD. 
 
¶¶ Positive immunofixation alone in a patient previously classified as achieving a complete response will not 
be considered progression. For purposes of calculating time to progression and progression-free survival, 
patients who have achieved a complete response and are MRD-negative should be evaluated using criteria 
listed for progressive disease. Criteria for relapse from a complete response or relapse from MRD should be 
used only when calculating disease-free survival.  
 
|||| In the case where a value is felt to be a spurious result per physician discretion (e.g., a possible laboratory 
error), that value will not be considered when determining the lowest value. 
 

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14.1.3 Treatment Discontinuation Date 
The date the investigator makes the decision to permanently discontinue all protocol directed 
study treatment. See Section 9 for criteria for discontinuation of treatment. 
14.2 Sample Size Determination 
The primary objective is to evaluate the efficacy of daratumumab when combined with KRd, in 
terms of complete response or better, in subjects with newly diagnosed multiple myeloma, and 
compare to relevant historical controls.  For the newly diagnosed multiple myeloma patient 
population, 8 cycles of KRd induction provides a complete response or better rate of 
approximately 50% [8,10].  For this population of patients treated with KRd+daratumumab, the 
aim is to achieve a rate of CR or better of 70%.  A minimax 2-stage design will be used to test 
the hypothesis that the CR or better rate is less than or equal to 50%.  Twenty-three (23) 
evaluable subjects will be enrolled in the first stage, and if at least 12 of the 23 subjects have a 
complete response or better after induction therapy, an additional 16 evaluable subjects will be 
enrolled (a total of 39 subjects).  If at least 24 of 39 subjects have a complete response or better, 
the null hypothesis will be rejected.  Based on a one-sided alpha = 0.10 significance level, this 
sample size will provide 90% power to reject the null hypothesis, assuming the true complete 
response or better rate is 70%. 
14.3 Endpoint Definitions 
14.3.1 Complete Response or Better 
Complete response or better will be determined for each subject as a binary variable indicating 
whether or not the subject achieved a best overall response of CR or sCR, as determined by the 
IMWG 2016 response criteria (see Section 13.1). 
14.3.2 Overall Response 
Objective response will be determined for each subject as a binary variable indicating whether or 
not the subject achieved a best overall response of PR or better.   
14.3.3 Overall Survival (OS) 
OS is defined as the duration from enrollment to the study (treatment start date) to the date of 
death from any cause.  Subjects who are alive or lost to follow-up at the time of the analysis will 
be censored at the last known date they were alive. 
14.3.4 Progression Free Survival (PFS) 
PFS is defined as the duration of time from enrollment to the study (treatment start date) to first 
occurrence of either progressive disease or death (from any cause), whichever comes first.  
Disease progression must be objectively determined per IMWG 2016 criteria (see Section 13.1), 
where the date of progression is the date of the last assessment that identified progressive 
disease.  If the subject died without documented disease progression, the date of progression will 
be the date of death.  For surviving subjects who do not have documented disease progression, 
PFS will be censored at the date of last disease assessment.  For subjects who receive subsequent 
anti-cancer treatment prior to documented disease progression, PFS will be censored at the date 
of last disease assessment prior to the commencement of subsequent treatment.  Subjects who 
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assessments will be censored at the date of the last assessment prior to those missed assessments.  
For participants with only one missed assessment, the documented progressive disease status and 
assessment date will be used.  
14.3.5 Time to Disease Progression 
Time to disease progression (TTP) will be calculated in the same fashion as described for PFS 
with the exception that for subjects who die for causes other than disease progression, TTP will 
be censored at the date of the other cause mortality.  Otherwise, the censoring mechanism for 
TTP will be the same as previously described for PFS. 
14.3.6 Duration of Response (DoR) 
Duration of response (DoR) will be calculated for each subject achieving a PR or better and will 
be calculated from the time of the first assessment that identified response until disease 
progression or death.  The censoring mechanism for DoR will be the same as described for PFS. 
14.3.7 Time to Next Treatment 
Time to next treatment (TTNT) will be calculated from the time of treatment start until the start 
of the first subsequent anti-cancer treatment after all protocol directed therapy is completed.  For 
surviving subjects who do not receive subsequent treatment, TTNT will be censored at the last 
contact date.  For subjects who die before beginning subsequent anti-cancer treatment, TTNT 
will be censored at the date of death. 
14.3.8 Minimal Residual Disease (MRD) 
MRD will be determined for each subject at baseline and for each subject with a post-induction 
VGPR or better after post induction therapy and at subsequent time points as described in the 
study calendar (Section 7).  The MRD assessment will be determined via flow cytometry and 
DNA sequencing and will be coded as either MRD (+) or MRD (-).  Subjects who experience 
less than a VGPR will be considered to have MRD (+) disease.  If a subject does not have an 
NGS test report available (for whatever reason), the subject will be assumed to be MRD + and 
will be treated as such per the algorithm. Note: The 10-⁵ MRD result from the NGS MRD test 
will be used for treatment decisions. 
14.3.9 PET/CT Endpoints 
For each subject at each time point, number of lesions identified by PET/CT and SUV max will 
be captured. 
14.3.10 Stem Cell Mobilization Endpoints 
For each subject, stem cell yield, number of stem cell mobilization attempts, and number of 
collection days will be captured. 
14.3.11 Safety Endpoints 
Safety endpoints will include treatment administration (dose intensity, planned dose intensity, 
and relative dose intensity), AEs, SAEs, deaths while on study treatment.  
 
