Carfilzomib, Lenalidomide, and Dexamethasone in Newly-Diagnosed Multiple Myeloma: A Clinical and Correlative Phase I/II Dose Escalation Study
Phase: PHASE1
Conditions: Multiple Myeloma
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-326 A(11) 
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MSK PROTOCOL COVER SHEET 
Carfilzomib, Lenalidomide, and Dexamethasone in Newly-Diagnosed Multiple 
Myeloma: A Clinical and Correlative Phase I/II Dose Escalation Study 
Principal Investigator/Department: Neha Korde, MD 

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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ...................................................................... 3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ............................................................................... 6 
3.0 
BACKGROUND AND RATIONALE .................................................................................... 6 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ........................................................... 10 
4.1 
Design ........................................................................................................................... 11 
4.2 
Intervention .................................................................................................................... 11 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS .......................................................................... 14 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .......................................................................... 19 
6.1 
Subject Inclusion Criteria ................................................................................................ 19 
6.2 
Subject Exclusion Criteria .............................................................................................. 20 
7.0 
RECRUITMENT PLAN ...................................................................................................... 21 
8.0 
PRETREATMENT EVALUATION ..................................................................................... 22 
9.0 
TREATMENT/INTERVENTION PLAN............................................................................... 24 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ................................................... 32 
11.0 
TOXICITIES/SIDE EFFECTS ............................................................................................ 39 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ....................... 44 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ...................................................................... 46 
14.0 
BIOSTATISTICS ............................................................................................................... 47 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
49 
15.1 
Research Participant Registration .................................................................................. 49 
15.2 
Randomization ............................................................................................................... 49 
16.0 
DAT A M ANAGEMENT ISSUES........................................................................................ 49 
16.1 
Quality Assurance .......................................................................................................... 50 
16.2 
Data and Safety Monitoring ............................................................................................ 50 
17.0 
PROTECTION OF HUMAN SUBJECTS ............................................................................ 50 
17.1 
Privacy ........................................................................................................................... 51 
17.2 
Serious Adverse Event (SAE) Reporting ........................................................................ 53 
17.2.1 
 54 
18.0 
INFORMED CONSENT PROCEDURES ........................................................................... 57 
19.0 
REFERENCES .................................................................................................................. 58 
20.0 
APPENDICES ................................................................................................................... 60 

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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
Primary Objective This is a phase I/II study to assess the safety and efficacy of maximum 
up to 12 cycles of combinational therapy with dexamethasone, lenalidomide, and higher 
doses of carfilzomib in newly diagnosed MM patients. Total number of cycles delivered will 
be determined by response status. The primary objective of the phase I study will be to 
determine the MTD of carfilzomib when used in combination with dexamethasone, and 
lenalidomide. The primary objective of the phase II study is to assess the rate of MRD 
negativity after completion of the combination therapy using multiparametric flow 
cytometry 
Secondary Objective of both phase I/II: 
1. To evaluate the rates of overall response (partial response (PR) or better), very good 
partial response (VGPR) or better, and complete response (CR) or stringent CR (sCR). 
See section 12.0 for response definitions. 
2. To estimate overall and progression-free survival. 
3. To compare MRD techniques of multi-parametric flow cytometry with next-generation 
sequencing and mass spectrometry. 
4. To create a bone marrow and peripheral blood sample bank. These samples may be 
used to later evaluate biological activity of carfilzomib, lenalidomide, and 
dexamethasone. Potential analyses include sequencing and gene expression profiling 
on pre and post therapy bone marrow samples, identification of potential biomarkers 
(blood, urine, bone marrow aspirates), and evaluation of proteasome activity. 
 
