A Phase II Study of Once Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Isatuximab in Newly Diagnosed, Transplant-Eligible Multiple Myeloma
Phase: PHASE2
Conditions: Multiple Myeloma
Sponsor: Massachusetts General Hospital

DF/HCC Protocol #: 19-568
TITLE:  A Phase II Study of once weekly Carfilzomib, Lenalidomide, Dexamethasone, and 
Isatuximab in Newly Diagnosed, Transplant-Eligible Multiple Myeloma
*Principal Investigator (PI):
Noopur Raje, MD 
Massachusetts General Hospital
55 Fruit St, Boston, MA 02114
617-726-0711 
Fax:  617-724-3166
nraje@mgh.harvard.edu  
Other Investigators:
Jacalyn Rosenblatt, MD
Beth Israel Deaconess Medical Center
330 Brookline Ave, Boston, MA 02214
Jrosenb1@bidmc.farvard.edu
Clifton Mo, MD
Dana-Farber Cancer Institute
450 Brookline Ave, Boston, MA 02215
Clifton_Mo@dfci.harvard.edu 
Statistician:
Study Coordinator: 
Nora Horick, MS
Alicia Marggraf
Massachusetts General Hospital
Massachusetts General Hospital
55 Fruit St, Boston, MA 02114
55 Fruit St, Boston, MA 02114
617-724-0746
617-724-7319
nhorick@mgh.harvard.edu
      amarggraf@mgh.harvard.edu
Responsible Research Nurse:
Kathleen Lively
Massachusetts General Hospital
55 Fruit St, Boston, MA 02114
klively@partners.org
617-643-5389
NCT# NCT04430894 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
2
Agents
Carfilzomib:  Amgen
Isatuximab:  Sanofi
Lenalidomide:  commercially available
Dexamethasone:  commercially available
This is an investigator-initiated study with funding provided by Amgen and Sanofi.
IND #: 147867
IND Sponsor:  Noopur Raje, MD 
Protocol Version Date: March 2nd, 2023 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
3
SCHEMA
  
* Dexamethasone will be given as a preinfusion medication for isatuximab when isatuximab is administered during maintenance
Screening
Enrollment
Induction (C1-4)
•
Lenalidomide
•
Carfilzomib
•
Dexamethasone
•
Isatuximab
Stem cell collection (SCT)
Consolidation (C5-6)
•
Lenalidomide
•
Carfilzomib
•
Dexamethasone
•
Isatuximab
Autologous SCT
Transplant Deferred
Induction (C5-8)
•
Lenalidomide
•
Carfilzomib
•
Dexamethasone
•
Isatuximab
Maintenance (stratified based on cytogenetics)
Standard-risk:
•
Lenalidomide
High-risk:
•
Lenalidomide
•
Carfilzomib
•
Isatuximab (discontinue after 24 cycles/2 years of maintenance)*

DF/HCC #: 19-568
Version Date: March 2nd 2023 
4
TABLE OF CONTENTS
1. OBJECTIVES..........................................................................................................................10
1.1 Study Design................................................................................................................10
1.1.1 Primary Objectives....................................................................................................10
1.1.2  Secondary Objectives...............................................................................................10
2. 2. BACKGROUND .................................................................................................................10
2.1 Multiple Myeloma .......................................................................................................10
2.2 Isatuximab....................................................................................................................11
2.3 Carfilzomib ..................................................................................................................17
2.4 Lenalidomide ...............................................................................................................23
2.5 Rationale ......................................................................................................................24
3. PARTICIPANT SELECTION.................................................................................................27
3.1 Eligibility Criteria........................................................................................................27
3.2 Exclusion Criteria ........................................................................................................28
3.3 Inclusion of Women and Minorities ............................................................................30
4. REGISTRATION ....................................................................................................................30
4.1 General Guidelines for Dana-Farber/Harvard Cancer Center (DF/HCC) 
Institutions .............................................................................................................30
4.2 Registration Process for DF/HCC Institutions.............................................................31
4.3 General Guidelines for Other Investigative Sites ........................................................31
4.4 Registration Process for Other Investigative Sites.......................................................31
5. TREATMENT PLAN..............................................................................................................31
5.1 Treatment Regimen......................................................................................................31
5.2 Pre-Treatment Criteria .................................................................................................33
5.3 Agent Administration and Pharmaceutical Information .............................................34
5.4 General Concomitant Medication and Supportive Care Guidelines............................43
5.5 Criteria for Taking a Participant Off Protocol Therapy...............................................45
5.6 Duration of Follow Up.................................................................................................46
5.7 Criteria for Taking a Participant Off Study .................................................................46
6. DOSING DELAYS/DOSE MODIFICATIONS .....................................................................46
6.1 Dose and Treatment Modifications..............................................................................47
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ..................................59
7.1 Definitions....................................................................................................................61
7.2 Adverse Event Recording and Reporting ....................................................................66
7.3 Reporting Requirements ..............................................................................................66
7.4 Reporting to the Study Sponsor...................................................................................67
7.5 Reporting to the Food and Drug Administration (FDA) .............................................68
7.6 Reporting to Hospital Risk Management.....................................................................68
7.7 Routine Adverse Event Reporting ...............................................................................68

DF/HCC #: 19-568
Version Date: March 2nd 2023 
5
8. STUDY CALENDAR .............................................................................................................69
9. MEASUREMENT OF EFFECT .............................................................................................73
9.1 International Myeloma Working Group (IMWG) Response Categories.....................73
9.2 Minimal Residual Disease Assessment .......................................................................75
9.3 Assessment of Lytic Bone Disease..............................................................................75
9.4 Documentation of Extramedullary Plasmacytomas.....................................................76
9.5 Isatuximab Interference with Indirect Antiglobulin Test Results................................77
9.6 Evaluation of Body Composition.................................................................................77
9.7 Patient Reported Outcomes..........................................................................................77
10. DATA REPORTING
11. DATA SAFETY MONITORING............................................................................................77
12. STATISTICAL CONSIDERATIONS.....................................................................................78
Study Design/Endpoints ....................................................................................................78
Analysis of Secondary Endpoints......................................................................................81
13. PUBLICATION PLAN ...........................................................................................................81
14. REFERENCES ........................................................................................................................82
15. APPENDICES……………………………………………………………………………….86
APPENDIX A   Performance status…………………………………………………………87
APPENDIX B   Serum M-protein interference sampling……………………………………87
APPENDIX C   Quality of life assessments…………………………………………………88
APPENDIX F   Minimal Residual Disease Collection and Processing ……………………107

DF/HCC #: 19-568
Version Date: March 2nd 2023 
6
Abbreviations
Absolute Neutrophil Count
ANC
Adult Respiratory Distress Syndrome 
ARDS
Adverse Events
AE
Adverse Event of Special Interest 
AESI
Area Under the Drug Concentration-Time Curve 
AUC
Aspartate Aminotransferase 
AST
Alanine Aminotransferase 
ALT
Beta2-Microglobulin
B2M
Blood Urea Nitrogen 
BUN
Bone Marrow
BM
Case Report Form 
CRF
Celsius
C
Chronic Obstructive Pulmonary Disease 
COPD
Clinical Benefit Rate
CBR
Clinical Trials Management System 
CTMS
Cluster of Differentiation
CD
Complete Blood Count 
CBC
Complete Response
CR
Computerized Tomography 
CT
Confidence Interval 
CI
Creatinine Clearance 
CrCl
Cyclophosphamide, Bortezomib, and Dexamethasone 
CBd
Cytochrome P450 
CYP
Dana-Farber/Harvard Cancer Center 
DF/HCC
Data Safety Monitoring Committee
DSMB
Data Safety Monitoring Committee
DSMC
Deci-liter
dL
Deletion
del
Dissociation constant
Kd
Dose Escalation
DE
Dose-Limiting Toxicity
DLT
Dual-Energy X-Ray Absorptiometry
DXA
Duration of Response
DOR
Echocardiogram
ECG
Eastern Cooperative Oncology Group 
ECOG
Efficacy Evaluable 
EE
European Organisation for Research and Treatment of Cancer
EORTC

DF/HCC #: 19-568
Version Date: March 2nd 2023 
7
European Society for Blood and Marrow Transplantation 
EBMT
Every
Q
Every Four Weeks
Q4W
Every Two Weeks
Q2W
Every Week
QW
Example Given
eg
Fahrenheit
F
Fluorescent in situ hybridization 
FISH
Fibroblast Growth Factor 
FGF
Food and Drug Administration 
FDA
Forced Expiratory Volume 
FEV
Glomerular Filtration Rate
GFR
Good Lab Practice
GLP
Gram
g
Granulocyte Colony Stimulating Factor
GCSF
Half-life
t1/2
Highest Nonseverely Toxic Dose 
HNSTD
Histamine
H
Human Immunodeficiency Virus 
HIV
Immunofixation
IFE
Immunomodulatory Drug 
IMiD
Immunoglobulin
Ig
Informed Consent Form 
ICF
Infusion Reaction
IR
Infusion-Associated Reaction
IAR
Institutional Review Board 
IRB
Intent-to-Treat 
ITT
Interferon
IFN
Interleukin
ILBd
International Staging System
ISS
Intramuscular
IM
Intrauterine Device 
IUD
Intravenous immunoglobulin 
IVIG
Investigational Medical Product 
IMP
Investigator's Brochure
IB
Kilogram
kg
KiloDalton
kDa
Lactate Dehydrogenase
LDH
Liter
L

DF/HCC #: 19-568
Version Date: March 2nd 2023 
8
Lenalidomide, Bortezomib, and Dexamethasone 
LBd
Lenalidomide and Dexamethasone 
Rd
Magnetic Resonance Image 
MRI
Maximum Concentration
Cmax
Maximum Tolerated Dose 
MTD
Melphalan, Prednisone, Thalidomide 
MPT
Meter
m
Milligrams
mg
Milliliter
mL
Millimeter
mm
Millimol
mmol
Minimal Residual Disease
MRD
Minimal Response
MR
Minute
min
Monoclonal Antibody
mAb
Monoclonal Protein
M-
protein
Multiple Myeloma
MM
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NCI 
CTCAE
Near Complete Response
nCR
Newly Diagnosed Multiple Myeloma
NDMM
Nonsteroidal Anti-inflammatory Drug 
NSAID
No-Observed Adverse Effect Level
NOAEL
Number
N
Oral
POEMS
Overall Response Rate
ORR
Partial Response 
PR
Polyneuropathy,Organomegaly,Endocrinopathy, Monoclonal 
Protein, Skin Changes
POEMS
Positron Emission Tomography 
PET
Posterior Reversible Encephalopathy Syndrome
PRES
Principal Investigator
PI
Progression Free Survival
PFS
Progressive Disease
PD
QT interval as corrected by Fridericia’s formula 
QTcF
Quality of Life 
QOL
Red Blood Cell
RBC
Relapsed Refractory Multiple Myeloma
RRMM

DF/HCC #: 19-568
Version Date: March 2nd 2023 
9
Stable Disease
SD
Serious Adverse Event
SAE
Serum Protein Electrophoresis
SPEP
Severely Toxic Dose to 10%
STD10
Stem Cell Transplant
SCT
Stringent Complete Response
sCR
Subcutaneous
SC
System Organ Class 
SOC
Thrombotic Microangiopathy
TMA
Time to Response
TTR
Translocation
t
Tumor Lysis Syndrome
TLS
Tumor Necrosis Factor 
TNF
United States
US
Upper Limit of Normal 
ULN
Urine Protein Electrophoresis
UPEP
Vascular Endothelial Growth Factor 
VEGF
Very Good Partial Response
VGPR
Volume of Distribution at Steady State 
Vss
World Health Organization 
WHO

DF/HCC #: 19-568
Version Date: March 2nd 2023 
10
1. OBJECTIVES
1.1 Study Design
A phase II study to evaluate the efficacy of once weekly carfilzomib, lenalidomide, 
dexamethasone, and isatuximab (KRDI) in patients with newly diagnosed, transplant-eligible 
multiple myeloma.
1.1.1 Primary Objectives
To estimate the Complete Response (CR + stringent CR) rate to treatment after 4 cycles as 
assessed by site Investigators using the International Myeloma Working Group (IMWG) 
Uniform Response criteria after 4 cycles of KRDI.
1.1.2 Secondary Objectives
To describe the following in this study population:
- Safety and tolerability of once-weekly KRDI
- Minimal residual disease (MRD) after 4 cycles, at completion of consolidation (post-transplant) 
or induction (transplant-deferred) and at 24 months
- Complete response (CR + stringent CR) rate after 6 cycles in patients who undergo transplant, 
after 8 treatment cycles in transplant-deferred patients, and at 24 months for all patients- Overall 
response rate (ORR)
- Progression free survival (PFS)
- Overall survival (OS)
- Quality of life (QOL)
Exploratory 
- Change in body composition
- PFS by MRD status
2. BACKGROUND
2.1 Multiple Myeloma
Multiple myeloma (MM) is a malignant proliferation of plasma cells. It is the second most 
common hematologic malignancy, accounting for an estimated 30,770 cases and 12,770 deaths 
in the United States (US) in 2018.[1] MM is a disease of older adults with the median age at 
diagnosis of 66 years.[2] Over the last 10 years, the reduced treatment-related morbidity and 
mortality associated with autologous stem cell transplantation (SCT) and the availability of 
effective new drugs with acceptable toxicity, such as the immunomodulatory drugs  (IMiD) 
(thalidomide, lenalidomide, and pomalidomide) and the proteasome inhibitors (bortezomib, 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
11
carfilzomib, and ixazomib) have greatly modified the traditional treatment paradigms in patients 
with MM with an improvement in the quality and the duration of life for people with this disease.  
However, MM remains incurable with standard chemotherapy, despite the availability of multi-
agent therapy. Strategies directed at improving and maintaining response for longer periods of 
time and new treatment options directed at alternative mechanisms are urgently needed for 
patients with MM.
2.2 Isatuximab
Isatuximab is a naked immunoglobulin (Ig) G1 monoclonal antibody (mAb) that selectively 
binds to the human cell surface antigen molecule classified as cluster of differentiation (CD) 38. 
CD38 is expressed in a number of hematological malignancies from B-lymphocyte, T-
lymphocyte, and myeloid origin; therefore, isatuximab has the potential to treat a number of 
hematological malignancies.
Nonclinical studies
In vivo antitumor activity of isatuximab was demonstrated in several subcutaneous (SC) or 
intravenous (IV) implanted hematological tumor models. As a single agent, antitumor activity 
was observed in MM.  In ex vivo primary patient tumor samples, isatuximab has demonstrated a 
direct proapoptotic effect in MM samples.
In Good Laboratory Practice (GLP) cross-reactivity studies with normal human tissues, 
isatuximab was bound specifically to lymphoid tissues (spleen, thymus, lymph node, and tonsil), 
bone marrow, pituitary gland (endothelial cells), prostate gland (glandular epithelial cells), and 
infiltrating or resident round cells (macrophages and/or lymphocytes) of the innate immune 
system including Kupffer cells in the liver. In preliminary non-GLP tissue cross-reactivity 
studies using a different isatuximab batch and different mAb concentrations, additional staining 
was also observed in the brain (astrocytes) and lung (bronchial epithelium). Staining of all 
nonlymphoid tissue elements was interpreted as evidence of cross-reactivity, indicating potential 
unintended off-target sites.
Isatuximab is specific for human CD38 protein. In the absence of a relevant animal species for 
toxicity testing, a repeat-dose IV (once weekly for 3 weeks) study was conducted in cynomolgus 
monkeys (a non-pharmacologically-reactive species) in order to evaluate potential non-targeted 
and nonspecific general toxicity. In this cynomolgus monkey toxicity study, no compound-
related changes were noted in any parameters evaluated, and the no-observed adverse effect level 
(NOAEL) was 100 mg/kg/week (highest dose tested). In rabbits (a non-pharmacologically 
reactive species), isatuximab was well tolerated locally after IV (clinical route of administration), 
intramuscular (IM), intra-arterial, SC, or paravenous injection (routes by which it might be 
administered by accident or accidental extravasations) at concentrations up to 5 mg/mL. Plasma 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
12
compatibility and the hemolytic potential of isatuximab in human whole blood were tested in 
vitro at concentrations up to 2.5 mg/mL. No hemolytic effect or plasma incompatibility was 
observed.
Clinical Studies
Study TED10893 (Phase 1); Monotherapy in Relapsed Refractory MM (RRMM) and other hematological 
malignancies
From June 2010 to August 2016, a total of 89 patients with CD38+ hematological malignancies 
were treated with isatuximab. Overall, the median time on treatment was 10.1 weeks (range: 2 to 
120 weeks) and the median age was 64.0 years (range: 40 to 85 years).
In patients with MM (n = 84), the median time from diagnosis to first isatuximab dosing was 
5.84 years (range: 1.2 to 22.8 years). Median number of prior lines of therapies was 5.0 (range: 1 
to 13 prior lines), with 94.0% receiving prior lenalidomide, 40.5% receiving prior pomalidomide, 
98.8% receiving prior bortezomib, and 42.9% receiving prior carfilzomib. Overall response rate 
([ORR] ≥ partial response [PR]) according to Investigator assessment by European Society for 
Blood and Marrow Transplantation (EBMT) criteria among the 84 MM treated-patients was 
20.2% (1 complete response, 16 PRs). Clinical benefit response (≥minimal response [MR]) was 
26.2% and best response was stable disease (SD) in 42.9% of the MM treated-patients. The MR 
or better occurred at all DLs ≥1 mg/kg. In patients treated at doses ≥10 mg/kg in dose escalation 
and expansion cohorts (n = 63), ORR was 23.8% (15/63), and the clinical benefit rate (CBR) was 
30.2% (19/63). In patients treated at 10 mg/kg Q2W in the high-risk cohort (n = 18), ORR was 
16.7% (n = 3/18) and CBR was 27.8% (5/18) (see Table 1).
Table 1 - TED10893 (Phase 1): Best overall response according to Investigator assessment 
(EBMT criteria) – All MM treated patients
Isatuximab (dose level and schedule)
≤1mg/kg 
Q2W
3mg/kg 
Q2W
5mg/kg 
Q2W
10mg/kg Q2W- 
DE+EC1
10mg/kg 
Q2W-HR
10mg/kg 
QW
20mg/kg 
Q2W
20mg/kg 
QW
All
(N=13)
(N=5)
(N=3)
(N=25)
(N=18)
(N=6)
(N=7)
(N=7)
(N=84)
Overall 
response rate
(≥PR)
1 (7.7%)
0
1 (33.3%)
7 (28.0%)
3 (16.7%)
2 (33.3%)
1 (14.3%)
2 (28.6%)
17 (20.2%)
- Complete 
response
(CR)
0
0
0
0
0
1 (16.7%)
0
0
1 (1.2%)
- Partial 
response 
(PR)
1
(7.7%)
0
1 (33.3%)
7 (28.0%)
3 (16.7%)
1 (16.7%)
1 (14.3%)
2 (28.6%)
16 (19.0%)
Minimal 
response
(MR)
0
1 
(20.0%)
0
0
2 (11.1%)
0
1 (14.3%)
1 (14.3%)
5 (6.0%)
Stable disease (SD) 2 (15.4%)
3 
(60.0%)
2 (66.7%)
12 (48.0%)
9 (50.0%)
3 (50.0%)
2 (28.6%)
3 (42.9%)
36 (42.9%)

DF/HCC #: 19-568
Version Date: March 2nd 2023 
13
Progressive disease
(PD) 10 (76.9%)
1 
(20.0%)
0
5 (20.0%)
4 (22.2%)
1 (16.7%)
2 (28.6%)
0
23 (27.4%)
Not evaluable 0
0
0
1 (4.0%)
0
0
1 (14.3%)
1 (14.3%)
3 (3.6%)
Clinical benefit rate
(≥MR) 1 (7.7%)
1 
(20.0%)
1 (33.3%)
7 (28.0%)
5 (27.8%)
2 (33.3%)
2 (28.6%)
3 (42.9%)
22 (26.2%)
Study TED10893 (Phase 2 Stage 1); monotherapy in RRMM
From July 2014 to December 2016, a total of 97 patients were treated in Phase 2 Stage 1 of  
TED10893 study at 4 different doses and/or schedules of administration. The median age of 
patients was 62 years (range: 38 to 85 years). The median time from diagnosis to first isatuximab 
dosing was 5.82 years (range: 1.2 to 24.1 years). As per inclusion criteria, patients were heavily 
pretreated as shown by a median number of prior lines of 5 (range: 2 to 14 lines) with 18 (18.6%) 
patients having received 8 or more prior lines of treatment. During the study, the median number 
of isatuximab cycles started was 3. The median duration of exposure was 13 weeks (range: 2 to 
77 weeks). The median duration of exposure was the lowest in the 3 mg/kg Q2W (6.0 weeks) 
dose group and was consistently ≥14 weeks in the ≥10 mg/kg arms. Nine (9.3%) patients were 
still receiving treatment as of the analysis cutoff date (1 in the 3 mg/kg Q2W dose group, 4 in the 
10 mg/kg Q2W dose group, and 2 each in the 10 mg/kg Q2W/Q4W and 20 mg/kg QW/Q2W 
dose groups).
The ORR was lowest in the 3 mg/kg Q2W dose group. At doses ≥10 mg/kg, ORR ranged from 
20% to 29% (see Table 2). No CR was observed and more patients had VGPR in the 10 mg/kg 
arms (25.0% in Q2W and 12.0% in Q2W/Q4W) than in the 20 mg/kg arm (8.0%). However, the 
results of observed differences between the 20 mg/kg arm and the 3 other arms should be 
interpreted with caution because patients were not randomized to the 20 mg/kg QW/Q2W arm 
and the population could be different. Therefore, given the small sample size in each arm, and 
despite the efficacy data showing a dose response effect from the 3 mg/kg Q2W (ORR<10%) to 
the doses ≥10 mg/kg (ORR ≥20%), no conclusion can be drawn based on ORR at doses ≥10 
mg/kg.

DF/HCC #: 19-568
Version Date: March 2nd 2023 
14
Table 2 - TED10893 (Phase 2 Stage 1) – overall response rate as per the independent 
adjudication committee– all treated population
Isatuximab (dose level and schedule)
3mg/kg Q2W               10mg/kg Q2W          10mg/kg Q2W/Q4W                 20mg/kg QW/Q2W                        All
(N=23)
(N=24)
(N=25)
(N=25)
(N=97)
Overall 
Response Rate 
(≥PR)
1
(4.3%)
7 (29.2%)
5 (20.0%)
6 (24.0%)
19 (19.6%)
- Very Good 
Partial 
Response 
(VGPR)
0
6 (25.0%)
3 (12.0%)
2 (8.0%)
11 (11.3%)
- Partial 
response (PR)
1
(4.3%)
1 (4.2%)
2 (8.0%)
4 (16.0%)
8 (8.2%)
95% CIa (0.1% to 21.9%) (12.6% to 51.1%) (6.8% to 40.7%) (9.4% to 45.1%) (12.2% to 28.9%)
Minimal 
response (MR)
0
3 (12.5%)
3 (12.0%)
3 (12.0%)
9 (9.3%)
Stable disease 
(SD)
8 
(34.8%)
5 (20.8%)
6 (24.0%)
12 (48.0%)
31 (32.0%)
Progressive 
disease (PD)
5 
(21.7%)
3 (12.5%)
3 (12.0%)
3 (12.0%)
14 (14.4%)
Unconfirmed 
PD
4 
(17.4%)
3 (12.5%)
2 (8.0%)
0
9 (9.3%)
Not evaluable
5 
(21.7%)
3 (12.5%)
6 (24.0%)
1 (4.0%)
15 (15.5%)
Clinical benefit 
rate (≥MR)
1 
(4.3%)
10 (41.7%)
8 (32.0%)
9 (36.0%)
28 (28.9%)
95% CIa
(0.1% to 
21.9%)
(22.1% to 63.4%)
(14.9% to 53.5%)
(18.0% to 57.5%)
(20.1% to 
39.0%)
Confidence Interval (CI) a estimated by Clopper-Pearson Exact method;
Study TED14154 (monotherapy in RRMM; Part A)
As of the cutoff date of 05 January 2018, Part A was completed. A total of 26 patients with 
RRMM were treated in Part A, 12 patients at 10 mg/kg QW/Q2W and 14 patients at 20 mg/kg 
QW/Q2W. The median age was 67.0 years (range: 53 to 81 years). The median time from initial 
MM diagnosis to first study treatment dose was 6 years (range: 1.6 to 13.5 years). The median 
number of lines was 5.0 (range: 2 to 13 lines). All patients received prior combined lenalidomide 
and bortezomib, 61.5% received prior pomalidomide, 57.7% received prior carfilzomib, and 
38.5% received prior thalidomide. Overall, the median number of cycles was 4.5 (range: 1 to 22 
cycles). The median number of cycles was 3.0 (range: 1 to 22 cycles) at 10 mg/kg QW/Q2W and 
5.0 (range: 2 to 18 weeks) at 20 mg/kg QW/Q2W.