 
 

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“Events of Special Interest” (ESI) for Safety Stopping Rule #1    
 
Events of Special Interest (ESIs) will be continuously monitored during the induction phase of 
the study in subjects receiving the combination of daratumumab, carfilzomib, lenalidomide, and 
dexamethasone (KRdD) for the purposes of the pre-specified stopping rule described in Section 
14.5.6.  A binary variable will be determined for each subject indicating whether or not the 
subject experienced at least one Grade 3/4/5 adverse event related to the KRdD regimen for the 
following CTCAE terms: 
• Heart failure 
• Pneumonia 
• Dyspnea 
• Peripheral edema 
• Hypertension 
 
“Events of Special Interest”(ESI) for Safety Stopping Rule #2    
 
A second and separate Events of Special Interest (ESI)will be continuously monitored during the 
induction phase of the study in subjects receiving the combination of KRdD. The stopping rule 
for ESI#2 is described in Section 14.5.6.  A binary variable will be determined for each subject 
indicating whether or not the subject died due to an adverse event.  The Grade 5 AEs included 
for this stopping rule will be any hematologic or non-hematologic adverse event, regardless of 
causality.  
14.4 Analysis Populations 
The evaluable population consists of the population of subjects who initiate study treatment and 
who have measurable disease at the baseline disease assessment.  Baseline disease assessments 
are defined as disease assessments collected within 28 days of initiation of the first pre-study 
induction cycle (subjects who received prior therapy) or within 28 days prior to day 1 of study 
treatment (subjects with no prior therapy). Enrollment will continue (in both Stage 1 and Stage 2) 
until the targeted sample sizes are achieved in the evaluable population.  Complete and overall 
response will be analyzed based on the evaluable population.  Analyses of other efficacy and 
safety endpoints will be conducted on the population of subjects who initiate study treatment. 
Stem cell mobilization endpoints will be evaluated in all subjects who undergo attempt(s) at stem 
cell mobilization in preparation for ASCT. Exploratory analyses will be conducted on the 
population of patients who initiate study treatment and who have available biomarker data. 
14.5 Analysis Methods 
14.5.1 Timing of Analysis 
The primary analysis will occur after the best overall response to induction therapy has been 
determined for all Stage 1 and Stage 2 subjects.  Additional analyses are planned at 1 and 3 years 
after the primary analysis. A final analysis will be conducted after the PFS censoring rate reaches 
20% or after all surviving subjects have been on study for at least 5 years, whichever occurs first. 