Patient Population  
Newly diagnosed patients with histologically confirmed multiple myeloma. 
Study Design 
• 
Single arm, two-stage phase I/II trial of combination therapy (carfilzomib, lenalidomide, 
and dexamethasone [CRd]) for newly diagnosed multiple myeloma patients 
• 
Each cycle consists of 28 days 
• 
After 4 cycles of therapy, transplant eligible patients will undergo stem cell collection 
• 
Pre- and post-treatment bone marrow biopsies will be obtained for confirmation of 
diagnosis and correlative studies 
• 
Patients will receive maximum up to 12 cycles of induction combination therapy of 
CRd. Total number of cycles delivered will be determined by response status. 
Patients will also undergo evaluation for response at monthly intervals using traditional 
IMW uniform response criteria (Rajkumar. et al. Blood 2011) with SPEP, 24-hr UPEP 
(if applicable), serum free light chains (FLC), and immunofixation. 
• 
Patients with ≤PR at completion of 4 cycles, will stop therapy and be taken off 
protocol at completion of 4 cycles. 

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• 
For patients achieving >PR at end of 4 cycles, patients will continue to receive 
combination therapy with maximum up to 12 cycles. 
▪ 
Patients obtaining CR/sCR at any point during cycles in serum and urine 
will undergo MRD testing using multi-parametric flow cytometry. 
• 
Patients who attain minimal residual disease (MRD) negative 
status will stop treatment after 2 additional cycles (maximum 12 
cycles). 
• 
Patients who are MRD positive will stop treatment at completion of 
12 cycles. Patients converting from MRD positive status to 
negative status on subsequent MRD testing can stop after 2 
additional cycles 
▪ 
Patients achieving <CR/sCR (and >PR at end of 4 cycles) will stop 
treatment at completion of 12 cycles. 
• 
Upon completion of protocol therapy, patients will be encouraged to proceed onto 
maintenance therapy or high dose therapy with stem cell rescue under a separate 
treatment protocol or standard of care. If clinically indicated, patients may need 
alternative therapy. 
• 
After completion of protocol therapy, patients will remain on study for an additional 3 
years for survival analysis. 
 
 
Treatment Plan (see schema below) 
• 
Cycle 1 ONLY: Carfilzomib 20 mg/m2 per dose, days 1 and 2; Carfilzomib 45 or 
56 mg/m2 per dose, days 8, 9, 15, and 16 
• 
Cycles 2- up to 12: Carfilzomib 45 or 56 mg/m2 per dose, days 1, 2, 8, 9, 15, and 
16 
• 
Cycles 1- up to 12: Lenalidomide 25 mg/day, days 1–21 every 28 days 
• 
Cycles 1-4: Dexamethasone 20 mg/dose, days 1, 2, 8, 9, 15, 16, 22, and 23 
• 
Cycles 5- up to 12: Dexamethasone 10 mg/dose, days 1, 2, 8, 9, 15, 16, 22 and 
23 
• 
After receiving first 4 cycles, patients who are considered to be eligible for 
subsequent high dose therapy/autologous stem cell transplant (ASCT) will 
undergo autologous stem cell harvesting for potential use in the future. For 
patients who choose to undergo stem cell harvest, next cycle may be delayed 
for up to 7 weeks. 
• 
If patients achieve > PR after completion 4 cycles, patients may receive 
additional combination therapy (maximum permissible 12 cycles). Patients may 
go onto receiving additional maintenance phase therapy with lenalidomide under 
a separate treatment protocol. 
o Patients obtaining CR/sCR and MRD negative status by flow cytometry 
will stop treatment after 2 additional cycles (maximum 12 cycles) 
delivered. 
o Patients obtaining CR/sCR and MRD positive status by flow cytometry will 
stop treatment after completing 12 cycles. Patients converting from MRD 
positive status to negative status on subsequent MRD testing can stop 

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≤PR at completion of 4 
cycles 
 