DF/HCC #: 19-568
Version Date: March 2nd 2023 
15
Overall, the ORR was 23.1%, including 3 (11.5%) patients with VGPR and 3 (11.5%) patients 
with PR (Table 3). The ORR was 25.0% and 21.4% at 10 and 20 mg/kg QW/Q2W, respectively. 
The CBR was 38.5% overall (33.3% and 42.9% at 10 and 20 mg/kg QW/Q2W, respectively).
Table 3 – TED14154 Part A – overall response rate – all treated population
Isatuximab (dose level and schedule)
10 mg/kg 
QW/Q2W
20 mg/kg 
QW/Q2W
All
(N=12)
(N=14)
(N=26)
Overall response rate (≥PR)
3 (25.0%)
3 (21.4%)
6 (23.1%)
- Very good partial response (VGPR)
2 (16.7%)
1 (7.1%)
3 (11.5%)
- Partial response (PR)
1 (8.3%)
2 (14.3%)
3 (11.5%)
95% CIa
(5.5% to 57.2%)
(4.7% to 50.8%)
(9.0% to 43.6%)
Minimal response (MR)
1 (8.3%)
3 (21.4%)
4 (15.4%)
Stable disease (SD)
6 (50.0%)
7 (50.0%)
13 (50.0%)
Progressive disease (PD)
2 (16.7%)
1 (7.1%)
3 (11.5%)
Clinical benefit rate (≥MR)
95% CIa
4 (33.3%)
(9.9% to 65.1%)
6 (42.9%)
(17.7% to 71.1%)
10 (38.5%)
(20.2% to 59.4%)
a estimated by Clopper-Pearson Exact method
Study TCD11863 (Len/Dex in RRMM)
This was a Phase 1b, open-label dose escalation study to determine the maximum tolerated dose 
of 2 schedules (Q2W and QW/Q2W) of administration of isatuximab in combination with 
lenalidomide and dexamethasone in patients with relapsed or refractory MM. A total of 57 
patients with a median age of 61 years (range: 42 to 76 years) were enrolled. The median number 
of prior lines was 5 (range: 1 to 12 lines) with 15 (26.3%) patients having received 8 or more 
prior lines of treatment. Fifty-five (96.5%) patients were previously exposed to 
immunomodulatory drugs, including 54 (94.7%) patients with prior lenalidomide treatment. The 
efficacy evaluable population consists of 52 patients excluding 4 patients in the 20 mg/kg group 
who discontinued due to AE before completing treatment in Cycle 1 and 1 patient in the 3 mg/kg 
group who discontinued due to IR at the first infusion.
The first part of the trial evaluated 3 doses of isatuximab 3, 5 and 10 mg/kg using the Q2W 
schedule of administration; among the patients treated at 10 mg/kg (n = 24), the ORR was 62.5% 
with PR rate of 20.8%, very good PR (VGPR) rate of 33.3% and stringent complete response 
(sCR) rate of 8.3%. Among the patients treated in the second part of the trial (QW/Q2W 
schedule), the ORR was 50% for both 10 mg/kg (n = 12) and 20 mg/kg (n = 10) QW/Q2W. At 
10 mg/kg QW/Q2W, best overall response was PR for 2 patients and VGPR for 4 patients, 
whereas at the 20 mg/kg QW/Q2W dose, all responses were VGPR (Table 4).

DF/HCC #: 19-568
Version Date: March 2nd 2023 
16
Table 4 - TCD11863 – overall response rate – evaluable population
Isatuximab (dose level and schedule) + lenalidomide/dexamethasone
3 mg/kg 
Q2W
5 mg/kg 
Q2W
10 mg/kg 
Q2W
10 mg/kg 
QW/Q2W
20 mg/kg 
QW/Q2W
All
(N=3)
(N=3)
(N=24)
(N=12)
(N=10)
(N=52)
Overall response rate
1 (33.3%)
2 (66.7%)
15 (62.5%)
6 (50.0%)
5 (50.0%)
29 (55.8%)
(≥PR)
- Stringent complete 
response (SCR)
0
0
2 (8.3%)
0
0
2 (3.8%)
- Very good partial 
response (VGPR)
0
0
8 (33.3%)
4 (33.3%)
5 (50.0%)
17 (32.7%)
- Partial response (PR)
1 (33.3%)
2 (66.7%)
5 (20.8%)
2 (16.7%)
0
10 (19.2%)
Minimal response
1 (33.3%)
0
2 (8.3%)
4 (33.3%)
1 (10.0%)
8 (15.4%)
(MR)
Stable disease (SD)
1 (33.3%)
0
4 (16.7%)
2 (16.7%)
4 (40.0%)
11 (21.2%)
Progressive disease
0
1 (33.3%)
3 (12.5%)
0
0
4 (7.7%)
(PD)
Clinical benefit rate
2 (66.7%)
2 (66.7%)
17 (70.8%)
10 (83.3%)
6 (60.0%)
37 (71.2%)
(≥MR)
For this study, isatuximab will be dosed once weekly for 8 doses, every other week for 8 doses, 
and then monthly thereafter.  This dosing is based on scheduling conventions for monoclonal 
antibodies, daratumumab (e.g. NCT02874742) and elotuzumab (e.g. NCT03030261).  In 
NCT02874742, a phase 2 randomized study of daratumumab-RVD versus RVD, daratumumab is 
dosed once weekly for 8 doses, every other week for 8 doses, and then monthly thereafter.  The 
goal is to provide continued, effective therapy but minimize patient burden.  Ongoing clinical 
trials of isatuximab have incorporated this dosing schedule (e.g. NCT04270409). 
2.3 Carfilzomib
Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to N-
terminal threonine-containing active sites of the 20S proteasome. Carfilzomib had 
antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells. In 
animals, carfilzomib inhibited proteasome activity in blood and tissue and delayed tumor growth 
in models of multiple myeloma, hematologic, and solid tumors.
Non-clinical Studies
Nonclinical Pharmacology
Proteasome Inhibition After Intravenous Administration of Carfilzomib

DF/HCC #: 19-568
Version Date: March 2nd 2023 
17
The pharmacodynamics of carfilzomib has been determined by measurement of CT-L 
proteasome activity in tissue extracts after IV bolus administration in rats. Dose-dependent 
proteasome inhibition was observed 1 hour after dose administration in all tissues examined, 
with the exception of the brain [3]. Proteasome activity recovered in nucleated tissues with a t1/2 
of approximately 24 hours. With a 12-mg/m2 (2-mg/kg) dose (the severely toxic dose to 10% of 
animals [STD10] once daily for 5 days), proteasome inhibition exceeded 80% in multiple tissues 
(blood, adrenal, heart, lung, and bone marrow). Equivalent levels of proteasome inhibition were 
seen in blood and tissues when carfilzomib was delivered as a bolus administration or as a 30-
minute infusion indicating that the biodistribution and pharmacodynamics of carfilzomib are a 
function of the total dose administered and not the maximum observed drug concentration during 
a dosing interval (Cmax).
Efficacy of Carfilzomib in Mouse Tumor Studies
The antitumor efficacy of carfilzomib has been evaluated in immunocompromised mice 
implanted with a variety of human tumor cell lines[3, 4], including HT-29, a human colorectal 
adenocarcinoma cell line, and MM1.S, a multiple myeloma cell line. In both models, a 
statistically significant reduction in tumor size as compared with the control was seen when 
carfilzomib was administered on a weekly schedule of days 1 and 2.
Nonclinical Pharmacokinetics and Drug Metabolism
The pharmacokinetics of carfilzomib was examined after IV bolus administration to Sprague 
Dawley rats and cynomolgus monkeys. A dose-dependent increase in the area under the drug 
concentration-time curve (AUC) and a biphasic distribution profile after administration was 
observed. The t1/2 was calculated to be 5 to 17 minutes in rats and 7 minutes in monkeys. The 
plasma clearance of carfilzomib is 195 to 319 mL/min/kg in rats and 187 to 286 mL/min/kg in 
monkeys, which is higher than the liver blood flow for both species, indicating that clearance 
occurred largely extrahepatically in these species.
When carfilzomib was given as a 30-minute IV infusion at 8 mg/kg to rats, the concentration at 
steady state was approximately 28-fold lower than the Cmax with IV bolus at the equivalent 
doses. Other pharmacokinetic parameters (clearance, AUC, and t1/2) were comparable between 
bolus and infusion dosing. Similar pharmacodynamics (proteasome inhibition in blood and 
tissues) between bolus and infusion dosing supported accessibility of carfilzomib to target tissues 
using a 30-minute infusion.
Metabolism
Carfilzomib is rapidly and extensively metabolized after IV administration to rats, monkeys, and 
humans. The predominant metabolites are peptide fragments and the diol of carfilzomib, with no 
unique metabolites identified in humans, suggesting that peptidase cleavage and epoxide 
hydrolysis are the principal pathways of metabolism in all these species. The metabolites do not 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
18
inhibit proteasome activity. Cytochrome P450 (CYP)-mediated pathways are not significant in 
the overall metabolism of carfilzomib.
Carfilzomib is also rapidly metabolized by peptidases and epoxide hydrolases in vitro upon 
incubation with rat blood and tissue homogenates derived from the lung, kidney, and liver, 
further corroborating the extrahepatic mechanisms of metabolism in vivo.
Distribution
The volume of distribution at steady state (Vss) was 0.3 to 2.0 L/kg and 0.3 to 1.1 L/kg for rats 
and monkeys, respectively. Because of metabolism in a variety of tissues and the irreversible 
covalent binding of carfilzomib to the 20S proteasome, the Vss values may underestimate the 
extent of tissue distribution of carfilzomib. Potent proteasome inhibitory effects in a variety of 
tissues after IV administration to rats at different dose levels, and detection of radioactivity in a 
variety of tissues with an IV administration of tritium-labeled carfilzomib ([3H-Phe]-
carfilzomib) to rats at 2 mg/kg (12 mg/m2), indicated rapid and wide distribution of carfilzomib 
to tissues, except the brain. An in vitro protein-binding study using equilibrium dialysis 
demonstrated that approximately 97% of carfilzomib is bound to human plasma proteins, which 
is similar to rats and monkeys.
Elimination
Excretion of [3H-Phe]-carfilzomib was determined by quantitative whole-body autoradiography 
in rats receiving a single IV bolus administration of 2 mg/kg (12 mg/m2). Urine and feces 
accounted for 14.1% and 18.0% of the dosed radioactivity, respectively, at 168 hours after the 
dose. Approximately 44% of the administered radioactivity remained in tissues, indicating slow 
elimination of drug-derived radioactivity, likely because of incorporation of tritium-labeled 
phenylalanine (3H-phenylalanine) into cellular proteins. Excretion was also determined in bile 
duct–cannulated rats after a single IV bolus administration of 2 mg/kg unlabeled carfilzomib. 
Carfilzomib was excreted mainly in the form of metabolites, with less than 1% of the dose 
excreted intact. About 57% of the dose was recovered within 24 hours of dosing in both bile and 
urine samples as major metabolites. The limited recovery was likely because of minor 
metabolites, target binding in cells unable to synthesize new proteasomes (eg, red blood cells 
(RBCs)), and peptidic metabolites that cannot be differentiated from endogenous components.
Toxicology
Unless otherwise noted, toxicology studies described below were GLP-compliant.
Acute Toxicity Studies in Monkeys
In a 2-dose, 7-day IV study in carfilzomib-naïve monkeys, carfilzomib was administered on 2 
consecutive days at 2 mg/kg (24 mg/m2), a dose that exceeds the established multidose highest 
nonseverely toxic dose (HNSTD) of 1 mg/kg (12 mg/m2) and 6 mg/m2 (0.5 mg/kg) in 28-day 
(TR-0017-171) and 9-month (TR-0073-171) repeated-dose studies, respectively. Carfilzomib 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
19
induced a prerenal azotemia 24 hours after the first dose, as manifested by elevated blood urea 
nitrogen (BUN) and creatinine, concomitant with an increase in urine specific gravity. The 
second dose of carfilzomib did not exacerbate these effects, and the renal function returned to 
baseline within 72 hours. Other findings included signs of an acute phase response (increased 
fibrinogen and C-reactive protein) and cardiotoxicity (increased troponin-I in 4 of 6 animals with 
myocardial degeneration/necrosis in 1 animal), and a drop in platelets of approximately 80% that 
resolved within 5 days of dosing and was not associated with a change in megakaryocyte number 
or morphology in bone marrow smears.
Clinical Studies
Carfilzomib entered clinical studies in September 2005. Study PX-171-006 was the first to 
explore the option of combination therapy using carfilzomib and lenalidomide, the IMiD most 
widely employed for the treatment of MM [5]. This investigation was the model for another 
Phase 2 study of the carfilzomib, lenalidomide, dexamethasone (KRd) combination conducted by 
the Multiple Myeloma Research Consortium, and it used a maximum planned dose of 36 mg/m2 
twice weekly in patients with NDMM [6]. The Phase 3 ASPIRE study compared the efficacy of 
KRd versus lenalidomide and dexamethasone alone in a much larger trial that enrolled 792 
RRMM subjects. ASPIRE showed an improved overall response rate and progression free 
survival PFS with KRd therapy and provides a strong incentive to optimize the KRd regimen[7].
The Phase 1/Phase 2 CHAMPION 1 trial of subjects with relapsed or progressing MM who had 
received 1 to 3 prior regimens evaluated the safety and efficacy of carfilzomib administered once 
weekly at doses higher than the 56 mg/m2 maximum tolerated dose (MTD) previously 
established for the twice-weekly administration routine [8]. All subjects received carfilzomib (20 
mg/m2) on Cycle 1 Day 1 but received the cohort-assigned test dose on Cycle 1 Days 8 and 15. 
Testing started at 45 mg/m2 in the first cohort and was escalated to 56, 70, and 88 mg/m2 in 
successive cohorts until the MTD was determined. Subjects received dexamethasone 40 mg (IV 
or orally) on Days 1, 8, 15, and 22 of Cycles 1 through 8 and on Days 1, 8, and 15 from Cycle 9 
onward.
The ARROW study provided further support for the safety and efficacy of once weekly 
carfilzomib dosing.[9]  478 patients were randomly assigned and included in the efficacy 
analyses (240 to receive once weekly carfilzomib; 238 to receive twice weekly carfilzomib). 
Median progression-free survival was higher in the once weekly group than the twice weekly 
group (11·2 months [95% CI 8·6–13·0] vs 7·6 months [5·8–9·2]; hazard ratio [HR] 0·69, 95% 
CI 0·54–0·83; p=0·0029). The incidence of grade 3 or worse adverse events was higher in the 
once weekly group than the twice weekly group (68% [n=161] vs 62% [n=145]); the most 
common events were anemia, pneumonia, and thrombocytopenia (42 [18%] vs 42 [18%], 24 
[10%] vs 16 [7%], and 17 [7%] vs 16 [7%], respectively for once weekly carfilzomib vs twice 
weekly carfilzomib). A lower proportion of patients had grade 3 or worse cardiac failure in the 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
20
once weekly group (7 [3%]) than in the twice weekly group (10 [4%]). Treatment-related deaths 
occurred in five (2%) of 238 patients in the once weekly group (sepsis [n=1], death [n=1], acute 
lung injury [n=1], acute respiratory distress syndrome [n=1], and tumor lysis syndrome [n=1]) 
and in two (1%) of 235 patients in the twice weekly group (plasma cell myeloma [n=1] and 
congestive heart failure [n=1]). There were 58 deaths in the once weekly group and 68 deaths in 
the twice weekly group at the time of data cutoff.  The once weekly dosing demonstrated 
superior efficacy with comparable toxicity.  
The combination of carfilzomib (twice-weekly), lenalidomide, and dexamethasone is a highly 
efficacious regimen in RRMM and NDMM subjects [6, 7].  Of specific note, 23 of 26 subjects 
who reached nCR/CR achieved negative minimal residual disease (MRD[-]) status in one study 
[6]. More recently, a phase 1b study evaluated weekly carfilzomib, lenalidomide, and 
dexamethasone in RRMM.[10] Patients received carfilzomib once weekly (30‐minute IV 
infusion) on days 1, 8, and 15. In the dose‐evaluation component of the study, patients received 
carfilzomib 20 mg/m2 on cycle one, day one, and then 56 or 70 mg/m2 starting on cycle one, day 
eight. In the dose‐expansion component of the study, patients received KRd on the same 
schedule. All patients also received oral lenalidomide 25 mg once daily on days 1‐21 and 
dexamethasone 40 mg (oral or IV) on days 1, 8, and 15. Dexamethasone was also given on day 
22 for cycles 1‐8. The ORRs were 90.0% in the 56‐mg/m2 group and 89.1% in the 
70‐mg/m2 group. A VGPR or better was observed in 50.0% and 73.9% of patients in the two 
groups, respectively. A complete response (CR) or better in 20.0% and 30.4% of patients in the 
two groups, and a stringent CR in 10.0% and 17.4% of patients in the 2 groups was reported. 
Among all patients (n = 56), the ORR was 89.3%, the ≥VGPR rate was 69.6%, and the ≥CR rate 
was 28.6%. Median PFS was not reached in either the 56‐mg/m2 group (95% CI, 14.8 
months‐not evaluable [NE]) or the 70‐mg/m2 group (95% CI, 21.1 months‐NE). As of the data 
cutoff date, 1 patient (10.0%) in the 56‐mg/m2 group and 7 patients (15.2%) in the 
70‐mg/m2 group experienced disease progression. The incidence of grade ≥3 AEs observed with 
once‐weekly KRd (56 mg/m2, 70.0%; 70 mg/m2, 69.6%) were lower than previously reported for 
the twice‐weekly KRd regimen in the ASPIRE study (83.7%).[7] Overall, the safety profile 
observed with once‐weekly KRd was consistent with the safety profile for twice‐weekly KRd in 
the ASPIRE study. There were no patients who experienced cardiac arrest, cardiac disorder, or 
cardiac failure in the 56‐mg/m2 group; in the 70‐mg/m2 group, one patient had grade ≥3 cardiac 
failure, and two other patients had fatal cardiac events (cardiac arrest and cardiac disorder). 
Based on the results of this study, the 56‐mg/m2 dose was chosen to move forward with and is 
being evaluated further in the randomized phase 3 study of weekly versus twice weekly KRd 
(NCT03859427).
For this study, every other week carfilzomib dosing was chosen for maintenance based on the 
study design of the HOVON trial and recent data presented for every other week carfilzomib 
maintenance. In the HOVON study, patients received induction with either vincristine, 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
21
doxorubicin, and dexamethasone (VAD) or bortezomib, doxorubicin, and dexamethasone (PAD) 
followed by high-dose melphalan and autologous stem-cell transplantation. Maintenance 
consisted of thalidomide 50 mg (VAD) once per day or bortezomib 1.3 mg/m2 (PAD) once every 
2 weeks for 2 years. In high-risk patients presenting with increased creatinine more than 2 
mg/dL, bortezomib significantly improved PFS from a median of 13 months to 30 months (HR, 
0.45; 95% CI, 0.26 to 0.78; P = .004) and OS from a median of 21 months to 54 months (HR, 
0.33; 95% CI, 0.16 to 0.65; P < .001). Bortezomib-based induction and maintenance showed an 
improved outcome for patients with del(17p) (median PFS 26 vs 12 months; 3-year OS 69% vs 
17%)). At long-term follow-up, this advantage was still present. Based on this result, every other 
week has become the clinical convention for maintenance dosing of bortezomib. Further support 
of every other week maintenance for carfilzomib was derived from the Mukfive trial. The 
MUKfive phase 2 trial studied the safety and activity of carfilzomib, cyclophosphamide and 
dexamethasone (KCd) for patients at first relapse or refractory to one prior line, and compared 
activity and safety of maintenance K vs observation after fixed duration KCd. Participants with 
≥SD after KCd were randomised (R2) 1:1 to receive maintenance K (36mg/m2 days 1, 2, 15, 16 
for 6m, then days 1, 2 for 12m) or no further treatment.  Median PFS from randomization 2 (R2) 
for maintenance for K was 11.9 m vs 5.6 m obs (HR 0.59, p=0.009). At time of R2, 8/69 (11.6%) 
and 10/72 (13.9%) of patients were MRD- in the K and obs arms respectively. MRD- rate 
increased after 6m of K to 11/45 (24.4%), while in the obs group, only 1/30 (3.3%) remained 
MRD-. At 12m, 12.5% in the K arm were MRD- compared to only 4.5% in obs group. Of 8 
patients who were MRD- at start of K, 5 remained MRD- at 6m (3 inadequate sample) and 2 at 
12m, of 40 MRD+ patients, 4 became MRD- at 6m, 1 remaining so at 12m. In contrast, only 1 
patient who was MRD- at start of observation remained so at 6m, remaining negative at 12m. 
Forty-four percent of patients completed 6 cycles of K, 18% completed 18 cycles. 82.1% of 
patients had a dose modification, but 88.7% of all cycles were received on time. Reasons for 
stopping K were completed treatment (18%), disease progression (65.6%), toxicity (4.9%), 
withdrew consent (6.6%). The results of this trial support both the use of carfilzomib as a potent 
maintenance drug band the safety and tolerability of an every other week dosing schedule as a 
maintenance strategy. 
Carfilzomib in combination with isatuximab has also been explored in the RR setting with a 
favorable safety profile.[11]  The median number of cycles given was 6. No DLT's or severe 
adverse drug reactions have been observed. No dose reduction for isatuximab or carfilzomib 
were needed. The most frequent occurring non-hematologic adverse events (occurring in ≥ 15%) 
at all dose levels were dyspnea (45%), fatigue (45%), nausea (45%), pain (back, chest wall and 
pelvis; 36%), peripheral neuropathy (36%), HTN (27%), cough (27%), anorexia (27%), 
gastroesophageal reflux disease (18%), constipation (18%), diarrhea (18%), nasal congestion 
(18%) and hypokalemia (18%); <5% of these adverse events were grade 3/4. Hematologic 
toxicity was mild; 9% grade 3/4 anemia, 9% grade 3/4 neutropenia, 64% grade 3/4 lymphopenia. 
The most frequent serious adverse event was grade 3 pneumonia (18%). Six patients (54%) had 
infusion reactions (grade 1 [n=4] or grade 2 [n=2]) but all completed therapy. 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
22
Building off these data, a favorable safety profile and promising preliminary efficacy for once-
weekly carfilzomib in RRMM subjects was observed in the CHAMPION 1 study[8] and the 
ARROW [9] studies and more recently the phase 1b study of once weekly carfilzomib in 
combination with lenalidomide and dexamethasone, this study will explore the safety and 
tolerability of once-weekly carfilzomib administered with lenalidomide and dexamethasone with 
the addition of isatuximab in NDMM. 
2.4 Lenalidomide
Lenalidomide is a second generation IMiD, with a chemical structure similar to thalidomide, and 
is widely used at all stages of illness.  The specific mechanism of action of IMiDs has only 
recently been determined.  Immunomodulatory drugs as a class bind to cereblon, a component of 
E3 ubiquitin ligase complexes.  This then promotes the degradation of transcription factors 
critical to MM proliferation:  IKZF1/3, MYC, and IRF4 [12-14].  Compared to thalidomide, 
lenalidomide is associated with significantly less peripheral neuropathy, sedation, and 
constipation but is associated with more myelosuppression.  Two phase III trials, MM-009 [15] 
and MM-010 [16], showed that the combination of lenalidomide and dexamethasone was 
superior to dexamethasone alone and established the role for lenalidomide in treating relapsed 
disease.  These trials shared a similar design:  lenalidomide was given as 25 mg daily on days 1-
21 on a 28-day cycle with dexamethasone 40 mg on days 1-4, 9-12, and 17-20 for the first four 
cycles and then on days 1-4.  About two-thirds of patients had two or more prior lines of 
therapy.  Pooling these trials together, the combination had a higher overall response rate (i.e. 
partial response or better; ORR), 60.6 vs. 21.9% [17].  The median time to progression and 
overall survival were also higher, 13.4 vs. 4.6 months and at least 38 months vs. 31.6 months, 
respectively.  The benefit in survival was seen even when 47.6% of patients randomized to the 
dexamethasone alone arm crossed over after disease progression or study unblinding.  Given 
these findings, lenalidomide was approved by the FDA for treating relapsed disease in June 
2006.  
A large, randomized Phase 3 study (FIRST Study) compared lenalidomide and dexamethasone 
(Rd) given until disease progression (Arm A) or for eighteen 28-day cycles (Arm B) with 
melphalan, prednisone, thalidomide (MPT) (Arm C) in subjects newly diagnosed with MM[18]. 
Continuous treatment with Rd (Arm A) significantly improved the primary endpoint of PFS 
compared with MPT (Arm C). Secondary endpoints (ORR, defined as PR or better, duration of 
response, and PFS2) consistently showed improvement in favor of Arm A over Arm C. The 
safety profile of Rd was manageable, with reduced hematologic second primary malignancies 
compared with MPT.
Motivated by in vitro data showing synergistic activity between bortezomib and 
lenalidomide,[19] a  major step forward has been combining lenalidomide, bortezomib, and 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
23
dexamethasone (RVD).[20, 21]  Among patients treated at the maximum tolerated dose of 
lenalidomide 25 mg days 1-14, bortezomib 1.3 mg/m2 IV days 1, 4, 8, 11, dexamethasone 20 mg 
day of and day after bortezomib on a 21-day cycle, the ORR rate was 100% with rates of VGPR 
or better seen in 74% patients. The Southwest Oncology Group (SWOG) study S0777 validated 
this triplet regimen, showing superior PFS, OS, and ORR with the triplet combination of RVD 
versus the doublet combination of Rd alone in patients with NDMM without intention for 
immediate autologous stem cell transplant (SCT).[22]  
Lenalidomide (REVLIMID®) in combination with dexamethasone was approved by both U.S. 
Food and Drug Administration (FDA) and the European Commission for the treatment of adult 
patients with previously untreated multiple myeloma who are not eligible for transplant, on 18 
February 2015 and 20 February 2015, respectively.
Complete and updated adverse events AEs are available in IB.
2.5 Rationale
Clinical data support the combination of a proteasome inhibitor, an IMiD, and a 
glucocorticosteroid for the treatments of NDMM.[18] The combination of bortezomib, 
lenalidomide, and low-dose dexamethasone is very active and well-tolerated in the NDMM 
population. [20] Carfilzomib, another proteasome inhibitor was recently approved by the FDA in 
combination with dexamethasone or with lenalidomide plus dexamethasone for patients with 
relapsed or refractory disease who have received one to three lines of therapy. Given that 
carfilzomib has improved binding kinetics and pharmacologic profile compared with 
bortezomib, it is expected that these differences will translate into similar, if not improved, 
efficacy and safety profiles in the upfront setting. The data available with bortezomib forms the 
foundation for the proteasome inhibitor in this upfront combination in this study. The 
combination of carfilzomib (twice-weekly), lenalidomide, and dexamethasone is a highly 
efficacious regimen [6, 23]. Of specific note, 23 of 26 subjects who reached nCR/CR achieved 
negative minimal residual disease (MRD[-]) status in one study [6], while in another trial 27 of 
27 subjects who reached nCR/CR achieved MRD[-] status [23], further emphasizing the efficacy 
of this combination. A favorable safety profile and promising preliminary efficacy for once-
weekly carfilzomib has been observed in the phase 1b study of once weekly carfilzomib in 
combination with lenalidomide and dexamethasone.[10] 
For maintenance, patients with standard-risk MM will be assigned to lenalidomide maintenance 
until disease progression, dose-limiting toxicity, patient withdrawal, or death. The rationale for 
continuous maintenance is based on the results of the FIRST trial that demonstrated improved 
PFS for patient receiving continuous lenalidomide and dexamethasone maintenance versus a 
defined 18-cycle course.[18]  Patients with high-risk cytogenetic abnormalities (HR-CA) will 
receive ongoing maintenance with lenalidomide, carfilzomib, and isatuximab.  The rationale for 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
24
multi-agent maintenance is based on the International Myeloma Working Group consensus 
statement of the treatment of multiple myeloma with high-risk (HR) cytogenetics that 
recommends the combination of a proteasome inhibitor with lenalidomide or pomalidomide and 
dexamethasone[24] and further supported by the prospective evaluation of consolidation and 
maintenance therapy with RVD in HRMM.[25] The recommendation from the IMWG is derived 
from several randomized trials have evaluated bortezomib for induction, consolidation, or 
maintenance treatment in cytogenetic subgroups. In IFM-2005-01, bortezomib/dexamethasone 
showed a superior response and OS compared with vincristine/doxorubicin/dexamethasone. This 
combination resulted in a better EFS and OS for patients with t(4;14), but did not improve 
outcome in del(17p) (4-year OS 50% vs 79%).[26] In HOVON65/GMMG-HD4, bortezomib-
based induction and maintenance showed an improved outcome for patients with del(17p) 
(median PFS 26 vs 12 months; 3-year OS 69% vs 17%)). At long-term follow-up, this advantage 
was still present. However, OS remains inferior to patients without del(17p) (3-year OS 85%). In 
patients with t(4;14), PFS was not better with bortezomib (25 vs 22 months), whereas OS was 
improved (3-year OS 69% vs 44%) compared with 85% in patients without t(4;14).[27] In the 
GEM 2005 trial, bortezomib/thalidomide/dexamethasone (VTD) followed by ASCT and 
maintenance did not improve OS in HR CA (3-year OS 60% vs 88%).[28] The GIMEMA group 
compared VTD with thalidomide/dexamethasone (TD) for induction and consolidation with 
double ASCT. In the subgroup of 25% with t(4;14), OS was 69% vs 37% in favor of VTD 
compared with 74% vs 63% without t(4;14) and/or del(17p).[29] A meta-analysis of 4 
randomized trials showed that the odds of post-transplantation complete response (CR) + near 
CR in bortezomib-treated patients were similar for HR (del(17p) + t(4;14)) and standard-risk 
(SR) cytogenetics (2.44 vs 1.67, n.s.).[30] These trials (1874 patients) showed that bortezomib 
plus ASCT was superior (PFS 41 vs 33 months) (P < .0001). In patients with HR FISH, this was 
32 vs 22 months (P < .0001). PFS benefit was observed in patients with t(4;14) but lacking 
del(17p) (36 vs 24 months, P = .001) and in del(17p) lacking t(4;14) (27 vs 19 months, P = 
.014), but not in patients carrying both CA.[31] In TT3, OS was significantly shorter in patients 
with a HR profile (2-year OS 56% vs 88%) compared with SR GEP profile, with the exception 
of low TP53 expression.[32] Addition of bortezomib improved OS compared with TT2 in LR 
MM.[32, 33]
Data for lenalidomide in first-line therapy for HR-CA patients is limited. In HR-CA, PFS with 
lenalidomide was inferior compared with SR patients (18 vs 26 months).[34] In the GIMEMA 
trial comparing high-dose melphalan with MPR, there was a trend for better PFS with 
lenalidomide maintenance in SR compared with HR-CA (HR 0.38 [0.24-0.62] vs 0.73 [0.37-
1.42]). However, there was no effect on OS.[35] In the IFM 2005-02 trial, lenalidomide 
maintenance did not overcome the poor prognosis of t(4;14) (27 vs 24 months) and only partly of 
del(17p) (29 vs 14 months vs 42 months in all patients).[36] Convincing data for continuous 
lenalidomide in CA groups are lacking.[37, 38] Subgroup analysis of the FIRST trial in NDMM 
did not demonstrate a benefit of continuous lenalidomide in HR CA.[18] In relapse MM, 
carfilzomib combined with lenalidomide and dexamethasone (K-RD) was effective across HR 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
25
and SR patients (23 vs 29 months, P = NS), whereas RD showed less activity (13 vs 19 
months, P = .004).[7] Data of IFM did not show a benefit of RD in relapse/refractory multiple 
myeloma (RRMM) with del(13q) or t(4;14).[39] In the Eloquent 2 trial for RRMM, elotuzumab 
with RD (E-RD) improved outcome over RD in del(17p).[40] Recent data of the effect of 
pomalidomide with dexamethasone in patients with RRMM show that this combination does not 
abrogate overall adverse outcome in HR-CA, whereas OS may improve in del(17p).[41] In phase 
2 trials, a response benefit of pomalidomide with dexamethasone was shown in patients with 
del(17p).[42] 
Bortezomib combined with RD (VRD) in a phase 1/2 trial in 66 patients with NDMM showed 
18-month PFS of 100% in 13 patients with del(17p) and/or t(4;14).[20] The EVOLUTION trial 
examined several schedules including VRD in NDMM. One-year PFS was similar in HR-CA 
(17% of all patients) and SR patients.[21] VRD in transplant-eligible patients with NDMM had 
similar 3-year PFS (86%) in patients with >60% del(17p) or t(4;14) or del(13q) compared with 
all patients.[43] In the phase 2 evaluation of consolidation and maintenance with RVD in 
HRMM, best responses with the current triplet maintenance strategy following melphalan high-
dose therapy were stringent complete response among 51%, ⩾VGPR among 96%, with all 
patients achieving ⩾ PR. The median PFS for all patients was 32 months with a 3-year OS of 
93%. A median PFS of 20 months was observed among patients achieving ⩾PR. The survival 
among all high-risk patients vs patients with del 17p was not different (median PFS of 32 months 
vs 28 months; P=0.86; 3-year OS of 93% vs 94%, P=0.51, respectively. No patient developed 
grade 3 or 4 neuropathy, and no patient discontinued maintenance therapy owing to adverse 
events.[25] 
Carfilzomib monotherapy did not improve PFS/OS in t(4;14) or del(17p) in 
RRMM.[44] Carfilzomib combined with pomalidomide/dexamethasone had equivalent PFS and 
OS in HR vs SR RRMM.[45] In the Aspire trial, in RRMM, KRD was superior to RD for PFS 
across cytogenetic risk groups, suggesting that this combination (partly) abrogates the negative 
impact of t(4;14) and del(17p).[7] Similarly, in Tourmaline-MM1, ixazomib combined with RD 
showed identical PFS in patients with HR-CA or no CA (21.4 vs 20.6 months).[46] More 
recently, carfilzomib combined with lenalidomide (KRd) or thalidomide (KTd) and 
dexamethasone in NDMM showed similar CR rate (>60%) and PFS between HR and SR 
patients.[6, 47]
The anti-CD38 monoclonal antibody, isatuximab in combination with 
lenalidomide/dexamethasone and pomalidomide/dexamethasone demonstrated significant 
clinical responses, even in patients who were resistant to the combination partner. The addition 
of isatuximab to carfilzomib, lenalidomide, and dexamethasone is expected to increase response 
rates and depth of response with limited additional toxicity.  The rationale for a 4-drug 
combination is to create a potentially curative upfront regimen where one does not currently 
exist.