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14.5.2 Subject Disposition 
An accounting of all consenting subjects will be provided at the end of the study. This will 
include a breakdown of subjects who consented, were treated, permanently discontinued 
treatment, died, and were lost to follow-up or withdrew consent. 
14.5.3 Baseline Subject and Disease Characteristics 
A summary of subject demographics and disease-related characteristics will be completed and 
subject medical history will be assessed. 
14.5.4 Primary Analysis 
The frequency and proportion of subjects experiencing a CR or better will be calculated.  A 
corresponding 95% confidence interval will be estimated using the Clopper-Pearson method.  A 
one-sided test for binomial proportions using the rejection regions described in the sample size 
section (see Section 14.2) will be carried out, testing the null hypothesis that the CR or better rate 
is less than or equal to 50%.   
14.5.5 Secondary Analysis 
The frequency and proportion of overall response will be calculated.  Corresponding 95% 
confidence intervals will be estimated using the Clopper-Pearson method.  OS, PFS, TTP, DoR, 
and TTNT endpoints will be analyzed using Kaplan Meier techniques.  Selected landmarks will 
be estimated and reported.  Logistic regression models and Cox proportional hazards models will 
be used to analyze the treatment response endpoints, complete response, overall response, OS, 
PFS, TTP, and DoR to correlate outcomes to baseline subject and disease characteristics, and 
results from biomarker studies as previously described.  This will include univariate and 
multivariable regression model techniques to identify individual and independent prognostic 
factors. 
14.5.6 Safety Analysis 
The number of study treatment cycles administered, dose intensity, and relative dose intensity 
will be summarized quantitatively. 
Incident rates for TEAEs, AEs leading to study drug discontinuation, SAEs and deaths while on 
study therapy will be summarized.  TEAEs are defined as follows: 
• An AE that occurs after treatment start that was not present at the time of treatment start; 
OR 
• An AE that increases in severity after treatment start if the event was present at the time 
of treatment start. 
 
 
Induction Phase Stopping Rule #1 
 
It is estimated that the composite rate of Grade 3/4/5 ESIs (as defined in Section 14.3.10) in 
newly diagnosed multiple myeloma patients treated with carfilzomib, lenalidomide, and 
dexamethasone is approximately 0.40. If it becomes evident that the Grade 3/4/5 ESI rate 
convincingly exceeds 0.40, then enrollment to the study will be suspended. The decision to 
suspend enrollment will occur if the posterior probability of the Grade 3/4/5 ESI rate exceeding 
0.40 is 0.75 or higher.  The prior distribution for this monitoring rule is beta (8,12).  This means 

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that our prior assumptions regarding the Grade 3/4/5 ESI rate are 1) the mean of the prior 
distribution is 0.40, and 2) there is a 90% probability that this rate is between 0.230 and 0.582.  
The operating characteristics of the stopping rule are given in the following table and are based 
on 5000 simulations. 
 
Operating Characteristics of the Stopping Rule #1 
Number of Subjects with an 
ESI #1 
Number of Treated Subjects 
Posterior Probability: 
Pr(ESI #1 Rate>0.40|Data) 
3 
3 
0.779 
4 
5 
0.795 
5 
8 
0.755 
6 
10 
0.774 
7 
12 
0.771 
8 
14 
0.793 
9 
17 
0.759 
10 
19 
0.774 
11 
21 
0.788 
12 
24 
0.759 
13 
26 
0.778 
14 
28 
0.788 
15 
31 
0.755 
16 
33 
0.772 
17 
35 
0.806 
18 
38 
0.767 
 
 
Induction Phase Stopping Rule #2 
 
The stopping rule for the Grade 5 ESI was calculated in a similar fashion as described above.  
We pooled ESI results from two daratumumab containing regimens [35,36] and estimated the 
Grade 5 ESI rate to be approximately 0.05.  If it becomes evident that the Grade 5 ESI rate 
convincingly exceeds 0.05, then enrollment to the study will be suspended. The decision to 
suspend enrollment will occur if the posterior probability of the Grade 5 ESI rate exceeding 0.05 
is 0.75 or higher.  The prior distribution for this monitoring rule is beta (1,19).  This means that 
our prior assumptions regarding the Grade 5 ESI rate are 1) the mean of the prior distribution is 
0.05, and 2) there is a 90% probability that this rate is between 0.002 and 0.146.  The stopping 
rule boundaries are given in the following table.  Specifically, the study will be halted if a second 
death due to an ESI occurs among the first 15 enrolled subjects in the safety population.  
Otherwise, the study will be halted if a third death due to an ESI occurs among the first 31 
subjects enrolled in the safety population.  Otherwise, the study will be halted if a fourth death 
occurs among the first 39 subjects enrolled in the safety population.   
 