 
Off-protocol 
12 Maximum Cycles of Carfilzomib, Lenalidomide and Dexamethasone * 
<CR/sCR 
(and >PR at 
completion of 4 
cycles) 
Receive up to 12 CRd 
CR/sCR at any point 
Offered option of High dose therapy with stem cell rescue or Maintenance therapy on a 
separate protocol or standard of care. If clinically indicated, patients may require 
alternative next line of therapy. Patient will be followed for additional 3 years for 
survival analysis. 
MRD positive 
by flow cytometry 
 
Receive up to 12 
CRd cycles 
MRD negative 
by flow cytometry 
 
Receive 2 additional 
CRd cycles 
(max 12) 
after 2 additional cycles 
o Patients achieving <CR/sCR will stop treatment after completing 12 
cycles. 
• 
Patients ≤PR after completing 4 cycles will go off study therapy. 
• 
Upon completion of protocol therapy, patients will be encouraged to proceed onto 
maintenance therapy or high dose therapy with stem cell rescue under a 
separate treatment protocol or standard of care. If clinically indicated, patients 
may need alternative therapy 
• 
After completion of protocol therapy, patients will remain on study for an 
additional 3 years for survival analysis. 
 
 
 
 
 
 
Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRD assessment? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* After 4 or more cycles, patients considered transplant eligible will be recommended for stem cell collection. 
Stem cell collection is not part of the current protocol. 

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**For patients with non-evaluable samples at MRD assessments byflow cytometry, patients can opt for a 
repeat assessment or continue with up to 12 cycles of CRd therapy. 
***Patients converting from MRD positive status to negative status on subsequent MRD testing can stop after 
2 additional cycles 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
Primary Objective: 
This is a phase I/II study to assess the safety and efficacy of up to12 cycles of 
combinational therapy with dexamethasone, lenalidomide, and higher doses of carfilzomib 
in newly diagnosed MM patients. The primary objective of the phase I study will be to 
determine the MTD of carfilzomib when used in combination with dexamethasone, and 
lenalidomide. The primary objective of the phase II study is to assess the rate of MRD 
negativity after completion of the combination therapy using multiparametric flow 
cytometry 
 
 
Secondary Objectives of Phase I and II: 
1. To evaluate the rates of overall response (PR or better), VGPR or better, and CR. 
2. To estimate overall and progression-free survival. 
3. To compare MRD techniques of multi-parametric flow cytometry with next-generation 
sequencing and mass spectrometry 
4. To create a bone marrow and peripheral blood sample bank. These samples may be 
used to later evaluate biological activity of carfilzomib, lenalidomide, and dexamethasone. 
Potential analyses include sequencing and gene expression profiling on pre and post 
therapy bone marrow samples, identification of potential biomarkers (blood, urine, bone 
marrow aspirates), and evaluation of proteasome activity. 
 
 
3.0 
BACKGROUND AND RATIONALE 
3.1 
Introduction 
 
Multiple Myeloma and Carfilzomib 
Multiple myeloma is characterized by clonal proliferation of malignant plasma cells in the 
bone marrow, affecting an estimated 22,000 people in the US annually 1; about 75,000 
people are living with, or in remission from, multiple myeloma. Disease hallmarks include 
presence of monoclonal protein in serum or urine and features of end organ damage, 
including hypercalcemia, renal insufficiency, anemia, and bone lytic lesions 2. Multiple 
myeloma remains incurable with an estimated median survival of 3-4 years with 
conventional therapies and longer with newer agents 3,4. 
Proteasomes play a critical role in protein turnover and degradation, thereby affecting 
essential cell functions of cell cycle control, signal transduction, apoptosis, and stress 