DF/HCC #: 19-568
Version Date: March 2nd 2023 
26
3. PARTICIPANT SELECTION
Screening for eligible subjects will be performed within 28 days of study enrollment.
Eligibility Criteria 
3.1 Inclusion Criteria
1. Subject must be at least 18 years of age.
2. Subject must have documented multiple myeloma satisfying the CRAB criteria and 
measurable disease defined as:
•
Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy-proven 
Plasmacytoma.
•
Measurable disease as defined by any of the following:
− IgG myeloma: Serum monoclonal paraprotein (M-protein) level ≥.5 g/dL or
urine M-protein level ≥200 mg/24 hours; or
− IgA, IgM, or IgD multiple myeloma: serum M-protein level ≥0.25 g/dL or
urine M-protein level ≥200 mg/24 hours; or
− Light chain multiple myeloma: Serum immunoglobulin free light chain ≥10 mg/dL and 
abnormal serum immunoglobulin kappa lambda free light chain ratio.
•
Sixty percent or greater clonal plasma cells on bone marrow examination.
•
Serum involved / uninvolved free light chain ratio of 100 or greater, provided the 
absolute level of the involved free light chain is at least 100 mg/L (a patient’s “involved” 
free light chain – either kappa or lambda – is the one that is above the normal reference 
range; the uninvolved light chain is the one that typically is in, or below, the normal 
range).
•
More than one focal lesion on magnetic resonance image (MRI) that is at least 5 mm or 
greater in size.
3. Newly diagnosed and considered candidate for high-dose chemotherapy with stem cell 
transplant. 
4. Subject must have an Eastern Cooperative Oncology Group (ECOG) performance status score 
of 0, 1, or 2.
5. Subject must have pretreatment clinical laboratory values meeting the following criteria
during the Screening Phase:
a) hemoglobin ≥7.5 g/dL (≥5 mmol/L; prior RBC transfusion or recombinant human 
erythropoietin use is permitted);
b) absolute neutrophil count ≥1.0 x 109/L (granulocyte colony stimulating factor [GCSF] 
use is permitted);

DF/HCC #: 19-568
Version Date: March 2nd 2023 
27
c) platelet count ≥70 x 109/L for subjects in whom <50% of bone marrow nucleated cells 
are plasma cells; otherwise platelet count >50 × 109/L (transfusions are not permitted to 
achieve this minimum platelet count)
d) aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN);
e) alanine aminotransferase (ALT) ≤2.5 x ULN;
f) total bilirubin ≤2.0 x ULN, except in subjects with congenital bilirubinemia, such as 
Gilbert syndrome (direct bilirubin ≤2.0 x ULN)
g) creatinine clearance ≥30 mL/min  
h) corrected serum calcium ≤14 mg/dL (≤3.5 mmol/L); or free ionized calcium <6.5 
mg/dL (<1.6 mmol/L). 
6. Women of childbearing potential must commit to either abstain continuously from 
heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously. This 
includes one highly effective form of contraception (tubal ligation, intrauterine device [IUD], 
hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or 
partner’s vasectomy) and one additional effective contraceptive method (male latex or synthetic 
condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing. 
Reliable contraception is indicated even where there has been a history of infertility, unless due 
to hysterectomy or bilateral oophorectomy.
7. A man who is sexually active with a woman of childbearing potential must agree to use a latex 
or synthetic condom, even if they had a successful vasectomy. All men must also not donate 
sperm during the study, for 4 weeks after the last dose of lenalidomide, for 90 days after the last 
dose of carfilzomib, and for 4 months after the last dose of isatuximab.
8. A woman of childbearing potential must have 2 negative serum or urine pregnancy tests at 
Screening, first within 10 to 14 days prior to dosing and the second within 24 hours prior to 
dosing. 
9. Each subject (or their legally acceptable representative) must sign an informed consent form 
(ICF) indicating that he or she understands the purpose of and procedures required for the study 
and are willing to participate in the study. Subject must be willing and able to adhere to the 
prohibitions and restrictions specified in this protocol, as referenced in the ICF.
3.2 Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating
in the study.
1. Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined 
significance, or smoldering multiple myeloma. Monoclonal gammopathy of undetermined 
significance is defined by presence of serum M-protein <3 g/dL; absence of lytic bone lesions, 
anemia, hypercalcemia, and renal insufficiency related to the M-protein; and (if determined) 
proportion of plasma cells in the bone marrow of 10% or less.  Smoldering multiple myeloma is 
defined as asymptomatic MM with absence of related organ or tissue impairment end organ 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
28
damage 
2. Subject has a diagnosis of Waldenström’s disease, or other conditions in which IgM M-protein 
is present in the absence of a clonal plasma cell infiltration with lytic bone lesions
3. Subject has prior or current systemic therapy or SCT for MM, with the exception of an 
emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4 
days) of corticosteroids before treatment.
4. Subject has a history of malignancy (other than MM) within 5 years before the date of 
enrollment (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ 
of the cervix, or malignancy that in the opinion of the investigator, with concurrence with the 
sponsor's medical monitor, is considered cured with minimal risk of recurrence within 5 years).
5. Subject has had radiation therapy within 7 days of enrollment.
6. Subject has had plasmapheresis within 28 days of enrollment.
7. Subject is exhibiting clinical signs of meningeal involvement of MM.
8. Subject has known chronic obstructive pulmonary disease (COPD) (defined as a forced 
expiratory volume [FEV] in 1 second <60% of predicted normal), persistent asthma, or a history 
of asthma within the last 2 years (intermittent asthma is allowed). Subjects with known or 
suspected COPD or asthma must have a FEV1 test during screening.
9. Subject is known to be seropositive for history of human immunodeficiency virus (HIV)
or known to have active hepatitis B or hepatitis C.
10. Subject has any concurrent medical or psychiatric condition or disease (eg, active systemic 
infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to 
interfere with the study procedures or results, or that in the opinion of the investigator, would 
constitute a hazard for participating in this study.
11. Subject has clinically significant cardiac disease, including:
•
myocardial infarction within 1 year before enrollment, or an unstable or 
uncontrolled disease/condition related to or affecting cardiac function (eg, unstable
angina, congestive heart failure, New York Heart Association Class III-IV;
•
uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology 
Criteria for Adverse Events [NCI CTCAE] Version 4 Grade ≥2) or clinically significant 
ECG abnormalities;
•
screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s 
formula (QTcF) >470 msec.
•
uncontrolled hypertension
12. Subject has known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal 
antibodies or human proteins, or their excipients (refer to respective package inserts or IB) or 
known sensitivity to mammalian-derived products.
13. Subject has plasma cell leukemia (according to World Health Organization [WHO] criterion: 
≥20% of cells in the peripheral blood with an absolute plasma cell count of more than 2 × 109/L) 
or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and 
skin changes).

DF/HCC #: 19-568
Version Date: March 2nd 2023 
29
14. Subject is known or suspected of not being able to comply with the study protocol (eg, 
because of alcoholism, drug dependency, or psychological disorder). Subject has any condition 
for which, in the opinion of the investigator, participation would not be in the best interest of the 
subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-
specified assessments. 
15. Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant while 
enrolled in this study within 30 days after the last dose of lenalidomide or carfilzomib, or within 
4 months after the last dose of isatuximab. Or, subject is a man who plans to father a child while 
enrolled in this study, within 4 weeks after the last dose of lenalidomide, within 90 days of the 
last dose of carfilzomib, or within 4 months after the last dose of isatuximab.
16. Subject has had major surgery within 2 weeks before enrollment or has not fully recovered 
from surgery, or has surgery planned during the time the subject is expected to participate in the 
study. Kyphoplasty or vertebroplasty is not considered major surgery. 
17. Subject has received an investigational drug (including investigational vaccines) or used an 
invasive investigational medical device within 4 weeks before enrollment or is currently enrolled 
in an interventional investigational study.
18. Subject has contraindications to required prophylaxis for deep vein thrombosis and 
pulmonary embolism.
19. Incidence of gastrointestinal disease that may significantly alter the absorption of oral drugs.
20. Peripheral neuropathy ≥ Grade 2 on clinical examination during the screening period.
21. Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin), strong 
inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, 
nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, 
carbamazepine, phenytoin, phenobartital), or use of Ginkgo biloba, St. John’s wort within 14 
days before the first dose of study treatment.
3.3 Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial.
4.
REGISTRATION 
4.1 General Guidelines for Dana-Farber/Harvard Cancer Center (DF/HCC) Institutions
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of any protocol-specific therapy or 
intervention. Any participant not registered to the protocol before protocol-specific therapy or 
intervention begins will be considered ineligible and registration will be denied.
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist.

DF/HCC #: 19-568
Version Date: March 2nd 2023 
30
Following registration, participants may begin protocol-specific therapy and/or intervention. 
Issues that would cause treatment delays should be discussed with the Overall Principal 
Investigator (PI). If the subject does not receive protocol therapy following registration, the 
subject must be taken off-study in the CTMS (OnCore) with an appropriate date and reason 
entered.  
4.2 Registration Process for DF/HCC Institutions
Applicable DF/HCC policy (REGIST-101) must be followed.  
4.3 General Guidelines for Other Investigative Sites
Not applicable 
4.4 Registration Process for Other Investigative Sites
Not applicable 
5. TREATMENT PLAN
5.1 Treatment Regimen
Carfilzomib, lenalidomide, dexamethasone, and isatuximab will be administered on a 28-day 
treatment cycle.  All subjects will perform stem cell collection after 4 cycles of therapy. 
For patient undergoing upfront stem cell transplant (SCT):
4 cycles of therapy followed by stem cell collection, high-dose chemotherapy, and autologous 
SCT followed by 2 additional cycles of therapy then maintenance.
For patients deferring SCT following collection:
4 cycles of therapy followed by stem cell collection followed by 4 additional cycles of therapy 
then maintenance.
Carfilzomib 56 mg/m2 IV on Days 1, 8, 15
Lenalidomide 25 mg orally (po) on Days 1-21
Isatuximab 10 mg/kg IV Q1 week for 8 weeks, then Q2 weeks for 16 weeks, thereafter Q4 weeks 
Dexamethasone 20 mg po will be administered day of and day after all doses of carfilzomib 
(Days 1, 2, 8, 9, 15, and 16) and isatuximab (Cycles 1 and 2 Days 22 and 23).  The 
dexamethasone 20 mg oral or IV dose administered as a preinfusion medication on isatuximab 
infusion days (Days 1, 8, 15, 22) replaces the oral dexamethasone dose for that day.