 
 
 

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Operating Characteristics of the Stopping Rule #2 
Number of Subjects with an 
ESI #2 
Number of Treated Subjects 
Posterior Probability: 
Pr(ESI #2 Rate>0.05|Data) 
2 
15 
0.759 
3 
31 
0.760 
4 
39 
0.836 
 
14.5.7 Interim Analysis 
A Stage 1 analysis will be conducted after the best overall response has been determined on the 
first 23 subjects have been enrolled in the evaluable population.  Results of the Stage 1 analysis 
will inform the decision to terminate the study due to futility or continue enrollment to Stage 2. 
 
14.5.8  Exploratory Analysis 
The frequency and proportion of subjects achieving MRD (-) evaluated via post-induction DNA 
sequencing will be summarized, along with a 95% Clopper-Pearson confidence interval. Logistic 
regression models and Cox proportional hazards models will be used to analyze correlation 
between systemic immune profiling and clinical response (including outcomes such as MRD [via 
DNA sequencing], ORR, PFS, and OS).  Similar models will be used to assess correlation 
between circulating T-cell receptor parameters and clinical response. MRD results via flow 
cytometry and DNA sequencing will be compared using concordance analysis using two by two 
contingency tables. The MRD agreement rates between the two methods will be estimated.  
PET/CT response will be determined as a binary variable indicating disappearance of all lesions 
identified by PET/CT.  Correlation between PET/CT response and standard IMWG response will 
be assessed using Fisher’s exact test. The same method will be used to analyze correlation 
between MRD results (via DNA sequencing) and PET/CT response. Differentially expressed 
genes between MRD (+) and MRD (-) subjects (via DNA sequencing) will be identified using 
global gene expression profiling data. 
 
Kaplan-Meier techniques and Cox proportional hazards models will be used to evaluate duration 
of response, OS, PFS, time to disease progression, and time to next treatment as a function of 
post-induction MRD status (MRD(-) vs MRD(+)).  Logistic regression models will be used to 
evaluate selected TEAEs as a function of post-induction MRD status. 
 
15. STUDY COMPLETION OR TERMINATION 
15.1 Completion 
The study will be considered complete when one or more of the following conditions is met: 
• All subjects have died and/or are withdrawn from the study 
• All subjects have discontinued from the study 
• The IRB, FDA, LCI DSMC, or Sponsor-Investigator discontinues the study because of 
safety considerations 
• The Sponsor-Investigator defines an administrative or clinical cut-off date 

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15.2 Termination 
The study will be terminated when one or more of the following conditions occur: 
• If risk-benefit ratio becomes unacceptable owing to, for example, 
o Safety findings from this study (e.g. SAEs) 
o Results of any interim analysis 
o Results of parallel clinical studies 
o Results of parallel animal studies (e.g. toxicity, teratogenicity, carcinogenicity or 
reproduction toxicity). 
o If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable 
time frame. 
• The Sponsor-Investigator has decided to close the trial at any site and at any time 
 
For any of the above closures, the following applies: 
• Closures should occur only after consultation between involved parties. 
• All affected institutions must be informed as applicable according to local law.   
• In case of a partial study closure, ongoing subjects, including those in follow- up, must be 
taken care of in an ethical manner. 
16. STUDY MANAGEMENT 
16.1 IRB Approval  
The final study protocol and the final version of the informed consent form(s) must be approved 
in writing by the Sponsor IRB.  
 
The Sponsor-Investigator is responsible for informing the Sponsor IRB of any amendment to the 
protocol in accordance with local requirements. The protocol must be re-approved by the IRB 
annually, as local regulations require.  
16.2 Informed Consent 
Before recruitment and enrollment onto this study, the subject will be given a full explanation of 
the study and will be given the opportunity to review the consent form. Prior to a subject’s 
participation in the trial, the written informed consent form should be signed and personally 
dated by the subject and by the person who conducted the informed consent discussion. Written 
informed consent may include electronic signatures when use of electronic informed consent is 
obtained from the subject on site or remotely. 
16.3 Protocol Adherence 
Except for an emergency situation in which proper care for the protection, safety, and well-being 
of the study subject requires alternative treatment, the study shall be conducted exactly as 
described in the approved protocol.   