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responses. The 26S proteasome complex consists of the 20S barrel–like core and 19S 
regulating component. The 20S proteasome has three main catalytic domains that 
contribute to protein breakdown: chymotryptic-like activity site, tryptic-like activity site, and 
caspase-like activity site 5. Inhibiting proteasomes in malignant cells lead to buildup of 
ubiquinated proteins, resulting in eventual cell death. Such inhibitor effects likely extend 
beyond just a simple over-accumulation of cell waste. Rather, proteasome inhibitors also 
exert direct effects on the myeloma microenvironment and enable neoplastic cells to “re- 
direct” cell proliferation/apoptotic signaling while overcoming drug resistance mechanisms. 
Carfilzomib (Cfz) is a tetrapeptide ketoepoxide-based irreversible inhibitor that forms a 
covalent bond with N-terminal threonine residue of the chymotrypsin domain. Compared 
to bortezomib, carfilzomib demonstrates equal potency but greater selectivity for the 
chymotrypsin activity site over the tryptic and caspase domains. Also, carfilzomib is less 
reactive to non-proteasome proteases compared to bortezomib, likely contributing to lower 
levels of neuropathy and myelosuppression6-8. In vitro models suggest carfilzomib has 
activity against bortezomib resistant myeloma cell lines7. Carfilzomib can also work 
synergistically with dexamethasone to enhance tumor cell death7. In the pivotal, phase II, 
noncomparative study of heavily pre-treated patients (n=266) with relapsed and refractory 
multiple myeloma, intravenous carfilzomib administered in 28-day cycles for up to 12 
cycles produced an overall response rate of 23.7% in the response-evaluable patients9. 
The median duration of response was 7.8 months, the median progression-free survival 
was 3.7 months and the median overall survival was 15.6 months. An integrated analysis 
of 3 phase 2 studies with single-agent carfilzomib in patients with relapsed and refractory 
myeloma (N = 526) showed that the most common grade 3/4 adverse events (AEs) were 
thrombocytopenia (23%), anemia (22%), and lymphopenia (18%); peripheral neuropathy 
was 14% for any grade and 1.3% for grade 3 with no grade 4 events10. 
Carfilzomib in Combination with Lenalidomide and Dexamethasone 
More recently, Jakubowiak et al published the results of a Phase 1/2 study in patients with 
newly diagnosed multiple myeloma where carfilzomib was administered in combination 
with lenalidomide (Revlimid®) and dexamethasone (CRd)11. No maximum tolerated dose 
(MTD) was reached. The maximum planned dose level (carfilzomib 36 mg/m 2) was 
expanded in phase 2 (n = 36). Grade 3/4 toxicities included hypophosphatemia (25%), 
hyperglycemia (23%), anemia (21%), thrombocytopenia (17%), and neutropenia (17%); 
peripheral neuropathy was limited to grade 1/2 (23%). After a median of 12 cycles (range, 
1-25), 62% (N = 53) achieved at least near-complete response (nCR) and 42% stringent 
CR (sCR). Responses were rapid and improved during treatment. In 36 patients 
completing 8 or more cycles, 78% reached at least near CR and 61% stringent CR. With 
median follow-up of 13 months (range, 4-25 months), 24-month progression-free survival 
estimate was 92%. 
At the National Cancer Institute, we recently published results of a phase II clinical and 
correlative study of CRd in patients with newly diagnosed MM patients1{Korde, 2015 
#4573}. Patients were administered eight 28-day cycles of therapy including carfilzomib IV 
20/36 mg/m2 (based on prior Jakubowiak trial) on days 1, 2, 8, 9, 15, 16. After 8 cycles of 
CRd, all patients with stable disease (SD) or better receive cycles 9–20 of lenalidomide 