DF/HCC #: 19-568
Version Date: March 2nd 2023 
31
*All subjects with receive carfilzomib 20 mg/m2 on Day 1 Cycle 1
Maintenance:
Patients must achieve a PR or better to continue onto maintenance therapy on the study.
28-day Maintenance Cycle until progressive disease (PD) or unacceptable toxicity.  Subjects will 
be stratified based on cytogenetics (deletion (del) 17, translocation (t)(4:14), t(14;16), t(14;20), 
1q duplication).  
Standard-risk:
Lenalidomide 10 mg po Days 1-21
High-risk:
Carfilzomib 56 mg/m2 (or last tolerated dose) IV Days 1, 15
Lenalidomide 10 mg po Days 1-21
Isatuximab 10 mg/kg IV Day 1 for up to 24 cycles of maintenance (two years), then discontinue
In the maintenance phase, dexamethasone, 20 mg orally or IV will be administered to subjects as 
a preinfusion medication prior to isatuximab dosing.  When dexamethasone is reduced to 20 
mg/week and is given as preinfusion medication, subjects may receive low-dose 
methylprednisolone (≤20 mg) orally (or equivalent in accordance with local standards) for the 
prevention of delayed infusion-associated reactions (IARs), as clinically indicated.
Because lenalidomide is primarily excreted unchanged by the kidney, adjustments to the 
starting dose of lenalidomide are recommended to provide appropriate drug exposure in 
patients with renal impairment. Lenalidomide dose adjustment should be instituted for patients 
with a CrCl ≤50 mL/min. The recommended doses for patients with multiple myeloma and 
renal impairment are shown below in Table 9. If during treatment a patient’s renal status 
changes, the dose should be adjusted as shown in Table 9. Similarly, adjustments to the starting 
and ongoing dosing of carfilzomib are recommended in the setting of hepatic impairment. The 
doses should be adjusted as shown in Table 10.
Stem cell collection and SCT should be done per institutional and FACT guidelines. The 
decision whether a patient will proceed to stem cell transplant will be made on the basis of 
treating physician recommendations and patient preference. Physician recommendations are 
typically based on disease response and on how well subjects are tolerating treatment. This kind 
of decision-making process related to stem cell transplant is considered standard of care in the 
multiple myeloma field. Subjects who do not proceed to stem cell transplant may receive a total 
of 8 cycles of therapy followed by maintenance. Those patients proceeding with stem cell 
transplant will receive an additional 2 cycles of therapy post-SCT followed by maintenance. 
Prior to continuing induction therapy, all stem cell harvest-related toxicity or stem cell 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
32
transplant-related toxicity must be improved such the patient meets criteria to treat outlined in 
section 5.2 of the protocol.
5.2 Pre-Treatment Criteria
A new cycle of treatment may begin on the scheduled Day 1 of a new cycle if the following 
criteria are met within 24 hours of Day 1:
•
ANC ≥1,000/mm3 (growth factor support is permitted during cycles with the exception of 
Cycle 1 Day 1 (C1D1); it is allowed on the same day as treatment administration).
•
Platelet count ≥50,000/mm3 (platelet support is permitted during cycles of treatment; it is 
allowed on the same day as treatment administration, including C1D1).
•
Any lenalidomide-related allergic reaction/hypersensitivity or sinus bradycardia/other 
cardiac arrhythmia AE that may have occurred has resolved to < Grade 1.
•
Any other lenalidomide, carfilzomib, or isatuximab-related adverse event that may have 
occurred has resolved to <Grade 2. 
•
Herpes zoster lesions, if present, are dry.
If these conditions are not met on Day 1 of a new cycle, the subject will be evaluated weekly and 
a new cycle of therapy will not be initiated until the toxicity has resolved as described above. The 
maximum amount of time that treatment may be held for these toxicities to resolve is 3 weeks. If 
drug is held for more than 3 weeks due to toxicity, the patient is to discontinue all study treatment 
and enter the survival follow-up phase of the study. 
For intra-cycle dosing on days where laboratory studies are scheduled, the following criteria 
must be met:
•
Platelet count ≥ 30,000 (platelet transfusion support is permitted to meet criteria)
•
Absolute neutrophil ≥ 500/mm3 (growth factor support is permitted during cycles with 
the exception of Cycle 1 Day 1 (C1D1); it is allowed on the same day as treatment 
administration).
Intra-cycle dose modifications for all drugs will be allowed based on toxicity and according to 
dose modifications outline in Section 6.1, Table 9.
5.3 Agent Administration and Pharmaceutical Information
5.3.1 
Isatuximab
5.3.1.1
 Description
Isatuximab (SAR650984) is an IgG1 derived mAb binding selectively the human CD38 
membrane protein. The protein structure is composed of 2 kappa light chains each with 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
33
molecular weight of approximately 23 kDa and 2 IgG1 heavy chains each with a molecular 
weight of approximately 49 kDa (deglycosylated form) linked through disulfide bridges. Each 
light chain consists of 214 amino acid residues and each heavy chain consists of 450 amino acid 
residues. 
Appearance: Colorless to slightly yellow liquid which may contain visible particles.
Antigen binding: Isatuximab binds to CD38 with an apparent dissociation constant (Kd) of about 
3 nM, determined by Surface Plasmon Resonance using monomeric CD38 protein.
5.3.1.2
Formulation
Isatuximab (SAR650984) drug product is supplied as concentrate for solution for infusion in the 
following formulations:
•
100 mg/5 mL (20 mg/mL) in single-dose vial  
•
500 mg/25 mL (20 mg/mL) in single-dose vial
5.3.1.3
Storage and Stability 
Storage of isatuximab should be in a secure area with restricted access. Isatuximab vials should 
be stored in a refrigerator  at +2°C to +8°C in the original carton to protect from light. Do not 
freeze. Do not shake.   Details of the stability for the diluted solution are provided below in the 
preparation section.
5.3.1.4 
Preparation 
Prepare the solution for infusion using aseptic technique as follows [49]: 
•
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration.
•
Remove the volume of diluent from a 250 mL bag of 0.9% Sodium Chloride Injection, 
USP, or 5% Dextrose Injection, USP that is equal to the required dose volume of 
Isatuximab plus manufacturer overfill in order to prepare a total volume of 250 mL.
•
Withdraw the required dose volume of isatuximab based on a concentration of 20 mg/mL 
and dilute by adding to the infusion bag of 0.9% Sodium Chloride Injection, USP or 5% 
Dextrose Injection, USP 
•
The infusion bag must be made of polyolefins (PO), polyethylene (PE), polypropylene 
(PP),polyvinyl chloride (PVC) with di-(2-ethylhexyl) phthalate (DEHP) or ethyl vinyl 
acetate (EVA).
•
Gently homogenize the diluted solution by inverting the bag. Do not shake.
•
The prepared isatuximab infusion solution should be administered by intravenous 
infusion using an intravenous tubing infusion set (in PE, PVC with or without DEHP, 
polybutadiene [PBD], or polyurethane [PU]) with a 0.22 micron in-line filter 
(polyethersulfone [PES], polysulfone, or nylon).

DF/HCC #: 19-568
Version Date: March 2nd 2023 
34
•
The prepared isatuximab infusion solution should be used within 48 hours when stored 
refrigerated at 2°C to 8°C, followed by 8 hours (including infusion time) at room 
temperature.
•
Do not administer isatuximab infusion solution concomitantly in the same intravenous 
line with other agents.
•
5.3.1.5 
Administration
Do not administer isatuximab infusion solution concomitantly in the same intravenous line with 
other agents. On days when both isatuximab and carfilzomib are given, order of administration is 
per institutional preference. Administer the prepared isatuximab infusion solution according to 
the Infusion Rates in the table below.  Incremental escalation of the infusion rate should be 
considered only in the absence of infusion-related reactions [49]
Dilution 
Volume
Initial 
Rate
Absence of Infusion-
Related Reaction
Rate Increment
Maximum 
Rate
First 
Infusion
250 mL
25 
mL/hour
For 60 minutes
25 mL/hour every 
30 minutes
150 
mL/hour
Second 
Infusion
250 mL
50 
mL/hour
For 30 minutes
50 mL/hour for 
30 minutes then 
increase by 100 
mL/hour every 30 
minutes
200 
mL/hour
Subsequent 
Infusions
250 mL
200 
mL/hour
-
-
200 
mL/hour
5.3.1.6 
Treatment Schedule
Isatuximab (10 mg/kg) will be administered as an IV infusion. Each subject’s dose will be 
calculated based on the subject’s weight at C1D1. The dose of isatuximab will remain constant 
throughout the study, unless the subject’s weight changes more than 10% (or per institutional 
standard policy) from C1D1. Isatuximab will be administered weekly during induction treatment 
in Cycle 1 to Cycle 2 (Days 1, 8, 15, and 22); every 2 weeks in Cycles 3-6 (Days 1 and 15), and 
every 4 weeks thereafter. For high-risk patients isatuximab will be administered every 4 weeks 
on Day 1 of each 28-day cycle during maintenance treatment until progressive disease (PD) or 
unacceptable toxicity for a maximum of 24 maintenance cycles (2 years) and then discontinued. 
5.3.1.7 
Premedications
To minimize the incidence and severity of infusion reactions, all the patients treated with 
isatuximab should routinely receive primary prophylactic treatment with diphenhydramine 25 to

DF/HCC #: 19-568
Version Date: March 2nd 2023 
35
50 mg IV (or equivalent), methylprednisolone 100 mg IV (or equivalent), montelukast 10mg 
orally (or equivalent), fexofenadine 60mg orally (or equivalent), and acetaminophen 650 to 1000 
mg orally (or equivalent), approximately 15–60 minutes (but never >60 minutes) prior to the 
start of the isatuximab infusion. 
Detailed guidelines for the management of infusion reactions (Table 5) are provided in each 
study protocol. In the event of an infusion reaction, the isatuximab infusion may be interrupted 
and can be subsequently resumed after recovery (if the reaction was mild-to-moderate), at a 
slower infusion rate, under close monitoring, and with supportive care as needed. Prior to 
restarting the infusion in case of moderate reactions, patients may receive additional medication 
based on the judgment of the Investigator; recommended medications consist of 
diphenhydramine 25 mg IV and methylprednisolone 100 mg IV (or equivalent). In the event of a 
severe hypersensitivity reaction, however, treatment with isatuximab is to be immediately and 
permanently discontinued. Patients who experience infusion reactions must also be informed of 
the potential risk of recurrent reactions at subsequent infusions. Patients who do not experience 
an infusion reaction during the first 4 isatuximab infusions may have their need for subsequent 
premedication reconsidered at the Investigator’s discretion to avoid unnecessary sedation.
Table 5 - Management of Infusion Reactions (IR)
Symptom Severity (CTACAE ver 
5.0)
Recommended Intervention
Mild (Grade 1)                                       
Infusion interruption or intervention 
not indicated
Continuation of isatuximab infusion per the 
judgement of the investigator following close 
direct monitoring of the patient's clinical 
status.  Isatuximab infusion may be stopped at 
any time if deemed necessary. If stopped, IR 
will be classified as Grade 2 as per NCI-
CTCAE
Moderate (Grade 2)                              
Therapy or infusion interruption 
indicated but responds promptly to 
symptomatic treatment (eg, 
antihistamines, nonsteroidal anti-
inflammatory drugs (NSAIDs), 
narcotics, IV fluids); prophylactic 
medications indicated for ≤24 hours
Stop isatuximab infusion. Give additional 
medication with IV diphenhydramine 25 mg 
IV (or equivalent) and/ or IV 
methylprednisolone 100 mg (or equivalent) as 
needed. Isatuximab may be resumed only after 
patient recovery, with
slower infusion rate and with close 
monitoring. 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
36
Severe or life-threatening (Grade 3 or 
4) Grade 3: prolonged (eg, not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of symptoms 
following initial improvement; 
hospitalization indicated for clinical 
sequelae                                 Grade 4: 
life-threatening consequences; urgent 
intervention indicated
Stop isatuximab infusion. Give additional 
medication with diphenhydramine 25 mg IV 
(or equivalent) and/ or IV methylprednisolone 
100 mg (or equivalent) and/or epinephrine as 
needed. Definitive treatment discontinuation.
Patients who experience Grade 2 IAR may subsequently resume isatuximab infusion under close 
monitoring and supportive care as needed. Patients may receive additional premedication per the 
judgment of the Investigator. These patients must be informed of the potential risk of recurrent 
allergic reactions. The infusion must be completed within the time specified in the Package 
Insert.
Patients with Grade 3 or 4 isatuximab IAR must have isatuximab permanently discontinued and 
appropriate therapy should be administered. Should an isatuximab infusion reaction of Grade ≥2 
occur, the infusion reaction and the therapy administered must be documented in the case report 
form (CRF).
All IARs must be reported as an adverse event of special interest (AESI). Study personnel should 
consult the Medical Monitor for further guidance regarding re treatment of patients with infusion 
reactions and regarding issues of premedication management (eg, alternative medications for 
patients allergic or intolerant to premedication agents) or to determine if locally used equivalent 
medications are acceptable.
5.3.1.8
Responsibilities
The Investigator, the Hospital Pharmacist, or other personnel allowed to store and dispense 
isatuximab will be responsible for ensuring that isatuximab is used in the clinical trial is securely 
maintained as specified by Sanofi and in accordance with the applicable regulatory requirements.
All isatuximab shall be dispensed in accordance with the Investigator’s prescription and it is the
Investigator’s responsibility to ensure that an accurate record of Investigational Product issued 
and returned is maintained.
Any quality issue noticed with the receipt or use of isatuximab (deficiency in condition, 
appearance, pertaining documentation, labeling, expiration date, etc) should be promptly notified 
to the Sponsor. Some deficiencies may be recorded through a complaint procedure.

DF/HCC #: 19-568
Version Date: March 2nd 2023 
37
A potential defect in the quality of isatuximab may be subject to initiation by Sanofi of a recall 
procedure. In this case, the Investigator will be responsible for promptly addressing any request 
made by Sanofi, in order to recall Investigational Product and eliminate potential hazards. Under 
no circumstances will the Investigator supply the isatuximab to a third party, allow the 
isatuximab to be used other than as directed by this Clinical Trial Protocol, or dispose of 
isatuximab in any other manner.
5.3.1.9
Retrieval of treatments and/or destruction
All used treatments vials of isatuximab will be destroyed at the study site after an accurate 
accountability has been performed and signed by the investigator (or the pharmacist). All 
partially-used and unused isatuximab may be retrieved by Sanofi or they will be destroyed on 
site, after final batch accountability has been validated by the Sponsor monitoring team 
representative, according to the standard practices of the site and /or to local regulations. The 
destruction is recommended to be performed at site depending on investigational medical 
product (IMP) specificities and local requirements, but IMP can be returned to the sponsor for 
destruction. A detailed treatment log form of the returned isatuximab will be established with the 
Investigator (or the pharmacist) and countersigned by the Investigator and the Monitoring Team.
The Investigator will not destroy the unused IMP unless Sanofi provides written authorization.
5.3.1.10 
Availability and Ordering
Sanofi will supply isatuximab free-of-charge, shipped directly to the pharmacy at the study site. 
The investigator or designee will order isatuximab from Sanofi according to the ordering 
instructions provided by the company. 
5.3.2
Carfilzomib
5.3.2.1
Description
Carfilzomib is a synthetic small molecule peptide bearing the chemical name (2S)-N-((S)-1-
((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-
((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide. The molecular 
formula is C40H57N5O7 and the molecular weight is 719.91. It specifically functions as an 
inhibitor of the chymotrypsin-like activity of the 20S proteasome which leads to the 
accumulation of protein substrates within the cell and induction of apoptosis. Carfilzomib for 
Injection will be provided as a lyophilized powder which, when reconstituted, contains a 2 
mg/mL isotonic solution of carfilzomib Free Base in 10 mM sodium citrate buffer (pH 3.5) 
containing 10% (w/v) sulfobutylether-beta-cyclodextrin (SBE beta CD, Captisol).

DF/HCC #: 19-568
Version Date: March 2nd 2023 
38
5.3.2.2 
Formulation 
Carfilzomib for Injection is supplied as 60 mg lyophilized powder in single-use vials for 
reconstitution. Upon reconstitution with preservative-free sterile water for injection, USP, the 
reconstituted solution contains 2mg/mL carfilzomib.  Additional information on carfilzomib may 
be found in the IB.
5.3.2.3
Storage and Stability
Study drugs should be stored in a securely locked area with access limited to appropriate study 
personnel. Lyophilized carfilzomib for Injection must be stored at 2°Celcius (C) to 8°C 
(36°Fahrenheit −46°F) in a refrigerator. Vials must be kept in cartons in order to protect from 
light until ready for reconstitution. Once a drug vial is reconstituted and inspected, the clear 
solution can be stored in a refrigerator (recommended) controlled temperature from 2°C to 8°C 
(36°F–46°F) for up to 24 hours. If kept at room temperature after reconstitution, it must be used 
within 4 hours. Once reconstituted, carfilzomib for Injection must be used by the time points 
outlined in Table 6 below.
Table 6 - Stability of Reconstituted Carfilzomib for Injection (60 mg/vial)
Stability (in Hours) per Container
Storage Conditions of Reconstituted 
Carfilzomib
Vial
Syringe
IV Bag 
(D5W)
Refrigerated (2°C to 8°C; 36°F to 46°F)
24
24
24
Room Temperature (15°C to 30°C; 59°F to 
86°F)
4
4
4
5.3.2.4
Preparation
Carfilzomib will be prepared according to the provided Carfilzomib Investigator Sponsored 
Study (ISS) Pharmacy Information Guide. 
5.3.2.5
Administration
On days when both isatuximab and carfilzomib are given, order of administration is per 
institutional preference. Administer the prepared carfilzomib infusion solution according to the  
Carfilzomib Investigator Sponsored Study (ISS) Pharmacy Information Guide and/or 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
39
Institutional Guidelines. Deliver the entire volume as a continuous infusion over a period of 10 
minutes for carfilzomib doses < 27 mg/m2 or 30 minutes for carfilzomib doses > 27 mg/m2.  
5.3.2.6
Treatment Schedule 
Carfilzomib will be administered once weekly during induction at a dose of 56 mg/m2 IV on 
Days 1, 8, 15 of each 28-day cycle.  All subjects with receive carfilzomib 20 mg/m2 on Day 1 
Cycle 1. For high-risk patients carfilzomib will be administered at a dose of 56mg/m2 (or last 
tolerated dose) IV on Days 1 and 15 of each 28-day cycle during maintenance treatment until 
progressive disease (PD) or unacceptable toxicity. Subjects with a BSA > 2.2 m2 will receive a 
dose based upon a BSA of 2.2 m2, for all carfilzomib study treatment doses 
5.3.2.7
Hydration
Adequate hydration is required prior to carfilzomib dosing in Cycle1, especially in patients at 
high-risk of tumor lysis syndrome (TLS) or renal toxicity. Consider hydration with both oral 
fluids (30mL per kg at least 48hours before Cycle1, Day1) and intravenous fluids (250mL to 
500mL of appropriate intravenous fluid prior to each dose in Cycle1). If needed, give an 
additional 250mL to 500mL of intravenous fluids following carfilzomib administration. 
Continue oral and/or intravenous hydration, as needed, in subsequent cycles. Monitor patients for 
evidence of volume overload and adjust hydration to individual patient needs, especially in 
patients with or at risk for cardiac failure. [50]
5.3.2.8 
Accountability, Handling and Destruction
Refer to provided Carfilzomib Investigator Sponsored Study (ISS) Pharmacy Information Guide.
5.3.2.9 
Availability and Ordering
Amgen will supply carfilzomib free-of-charge, shipped directly to the pharmacy at the study site. 
The investigator or designee will order carfilzomib from Amgen according to the ordering 
instructions provided by the company. 
5.3.3 
Lenalidomide
5.3.3.1
Description
Lenalidomide (REVLIMID®), a thalidomide analogue, is an immunomodulatory agent with 
antiangiogenic properties. Lenalidomide is available for this study as 5 and 25 mg capsules for 
oral administration and does not require any other preparation. Each capsule contains 
lenalidomide as the active ingredient and the following inactive ingredients:  lactose anhydrous, 
microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

DF/HCC #: 19-568
Version Date: March 2nd 2023 
40
5.3.3.2
Storage and Stability
At the study site, all investigational study drugs will be stored in a locked, safe area to prevent 
unauthorized access. Lenalidomide should be stored at room temperature away from direct 
sunlight and protected from excessive heat and cold.  
5.3.3.3
Handling
Females of childbearing potential should not handle or administer lenalidomide unless they are 
wearing gloves.
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment.
5.3.3.4
Ordering 
Lenalidomide will be obtained through commercial supply through the REMS® program. 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. 
Lenalidomide (Revlimid®) will be prescribed in accordance with Celgene Corporation’s 
Revlimid REMS® program. Further information about the Revlimid REMS® program is 
available at: www.celgeneriskmanagement.com.
5.3.3.5
Treatment Schedule and Administration 
During the induction phase of treatment, lenalidomide will be self-administered at a dose of 25 mg 
orally each day on Days 1 through 21 of each 28-day cycle for subjects with creatinine clearance 
(CrCl) >50 mL/min. During the maintenance phase for all patients, lenalidomide 10 mg will be 
administered daily on days 1-21 throughout each 28-day cycle until progressive disease (PD) or 
unacceptable toxicity. 
Lenalidomide should be taken orally at about the same time each day. The capsules should not 
be opened, broken, or chewed. Lenalidomide capsules should be swallowed whole, preferably 
with water, either with or without food.
If less than 12 hours has elapsed since missing a dose, the patient can take the dose. If more than 
12 hours has elapsed since missing a dose at the normal time, the patient should not take the 
dose, but take the next dose at the normal time on the following day. Do not take 2 doses at the 
same time.
5.3.4
Dexamethasone
5.3.4.1
 Description
Dexamethasone is a synthetic adrenocortical steroid. Corticosteroids are naturally occurring 
chemicals produced by the adrenal glands located above the kidneys. Corticosteroids affect the 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
41
function of many cells within the body and suppress the immune system. Corticosteroids also 
block inflammation and are used in a wide variety of inflammatory diseases affecting many 
organs. 
The molecular weight for dexamethasone is 392.47. It is designated chemically as 9-fluoro-
11β,17,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione. Dexamethasone is stable in air 
and almost insoluble in water. 
5.3.4.2
Formulation
Dexamethasone is a white to practically white, odorless, crystalline powder. It is available in 2- 
or 4-mg tablets (commercially) for oral administration. Each tablet contains dexamethasone as 
the active ingredient, and the following inactive ingredients:  calcium phosphate, lactose, 
magnesium stearate, and starch. The tablet shell may contain the following:  D&C Yellow 10, 
FD&C Yellow 6, and/or FD&C Blue 1.
5.3.4.3
Storage and Stability
Dexamethasone should be stored at controlled room temperature, 68-77◦F (20-25◦C) and not 
frozen, and according to label requirements.
5.3.4.4
Availability
Dexamethasone supply will be obtained through commercial supply.
5.3.4.5
Preparation
Dexamethasone is an oral drug and does not require specific preparation details.
5.3.4.6
Ordering
Dexamethasone will be ordered from retail pharmacy using commercial drug supply.
5.3.4.7
Accountability
As drug is from commercial supply, sites should keep records per their institutional policies. 
5.3.4.8
Treatment Schedule and Administration
Dexamethasone will be self-administered orally at a dose of 20 mg on the day of and day after all 
doses of carfilzomib (Days 1, 2, 8, 9, 15, and 16) and isatuximab (Cycles 1 and 2 Days 22 and 
23).  The dexamethasone 20 mg oral or IV dose administered as a preinfusion medication on 
isatuximab infusion days (Days 1, 8, 15, 22) replaces the oral dexamethasone dose for that day.
For high-risk patients in the maintenance phase, dexamethasone, 20 mg orally or IV will be 
administered to subjects as a preinfusion medication prior to isatuximab dosing.  After 24 cycles 
of maintenance (2 years) both dexamethasone and isatuximab should be discontinued. When 
dexamethasone is reduced to 20 mg/week and is given as preinfusion medication, subjects may 
receive low-dose methylprednisolone (≤20 mg) orally (or equivalent in accordance with local 
standards) for the prevention of delayed IARs, as clinically indicated.
Dexamethasone will be given according to institutional practice. 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
42
Each oral dexamethasone dose should be taken with food and at the same time each 
day.  Dexamethasone should not be crushed, chewed, or dissolved, in water.   
During the days when isatuximab is not given, if a dose is missed (more than 12 hours since the 
expected time) or vomited, the dose should not be made up and the participant should continue 
with regular scheduling of the drug.  
On the days of isatuximab infusion, the investigator should be notified if the oral dose is missed 
to determine if it should be made up prior to the isatuximab infusion.
5.4 General Concomitant Medication and Supportive Care Guidelines
Supportive Care and Concomitant Medications 
Prestudy and Concomitant Therapy
The following prestudy therapies given at any time before first dose of study treatment must be 
recorded at screening:  steroids of any dose or duration given for MM. 
Throughout the study, investigators may prescribe any concomitant medications or treatments 
deemed necessary to provide adequate supportive care. The sponsor must be notified in advance 
(or as soon as possible thereafter) of any instances in which prohibited therapies are 
administered. 
Systemic use of the following concomitant medications will be collected in the CRF and 
recorded in the source documents beginning with signing of the ICF to 30 days after the last dose 
of the last study treatment or until the start of next-line anticancer treatment, if earlier: growth 
factors, transfusions, anti-infective medications (antibacterials, antivirals, and antimycotics), 
steroids, anti-arrhythmic medications and other cardiac supportive therapy, anti-epileptic 
medications, centrally acting psychiatric medications, anti-histamines and other medications 
targeting post-infusion systemic reactions, and any anticancer therapy (including radiation).
Recommended Therapy
Bone-Directed Therapy
For subjects who have not previously received bisphosphonates or denosumab, bone-directed 
therapy is recommended for all subjects with evidence of lytic destruction of bone or with 
osteopenia. 
Commercially available IV bisphosphonates (pamidronate and zoledronic acid) or denosumab 
are preferred when available, and should be used according to the manufacturer’s 
recommendations, as described in the prescribing information, for subjects with osteolytic or 
osteopenic myelomatous bone disease. Oral bisphosphonates may be used as alternatives if IV 
bisphosphonates are not available at the study site. Subjects who are currently using bone-

DF/HCC #: 19-568
Version Date: March 2nd 2023 
43
directed therapy when they enter the study should continue the same treatment. Subjects who 
are not using bone-directed therapy at the time of study entry should start bone-directed therapy 
as soon as possible. 
Prophylaxis for Bacterial Infection
Prophylaxis for bacterial infections should be considered per institutional guidelines, especially 
for subjects with a history of recurrent bacterial infections or severe hypogammaglobulinemia.
Prophylaxis for Deep Vein Thrombosis (DVT)
Full-dose aspirin recommended. Therapeutic anticoagulation recommended for those at high-risk 
of thrombosis. 
Prophylaxis for Herpes Zoster Reactivation
Prophylaxis for herpes zoster reactivation should be given unless contraindicated. 
Acceptable antiviral therapy includes acyclovir (eg, 400 mg given orally 2 times a day), 
famciclovir (eg, 125 mg given orally twice a day or per institutional standards), or valacyclovir 
(eg, 500 mg given orally, twice a day or per institutional standards), initiated within 1 week 
after the start of study treatment and continued at least throughout.
Therapy for Pneumocystis Carinii
Pneumocystis carinii pneumonia (PCP) prophylaxis should be considered, as per institutional 
guidelines.
Prevention of Steroid-Induced Gastritis
Dexamethasone and other steroids may induce gastritis. Medications to prevent gastritis are 
permitted per institutional guidelines, for example proton pump inhibitors (omeprazole or 
equivalent) or sucralfate, or histamine (H)2 blockers (ranitidine or equivalent).
Permitted Therapies
In addition, subjects are to receive full supportive care. The following medications and 
supportive therapies are examples of support therapies that may be used at any time during the 
study:
•
Antiviral medications should be considered per institutional guidelines.
•
Colony stimulating factors, erythropoietin, and transfusion of platelets and RBCs. If 
erythropoietin is given, then this should be given according to the US prescribing 
information for lenalidomide and epoetin alfa, as there is an increased risk of thrombosis 
with lenalidomide.
•
It is important to prevent constipation (eg, adequate hydration, high-fiber diet, and 
stool softeners if needed).
•
Adequate hydration is recommended for prevention of myeloma-related kidney disease.
•
Intravenous immunoglobulin (IVIG) may be considered for subjects with recurrent 
infection related to hypogammaglobulinemia.