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16.4 Changes to the Protocol and/or Informed Consent 
16.4.1 Amendments to the Protocol 
If it is necessary for the study protocol to be amended and/or the informed consent revised, the 
amendment or a new version of the study protocol (amended protocol) and/or the revised 
informed consent must be approved by the Sponsor-Investigator, funding company(ies) (if 
required by the contract(s), the FDA (as applicable) and the Sponsor IRB. 
16.4.2 Emergency Modification 
The Investigators may implement a deviation from, or a change of, the protocol to eliminate an 
immediate hazard(s) to the trial subjects without prior approval from applicable agencies.  As 
soon as possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the appropriate agencies.  Any deviations 
from the protocol must be explained and documented by the investigator. 
16.5 Other Protocol Deviations 
If a deviation occurs, the event should be reported to the Sponsor-Investigator promptly. Any 
IRB reportable event that occurs must be reported to the IRB per IRB requirements.  
Protocol deviations that, in the Investigator’s judgment, potentially caused harm to participants 
or others or indicates that the participants or others are at an increased risk of harm, or has 
adversely impacted data integrity will be reported promptly to the IRB per IRB reporting 
requirements. 
All planned (intentional) protocol deviations must be submitted to the Sponsor-Investigator for 
approval prior to implementation or planned occurrence. After Sponsor approval has been 
obtained, planned deviations must be submitted and approved by the IRB prior to the anticipated 
deviation occurring. Exceptions for eligibility criteria are not allowed. 
Planned protocol deviations will be submitted to the FDA and IRB, respectively, for prior 
approval only if the deviation affects the scientific validity of the study and/or the rights, safety, 
or welfare of subjects. 
16.6 Retention of Records 
Essential documentation (e.g. source documents, AEs, records of study drug receipt and 
dispensation, Sponsor-Investigator correspondence, monitoring reports, and regulatory 
documents), including all IRB correspondence, will be retained for at least 2 years after the 
investigation is completed.  Documentation will be readily available upon request. 
16.7 Ethical and Legal Conduct of the Study 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation 
of this study, are designed to ensure that the Investigator abide by GCP guidelines.  The study 
will also be carried out in full conformity with Regulations for the Protection of Human Subjects 
of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, and/or the ICH E6 and 
in keeping with applicable local law(s) and regulation(s). 
 

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Documented approval from appropriate agencies (e.g. DSMC, IRB, FDA) will be obtained for 
all participating centers before the start of the study, according to GCP, local laws, regulations 
and organizations.  
 
Strict adherence to all specifications laid down in this protocol is required for all aspects of study 
conduct; the investigators may not modify or alter the procedures described in this protocol.   
The Sponsor-Investigator is responsible for the conduct of the clinical trial at the sites in 
accordance with Title 21 of the CFR and/or the Declaration of Helsinki.  The Sponsor-
Investigator is responsible for overseeing the treatment of all study subjects.  The Sponsor-
Investigator must assure that all study site personnel, including sub-investigators and other study 
staff members, adhere to the study protocol and all applicable regulations and guidelines 
regarding clinical trials both during and after study completion. 
 
The Sponsor-Investigator will be responsible for assuring that all the required data will be 
collected and properly documented. 
16.8 Confidentiality of Records 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. 
16.9 Compliance with ClinicalTrials.gov 
The Sponsor-Investigator is solely responsible for determining whether the trial and its results 
are subject to the requirements for submission to ClinicalTrials.gov 
(http://www.clinicaltrials.gov). 
 