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maintenance 10 mg days 1–21. Of the 45 patients evaluable for toxicity and response, 
none reported  grade 3 neuropathy. This finding stands in sharp contrast with 
bortezomib, which can be associated with sensory neuropathy in up to 80% of treated 
patients when used in combination with lenalidomide and dexamethasone13. The CRd 
regimen (using 36 mg/ m2) resulted in rapid and deep responses with an overall response 
rate of 98% (n=42) and sCR/CR in 56% (n=25). The median time to sCR was 5 cycles 
(range 2-18). 
Minimal Residual Disease Testing in Myeloma 
In the past decade, multiple myeloma patients have reached deeper response rates with 
use of effective anti-myeloma therapeutics, immunomodulatory agents and proteasome 
inhibitors, approximating up to 75% patients achieving near-complete response (>90% 
decrease in monoclonal protein) or complete response (100% decrease in monoclonal 
protein){Kumar, 2008 #716}. In general, improved therapeutics and deeper response 
rates have resulted in improved overall survival of multiple myeloma patients across most 
age groups. As a result, there has been an increasing demand for the development of 
sensitive assays to detect minimal residual disease (MRD) in treated MM patients. In MM 
patients receiving autologous stem cell transplant, MRD-negative status using multi- 
parametric flow cytometry (MFC) is associated with improved progression free survival 
and overall survival. Similar studies using next generation sequencing methods for MRD 
have also been shown to be associated with improved outcomes in MM MRD-negative 
patients. In our prior study, among the 25 patients with CR/sCR that were assessed by 
MFC for immunophenotypic abnormal plasma cells; 25 out of 25 were negative for (MRD 
with an overall MRD negative rate of 25/43 (58)% (*2 patients did not have evaluable 
samples) using MFC. Using next generation sequencing molecular tests, the CR/sCR 
MRD negative rate was 13/33 (39%) (*12 patients did not have evaluable samples) 
(Sequenta platform). In patients with NDMM treated with CRd, 12-month progression-free 
survival for MRD-negative vs MRD-positive status by flow cytometry and next-generation 
sequencing was 100% vs 79% (95% CI, 47%-94%; P < .001) and 100% vs 95% (95% CI, 
75%-99%; P = .02), respectively. 
Minimal Residual Disease Platforms 
A recent survey including 30 major institutions in the US found major heterogeneity in 
MRD testing of multiple myeloma by flow cytometry16. In brief, there was considerable 
variation in the number of bone marrow cells analyzed (events) and number of abnormal 
plasma cells needed to define the presence of MRD, which affects maximum possible 
sensitivity. The maximum detection sensitivity ranged from 0.0005% to 0.02%, a 100-fold 
difference in sensitivity. Also, the variation in antibodies studied and definition of an 
abnormal plasma cell by flow cytometry affected the ability to differentiate normal from 
neoplastic plasma cells. 
In 2015, the Department of Laboratory Medicine developed, validated and implemented 
the 10-color flow cytometry platform in collaboration with the Myeloma Service and 
the International Myeloma Foundation. The MSK single tube 10-color flow cytometry 
platform demonstrates similar results to Euroflow and is already in use under clinical 
practice (publication submitted). Because there is currently no data available to compare 

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the sensitivity of the MSK model and molecular MRD assays, as a secondary endpoint, 
we will compare our 10-color flow cytometery platform against next generation sequencing 
and mass spectrometry. These studies will help us to better understand and further 
develop details of various MRD methods. 
3.2 
Proposed Study Investigation with Correlative Studies 
Given the potent anti-myeloma activity of the CRd combination as demonstrated by rapid and 
deep remissions and the lack of a defined MTD, as a logical extension to the above mentioned 
studies, we propose a phase I/II investigation in newly diagnosed MM employing 2 escalated 
dose levels of carfilzomib at 20/45mg/m2 and 20/56mg/m2 in combination with lenalidomide and 
dexamethasone administered over a maximum 12 twenty-eight day cycles. These two dose levels 
were chosen based on information provided by Amgen Pharmaceuticals and based on phase 1 
studies in relapsed-refractory MM showing the safety and efficacy of the drug as well as evidence 
of a dose-response relationship on multivariate modeling analysis17-19. 
 