DF/HCC #: 19-568
Version Date: March 2nd 2023 
44
•
Prophylactic antiemetics, with the exception of corticosteroids
•
Loperamide is recommended for the treatment of diarrhea, starting at the time of the 
first watery stool. The loperamide dose and regimen is according to institutional 
guidelines. Prophylactic loperamide is not recommended.
Prohibited Therapies
Concomitant administration of any other antineoplastic therapy for the intention of treating MM 
is prohibited, including medications that target CD38, as well as medications used for other 
indications that have anti-myeloma properties (for example, interferon).
 
During Cycle 1, the prophylactic use of hematopoietic growth factors is prohibited.
Concomitant administration of investigational agents is prohibited. Administration of 
commercially available agents with activity against or under investigation for MM, including 
systemic corticosteroids (>10 mg prednisone per day or equivalent) (other than those given for 
IARs as described for Management of Infusion-Associated Reactions) should be avoided. 
Nonsteroidal anti-inflammatory agents (NSAIDs) should be avoided to prevent myeloma-related 
kidney disease.
5.5 Criteria for Taking a Participant Off Protocol Therapy
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue for 
until one of the following criteria applies:
•
Disease progression
•
Intercurrent illness that prevents further administration of treatment
•
Unacceptable adverse event(s)
•
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements
•
Participant decides to withdraw from the protocol therapy
•
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the CRF. Alternative care options will be discussed with the participant.

DF/HCC #: 19-568
Version Date: March 2nd 2023 
45
When a participant is removed from protocol therapy and/or is off of the study, the relevant Off-
Treatment/Off-Study information will be updated in OnCore.
5.6 Duration of Follow Up
Participants will be followed every three months after removal from protocol therapy for 2 years 
or until confirmation of progressive disease, initiation of subsequent myeloma therapy, death, 
withdrawal of consent, or loss of follow up, whichever occurs first. Participants removed from 
protocol therapy for unacceptable adverse event(s) will be followed until resolution or 
stabilization of the adverse event and then every three months until PD or initiating subsequent 
therapy. 
The first follow up visit should occur three months after the end of treatment visit. 
Following disease progression or initiation of subsequent myeloma therapy, participants may be 
followed-up for survival by telephone contact every three months or chart review for a period of 
five years from study enrollment. 
5.7 Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:
•
Lost to follow-up
•
Withdrawal of consent for data submission
•
Death
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the CRF. In addition, the study team will ensure Off Treatment/Off Study 
information is updated in OnCore in accordance with DF/HCC policy REGIST-101.
6. DOSING DELAYS/DOSE MODIFICATIONS
Dose delays and modifications will be made as indicated in the following table(s). The 
descriptions and grading scales found in the revised NCI CTCAE version 5.0 will be utilized for 
dose delays and dose modifications. A copy of the CTCAE version 5.0 can be downloaded from 
the CTEP website
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
46
6.1 Dose and Treatment Modifications 
Isatuximab Modifications and Dose Delays
Dose Modification of Isatuximab
No isatuximab dose modification (increase or decrease) will be permitted.
Isatuximab Infusion-Associated Reactions
General guidelines for the management of the Infusion-Associated Reactions
Table 7 - Management of Infusion Reactions
Symptom Severity (CTACAE ver 
5.0)
Recommended Intervention
Mild (Grade 1)                                       
Infusion interruption or intervention 
not indicated
Continuation of isatuximab infusion per the 
judgement of the investigator following close 
direct monitoring of the patient's clinical 
status.  Isatuximab infusion may be stopped at 
any time if deemed necessary. If stopped, IR 
will be classified as Grade 2 as per NCI-
CTCAE
Moderate (Grade 2)                              
Therapy or infusion interruption 
indicated but responds promptly to 
symptomatic treatment (eg, 
antihistamines, NSAIDs, narcotics, 
IV fluids); prophylactic medications 
indicated for ≤24 hours
Stop isatuximab infusion. Give additional 
medication with IV diphenhydramine 25 mg 
IV (or equivalent) and/ or IV 
methylprednisolone 100 mg (or equivalent) as 
needed. Isatuximab may be resumed only after 
patient recovery, with
slower infusion rate and with close 
monitoring. 
Severe or life-threatening (Grade 3 or 
4) Grade 3: prolonged (eg, not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of symptoms 
following initial improvement; 
hospitalization indicated for clinical 
sequelae                                 Grade 4: 
life-threatening consequences; urgent 
intervention indicated
Stop isatuximab infusion. Give additional 
medication with diphenhydramine 25 mg IV 
(or equivalent) and/ or IV methylprednisolone 
100 mg (or equivalent) and/or epinephrine as 
needed. Definitive treatment discontinuation.

DF/HCC #: 19-568
Version Date: March 2nd 2023 
47
Patients who experience Grade 2 IAR may subsequently resume isatuximab infusion under close 
monitoring and supportive care as needed. Patients may receive additional premedication per the 
judgment of the Investigator. These patients must be informed of the potential risk of recurrent 
allergic reactions. The infusion must be completed within the time specified in the pharmacy 
manual.
Dose Delay and Toxicity Management
ONLY if any of the following criteria are met and the event cannot be ascribed to lenalidomide, 
carfilzomib, dexamethasone, or underlying MM, the isatuximab infusion must be held to allow 
for recovery from toxicity. The criteria for a dose delay are:
-Grade 4 hematologic toxicity (except for Grade 4 lymphopenia), or Grade 3 or higher 
thrombocytopenia with bleeding.
-Febrile neutropenia of any grade.
-Neutropenia with infection, of any grade.
-Grade 3 or higher nonhematologic toxicities with the following exceptions:
-Grade 3 nausea or Grade 3 vomiting that responds to antiemetic treatment.
-Grade 3 diarrhea that responds to antidiarrheal treatment.
-Grade 3 fatigue or asthenia that was present at baseline and lasts for <7 days after 
the last administration of isatuximab.
-Grade 3 or 4 electrolyte disturbances which can be managed with replacement 
therapy.
If isatuximab administration does not commence within the prespecified window (Table 8) of the 
scheduled administration date, then the dose will be considered a missed dose. Administration 
may resume at the next planned dosing date. 
The maximum delay for toxicity before treatment is permanently discontinued will be 3 weeks; 
however, delays due to other circumstances should be discussed with the Principal Investigator. 
Delays of >3 weeks must be discussed with the Principal Investigator. Re-treatment will be at the 
discretion of the Principal Investigator. 
Table 8:
Isatuximab-Related Toxicity Management
Cycles
Frequency
Missed Dose
Dosing Resumption
1-2
Weekly (every 1 week)
>3 days
Next planned weekly dosing date
3-6
Every cycle (every 2 
weeks)
>14 days
Next planned every 2 weeks 
dosing date
7 and 
beyond
Every cycle (every 4 
weeks)
>28 days
Next planned every 4 weeks 
dosing date
A missed dose will not be made up. Any AE deemed to be related to isatuximab that requires a 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
48
dose hold of more than 28 days in the induction or consolidation phase will result in permanent 
discontinuation of isatuximab. 
Interruption or Missed Doses
An isatuximab dose held for more than 8 days during induction or 14 days during maintenance 
from the per-protocol administration date for any reason other than toxicities suspected to be 
related to isatuximab should be brought to the attention of the sponsor at the earliest possible time. 
Subjects who miss ≥3 consecutive planned doses of isatuximab for reasons other than toxicity will 
be withdrawn from treatment, unless, upon consultation with the sponsor and the review of safety 
and efficacy, continuation is agreed upon.
Carfilzomib and Lenalidomide Dose Modification Guidelines
Dose adjustments of lenalidomide will follow the approved labeling as follows:
•
Starting dose:  25 mg
•
Dose level -1:  15 mg
•
Dose level -2:  10 mg
•
Dose level -3:  5 mg 
Dose adjustments should be based on the highest grade of toxicity that is ascribed to 
lenalidomide.
Dose adjustments of carfilzomib as follows:
•
Starting dose: 56 mg/m2 (Cycle 1 Day 1: 20 mg/m2)
•
Dose level -1:  45 mg/m2
•
Dose level -2:  36 mg/m2
•
Dose level -3:  27 mg/m2
The maximum delay for toxicity before treatment is permanently discontinued will be 3 weeks; 
however, delays due to other circumstances should be discussed with the Principal Investigator. 
Delays of >3 weeks must be discussed with the Principal Investigator. Re-treatment will be at the 
discretion of the Principal Investigator. 
If either the lenalidomide or carfilzomib dose level is reduced during a given cycle, the reduced 
dose level will be continued for the next cycle. If the reduced dose level is tolerated for a 
complete cycle, the subject may, at the investigator’s discretion, resume the dose level prior to 
the reduction at the start of the subsequent cycle.
Table 9 – Lenalidomide and Carfilzomib Dose Modifications
Recommended Actions
  Thrombocytopenia
Lenalidomide
Carfilzomib

DF/HCC #: 19-568
Version Date: March 2nd 2023 
49
Return to ≥ 30 x 109/L
Resume lenalidomide at full dose
Resume carfilzomib at full dose.
Subsequently drop to < 30 x 
109/L
Hold lenalidomide and follow 
CBC weekly
Hold carfilzomib and follow CBC 
weekly
Return to ≥ 30 x 109/L
Resume lenalidomide at 1 dose 
decrement
Resume carfilzomib at one dose 
decrement if cyclical 
thrombocytopenia is still below 
levels considered safe by the 
Treating Investigator at one dose 
decrement (i.e., dose decrease only 
if Treating Investigator judgment is 
that Carfilzomib contributed to 
thrombocytopenia)
Platelet transfusions should also be considered for the management of 
thrombocytopenia as clinically indicated
Recommended Action
Neutropenia : When ANC
Lenalidomide
Carfilzomib
Falls to < 0.5 x 109/L or to <
1.0 x 109/L with fever
Hold lenalidomide,
add filgrastim if Grade 3 with fever 
or Grade 4, follow CBC weekly
Hold carfilzomib, add filgrastim if 
Grade 3 with fever or Grade 4, 
follow CBC weekly
Returns to 1.0 x 109/L (if 
neutropenia was the only 
toxicity noted)
Resume lenalidomide at full dose
Resume carfilzomib at full dose
Return to 1.0 x 109/L 
(if other toxicity 
noted)
Resume lenalidomide at 1 dose 
decrement
Resume carfilzomib at full dose 
unless marked cyclical 
thrombocytopenia is present, then 
reduce by 1 dose decrement
Subsequently drops to < 0.5 x 
109/L or to < 1.0 x 109/L 
with fever
Hold lenalidomide treatments
Hold carfilzomib treatments
Returns to 1.0 x 109/L
Resume lenalidomide at 1 dose 
decrement
Resume carfilzomib previous dose 
at 1 dose decrement (dose decrease 
required only if treating investigator 
judgment is that Carfilzomib 
contributed to neutropenia)
Absolute neutrophil count (ANC); Complete blood count (CBC)

DF/HCC #: 19-568
Version Date: March 2nd 2023 
50
Recommended Action
Toxicity
Lenalidomide
Carfilzomib
Non-Blistering 
Rash
Grade 3
Hold lenalidomide dose; follow 
weekly
If the toxicity resolves to ≤ Grade 
1 prior to Day 21 of the current 
cycle, restart at 1 dose decrement 
and continue the cycle until Day 
21 of the current cycle.
Hold (if Treating Investigator’s 
opinion is possibly related to 
Carfilzomib) until ≤ Grade 1, 
reinstitute at current dose
Grade 4
Discontinue lenalidomide study 
drug.
Hold until ≤ Grade 1, reinstitute at 
current dose.
Desquamating (blistering)
rash
– any grade
Discontinue lenalidomide study 
drug.
Hold until ≤ Grade 1, reinstitute at 
current dose.
Erythema multiforme ≥
Grade 3
Discontinue lenalidomide study 
drug.
Hold until ≤ Grade 1, reinstitute at 
current dose.
Sinus bradycardia/ other 
cardiac arrhythmia
 Grade 2
Hold lenalidomide dose. Follow 
at least weekly.
If the toxicity resolves to ≤ Grade 
1 prior to Day 21, restart at 1 dose 
decrement and continue the cycle 
until Day 21.
Hold until ≤ Grade 1, reinstitute at 
current dose.
≥ Grade 3
Discontinue lenalidomide study 
drug
Hold until ≤ Grade 1, reinstitute at 
current dose.
Allergic 
reaction/hypersensitivity
Grade 2 – 3
Hold lenalidomide dose. Follow 
at least weekly.
If the toxicity resolves to ≤ Grade 
1 prior to Day 21, restart at 1 dose 
decrement and continue the cycle 
until Day 21.
Hold until ≤ Grade 1, reinstitute at 
current dose.
Grade 4
Discontinue
Discontinue

DF/HCC #: 19-568
Version Date: March 2nd 2023 
51
Recommended Action
Toxicity
Lenalidomide
Carfilzomib
Tumor lysis syndrome
(≥ 3 of the following: ≥ 50% 
increase in creatinine,
uric acid, or phosphate;≥ 
30% increase in
potassium;≥ 20% 
decrease in calcium; or ≥ 
2-fold increase in LDH
Hold lenalidomide until all 
abnormalities in serum 
chemistries have resolved.
Reinstitute at full doses.
Hold carfilzomib until all 
abnormalities in serum chemistries 
have resolved.
Reinstitute at full doses.
Infection Grade 3 or 4
Hold lenalidomide until systemic 
treatment for infection is 
completed. If no neutropenia, 
restart both drugs at full dose. If 
neutropenic, follow neutropenic 
instructions.
Hold carfilzomib until systemic 
treatment for infection is completed 
If no neutropenia, restart both drugs 
at full dose. If neutropenic, follow 
neutropenic instructions.
Herpes zoster or simplex of 
any grade
Hold lenalidomide until lesions 
are dry.
Reinstitute at full doses.
Hold carfilzomib until lesions are 
dry.
Reinstitute at full doses.
Grade 2 neuropathy with 
pain or any Grade 3 
neuropathy
Hold until ≤ Grade 2.
Then restart lenalidomide at 1 
dose decrement
Hold until resolved to ≤ Grade 2. 
Then restart carfilzomib at 1 dose 
decrement
Grade 4 neuropathy
Discontinue
Discontinue
Recommended Action
Toxicity
Lenalidomide
Carfilzomib
Renal dysfunction
Serum creatinine > 2 mg/dL
Base dose reduction on calculated 
GFR (below)
Base dose reduction on calculated 
GFR (below)
CrCl>50 mL/min
Full dose
Full dose
CrCl <50 mL/min
> 30 mL/min
Reduce lenalidomide to 10 mg 
every 24 h; may reinstate prior 
dose if, after 2 cycles, CrCl 
normalizes
Full dose

DF/HCC #: 19-568
Version Date: March 2nd 2023 
52
CrCl< 30 mL/min
Reduce lenalidomide to 15 mg 
every 48 h
Hold carfilzomib until CrCl> 30 
mL/min; restart at 1 dose decrement
CrCl< 30 mL/min requiring
dialysis
5 mg. Once daily. On dialysis 
days the dose should be 
administered following dialysis.
Hold until resolved to ≤ Grade 2. 
Then restart carfilzomib at 1 dose 
decrement
Venous 
thrombosis/embolism
≥ Grade 3
Hold lenalidomide dose and 
adjust anticoagulation regimen; 
re-start at Treating Investigator’s 
discretion at full dose
No adjustment required
Hyperthyroidism or 
hypothyroidism
Omit lenalidomide for remainder 
of cycle, evaluate, and initiate 
appropriate therapy.
Restart lenalidomide next cycle at 
1 dose decrement
No adjustment required
Congestive heart failure 
(CHF)
Any subject with symptoms of 
CHF, whether or not 
lenalidomide related, must have 
the dose held until resolution or 
return to baseline. If CHF was 
felt to be lenalidomide related, 
reinstate by one dose decrement 
after return to baseline. If no 
resolution of CHF after 2 weeks, 
the subject will be withdrawn 
from the study.
Any subject with symptoms of CHF, 
whether or not carfilzomib related, 
must have the dose held until 
resolution or return to baseline. If 
CHF was felt to be carfilzomib 
related, reinstate by one dose 
decrement after return to baseline. If 
no resolution of CHF after 2 weeks, 
the subject will be withdrawn from 
the study.
Hypertension including 
Hypertensive Crises
NA
≥ Grade 3: Carfilzomib attribution, 
hold drug until resolved to ≤ Grade 2. 
Resume at one level dose reduction
Recommended Action
Toxicity
Lenalidomide
Carfilzomib

DF/HCC #: 19-568
Version Date: March 2nd 2023 
53
Heart problems, including 
rapid, strong, or irregular 
heartbeat
Heart attack, reduced 
blood flow to the heart, 
abnormal amount of fluid 
between the heart and 
lining around the heart, 
and swelling/irritation of 
the lining around the heart
NA
≥ Grade 3: Carfilzomib attribution, 
hold drug until resolved to ≤ Grade 1. 
Resume at one level dose reduction
Pericardial Effusion
NA
≥ Grade 3: Carfilzomib attribution, 
hold drug until resolved to Grade 1. 
Resume at one level dose reduction
Pericarditis
NA
≥ Grade 3: Carfilzomib attribution, 
hold drug until resolved to Grade 1. 
Resume at one level dose reduction
Recommended Action
Toxicity
Lenalidomide
Carfilzomib
Pulmonary Hypertension
NA
= Grade 2: Carfilzomib attribution, 
Reduce drug: one level dose 
reduction
≥ Grade 3: Carfilzomib attribution, 
hold drug until resolved to ≤Grade 2. 
Resume at one level dose reduction
Pulmonary Toxicities: 
Interstitial Lung Disease 
(inc. pneumonitis), Acute 
Respiratory Failure, and 
Adult Respiratory Distress 
Syndrome (ARDS), cough 
and cough with phlegm
NA
≥ Grade 2 for Pneumonitis
≥ Grade 3 for ARDS
≥ Grade 4 for Respiratory Failure
Carfilzomib attribution, hold drug 
until resolved to ≤Grade 1. Resume 
at one level dose reduction
Blood clot in the lungs, 
fluid in the lungs, bleeding 
in the lungs
NA
≥ Grade 3: Carfilzomib attribution, 
hold drug until resolved to ≤ Grade 1. 
Resume at one level dose reduction
Gastrointestinal 
Perforation
NA
≥ Grade 3: Carfilzomib attribution, 
hold drug until resolved to Grade 1. 
Resume at one level dose reduction