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17. REFERENCES 
 
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criteria for response and minimal residual disease assessment in multiple myeloma. 
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2. Demo SD, Kirk CJ, Aujay MA et al. Anti-tumor activity of PR-171, a novel irreversible 
inhibitor of the proteasome. Cancer Res. 2007; 67(13):6383-91. 
3. Arastu-Kapur S, Shenk K, Parlati F et al. Non-proteasomal targets of proteasome 
inhibitors bortezomib and carfilzomib. Blood (ASH Annual Meeting Abstracts), Nov 
2008; 112: 2657. 
4. Shaughnessy J, Qu P, Usmani S, et al. Pharmacogenomics of bortezomib test-dosing 
identifies hyperexpression of proteasome genes, especially PSMD4, as novel high-risk 
feature in myeloma treated with Total Therapy 3. Blood 2011;118(13):3512-24. 
5. Niesvizky R, Martin TG 3rd, Bensinger WI, et al. Phase Ib dose-escalation study (PX-
171-006) of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or 
progressive multiple myeloma. Clin Cancer Res. 2013;19(8):2248-2256.  
6. Wang M, Martin T, Bensinger W et al. Phase 2 dose-expansion study (PX-171-006) of 
carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive 
multiple myeloma. Blood. 2013;122(18):3122-3128. 
7. Stewart AK, Rajkumar SV, Dimopoulos MA et al. Carfilzomib, lenalidomide, and 
dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372:142-152. 
8. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in 
combination with lenalidomide and low-dose dexamethasone as a frontline treatment for 
multiple myeloma. Blood 2012; 120:1801-9. 
9. Jakubowiak A, Raje N, Vij R et al. Improved efficacy after incorporating autologous 
stem cell transplant (ASCT) into KRd treatment with carfilzomib, lenalidomide, and 
dexamethasone in newly diagnosed multiple myeloma. European Hematology 
Association 2016 Meeting; abstract S101.  
10. Korde N, Roschewski M, Zingone A et al. Treatment with carfilzomib-lenalidomide-
dexamethasone with lenalidomide extension in patients with smoldering or newly 
diagnosed multiple myeloma. JAMA Oncol. 2015;1(6):746-754. 
11. Zimmerman F, Raje NS, Vij R et al. Extended treatment with carfilzomib, lenalidomide, 
and dexamethasone plus autologous stem cell transplantation (ASCT) in newly diagnosed 
multiple myeloma (NDMM). Blood 2016;128:675.  
12. Roussel M, Lauwers-Cances V, Robillard N et al. Frontline therapy with carfilzomib, 
lenalidomide, and dexamethasone (KRd) induction followed by autologous stem cell 
transplantation, KRd consolidation and lenalidomide maintenance in newly diagnosed 
multiple myeloma (NDMM) patients: primary results of the Intergroupe Francophone du 
Myélome (IFM) KRd phase II study. Blood 2016;128:1142. 

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13. Lokhorst HM, Plesner T, Laubach JP et al. Targeting CD38 with daratumumab 
monotherapy in multiple myeloma. N Engl J Med. 2015;373:1207-1219. 
14. Lonial S, Weiss BM, Usmani SZ. Daratumumab monotherapy in patients with 
treatment-refractory multiple myeloma (SIRIUS):an open-label, randomised, phase 2 
trial. Lancet. 2016;387:1551-1559. 
15. Usmani SZ, Weiss BM, Plesner T et al. Clinical efficacy of daratumumab monotherapy 
in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 
2016;128:37-44. 
16. Dimopoulos MA, Oriol A, Nahi H et al. Daratumumab, lenalidomide, and 
dexamethasone for multiple myeloma. New Engl J Med. 2016;375:1319-1331. 
17. Palumbo A, Chanan-Khan A, Weisel K et al. Daratumumab, bortezomib and 
dexamethasone for multiple myeloma. N Engl J Med 2016;375:754-766. 
18. Yang G, Gao M, Zhang Y et al. Carfilzomib enhances natural killer cell-mediated lysis of 
myeloma linked with decreasing expression of HLA class I. Oncotarget 
2015:6(29):26982-26994. 
19. Braga WMT, Atanackovic D, Colleoni GWB. The role of regulatory T cells and TH17 
cells in multiple myeloma. Clin Dev Immunol 2012; 1-4. 
20. Hsu AK, Quach H, Tai T et al. The immunostimulatory effect of lenalidomide on NK-
cell function is profoundly inhibited by concurrent dexamethasone therapy. Blood 
2011;117(5):1605-1613. 
21. Xing K, Gu B, Zhang P et al. Dexamethasone enhances programmed cell death 1 (PD-1) 
expression during T cell activation: an insight into the optimum application of 
glucocorticoids in anti-cancer therapy. BMC Immunology 2015:16:39, 1-9. 
22. Weers Md, Tai Y-T, van der Veer MS et al. Daratumumab, a novel therapeutic human 
CD38 monoclonal antibody, induces killing of multiple myeloma and other 
hematological tumors. J of Immunol 2011;186:1840-1848.  
23. Krejcik J, Casneuf T, Nijhof IS et al. Daratumumab depletes CD38+ immune-regulatory 
cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood 
2016; 128:384-394. 
24. Mahnke, Y. D., Beddall, M. H., Roederer, M. OMIP-017: Human CD4+helper T-cell 
subsets including follicular helper cells. Cytometry 2013; 83A: 439–440.  
25. Eller, M. A., Currier, J. R. OMIP-007: Phenotypic analysis of human natural killer cells. 
Cytometry 2012;81A: 447–449. 
26. Rajkumar SV, Dimopoulos MA, Palumbo A et al. International Myeloma Working 
Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014 
Nov;15(12):e538-48.  
27. Major side effects of systemic glucocorticoids. In. UpToDate, Matteson EL (Ed), 
UpToDate, Waltham, MA. (Accessed on February 8, 2017). 