After 4 cycles of treatment with CRd, transplant eligible patients will be encouraged to undergo 
autologous stem cell harvesting. Harvested stem cells will be stored for future use at time of 
disease relapse or progression. All patients will receive combination therapy with CRd. M-spikes 
and FLCs will be monitored every month. Patients achieving ≤PR after completion of 4 cycles of 
therapy will stop protocol therapy. Patients that are <CR/sCR (but >PR after 4 completed cycles) 
will receive up to 12 cycles of CRd. At any point during protocol, if patients achieve CR/sCR by 
serum and/or urine assessments20, patients will undergo bone marrow biopsy to confirm CR per 
standard criteria. At work-up, if the bone marrow is found to be MRD negative by multiparametric 
flow cytometry, patient will receive 2 additional cycles of CRd (maximum 12 cycles). Patients that 
are CR/sCR but MRD positive by multiparametric flow cytometry will receive 12 cycles of CRd. 
The first pulled bone marrow sample will be sent for multi-parametric flow cytometry as a priority 
sample. Upon completion of protocol therapy, patients will be encouraged to proceed onto 
maintenance therapy or high dose therapy with stem cell rescue under a separate treatment 
protocol or standard of care. Some patients may need alternative therapy after completing 
protocol therapy. Collected bone marrow and peripheral blood samples will be processed and 
stored to create a sample bank used to later evaluate biological activity of carfilzomib, 
lenalidomide, and dexamethasone. 
The study is powered to assess safety of higher doses of carfilzomib in combination with 
lenalidomide/dexamethasone and to evaluate MRD status. Our study is novel since no prior 
myeloma study has been designed to use MRD as the primary endpoint or used a response- 
adapted strategy based on MRD status. Secondary endpoints include evaluation of response 
rates, 3-year progression-free survival, 3-year overall-survival, and comparison of MRD platforms. 
Based on the rapidly evolving field with new powerful drugs, the anticipation is that MRD will 
become a new endpoint for future myeloma trials. MSK myeloma service is a global leader in this 
context. 
3.3 
Federal Regulations: The Privacy Rule 
 
In the case of research repositories of tissue and biological specimens, the collection of such 
samples is treated as research under the Privacy Standards (67 Fed Reg 53231; HIPAA Privacy 
Rule and Public Health: Guidance from CGC and HHS). Under HIPAA, all subjects must agree to 

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sign research authorizations that describe the uses and disclosures of their protected health 
information, as well as informed consents that describe the risks and benefits of participating in 
the study. It is not acceptable to sign one or the other. Both documents must be signed by the 
subject to be considered a valid study participant (45 CFR 164.508(b)(3)). 
 
The aim of informed consent is to educate potential research participants about the risks and 
benefits of the study, how confidentiality of records will be protected, and other elements outlined 
in 45 CFR 46 and 21 CFR 50 and 56. HIPAA requires an authorization that can be incorporated 
into an informed consent document if both the Privacy Rule and either the Common Rule or FDA 
regulation apply to the research study. If the health information is de-identified under the privacy 
standards (eliminating the 18 elements of PHI), then the Privacy Rule does not apply. 
 
3.4 
Office of Human Research Protections Guidance 
The Office of Human Research Protections (OHRP, 1997) provides clarification, guidance, and 
oversight for research subject to the Common Rule. Research use of banked tissue or biological 
material is specifically addressed by an OHRP policy guideline. IRB oversight is recommended for 
the process of specimen acquisition into the repository as well as for the process of distributing 
samples to subsequent researchers and their local IRBs. OHRP suggests informed consent 
“should be as specific as possible” and include a “clear description” of the following basic 
elements: a) the operation of the cell repository; b) the specific types of research to be conducted; 
c) the conditions under which data and specimens will be released to recipient-investigators; and 
d) procedures for protecting the privacy of subjects and maintaining the confidentiality of data. 
 