DF/HCC #: 19-568
Version Date: March 2nd 2023 
54
Hepatic Toxicities (≥ Grade 
3 elevation of AST or ALT, 
Bilirubin, or other
≥ Grade 3 liver 
abnormalities)
Hold drug until resolved to
≤Grade 1 or baseline. Resume at 
the same dose or reduced dose as 
appropriate. If tolerated, the 
reduced dose may be escalated to 
the previous dose at the discretion 
of the physician. Frequent 
monitoring of liver function 
should then be implemented.
Hold drug until resolved to ≤Grade 1 
or baseline. Resume at the same dose 
or reduced dose as appropriate. If 
tolerated, the reduced dose may be 
escalated to the previous dose at the 
discretion of the physician. Frequent 
monitoring of liver function should 
then be implemented. Please see 
additional information on hepatic 
impairment in Table 9
Other non-hematologic 
toxicity assessed as 
lenalidomide-related
≥ Grade 3
Hold lenalidomide dose. Follow 
at least weekly.
If the toxicity ≤ Grade 1 before 
Day 21 of the current cycle, 
restart at 1 dose decrement and 
continue until Day 21 of the 
current cycle
Full dose
Other non-hematologic 
toxicity assessed as 
carfilzomib-related
Full dose
Hold carfilzomib dose until toxicity 
resolves to ≤ Grade 1 or baseline.
Restart at 1 dose decrement
Other non-hematologic
toxicity assessed as drug-
related ≥ Grade 3
Hold treatment and restart at 1
dose decrement when toxicity has
resolved to ≤ Grade 1 or 
baseline
Hold treatment and restart at 1 dose
decrement when toxicity has resolved
to ≤ Grade 1 or baseline
Table 10.  Additional Carfilzomib Dose modifications and Safety Measures:
Hepatic Impairment
Mild to moderate liver dysfunction 
defined as 2 consecutive values at least 
28 days apart, of:
-Total bilirubin (>33%) > 1x ULN or 
<3x ULN OR
-An elevation of AST and/or ALT with 
normal bilirubin
-25% dose reduction.  Dose may be re-escalated if liver 
function tests return to normal and drug-induced 
hepatoxoticity is excluded.
-Hold carfilzomib until resolution to baseline. Resume 
with a 25% dose reduction if drug-induced 
hepatoxicity is excluded.  Monitor bilirubin and direct 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
55
-Grade 3 elevation in total bilirubin
-Drug-induced 
hepatoxocity   
(attributable to carfilzomib)
bilirubin weekly.
-Upon resolution of total bilirubin to normal, resume 
carfilzomib doing with 25% dose reduction if drug-
induced hepatoxicity is excluded.
-Discontinue carfilzomib
Posterior 
Reversible 
Encephalopathy 
Syndrome (PRES)
If PRES is suspected, hold carfilzomib, Consider MRI for onset of 
visual or neurological symptoms suggestive of PRES.  If PRES 
confirmed, permanently discontinue carfilzomib.  If PRES excluded, 
carfilzomib administration may resume at same dose if clinically 
appropriate.
Thrombotic 
Microangiopathy 
(TMA) 
If the diagnosis is suspected, hold carfilzomib and manage per 
standard of care including plasma exchange as clinically appropriate.  
If TMA confirmed, permanently discontinue carfilzomib.  If TMS 
excluded, carfilzomib can be restarted.
Contraception/Female
Females of child-bearing potential and/or their male partners should 
use effective contraception methods or abstain from sexual activity 
during and for 30 days after treatment with carfilzomib.
Contraception/Male
Males and/or their female partners should use effective contraceptive 
methods or abstain from sexual activity while treated with 
carfilzomib and for 90 days after treatment.
Breastfeeding/Lactation
Breastfeeding women and women planning on breastfeeding may not 
participate in the clinical trial
Hepatitis B reactivation
Carriers of HBV who require treatment with Kyprolis should be 
closely monitored for signs and symptoms of active HBV infection 
throughout treatment. Any subject who becomes HBV DNA positive 
or develops reactivation of HBV should have carfilzomib treatment 
interrupted and receive appropriate anti-viral treatment as per a 
specialist in Hepatitis B. 
Progressive Multifocal 
Leukoencephalopathy
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, patients should be promptly referred to a specialist and 
appropriate diagnostic testing should be initiated. Discontinue 
Kyprolis if PML diagnosis is confirmed. 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
56
Tumor Lysis Syndrome 
Tumor lysis syndrome (TLS), which may be associated with multi-organ failure, has been 
observed in Cycles 1 and 2 of some subjects with multiple myeloma treated with carfilzomib. In 
addition, MM subjects with high tumor burden (e.g., Durie-Salmon or International Staging 
System (ISS) Stage II/III) or rapidly increasing M-protein or light chains or compromised renal 
function glomerular filtration rate (GFR) < 50 mL/min) should be considered to be at particularly 
high risk. All such subjects should be identified at screening.
During Cycles 1 and 2, serum electrolytes and chemistries are closely monitored. Subjects with 
laboratory abnormalities consistent with lysis of tumor cells (e.g., serum creatinine ≥ 50% 
increase, lactate dehydrogenase (LDH) ≥ 2-fold increase, uric acid ≥ 50% increase, phosphate ≥ 
50% increase, potassium ≥ 30% increase, calcium ≥ 20% decrease) prior to dosing should not 
receive the scheduled dose. Subjects with such abnormalities should be re-evaluated as clinically 
indicated. The Lead Principal Investigator should be consulted if there are further delays. 
Subjects should be informed of signs and symptoms that may be indicative of TLS such as 
fevers, chills/rigors, nausea, vomiting, muscle tetany, weakness, or cramping, seizures, and 
decreased urine output; subjects should be instructed to report such symptoms immediately and 
seek medical attention.
Grade 3 or 4 Adverse Events
For other Grade 3 or 4 toxicities judged by the investigator to be related to lenalidomide alone, 
treatment with lenalidomide should be interrupted and restarted at the next lower dose level 
once the toxicity has resolved to Grade 2 or less. If a Grade 3 toxicity can be controlled (eg, a 
Grade 3 electrolyte disturbance that can be controlled with repletion within 24 hours), the 
investigator should discuss the toxicity with the sponsor’s medical monitor before interrupting 
or lowering the lenalidomide dose. Treatment with isatuximab, carfilzomib, and dexamethasone 
may continue, as applicable depending on the study phase.
Dexamethasone Toxicity
For management of dexamethasone toxicity, see Table 11.
Table 11. If dexamethasone is permanently discontinued due to toxicity, pre- and post-infusion 
doses administered on the day of isatuximab dosing may be given at the investigator’s 
discretion. 
Table 11 represents suggested dose modifications of dexamethasone, but physician discretion 
and clinical judgment should prevail.
The maximum delay for toxicity before treatment is permanently discontinued will be 3 weeks; 
however, delays due to other circumstances should be discussed with the Principal Investigator. 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
57
Delays of >3 weeks must be discussed with the Principal Investigator. Re-treatment will be at the 
discretion of the Principal Investigator. 
Table 11: Dexamethasone Dose Modification Based on Toxicity (NCI-CTCAE v.5.0)
SOC
Toxicity
Dose
Grade 1-2 dyspepsia, 
gastric, or duodenal 
ulcer, gastritis 
requiring medical 
management 
Treat with H2 blockers, sucralfate, or 
omeprazole. If symptoms persist despite 
above measure, decrease dexamethasone 
dose by 50%.
Grade 3 requiring 
hospitalization or 
surgery
Omit dexamethasone until symptoms 
adequately controlled Restart at 50% of 
current dose along with concurrent therapy 
with H2 blockers, sucralfate, or 
omeprazole. If symptoms persist despite 
above measure, discontinue 
dexamethasone and do not resume.
Gastrointestinal
Acute pancreatitis
Discontinue therapeutic dose of 
dexamethasone and do not resume
Cardiovascular
≥Grade 3 edema 
limiting function and 
unresponsive to 
therapy or anasarca
Diuretics as needed and decrease 
dexamethasone dose by 25%. If edema 
persists despite above measures, decrease 
dose to 50% of initial dose. Discontinue 
dexamethasone and do not resume if 
symptoms persist despite 50% reduction.
Neurology/Psychiatric
≥Grade 2 interfering 
with function but not 
interfering with 
activities of daily 
living
Omit dexamethasone until symptoms 
adequately controlled. Restart at 50% of 
current dose. If symptoms persist How 
long is too long? despite above measure, 
discontinue dexamethasone and do not 
resume.
Musculoskeletal
≥Grade 2 muscle 
weakness 
symptomatic and 
interfering with 
function but not 
interfering with 
activities of daily 
living
Decrease dexamethasone dose by 25%. If 
weakness persists despite above measures, 
decrease dose to 50% of initial dose. 
Discontinue dexamethasone and do not 
resume if symptoms persist despite 50% 
reduction.
Metabolic
≥Grade 3 
≥Grade 3 hyperglycemia. Treat with insulin 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
58
hyperglycemia
or oral hypoglycemic agents as needed. If 
uncontrolled despite above measures, 
decrease dose by 25% decrements until 
levels are satisfactory.
Abbreviations: NCI-CTCAE = National Cancer Institute Common Terminology Criteria for 
Adverse Events; SOC=system 
Treatment Discontinuation
Administration of isatuximab, carfilzomib, lenalidomide and dexamethasone can be discontinued
permanently in the event of a treatment-related toxicity at the Treating Investigator's discretion.
If a delay of starting a new cycle is greater than 21 days, the subject should be discontinued from
treatment, unless continuing treatment is mutually agreed upon by the Treating Investigator and
the Lead Principal Investigator.
If isatuximab, carfilzomib, or lenalidomide requires permanent discontinuation before Cycle 4
induction, the subject’s treatment will be discontinued at the end of Cycle 4 induction. If 
isatuximab, carfilzomib or lenalidomide requires permanent discontinuation during maintenance 
cycles, the subject may remain on study with the remaining drug(s). Dexamethasone may be 
discontinued without the subject discontinuing study treatment.
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  
Pretreatment symptoms/conditions to be graded at baseline and AEs to be graded at each 
evaluation per NCI-CTCAE v 5.0 grading. 
Adverse Event List for Investigational Agent, Isatuximab:
Possible risks
Beside hematological malignancies, the CD38 antigen is expressed on normal immune cells and 
despite the lack of significant depletion in the in vitro studies, isatuximab could modulate cell 
survival and differentiation of both lymphoid and myeloid cells in cancer patients. This 
modulation could increase the risk for infections. In addition, while no association between 
transient cytokine increases and the occurrence of IRs has been demonstrated in patients, 
administration of isatuximab in the clinical setting has been correlated with a single occurrence 
of nonserious Grade 2 cytokine release syndrome at Cycle 1, reported as a medical diagnosis in a 
patient who subsequently received further administrations of single agent isatuximab without 
recurrence of symptoms suggestive of cytokine release syndrome.

DF/HCC #: 19-568
Version Date: March 2nd 2023 
59
The CD38 antigen is also expressed in several normal nonlymphoid human tissues:
• Strong specific staining was observed in the glandular epithelial cells of prostate tissues.
• Moderate to strong specific staining was observed in the endothelial cells lining the pituitary 
gland.
• Moderate focal staining of round cells compatible with Kupffer cells was observed in the liver.
• Staining of astrocytes in the brain and bronchial epithelium cells in the lungs was observed
in a non-GLP study, though this finding was not observed in the definitive GLP tissue cross-
reactivity study.
Evaluation of prostate specific antigen and pituitary hormone values were systematically 
assessed
before each isatuximab treatment cycle in the first-in-human Phase 1 single agent trial 
TED10893.
Among the 89 patients treated in Study TED10893 Phase 1, the reported laboratory 
abnormalities
and AE do not suggest an effect of the study treatment on these organ functions. Therefore, those
systematic laboratory assessments during study treatment have no longer been considered 
necessary in the subsequent clinical studies.
Close monitoring of safety is required during the clinical studies and clinical exams are 
systematically recorded in the case report forms. Beside any tests to be performed when 
clinically indicated, parameters analyzed routinely until the end of treatment visit in the study 
protocols include: physical examination, vital signs, all AEs/Serious AEs (SAE), 
echocardiogram (ECG), and laboratory findings. These analyses required in all the patients 
during the clinical studies provide an adequate method to detect specific organ function 
abnormalities.
Possible adverse drug reactions
Within the context of IARs, anaphylactic reaction, cytokine release syndrome, and pyrexia are 
among the adverse reactions observed in patients treated with isatuximab; these reactions may 
involve immunogenicity mechanisms (human antihuman antigen) and hypersensitivity reactions, 
and are well-known to occur in association with other therapeutic mAb proteins. These adverse 
reactions, whether acute or delayed, may be serious and systemic.
Drug interactions
No drug-drug interaction has been observed between isatuximab other drugs used in combination
(lenalidomide, pomalidomide).
Contraindications
Contraindications include:

DF/HCC #: 19-568
Version Date: March 2nd 2023 
60
• Known intolerance or hypersensitivity to infused proteins products, sucrose, histidine, and
polysorbate 80.
• Pregnant or lactating women.
Adverse Event List(s) for Commercial Agent(s):  carfilzomib, lenalidomide, dexamethasone
For each commercial agent, please refer to the package insert(s) for the comprehensive list of 
adverse events.
Adverse Events
7.1 Definitions
Adverse Event (AE)
An AE is any undesirable sign, symptom or medical condition or experience that develops or 
worsens in severity after starting the first dose of study treatment or any procedure specified in the 
protocol, even if the event is not considered to be related to the study. 
An adverse event is any change in health occurring in a person who is a participant in biomedical 
research, whether this change is related or not to the research or to the product that the research is 
being conducted on.  This includes any newly occurring event or previous condition that has 
increased in severity or frequency since the administration of drug.
For this protocol, an abnormal laboratory value will not be assessed as an AE unless that value 
leads to discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline.  
Serious adverse event (SAE) and events requiring expedited reporting
A serious adverse event is an undesirable sign, symptom, or medical condition, regardless of 
causality that:
•
Results in death;
•
Is life-threatening.  Life-threatening means that the participant was at immediate risk of 
death from the reaction as it occurred, i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form;
•
Requires hospitalization or prolongation of existing hospitalization (i.e., the event required 
at least a 24-hour hospitalization or prolonged a hospitalization beyond the expected length 
of stay). Hospitalization admissions and/or surgical operations scheduled to occur during 
the study period, but planned prior to study entry are not considered SAEs if the illness or 
disease existed before the participant was enrolled in the trial, provided that it did not 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
61
deteriorate in an unexpected manner during the trial (e.g., surgery performed earlier than 
planned); 
•
Results in persistent or significant disability/incapacity.  Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions;
•
Is a congenital abnormality or birth defect;
•
Is an important medical event.  An important medical event is an event that, when based 
upon appropriate medical judgment may jeopardize the participant and require medical or 
surgical intervention to prevent one of the outcomes listed above.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, the development of drug dependency or drug abuse, or suspected 
transmission of infectious agents by medicinal product.
The following event must also be reported in an expedited manner:
•
Results in pregnancy.
•
Any adverse event arising after study treatment discontinuation/study termination that is 
possibly related to study treatments/procedures must be reported regardless of the delay 
between event onset and study treatment discontinuation/study termination. 
•
Secondary malignancies must be reported as serious adverse events regardless of when 
they occur and regardless of their relationship to the study treatments/procedures.
Events not considered to be serious adverse events are hospitalizations for:
•
Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures of a condition unrelated to the studied 
indication or its treatment.
•
Elective or pre-planned treatment for a pre-existing condition that did not worsen.
•
Emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission.
•
Respite care.
Please note the distinction between seriousness and severity of an AE.  Severity is a measure 
of intensity of an event (mild, moderate, severe).  However, the event itself may be of relatively 
minor medical significance; thus, a severe reaction may not necessarily be classified as a serious 
reaction.  This differs from seriousness, which is based on patient/event outcome or action criteria 
described above and are usually associated with events that pose a threat to a patient’s life or 
functioning.  A severe adverse event does not necessarily need to be considered serious. 
Seriousness (not severity) serves as a guide for defining regulatory reporting obligations.
Adverse Events of Special Interest 
Adverse events of special interest (AESIs): An AE of special interest (serious or non-serious) is 
one of scientific and medical concern specific to the sponsor’s product or program, for which 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
62
ongoing monitoring and rapid communication by the investigator to the sponsor can be 
appropriate. Such an event might warrant further investigation in order to characterize and 
understand it. Depending on the nature of the event, rapid communication by the trial sponsor to 
other parties (eg, regulators) might also be warranted. The AEs for this study are: 
•
Infusion reactions: ≥Grade 3
•
Infections: ≥Grade 4
•
Cytopenias: ≥Grade 4
•
Tumor Lysis Syndrome (if present, qualifies as Grade 3 or higher per CTCAE 
V5.0 guidelines)
•
Intervascular Hemolysis – all grades
•
New primary malignancies (if present, qualifies as Grade 3 or higher per CTCAE 
V 5.0 guidelines), regardless of causal relationship to study drug(s), occurring at 
any time for the duration of the study, from the time of signing informed consent 
for at least 3 years, after the last dose of investigational product.  
Adverse Events of Special Interest are only reported by sites in an expedited manner if the 
event meets the criteria for an SAE (as per Section).  All other AESIs will be collected in the 
SDC, but do not require immediate submission.
Pregnancy
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female participant occurring while the participant is on study drug or within 28 
days of the participant’s last dose of study drug are to be reported immediately to Massachusetts 
General Hospital. If the participant is on study drug, the study drug is to be discontinued 
immediately and the participant is to be instructed to return any unused portion of the study drug 
to the Investigator.  The pregnancy, suspected pregnancy, or positive pregnancy test must be 
reported immediately of the investigator’s knowledge of the pregnancy by phone and e-
mail/facsimile to the lead site using the Pregnancy Reporting Form. Immediately upon receipt of 
this report, the lead site will inform study pharmaceutical partners using the Pregnancy Reporting 
Form.  
The female should be referred to an obstetrician/gynecologist experienced in reproductive toxicity 
for further evaluation and counseling.
The investigator will follow the female participant until completion of the pregnancy and must 
notify the lead site of the outcome of the pregnancy (including notification of false-positive tests) 
within 24 hours of having knowledge of the event by email/facsimile using the Follow-Up 
Pregnancy Reporting Form. 
If the outcome of the pregnancy meets the criteria for immediate classification as a SAE (i.e., 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
63
spontaneous abortion [any congenital anomaly detected in an aborted fetus is to be documented], 
stillbirth, neonatal death, or congenital anomaly [including that in an aborted fetus]), the 
investigator should follow the procedures for reporting SAEs (i.e., report the event to the lead site, 
within 24 hours of the investigator’s knowledge of the event by e-mail or facsimile).  
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 28 days that the investigator suspects is 
related to the in utero exposure to the study drug should also be reported to the lead site, within 24 
hours of the investigator’s knowledge of the event by e-mail or facsimile.  
In the case of a live “normal” birth, the lead site should be advised as soon as the information is 
available.  
If the female is found not to be pregnant, any determination regarding the participant’s continued 
participation in the study will be determined by the investigator.
Female partners of a male taking investigational product should be advised to call their healthcare 
provider immediately if they get pregnant. The male participant should notify the investigator of 
his partner’s pregnancy and her healthcare provider information. The investigator will then provide 
this information to the lead site for follow-up as necessary. 
The pharmaceutical partner may in accordance with local data privacy laws request the subject’s 
physicians’ contact information in order to follow-up the pregnancy until birth outcome. The 
lead site shall provide the pharmaceutical company with all reasonably requested information 
(within the timeframe requested by company) to enable company to evaluate and submit 
complete single case and aggregate safety reports to regulatory agencies according to regulatory 
reporting requirements, and otherwise comply with applicable law.
Expectedness
Adverse events can be “Expected” or “'Unexpected.”
Expected adverse event
Expected adverse events are those that have been previously identified as resulting from 
administration of the agent.  For the purposes of this study, an adverse event is considered expected 
when it appears in the current Investigator’s Brochure or is included in the informed consent 
document as a potential risk. Scheduled hospitalizations for the study treatment, participant follow-
up and medical conditions related to the progression of the disease are considered to be expected 
SAEs.
The investigator must evaluate all abnormal lab results to determine the clinical significance.  If 
an abnormal result appears to be clinically significant, it must be considered to be an AE. 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
64
Unexpected adverse event
For the purposes of this study, an adverse event is considered unexpected when it varies in nature, 
intensity or frequency from information provided in the current Investigator’s Brochure, section 6 
of the protocol, or when it is not included in the informed consent document as a potential risk.  
Attribution (Causality)
Attribution is the relationship between an adverse event or serious adverse event and the study 
treatment. It will be assigned by using the WHO causality method assessment linked to CTCAE 
grading system (as follows):
Term
Description
Certain/Definite
A clinical event, including laboratory test abnormality, occurring in a 
plausible time relationship to drug administration, and which cannot be 
explained by concurrent disease or other drugs or chemicals.  The response 
to withdrawal of the drug (de-challenge) should be clinically plausible.  
The event must be definitive pharmacologically or phenomenologically, 
using a satisfactory re-challenge procedure if necessary.  The AE is clearly 
related to the study treatment.
Likely/Probable
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and which follows a 
clinically reasonable response on withdrawal (de-challenge).  Re-challenge 
information is not required to fulfill this definition.  The AE is likely 
related to the study treatment.
Possible
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, but which could also be 
explained by concurrent disease or other drugs or chemicals.  Information 
on drug withdrawal may be lacking or unclear.  The AE may be related to 
the study treatment.
Unlikely
A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration which makes a causal relationship 
improbable, and in which other drugs, chemicals or underlying disease 
provide plausible explanations.  The AE is doubtfully related to the study 
treatment.
Unrelated
The AE is clearly NOT related to the study treatment.
An event will be considered possibly study-related if causality criteria will be “certain/definite,” 
“likely/probable,” and “possible.”
The causality criteria “unlikely” and “unrelated” is intended to be used when the exclusion of drug 
causality of a clinical event seems most plausible.  It will be used to define “not study-related” 
events. 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
65
An event will also be considered as “concomitant drug-related,” “disease progression-related” or 
“other cause related.”
Causality will be assessed for each investigational treatment used in the trial (bortezomib, 
lenalidomide and dexamethasone).
If a reported SAE is considered an unexpected and suspected serious adverse reaction (SUSAR), 
reporting/notification rules described below must be followed.
7.2 Adverse Event Recording and Reporting
Reporting participating investigators will assess the occurrence of AEs and SAEs at all participant 
evaluation time points during the study. All AEs and SAEs whether reported by the participant, 
discovered during questioning, directly observed, or detected by physical examination, laboratory 
test or other means, will be recorded in the participant’s medical record and on the appropriate 
study-specific case report forms.  All AEs must be recorded in the participant’s medical record, 
stating the duration and intensity of the event, action taken by the investigator and outcome of the 
event.  The investigator must evaluate the causal relationship between the study drug(s) and the 
adverse event.
The investigator must evaluate all abnormal laboratory results to determine the clinical 
significance.  
All AEs detected by the investigator or by the participant must be recorded on the appropriate 
study-specific CRFs, stating the duration and intensity of the event, action taken by the investigator 
and outcome of the event.  The investigator must evaluate the causal relationship for each AE.  
The descriptions and grading scales found in the CTEP Version 5.0 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. The CTEP 
Version 5.0 of the CTCAE is identified and located on the CTEP website at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
Each adverse event will be assessed to determine if it meets the criteria for SAE reporting. If an 
SAE occurs, expedited reporting will follow local policies and regulations as appropriate.
Hematologic adverse events will be recorded/reported only if >grade 2 or if an action on study 
drug was required.  These events should be captured on the adverse event pages of the CRF only.  
7.3 Reporting Requirements
For multi-site trials where a DF/HCC investigator is serving as the sponsor, each participating 
investigator is required to abide by the reporting requirements set by the DF/HCC.  The study must 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
66
be conducted in compliance with FDA regulations, local safety reporting requirements, and 
reporting requirements of the Principal Investigator/Sponsor. 
Each investigative site will be responsible to report SAEs that occur at that institution to their 
respective IRB.  It is the responsibility of each participating investigator to report serious adverse 
events to the Principal Investigator/Sponsor, the participating site’s IRB, and others as described 
below. 
7.4 Reporting to the Study Sponsor
Serious Adverse Event Reporting
The  lead site will be responsible for SAE reporting to the pharmaceutical partners (including 
SUSAR events). The lead site will report all reports/outcomes associated to pregnancy or lactation 
exposure to the pharmaceutical partners. 
If a patient experiences an SAE after signing informed consent, but prior to receiving study drug, 
the event will NOT be collected unless the investigator feels the event may have been caused by 
a protocol procedure. All serious adverse events that are related to study drug and occur \ during 
treatment or within 30 days of the last dose of treatment, with the exception of participants who 
withdraw from treatment, in whom adverse events will be collected until 60 days following the 
last treatment administration.  All DF/HCC Reportable Adverse Events must be reported to the  
study sponsors within 1 working day. This includes the following:
•
Grade 2 (moderate) and Grade 3 (severe) events that are unexpected and at least possibly 
related/associated with the intervention. 
Note: Grade 2 and Grade 3 lab abnormalities that are considered by the investigator to be 
clinically insignificant and do not require therapy, or adjustment in prior therapy, do not 
need to be reported.
•
All Grade 4 (life-threatening or disabling) events that are unexpected or not specifically 
listed in the protocol as not requiring reporting.
•
All Grade 5 (fatal) events while the participant is enrolled and actively participating in 
the trial OR when the event occurs within 30 days of the last study intervention. 
Note, if the participant is in long term follow up, report the death at the time of continuing 
review. 
Due to the additional expedited reporting criteria, the table below is a tool to summarize the 
reporting requirements and timelines for SAEs and DF/HCC reportable adverse events.