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28. Zamagni E, Nanni C, Mancuso K, et al. PET/CT improves the definition of complete 
response and allows to detect otherwise unidentifiable skeletal progression in multiple 
myeloma. Clin Cancer Res 2015; 21: 4384–90. 
29. Usmani SZ, Mitchell A, Waheed S, et al. Prognostic implications of serial 18-fl uoro-
deoxyglucose emission tomography in multiple myeloma treated with total therapy 3. 
Blood 2013;121: 1819–23. 
30. Nanni C, Zamagni E, Versari A, et al. Image interpretation criteria for FDG PET/CT in 
multiple myeloma: a new proposal from an Italian expert panel. IMPeTUs (Italian 
Myeloma criteria for PET USe). Eur J Nucl Med Mol Imaging 2015; 43: 414–21. 
31. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Multiple 
Myeloma. Version 3.2017. 
32. Palumbo A, Bringhen S, Mateos M, et al. Geriatric assessment predicts survival and 
toxicities in elderly myeloma patients: an International Working Group report. Blood 
2015 Mar 26; 125 (13): 2068-2074  
33. Barr H, Dempsey J, Waller A, et al. Ninety-minute daratumumab infusion is safe in 
multiple myeloma. Leukemia. 2018;32(11):2495-2518. 
34. Hamadeh IS, Arnall J, Kachur E, et al. Rapid Infusion Daratumumab Is Safe and Well 
Tolerated in Clinical Practice. Presented at: American Society of Hematology Annual 
Meeting; December 2018; San Diego, CA. 
35. Facon T, Kumar S, Plesner T et al. Daratumumab plus lenalidomide and dexamethasone 
for untreated myeloma. N Engl J Med 2019;380:2104-15. 
36. Mateos M-V, Dimopoulos MA, Cavo M et al. Daratumumab plus bortezomib, melphalan, 
and prednisone for untreated myeloma. N Engl J Med 2018;378:518-28. 
37. Landgren O, Hultcrantz M, Lesokhin AM, et al: Weekly carfilzomib, lenalidomide, 
dexamethasone, and daratumumab combination therapy provides unprecedented MRD 
negativity rates in newly diagnosed multiple myeloma: A clinical and correlative phase 2 
study. 2019 ASH Annual Meeting & Exposition. Abstract 862. Presented December 9, 
2019.  
38. Costa LJ, Chhabra S, Godby KN, et al: Daratumumab, carfilzomib, lenalidomide, and 
dexamethasone (Dara-KRd) induction, autologous transplantation and post-transplant, 
response-adapted, measurable residual disease–based Dara-KRd consolidation in patients 
with newly diagnosed multiple myeloma. 2019 ASH Annual Meeting & 
Exposition. Abstract 860. Presented December 9, 2019 
39. Mateos M-V, Nahi H, Legiec W, et al. Subcutaneous versus intravenous daratumumab in 
patients with relapsed of refractory multiple myeloma (COLUMBA): a multicentre, 
open-label, non-inferiority, randomised phase 3 trial. Lancet Haematol. 2020;7:e370-80 
doi:10.1016/S2352-3026(20)30070-3 
40. Paul, B., Atrash, S., Bhutani, M., Voorhees, P., Hamadeh, P. & Usmani, S.Z. (2020) An 
evaluation of subcutaneous daratumumab for the treatment of multiple myeloma, Expert 
Review of Hematology, 13:8, 795-802, DOI:10.1080/17474086.2020.1795829 

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41. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761145s000lbl.pdf 
42. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761036s020lbl.pdf 
43. Janssen Research & Development, LLC. (20 December 2019). Investigator’s Brochure: 
JNJ-54767414 (daratumumab). Edition No  
44. https://www.nhlbi.nih.gov/sites/default/files/media/docs/EPR-
3_Asthma_Full_Report_2007.pdf 
  
 
 
 

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18. APPENDICES 
18.1 
Appendix A: ECOG Performance Status 
 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Capable of only limited self-care, 
confined to bed or chair more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, 
confined to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
Reference: Oken MM, Creech RH, Hormey RH et al. Toxicity and Response Criteria of the 
Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5:649-655.  
 