DF/HCC #: 19-568
Version Date: March 2nd 2023 
67
SAEs
DF/HCC Reportable AEs
Attribution
All SAEs 
(section 7.1)
Gr. 2 & 3 AE
Expected#
Gr. 2 & 3 AE
Unexpected#
Gr. 4 AE
Expected#
Gr. 4 AE
Unexpected#
Gr. 5 AE
Expected or 
Unexpected
Unrelated
Unlikely
24 hours
Not required
Not required
5 calendar 
days*
5 calendar 
days
24 hours
Possible
Probable
Definite
24 hours
Not required
5 calendar days
5 calendar 
days*
5 calendar 
days
24 hours
# If event meets SAE criteria listed in section 7.1 in addition to grade, attribution and expectedness, event must be 
reported within 24 hours.
* If listed in protocol as expected and not requiring reporting, event does not need to be reported.
Participating investigators must report each serious and/or DF/HCC reportable adverse event in 
accordance with the table above using the MEDWATCH FDA Form 3500A form or local IRB 
report form. In the event that the participating investigator does not become aware of the serious 
adverse event immediately (e.g., participant sought treatment elsewhere) or within the time frames 
listed in the table above, the participating investigator is to report the event within 24 hours after 
learning of it and document the time of his or her first awareness of the adverse event. 
The Overall PI will submit AE reports from outside institutions to the DFCI OHRS according to 
DFCI IRB policies and procedures in reporting adverse events. 
Non-Serious Adverse Event Reporting
Non-serious adverse events will be reported on the adverse event Case Report Form.
7.5 Reporting to the Food and Drug Administration (FDA)
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA.
7.6 Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant 
safety reports, sentinel events or unanticipated problems that require reporting per institutional 
policy. 
7.7 Routine Adverse Event Reporting

DF/HCC #: 19-568
Version Date: March 2nd 2023 
68
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
Institutional Review Board (IRB), FDA, etc.) must also be reported in routine study data 
submissions.
8.
STUDY CALENDAR
Baseline evaluations are to be conducted within 28 days prior to start of protocol therapy.  Scans 
and x-rays must be done <4 weeks prior to the start of therapy.  In the event that the participant’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy.
Assessments must be performed prior to administration of any study agent. Study assessments 
and agents should be administered within + 8 days of the protocol-specified date, unless 
otherwise noted.
Table 12
Treatment Schedule-Representative Cycle for Induction Phase
Study 
treatment
Days
1
2
3
4
5
6
7
8
9
1
0
1
1
1
2
1
3
1
4
1
5
1
6
1
7
1
8
1
9
2
0
2
1
2
2
2
3
2
4
2
5
2
6
2
7
2
8
Lenalidomide
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Carfilzomib
X
X
X
Isatuximaba
X
X
X
X
Dexamethasone
X
X
X
X
X
X
X
X
 
a - IV every week (Q1W) for 8 weeks, then every 2 weeks (Q2W) for 16 weeks, thereafter, every 
4 weeks (Q4W). Note that this table is a representative cycle for the induction phase in 
the first 8 weeks.
Table 13
Treatment Schedule-Representative Cycle for Maintenance Phase
Study treatment
Days
1
2
3
4
5
6
7
8
9
1
0
1
1
1
2
1
3
1
4
1
5
1
6
1
7
1
8
1
9
2
0
2
1
2
2
2
3
2
4
2
5
2
6
2
7
2
8
Lenalidomide
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Carfilzomiba
X
X
Isatuximaba
X
a – Carfilzomib and isatuximab for high-risk patients only; lenalidomide alone for standard-risk. 
Isatuximab will discontinue after completing two years of maintenance. 
In the maintenance phase, dexamethasone 20mg PO or IV will be administered to patients as a 
pre-infusion medication prior to isatuximab dosing.

DF/HCC #: 19-568
Version Date: March 2nd 2023 
69
Table 14: Schedule of Assessments
Table 14A:  KRDI with Autologous Stem Cell Transplant
Induction Phase
Treatment Phase 
Treatment Phase
Auto-
SCT
Consolidation 
Phase 
(Cycles 1-2)
(Cycles 3-4)
 
(Cycles 5-6)
 
Screening 
(Within 28 
days prior to 
registration)1
 
 
 
 
Maintenance 
Phase (Cycles 
7+)
At treatment 
discontinuation 
(30 [d ± 7] 
days after last 
dose)
Follow up18
(Every 12 ± 3 
weeks)
 
Procedures (± 8-day window for obtaining all assessments)
 
Informed consent2
 
 
 
 
 
 
 
Demographics/Medical 
History
X
 
 
 
 
 
 
X
ECOG Performance 
Status
X
X
X
 
X
X
X
X
12 lead ECG
X
 
 
 
 
 
 
Physical Examination 
including height and 
weight3
X
X
X
 
X
X
X
X
Vital Signs 
(temperature, heart 
rate, blood pressure)4
X
X
X
 
X
X
X
X
AE evaluation
 
X
X
 
X
X
X
Blood type/indirect 
antiglobulin test
X
 
 
 
 
 
 
Pulmonary Function 
Test FEV15
X
 
 
 
 
 
 
Bone Marrow Biopsy6
X
After 4 cycles, at the completion of  consolidation, and after 24 cycles (± 3 weeks) if sCR 
or CR maintained (including subjects with VGPR or better and suspected isatuximab 
interference)
X7
Laboratory Assessments
CBC with diff8
X
D1, 8, 15, 22
D1, 15
 
D1, 15
X
X
X
Serum Chemistries9
X
D1, 8, 15, 22
D1, 15
 
D1, 15
X
X
X
Creatinine Clearance10
X
D1, 8, 15, 22
D1, 15
 
D1, 15
X
X
SPEP, IFE, B2M
X
X
X
 
X
X
X
X
Free light chain testing
X
X
X
 
X
X
X
X
UPEP 17
X
X
X17
 
X17
X17
X17
X17
24-hour urine, protein, 
creatinine 17
X
X
X17
 
X17
X17
X17
Pregnancy Test11
X
X
X
 
X
X
X
Interference Testing12
X
X
X
 
X
X
X
MRD (aspirate)13
 
After 4 cycles, at completion of consolidation, and after 24 cycles (± 3 weeks) if sCR or 
CR maintained (including subjects with VGPR or better and suspected isatuximab 
interference)
 
Imaging Assessments

DF/HCC #: 19-568
Version Date: March 2nd 2023 
70
Skeletal Survey14
X
 
 
 
 
 
 
Extramedullary 
Plasmacytoma 15
X
 
 
 
 
 
 
DXA16
X 
 
 
 
X 
 
Quality of Life Assessments
EORTC-QLQ-C30
 
X
X
 
X
X
X
EORTC-QLQ-MY20
 
X
X
 
X
X
X
Table 14B: KRDI with Transplant-Deferred
Induction Phase
Treatment 
Phase 
Treatment 
Phase 
(Cycles 1-2)
(Cycles 3-8)
 
Screening 
(Within 28 
days prior to 
registration)1
 
 
Maintenance 
Phase (Cycles 
9+)
At treatment 
discontinuation 
(30 [d ± 7] 
days after last 
dose)
 Follow up18
(Every 12 ± 3 
weeks)
 
Procedures (± 8-day window for obtaining all 
assessments)
 
Informed consent2
 
 
 
 
 
Demographics/Medical 
History
X
 
 
 
 
X
ECOG Performance 
Status
X
X
X
X
X
X
12 lead ECG
X
 
 
 
 
Physical Examination 
including height and 
weight3
X
X
X
X
X
X
Vital Signs 
(temperature, heart 
rate, blood pressure)4
X
X
X
X
X
X
AE evaluation
 
X
X
X
X
Blood type/indirect 
antiglobulin test
X
 
 
 
 
Pulmonary Function 
Test FEV15
X
 
 
 
 
Bone Marrow Biopsy6
X
After 4 cycles, at the completion of induction, and 
after 24 cycles (± 3 weeks) if sCR or CR maintained 
(including subjects with VGPR or better and 
suspected isatuximab interference)
X7
Laboratory Assessments
CBC with diff8
X
D1, 8, 15, 22
D1, 15
X
X
X
Serum Chemistries9
X
D1, 8, 15, 22
D1, 15
X
X
X
Creatinine Clearance10
X
D1, 8, 15, 22
D1, 15
X
X
SPEP, IFE, B2M
X
X
X
X
X
X

DF/HCC #: 19-568
Version Date: March 2nd 2023 
71
Free light chain testing
X
X
X
X
X
X
UPEP 17
X
X
X17
X17
X17
X17
24-hour urine, protein, 
creatinine17
X
X
X17
X17
X17
Pregnancy Test11
X
X
X
X
X
Interference Testing12
X
X
X
X
X
MRD (aspirate)13
X
After 4 cycles, at the completion of induction, and 
after 24 cycles (± 3 weeks) if sCR or CR maintained 
(including subjects with VGPR or better and 
suspected isatuximab interference)
X7
Imaging Assessments
Skeletal Survey14
X
 
 
 
 
Extramedullary 
Plasmacytoma 15
X
 
 
 
 
DXA16
X
 
 
X 
 
Quality of Life Assessments
EORTC-QLQ-C30
 
X
X
X
X
EORTC-QLQ-MY20
 
X
X
X
X
Abbreviations: AE= adverse events; ANC= absolute neutrophil count; B2M=Beta2-Microglobulin; Cycle= each cycle is 28 Days.; DXA = dual-
energy x-ray absorptiometry; IFE=Immunofixation; MRD = Minimal Residual Disease; SPEP= Serum protein electrophoresis, UPEP=Urine 
protein electrophoresis. 
1 ≤28 days prior to patient enrollment. Some pretreatment clinical laboratory values should be tested ≤14 days of registration.
2 Informed consent must be obtained before any study assessments are performed unless it is standard of care.
3 Physical examination:  A routine physical examination by the investigator (or the designated physician will include height 
(screening only) and weight. Height will be measured only once at screening. Weight will be measured on every visit day. 
Actual weight on C1D1 should be used for initial dose calculation. If a subject’s weight changes by more than 10% from 
C1D1, the dose of all study treatments should be re-calculated.
4 Vital signs (temperature, pulse/heart rate, respiratory rate, and blood pressure) will be measured in sitting position. For all 
infusions except C1D1 (see note below), these should be measured immediately before the start of isatuximab infusion, prior 
to each infusion rate increase, and at the end of isatuximab infusion.
5 Pulmonary function testing (spirometry) is required only for subjects with chronic obstructive pulmonary disease or asthma. 
FEV1 should be measured.
6 Bone marrow biopsy and aspirate for morphology, immunohistochemistry, or immunofluorescence, cytogenetics- Fluorescent 
in situ hybridization (FISH), and karyotype. FISH testing to include del(17p), t(4;14), t(14;16),  t(14;20), and 1q duplication. 
Bone marrow biopsy is recommended at the time of best response for confirmation of complete response.
7 Bone marrow biopsy recommended at time of progression.
8 CBC with differential:  Complete blood count with differential (includes white blood cells, red blood cells, platelets, ANC, 
lymphocyte and hemoglobin).
9 Serum chemistries:  To include sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphorus, blood urea, 
nitrogen, creatinine, glucose, albumin, total protein, alkaline phosphatase, total bilirubin, aspartate aminotransferase, alanine 
aminotransferase, lactate dehydrogenase, and uric acid. 
10 Creatinine clearance:  Estimated glomerular filtration rate will be calculated using Cockcroft-Gault equation.
11 Pregnancy test will be done at screening and once every cycle. Urine or serum HCG may be tested based on institutional 
preference.

DF/HCC #: 19-568
Version Date: March 2nd 2023 
72
12 For all patients with VGPR, a positive serum IFE, and a negative SPEP and/or patients with an M-protein of ≤.02 g/dL on 
SPEP and IgG kappa MM
13  At all visits, during the bone marrow aspirate procedure, the first aspirate sample that is drawn will be sent to the central 
laboratory to determine MRD. All bone marrow aspirates to be sent to the central laboratory should be at least 5 mL. Any 
patient with a residual IgG kappa M-protein obtaining a VGPR be tested. There should also be a note that patient with a non-
IgG kappa myeloma who have a measurable IgG kappa M-protein after treatment be tested as well. Additional bone marrow 
aspirate samples may be taken and used for local laboratory testing. MRD will be tested after 4 cycles, at the completion of 
induction, and after 24 cycles if CR maintained
14 Skeletal Survey:  Radiograph of skull, spine, chest, pelvis, upper extremities shoulder to elbow, lower extremities hip to knee.
15 Clinical examination or MRI may be used (subjects with history; physical or radiologic examination, as applicable).
16  DXA to be performed at baseline and at the completion of induction (transplant-deferred) or consolidation (post-SCT)
1724 hour urine & UPEP may be omitted after Cycle 2 if subjects disease is not followed by Urine M Protein. Except at time of 
suspected CR and sCR. 
18 The first follow up visit should occur three months after the end of treatment visit. 
9.0 MEASUREMENT OF EFFECT
9.1 International Myeloma Working Group (IMWG) Response Categories
Disease evaluations will be performed at the completion of each cycle of treatment during the 
induction phase and then at the completion of every even cycle (14, 16, 20, etc.) during 
maintenance phase until disease progression. 
Isatuximab detection on serum immunofixation electrophoresis (IFE) has been demonstrated in 
patients treated and may interfere with the traditional IMWG criteria of negative serum IFE for 
CR or sCR. To mitigate this interference, serum M-protein interference sampling will be 
performed. 
For all patients with VGPR, a positive serum IFE, and a negative M-protein by serum protein 
electrophoresis (SPEP), reflex IFE testing will be performed to confirm the presence of 
isatuximab on IFE.  In addition, patients who have an SPEP of ≤0.2 g/dL and IgG kappa MM, 
reflex testing will also be performed to determine whether the para-protein identified on 
SPEP/IFE is monoclonal isatuximab or the patient’s endogenous myeloma protein.
IMWG Uniform Response Criteria + Definition of Minimal Response as Adopted from the 
EBMT Criteria
The IMWG uniform response criteria will be used for determining response to therapy and progression of 
disease (Table 15). Source documentation for all biochemical and radiographic evaluations of disease will 
be collected for confirmation of response and disease progression.

DF/HCC #: 19-568
Version Date: March 2nd 2023 
73
Table 15: IMWG Uniform Response Criteria
Response Category
Response Criteria
Response Criteria for Disease 
Measurable by Serum FLC Testing 
Only
Complete Response (CR)
Negative serum immunofixation and 
24-hour urine immunofixation, 
disappearance of all extramedullary 
plasmacytomas (if present at baseline) 
and <5% plasma cells on repeat bone 
marrow examination.
All other criteria for CR met + normal 
serum free light chain ratio.
Stringent Complete 
Response (sCR)
All criteria for CR must be met + 
normal serum free light chain ratio + 
absence of clonal plasma cells on bone 
marrow examination by 
immunohistochemistry or 2- to 4-color 
flow cytometry.
All other criteria for sCR met + normal 
serum free light chain ratio.
Very Good Partial Response 
(VGPR)
Serum and urine M-protein detectable 
on immunofixation testing but not on 
electrophoresis OR ≥90% reduction in 
serum M-protein plus urine M-protein 
<100 mg/24 hours.
≥90% reduction in the difference 
between the involved and uninvolved 
serum free light chain level.
Partial Response (PR)
≥50% decrease in the serum M-protein 
+ ≥90% reduction in the urine M-
protein OR to <200 mg/24 hours + 
≥50% reduction in the size of 
extramedullary plasmacytomas (if 
present at baseline).
≥50% reduction in the difference 
between the involved and uninvolved 
serum free light chain level.
Minimal Response (MR)
25% - 49% decrease in the serum M-
protein + 50 – 89% reduction in the 
urine M-protein + 25% – 49% 
reduction in the size of extramedullary 
plasmacytomas (if present at baseline) 
+ no increase in size or number of lytic 
bone lesions (development of 
compression fracture does not exclude 
response).a
Stable Disease (SD)
Not meeting criteria for CR, sCR, VGPR, PR, MR, or PD

DF/HCC #: 19-568
Version Date: March 2nd 2023 
74
Progressive Disease (PD)
Increase of ≥25% from lowest response value (nadir)b in any of the following:
1)
Serum M-protein (absolute increase must be ≥0.5 g/dL) AND/OR:
2)
Urine M-protein (absolute increase must be ≥200 mg/24 hours) 
AND/OR:
3)
For patients without a measurable serum or urine M-protein but 
measurable disease by serum free light chain testing: Difference between 
the involved and uninvolved serum free light chain level (absolute 
increase must be ≥10 mg/dL) AND/OR:
4)
For patients without a measurable serum or urine M-component or serum 
free light chain level: % marrow involvement with myeloma (absolute 
increase must be ≥10%).
Definite development of new bone lesions or extramedullary plasmacytomas or 
definite increase in the size of existing bone lesions or extramedullary 
plasmacytomas.
a 
For patients who do not have measurable disease by M-protein measurement or serum free light chain levels but ≥30% 
involvement of the marrow at baseline, a ≥50% reduction of bone marrow involvement is required to meet criteria for a PR.
b
The lowest response value (nadir) does not have to be a value that has been confirmed by repeat measurement.

DF/HCC #: 19-568
Version Date: March 2nd 2023 
75
9.2 Minimal Residual Disease Assessment
Minimal residual disease (MRD) assessment will be assessed by next generation sequencing in 
both blood and bone marrow aspirate whenever a bone marrow (BM) sample is obtained as 
described in (Table 16) at the time points mentioned in and the Schedule of Assessments. Please 
see the Appendix F for details of MRD collection and processing.
Table 16: Bone Marrow Testing Requirements
Sample
Local Laboratory Testing
Central Laboratory Testing
Screening aspirate and 
biopsy
Cytogenetics (FISHa), 
morphology, 
immunohistochemistry, 
immunofluorescence, or 
flow cytometry
MRD: a portion of the BM aspirates (at least 5 mL) 
collected at screening will be sent to a central 
laboratory.
If a fresh BM aspirate will not be performed at 
screening because a sample is available within 
28 days prior to enrollment, then non-decalcified 
diagnostic tissue (BM aspirate smear or clot slides) 
should be collected for MRD assessment
Follow-up aspirate and/or 
biopsy
Morphology, 
immunohistochemistry, 
immunofluorescence, or 
flow cytometry
MRD: a portion of the BM aspirates (at least 5 mL) 
collected at screening will be sent to a central 
laboratory.
For response 
confirmation, additional 
BM aspirates or biopsies 
will be performed locally 
to confirm CR or sCR
To confirm CR or sCR at 
any time (including 
patients with VGPR or 
better and suspected 
istuximab interference) 
immunohistochemistry, 
immunofluorescence 
(requires kappa/lambda 
ration from analysis of ≥ 
100 cells) or 2- to 4- color 
flow cytometry
aFISH- testing to include del(17p), t(4;14), t(14;16), t(14;20), and 1q duplication
9.3 Assessment of Lytic Bone Disease
A complete skeletal survey (including skull, entire vertebral column, pelvis, chest, humeri, 
femora, and any other bones for which the investigator suspects involvement by disease) is to be 
performed and evaluated by the local roentgenography during the screening phase. Magnetic 
resonance imaging and/or low dose computerized tomography (CT)-scan, and/or positron 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
76
emission tomography (PET)/CT fusion studies are acceptable methods for evaluation of bone 
disease and may be included at the discretion of the investigator. If an alternative imaging 
modality (MRI, CT, or PET/CT) was used prior to registration in addition to the complete 
skeletal survey, then both methods must be used to document disease status. 
Sometimes subjects present with disease progression manifested by symptoms of pain due to 
bone changes. Therefore, disease progression may be documented, in these cases, by skeletal 
survey or other imaging studies, depending on the symptoms that the subject experiences. If the 
diagnosis of disease progression is obvious by radiographic investigations, then no repeat 
confirmatory x-rays are necessary. In instances where changes may be more subtle, a repeat 
x-ray may be needed in 1 to 3 weeks.
9.4 Documentation of Extramedullary Plasmacytomas
Sites of known extramedullary plasmacytomas must be documented prior to registration. 
Clinical examination or MRI may be used to document extramedullary sites of disease. 
Computed tomography scan evaluations are an acceptable alternative if there is no 
contraindication to the use of IV contrast. Positron emission tomography scan or ultrasound 
tests are not acceptable to document the size of extramedullary plasmacytomas. However, 
PET/CT fusion studies are acceptable.
Extramedullary plasmacytomas should be assessed for all subjects with a history of 
plasmacytomas, or if clinically indicated prior to registration, by clinical examination or 
radiologic imaging. Assessment of measurable sites of extramedullary disease will be performed 
and evaluated locally for subjects with a history of plasmacytomas or as clinically indicated 
during treatment until development of confirmed CR or confirmed disease progression. If 
assessment can only be performed radiologically, then evaluation of extramedullary 
plasmacytomas must be performed according to the Schedule of Assessments. For every 
subject, the methodology used for evaluation of each disease site should be consistent across all 
visits. Irradiated or excised lesions will be considered not measurable and will be monitored 
only for disease progression.
To qualify for PR, the sum of products of the perpendicular diameters of the existing 
extramedullary plasmacytomas must have decreased by at least 50%, and new plasmacytomas 
must not have developed. To qualify for disease progression, either the sum of products of the 
perpendicular diameters of the existing extramedullary plasmacytomas must have increased by 
at least 50% or a new plasmacytoma must have developed. In the cases where not all existing 
extramedullary plasmacytomas are reported, but the sum of products of the perpendicular 
diameters of the reported plasmacytomas have increased by at least 50%, this will also qualify as 
disease progression.

DF/HCC #: 19-568
Version Date: March 2nd 2023 
77
9.5 Isatuximab Interference with Indirect Antiglobulin Test Results
Based on information published in relation to a drug of the same class as isatuximab, 
daratumumab[48], the CD38 protein is weakly expressed on the surface of red blood cells. 
Because of this, anti-CD38 antibodies in patients’ plasma can lead to pan-reactivity and thus 
interfere with various blood bank serologic tests. For example, plasma samples from 
daratumumab-treated patients showed positive reactions in indirect antiglobulin tests, antibody 
detection (screening) tests, antibody identification panels, and antihuman globulin crossmatches. 
ABO/RhD typing is not affected by anti-CD38 antibody.
To avoid potential problems with blood transfusion, the American Association of Blood Banks
recommends that patients being treated with anti-CD38 antibodies have blood type and screen
tests performed at baseline. After treatment, and each time before blood transfusion, the antibody 
screen test (indirect Coombs test) should be performed.
9.6 Evaluation of Body Composition
Fat and lean mass will be measured using DXA (Hologic QDR 4500, Hologic Inc., Waltham, 
MA) at the three pre-specified time points. Total lean mass, extremity lean mass, total fat and 
trunk fat mass, as well as visceral adipose tissue mass will be quantified using Hologic APEX 
3.1 software (Hologic).
9.7 Patient-Reported Outcomes
The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 includes 
30 items resulting in 5 functional scales (physical functioning, role functioning, emotional 
functioning, cognitive functioning, and social functioning), 1 global health status scale, 3 
symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, 
insomnia, appetite loss, constipation, diarrhea, and financial difficulties. Administration time is 
approximately 11 minutes. 
The EORTC QLQ-MY20 is a disease-specific validated instrument, that contains 20 questions 
that measures 4 myeloma-specific PRO domains:  disease symptoms, side effects of treatment, 
future perspective, and body image. 
10. DATA REPORTING
10.1.1 Method
The DF/HCC Office of Data Quality (ODQ) will collect, manage, and perform quality checks
on the data for this study.
10.1.2 Responsibility for Data Submission
All participating sites are responsible for submitting data and/or data forms to the ODQ
according to the schedule set by the ODQ.