 
 

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18.2 Appendix B: Cockcroft-Gault Equation 
 
Female CrCl = (140 - age in years) x weight in kg x 0.85 
72 x serum creatinine in mg/dL 
 
Male CrCl = (140 - age in years) x weight in kg x 1.00  
72 x serum creatinine in mg/dL 
 
 
 

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18.3 
Appendix C: NYHA Classification 
 
Class 
Description 
I 
Subjects with cardiac disease but without resulting 
limitations of physical activity.  Ordinary physical activity 
does not cause undue fatigue, palpitation, dyspnea, or 
anginal pain. 
II 
Subjects with cardiac disease resulting in slight limitation 
of physical activity.  They are comfortable at rest.  
Ordinary physical activity results in fatigue, palpitation, 
dyspnea, or anginal pain. 
III 
Subjects with cardiac disease resulting in marked 
limitation of physical activity.  They are comfortable at 
rest.  Less than ordinary physical activity causes fatigue, 
palpitation, dyspnea, or anginal pain. 
IV 
Subjects with cardiac disease resulting in inability to carry 
on physical activity without discomfort.  Symptoms of 
cardiac insufficiency or of the anginal syndrome may be 
present event at rest.  If any physical activity is 
undertaken, discomfort is increased. 
Excerpt from Oxford Textbook of Medicine. Vol. 2, p.2228. Oxford 
Press. 1997. 
 
 
 
 

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18.4 
Appendix D: 2014 IMWG Diagnostic Criteria for MM 
Clonal bone marrow plasma cells* ≥10% or biopsy-proven bony or extramedullary 
plasmacytoma and any one or more of the following myeloma defining events: 
 
 
• Evidence of end organ damage that can be attributed to the underlying plasma cell 
 
proliferative disorder, specifically (1 or more of the following): 
o Hypercalcemia: serum calcium >1 mg/dL higher than the ULN or >11 mg/dL 
o Renal insufficiency: CrCl <40 mL/min (measured or estimated via Cockcroft-
Gault; see Appendix B, Section 18.2) or serum creatinine >2 mg/dL 
o Anemia: hemoglobin value of >2.0 g/dL below the lower limit of normal, or a 
hemoglobin value <10.0 g/dL 
o Bone lesions: 1 or more osteolytic lesions on skeletal radiography, computed 
tomography (CT), or positron emission tomography (PET)-CT‡ 
 
• Any one or more of the following biomarkers of malignancy 
o Clonal bone marrow plasma cell* ≥60% 
o Involved/uninvolved serum free light chain ratioÅò ≥100 
o >1 focal lesions on MRI studiesÅ˜ 
 
 
*Clonality should be established by showing κ/λ-light-chain restriction on flow cytometry, immunohisto-
chemistry, 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.  
‡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.  
ÅòThese values are based on the serum Freelite assay (The Binding Site Group, Birmingham, UK). The 
involved free light chain must be ≥100 mg/L.  
Å˜Each focal lesion must be 5 mm or more in size. 
 
See Reference [26] for full details. 
 
 
 

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18.5 Appendix E: Assessment of Asthma Severity 
 
 
 
 
 
Source:  Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma 
(nih.gov)44 
https://www.nhlbi.nih.gov/sites/default/files/media/docs/EPR-3_Asthma_Full_Report_2007.pdf 
 
 

Protocol: LCI-HEM-MYE-KRdD-001 
Version 8:  04/03/2023 
 
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18.6 Appendix F: Assessment of Asthma Control 
 
 
 
 
Source:  Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma 
(nih.gov)44 
https://www.nhlbi.nih.gov/sites/default/files/media/docs/EPR-3_Asthma_Full_Report_2007.pdf