DF/HCC #: 19-568
Version Date: March 2nd 2023 
78
11.0 DATA SAFETY MONITORING
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of medical oncologists, research 
nurses, pharmacists and biostatisticians with direct experience in cancer clinical research.  
Information that raises any questions about participant safety will be addressed with the Overall 
PI and study team.
The DSMC will review each protocol up to four times a year with the frequency determined by 
the outcome of previous reviews. Information to be provided to the committee may include: up-
to-date participant accrual; current dose level information; dose-limiting toxicity (DLT) 
information; all grade 2 or higher unexpected adverse events that have been reported; summary 
of all deaths occurring within 30 days of intervention for Phase I or II protocols; for gene therapy 
protocols, summary of all deaths while being treated and during active follow-up; any response 
information; audit results, and a summary provided by the study team. Other information (e.g. 
scans, laboratory values) will be provided upon request. 
12.0 STATISTICAL CONSIDERATIONS
12.1 Study Design/Endpoints
50 patients will be enrolled.
Statistical Power Calculations:
The reference CR rate after 4 cycles of treatment is assumed to be 0.27. A study with a sample 
size of 50 achieves 80% power to detect a difference (P1-P0) of 0.16 using a one-sided, one 
sample exact binomial test at a significance level of 0.10, assuming that the CR rate (P1) in the 
study population is at least 0.43. If 19 or more patients experience a CR, the study will reject the 
reference rate of 0.27 in favor of a higher CR rate.  If 10% of patients do not complete 4 cycles 
of treatment, the sample size of 45 evaluable patients still achieves 80% power to detect a 
difference of 0.16 based on the above assumptions. With 45 evaluable patients, the study will 
reject the reference CR rate of 0.27 in favor of a higher rate if 17 or more patients experience a 
CR.
Primary Analysis:  Efficacy analysis will be performed both the Intent-to-Treat (ITT) Population 
and Efficacy Evaluable (EE) Population. The ITT Population will include all treated patients, 
and the EE Population will include all patients who meet eligibility criteria, receive at least 1 
cycle of study drug, and have at least 1 post-baseline efficacy assessment. The primary analysis 
will be based on the EE population, and will use the Investigator-assessed response data 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
79
evaluated according to consensus recommendations based on the IMWG criteria. CR (CR+sCR) 
rate to treatment after 4 cycles of KRDI as assessed by site Investigators using the International 
Myeloma Working Group (IMWG) Uniform Response criteria will be reported with 90% 
confidence interval. Secondary analyses will evaluate CR rate at other pre-determined time-
points.
Secondary Analysis: Secondary analyses will evaluate overall response rate, MRD rate, PFS and 
OS. Overall response rate will be percent of patients who achieve at least partial response (PR). 
Percent of patients achieving MR or better will also be collected as clinical benefit response. 
MRD rate after 4 cycles, at completion of induction, and at 24 months will be determined by 
deep sequencing of genomic deoxyribonucleic acid from bone marrow samples using rearranged 
Ig locus-specific primers (Adaptive, Seattle, WA). PFS will be defined as the time from first 
dose of study treatment to the first documentation of PD or death from any cause during study. 
OS will be defined as the time from first dose of study treatment to death from any cause. For 
responders, time to response (TTR) and duration of response (DOR) will be analyzed. TTR will 
be defined as the time from first dose of study treatment to the first documentation of response 
(either PR, very good partial response (VGPR) or CR, nCR, and sCR). DOR will be defined as 
the time from the first PR, VGPR, or CR to the first documentation of PD or death, whichever 
occurs earlier. 
Response rates together with confidence intervals (CIs) will be provided. Kaplan-Meier curves 
will be used to characterize the time-to-event outcomes(PFS, OS, response duration) when there 
is censoring; univariate summary statistics will be provided for TTR.  In addition, outcomes 
including median PFS and median OS will be calculated within sub-groups based on risk status 
(standard vs high) and MRD status (positive vs negative).
A 90% CI for the response rate will be constructed for evaluating the efficacy of KRDI. Kaplan-
Meier curves will be constructed to characterize PFS, OS, and DOR. One sample standard 
inferences for PFS, OS, and DOR will be made accordingly.
Demographic, Disposition, Study Medication:
The baseline (C1D1) characteristics of patients enrolled in the study will be summarized. An 
accounting will be made of the study course for all patients who received study drug and, in 
particular, the number of patients who died or withdrew during treatment will be specified and 
reasons for withdrawal categorized. Study drug administration and information on dose 
reductions will be summarized.
Safety Analysis:
Safety data will be summarized when all patients have completed the first 28-day cycle (C1).
Safety data for patients undergoing SCT, as well as for patients who continued treatment without 
SCT, will be analyzed when all patients have completed consolidation therapy. All patients who 
received at least one dose of study drug will be included in the safety analyses. SAEs, treatment-

DF/HCC #: 19-568
Version Date: March 2nd 2023 
80
emergent AEs, vital sign measurements, clinical laboratory information, and concomitant 
medications will be tabulated and summarized when appropriate. Patient incidence rates of all 
AEs (including serious, Grade 3/4, treatment-related, and events requiring the discontinuation of 
investigational product), will be tabulated by system organ class (SOC), preferred term, and 
severity using Medical Dictionary for Regulatory Activities (MedDRA) terms and NCI CTCAE 
Version 5.0 severity grades.  Death, SAEs, and AEs resulting in study discontinuation will also 
be summarized. AEs leading to dose reduction or interruption will also be tabulated.  All other 
measurements will be summarized using means, standard deviations, medians, minimum, and 
maximum. Graphical displays will be provided where useful in the interpretation of results.
Safety Stopping Rule:
If 3 or more of the first 10 treated patients develop a Grade >= 4 adverse event (AE) that is 
possibly, probably or definitely related to treatment, enrollment to the trial will be temporarily 
suspended so that all AE data can be examined. Additionally, once the number of treated patients 
exceeds 10, if at any point during treatment 30% or more of patients develop a Grade >= 4 
adverse event (AE) possibly/probably/definitely related to treatment, enrollment will be 
temporarily suspended for review of AE data. These stopping rules apply to the cumulative 
number of Grade >=4 AEs and patients treated across study arms, not within arms separately. 
If 3 or more of the first 10 treated are unable to collect adequate stem cells for autologous stem 
cell transplant, enrollment to the trial will be temporarily suspended so that the stem cell 
collection data can be examined. Additionally, once the number of treated patients exceeds 10, if 
at any point during treatment 30% or more of patients are unable to collect adequate stem cells 
for autologous stem cell transplant, enrollment will be temporarily suspended for review of the 
stem cell collection data.
12.2 Analysis of Secondary Endpoints
QOL Evaluations
The QOL will be measured using the European Organisation for Research and Treatment of Cancer 
(EORTC) Quality of Life (QOL) Questionnaire - Core (QLQ-30), the MY20 questionnaire. 
Descriptive statistics will be presented for change from baseline in QOL over time.  Analyses will 
be performed on summary scores as well as individual items.
Body Composition
The endpoints for body composition will include changes in lean and fat mass from baseline to the 
final study assessment.  

DF/HCC #: 19-568
Version Date: March 2nd 2023 
81
11.3
Evaluation of toxicity
All participants will be evaluable for toxicity from the time of their first treatment.
13. PUBLICATION PLAN
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study. 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
82
14. REFERENCES
1.
Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2018. CA Cancer J Clin, 2018. 
68(1): p. 7-30.
2.
Kyle, R.A., et al., Review of 1027 patients with newly diagnosed multiple myeloma. Mayo 
Clin Proc, 2003. 78(1): p. 21-33.
3.
Demo, S.D., et al., Antitumor activity of PR-171, a novel irreversible inhibitor of the 
proteasome. Cancer Res, 2007. 67(13): p. 6383-91.
4.
Chauhan, D., et al., A novel orally active proteasome inhibitor ONX 0912 triggers in 
vitro and in vivo cytotoxicity in multiple myeloma. Blood, 2010. 116(23): p. 4906-15.
5.
Wang, M., 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): p. 3122-8.
6.
Jakubowiak, A.J., 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(9): p. 1801-9.
7.
Stewart, A.K., et al., Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple 
myeloma. N Engl J Med, 2015. 372(2): p. 142-52.
8.
Berenson, J.R., et al., CHAMPION-1: a phase 1/2 study of once-weekly carfilzomib and 
dexamethasone for relapsed or refractory multiple myeloma. Blood, 2016. 127(26): p. 
3360-8.
9.
Moreau, P., et al., Once weekly versus twice weekly carfilzomib dosing in patients with 
relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a 
randomised, phase 3 study. Lancet Oncol, 2018. 19(7): p. 953-964.
10.
Biran, N., et al., Weekly carfilzomib, lenalidomide, and dexamethasone in relapsed or 
refractory multiple myeloma: A phase 1b study. Am J Hematol, 2019. 94(7): p. 794-802.
11.
Martin, T., et al., A phase 1b study of isatuximab plus lenalidomide and dexamethasone 
for relapsed/refractory multiple myeloma. Blood, 2017. 129(25): p. 3294-3303.
12.
Kronke, J., et al., Lenalidomide causes selective degradation of IKZF1 and IKZF3 in 
multiple myeloma cells. Science, 2014. 343(6168): p. 301-5.
13.
Lopez-Girona, A., et al., Cereblon is a direct protein target for immunomodulatory and 
antiproliferative activities of lenalidomide and pomalidomide. Leukemia, 2012. 26(11): 
p. 2326-35.
14.
Lu, G., et al., The myeloma drug lenalidomide promotes the cereblon-dependent 
destruction of Ikaros proteins. Science, 2014. 343(6168): p. 305-9.
15.
Weber, D.M., et al., Lenalidomide plus dexamethasone for relapsed multiple myeloma in 
North America. N Engl J Med, 2007. 357(21): p. 2133-42.
16.
Dimopoulos, M., et al., Lenalidomide plus dexamethasone for relapsed or refractory 
multiple myeloma. N Engl J Med, 2007. 357(21): p. 2123-32.
17.
Dimopoulos, M.A., et al., Long-term follow-up on overall survival from the MM-009 and 
MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or 
refractory multiple myeloma. Leukemia, 2009. 23(11): p. 2147-52.
18.
Benboubker, L., et al., Lenalidomide and dexamethasone in transplant-ineligible patients 
with myeloma. N Engl J Med, 2014. 371(10): p. 906-17.

DF/HCC #: 19-568
Version Date: March 2nd 2023 
83
19.
Mitsiades, N., et al., Apoptotic signaling induced by immunomodulatory thalidomide 
analogs in human multiple myeloma cells: therapeutic implications. Blood, 2002. 99(12): 
p. 4525-30.
20.
Richardson, P.G., et al., Lenalidomide, bortezomib, and dexamethasone combination 
therapy in patients with newly diagnosed multiple myeloma. Blood, 2010. 116(5): p. 679-
86.
21.
Kumar, S., et al., Randomized, multicenter, phase 2 study (EVOLUTION) of 
combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in 
previously untreated multiple myeloma. Blood, 2012. 119(19): p. 4375-82.
22.
Durie, B.G., et al., Bortezomib with lenalidomide and dexamethasone versus 
lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma 
without intent for immediate autologous stem-cell transplant (SWOG S0777): a 
randomised, open-label, phase 3 trial. Lancet, 2017. 389(10068): p. 519-527.
23.
Korde, N., et al., Treatment With Carfilzomib-Lenalidomide-Dexamethasone With 
Lenalidomide Extension in Patients With Smoldering or Newly Diagnosed Multiple 
Myeloma. JAMA Oncol, 2015. 1(6): p. 746-54.
24.
Sonneveld, P., et al., Treatment of multiple myeloma with high-risk cytogenetics: a 
consensus of the International Myeloma Working Group. Blood, 2016. 127(24): p. 2955-
62.
25.
Nooka, A.K., et al., Consolidation and maintenance therapy with lenalidomide, 
bortezomib and dexamethasone (RVD) in high-risk myeloma patients. Leukemia, 2014. 
28(3): p. 690-3.
26.
Avet-Loiseau, H., et al., Bortezomib plus dexamethasone induction improves outcome of 
patients with t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol, 
2010. 28(30): p. 4630-4.
27.
Neben, K., et al., Administration of bortezomib before and after autologous stem cell 
transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood, 
2012. 119(4): p. 940-8.
28.
Rosinol, L., et al., Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as 
induction pretransplantation therapy in multiple myeloma: a randomized phase 3 
PETHEMA/GEM study. Blood, 2012. 120(8): p. 1589-96.
29.
Cavo, M., et al., Bortezomib with thalidomide plus dexamethasone compared with 
thalidomide plus dexamethasone as induction therapy before, and consolidation therapy 
after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: 
a randomised phase 3 study. Lancet, 2010. 376(9758): p. 2075-85.
30.
Sonneveld, P., et al., Bortezomib-based versus nonbortezomib-based induction treatment 
before autologous stem-cell transplantation in patients with previously untreated multiple 
myeloma: a meta-analysis of phase III randomized, controlled trials. J Clin Oncol, 2013. 
31(26): p. 3279-87.
31.
Cavo M, S.H., Rosinol L, et al. , Double vs single autologous stem cell transplantation 
after bortezomib-based induction regimens for multiple myeloma: an integrated analysis 
of patient-level data from phase European III studies [abstract]. Blood 2013;122(21) 
Abstract 767.
32.
van Rhee, F., et al., Total Therapy 3 for multiple myeloma: prognostic implications of 
cumulative dosing and premature discontinuation of VTD maintenance components, 
bortezomib, thalidomide, and dexamethasone, relevant to all phases of therapy. Blood, 
2010. 116(8): p. 1220-7.

DF/HCC #: 19-568
Version Date: March 2nd 2023 
84
33.
Pineda-Roman, M., et al., Sustained complete remissions in multiple myeloma linked to 
bortezomib in total therapy 3: comparison with total therapy 2. Br J Haematol, 2008. 
140(6): p. 625-34.
34.
Kapoor, P., et al., Impact of risk stratification on outcome among patients with multiple 
myeloma receiving initial therapy with lenalidomide and dexamethasone. Blood, 2009. 
114(3): p. 518-21.
35.
Palumbo, A., et al., Autologous transplantation and maintenance therapy in multiple 
myeloma. N Engl J Med, 2014. 371(10): p. 895-905.
36.
Attal, M., et al., Lenalidomide maintenance after stem-cell transplantation for multiple 
myeloma. N Engl J Med, 2012. 366(19): p. 1782-91.
37.
Palumbo, A., et al., Continuous lenalidomide treatment for newly diagnosed multiple 
myeloma. N Engl J Med, 2012. 366(19): p. 1759-69.
38.
McCarthy, P.L., et al., Lenalidomide after stem-cell transplantation for multiple 
myeloma. N Engl J Med, 2012. 366(19): p. 1770-81.
39.
Avet-Loiseau, H., et al., Impact of high-risk cytogenetics and prior therapy on outcomes 
in patients with advanced relapsed or refractory multiple myeloma treated with 
lenalidomide plus dexamethasone. Leukemia, 2010. 24(3): p. 623-8.
40.
Lonial, S., et al., Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N 
Engl J Med, 2015. 373(7): p. 621-31.
41.
Dimopoulos, M.A., et al., Cytogenetics and long-term survival of patients with refractory 
or relapsed and refractory multiple myeloma treated with pomalidomide and low-dose 
dexamethasone. Haematologica, 2015. 100(10): p. 1327-33.
42.
Leleu, X., et al., Pomalidomide plus low-dose dexamethasone in multiple myeloma with 
deletion 17p and/or translocation (4;14): IFM 2010-02 trial results. Blood, 2015. 125(9): 
p. 1411-7.
43.
Roussel, M., et al., Front-line transplantation program with lenalidomide, bortezomib, 
and dexamethasone combination as induction and consolidation followed by 
lenalidomide maintenance in patients with multiple myeloma: a phase II study by the 
Intergroupe Francophone du Myelome. J Clin Oncol, 2014. 32(25): p. 2712-7.
44.
Jakubowiak, A.J., et al., Treatment outcomes in patients with relapsed and refractory 
multiple myeloma and high-risk cytogenetics receiving single-agent carfilzomib in the 
PX-171-003-A1 study. Leukemia, 2013. 27(12): p. 2351-6.
45.
Shah, J.J., et al., Carfilzomib, pomalidomide, and dexamethasone for relapsed or 
refractory myeloma. Blood, 2015. 126(20): p. 2284-90.
46.
Mateos, M.V., et al., Impact of prior therapy on the efficacy and safety of oral ixazomib-
lenalidomide-dexamethasone vs. placebo-lenalidomide-dexamethasone in patients with 
relapsed/refractory multiple myeloma in TOURMALINE-MM1. Haematologica, 2017. 
102(10): p. 1767-1775.
47.
Sonneveld, P., et al., Phase 2 study of carfilzomib, thalidomide, and dexamethasone as 
induction/consolidation therapy for newly diagnosed multiple myeloma. Blood, 2015. 
125(3): p. 449-56.
48.
Giralt, S., et al., American Society of Blood and Marrow Transplantation, European 
Society of Blood and Marrow Transplantation, Blood and Marrow Transplant Clinical 
Trials Network, and International Myeloma Working Group Consensus Conference on 
Salvage Hematopoietic Cell Transplantation in Patients with Relapsed Multiple 
Myeloma. Biol Blood Marrow Transplant, 2015. 21(12): p. 2039-2051.

DF/HCC #: 19-568
Version Date: March 2nd 2023 
85
49. 
Sarclisa (isatuximab-irfc. Package insert. Sanofi; updated 3/2020. 
50. 
Kyprolis (carfilzomib). Package insert. Amgen; udpated 8/2020. 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
86
15.0 APPENDICES
16. APPENDIX A
PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease.
0
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of disease.
80
Normal activity with effort; some 
signs or symptoms of disease.
1
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs.
2
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours.
50
Requires considerable assistance and 
frequent medical care.
40
Disabled, requires special care and 
assistance.
3
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
20
Very sick, hospitalization indicated. 
Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.

DF/HCC #: 19-568
Version Date: March 2nd 2023 
87
17. APPENDIX B
SERUM M-PROTEIN INTERFERERENCE sampling 
Supplies stored labeled in kit box:
Collection Tube: 1 x Tube, 2.5 mL, SST w/gel [RD25; 8T3B in Japan]
Transfer Tube: 2 x Tube.Falsebottom,5mL,Clear,PP,For Serum[SS5C; 8SSC in Japan]
1. Fill tube completely with peripheral blood.
2. Gently invert 5 times.
3. Allow blood to clot for 45 minutes in an upright position.
4. Centrifuge at 1800 x g for 15 minutes.
5. Aliquot serum into 2 labeled 5 mL cryovial.
6. Freeze within 1 hour of collection at -80°C until shipment.
7. Discard cells.
8. Samples should be stored at ≤-80C until assay is available

DF/HCC #: 19-568
Version Date: March 2nd 2023 
88
18. APPENDIX C 
Quality of Life Assessments

DF/HCC #: 19-568
Version Date: March 2nd 2023 
89

DF/HCC #: 19-568
Version Date: March 2nd 2023 
90

DF/HCC #: 19-568
Version Date: March 2nd 2023 
91

DF/HCC #: 19-568
Version Date: March 2nd 2023 
92

DF/HCC #: 19-568
Version Date: March 2nd 2023 
93
APPENDIX F: MINIMAL RESIDUAL DISEASE COLLECTION AND 
PROCESSING
1. COLLECTION SCHEMA
After 4 cycles, at the completion of consolidation, and after 24 months (± 3 weeks) if sCR or CR 
maintained (including patients with VGPR or better and suspected isatuximab interference).
Sample
Screening
After C4
After C6 or 
C8***
C24*
MRD (Aspirate)
X**
X
X
X
* + 3 weeks
** A portion of the BM aspirates collected at screening (during the BM Biopsy) will be sent 
to the central laboratory along with the post-sample collected at the completion of cycle 4 
sample. If a fresh BM aspirate will not be performed at screening because a sample is 
available within 28 days prior to randomization, then non-decalcified diagnostic tissue (BM 
aspirate smear or FFPE clot slides) should be collected for MRD assessment.
*** Specimen will be collected after 6 cycles in those receiving a transplant after 8 cycles in 
those deferring a transplant
2. COLLECTION MATERIALS
2.1 NGS-MRD stored specimen kit (provided by Adaptive) – contains:
2.1.1
Two (2) slide case containers (holds up to 5 slides per case)  
2.1.2
Ambient gel pack, specimen bag, absorbent pad, FedEx next day return shipping label 
and packing instructions.
2.2 NGS-MRD fresh specimen kit (provided by Adaptive) – contains:
2.2.1
Two (2) K2EDTA tubes, one (1) 3ml and one (1) 10ml 
2.2.2
Ambient gel pack, specimen bag, absorbent pad, FedEx next day return shipping label 
and packing instructions.
3. METHODS FOR COLLECTION AND PROCESSING
3.1 Bone Marrow Aspirates
3.1.1
Collection
Bone marrow aspirates are collected following the schedule outlined above (section 1), at 
least one 3 mL tube should be filled with aspirate. BM aspirate smear slides or FFPE clot 
slides specimen will be stored per institutional practice.
3.1.2
Sample Preparation and Shipping
Label each specimen tube with the Subject ID and date the sample was collected.
Immediately after collection, package the sample in the NGS-MRD fresh specimen kit 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
94
following the directions provided in the kit.
•
If nearing a holiday, please contact Chelsea Mullins with the anticipated arrival dates. Each 
shipper contains two K2EDTA tubes (one (1) 3mL and one (1) 10mL), ambient gel pack, 
specimen bag, absorbent pad, FedEx next day return shipping label and packing instructions.  
•
Retain one copy of the Clinical Trial Sample Submission Form for your records.
4. SHIPPING
4.1 If possible, please avoid shipping samples for receipt on Saturday.  If there is a delay in shipping, 
the samples will not be received until Monday and there could be lysing of cells and 
degradation. Also, please note that shipments cannot be received on holidays. No samples 
should be shipped the day before a federal holiday. Please plan the biopsy time accordingly.
4.2 The first shipment (C5D1) to Adaptive Biotechnologies will include both stored and fresh 
samples.  
4.2.1
When you are ready to ship the BM aspirate smear slides or FFPE clot slides, complete 
the Clinical Trial Sample Submission Form (editable PDF) (Appendix 1) and print a hard 
copy to include in the NGS-MRD stored specimen kit.
4.2.1.1 Prepare the shipment by following the instructions included in the packaging kit 
provided.
4.2.2
When you are ready to ship the fresh BMA vacutainers, complete the Clinical Trial 
Sample Submission Form (Appendix 1) and print a hard copy to include in the NGS-
MRD fresh specimen kit.
4.2.2.1 Prepare the shipment by following the instructions included in the packaging kit 
provided. 
4.3 The second (C6/C8) and third shipments shipment (C24) to Adaptive Biotechnologies will 
include ONLY fresh samples.
4.3.1
When you are ready to ship the fresh BMA vacutainers, complete the Clinical Trial 
Sample Submission Form (Appendix 1) and print a hard copy to include in the NGS-
MRD fresh specimen kit.
4.3.1.1 Prepare the shipment by following the instructions included in the packaging kit 
provided. 
4.4 Ship by FedEx using the FedEx return label provided by Adaptive. Adaptive address is on the 
FedEx return label.
Please ensure the following address is listed on the return label:
Adaptive Biotechnologies
1551 Eastlake Ave. East, Suite 200
Seattle, WA 98102
Shipping Contact: 
Chelsea Mullins, Project Manager at cmullins@adaptivebiotech.com. 
4.5 After shipment arrival and review, Adaptive may reach out to the site contact listed in the 
“Submitting Site Information” section of the “Clinical Trial Sample Submission Form” to resolve 

DF/HCC #: 19-568
Version Date: March 2nd 2023 
95
any discrepancies between the specimen tube label and the Clinical Trial Sample Submission 
Form.