3.5 
New York State Law 
Under HIPAA, in instances where a state law is more stringent than the Privacy Rule, the state 
law is to be followed. In New York State, genetic test results (those that contain genetic 
information on inherited risk of disease) are confidential and cannot be disclosed to anyone 
without the written informed consent of the individual to whom the genetic test result relates (New 
York State Civil Rights Law §79-1(3)(a)). Genetic testing is defined by this law as: 
 
any laboratory test of human DNA, chromosomes, genes, or gene produc ts to 
diagnose the presence of a genetic variation linked to a predisposition to a genetic 
disease or disability in the individual or the individual’s offspring; such term shall 
also include DNA profile analysis… 
According to §79-1(4)(a), anonymous samples may be genetically tested for Institutional Review 
Board (IRB)-approved research in which the anonymity of the samples is assured. For research 
genetic testing using human tissue stored in repositories, a general waiver of informed consent 
may be obtained (§79-1(2)(c)) if the individuals who supplied the samples “have given prior 
written informed consent for the use of their sample for general research purposes and did not 
specify time limits or other factors that would restrict use of the sample” (§79-1(9)(a)). The 
samples must be either permanently de-identified or coded such that the researcher performing 
the genetic test is unable to re-identify the specimens. 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 

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4.1 
Design 
Patients with newly diagnosed MM will be enrolled on the Phase I/II study and treated with 3-drug 
combination of carfilzomib, lenalidomide, and dexamethasone. 
 
4.2 
Intervention 
• 
Cycle 1 ONLY: Carfilzomib 20 mg/m2 per dose, days 1 and 2; Carfilzomib 45 or 
56 mg/m2 per dose, days 8, 9, 15, and 16 
• 
Cycles 2- up to 12: Carfilzomib 45 or 56 mg/m2 per dose, days 1, 2, 8, 9, 15, and 
16 
• 
Cycles 1- up to 12: Lenalidomide 25 mg/day, days 1–21 every 28 days 
• 
Cycles 1-4: Dexamethasone 20 mg/dose, days 1, 2, 8, 9, 15, 16, 22, and 23 
• 
Cycles 5- up to 12: Dexamethasone 10 mg/dose, days 1, 2, 8, 9, 15, 16, 22 and 
23 
• 
After receiving first 4 cycles, patients who are considered to be eligible for 
subsequent high dose therapy/autologous stem cell transplant (ASCT) will 
undergo autologous stem cell harvesting for potential use in the future. For 
patients who choose to undergo stem cell harvest, the next cycle may be delayed 
for up to 7 weeks. 
• 
Patients will receive maximum up to 12 cycles of induction combination therapy 
of CRd. Total number of cycles delivered will be determined by response status. 
o Patients achieving ≤PR after completion of 4 cycles of therapy will stop 
protocol therapy. 
▪ 
For patients achieving >PR at end of 4 cycles, patients will 
continue to receive combination therapy with maximum up to 12 
cycles. 
▪ 
Patients obtaining CR/sCR at any point in serum and urine will 
undergo MRD testing using multi-parametric flow cytometry. 
• 
Patients who attain minimal residual disease (MRD) 
negative status by flow cytometry will stop treatment after 
2 additional cycles (maximum 12 cycles). 
• 
Patients who are MRD positive by flow cytometry will stop 
treatment at completion of 12 cycles. Patients converting 
from MRD positive status to negative status on subsequent 
MRD testing can stop after 2 additional cycles 
▪ 
Patients achieving <CR/sCR (and >PR at end of 4 cycles) will stop 
treatment at completion of 12 cycles. 
 
 
 
4.2.1 
Dose Limiting Toxicity 
 
1. A DLT is defined as any of the below toxicities with attribution to one or more of the study 
drugs that occur during Cycle 1. Toxicities that occur in subsequent cycles will be handled 
through dose modifications but will not figure into the definition of MTD. All AEs should be 

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considered relevant to determining dose-limiting toxicities and to reporting unless the 
event can clearly be determined to be UNRELATED to the drug. 
Non-hematologic 
• 
≥ Grade 2 neuropathy with pain 
• 
≥ Any Grade 3 toxicity (excluding nausea, vomiting, diarrhea, dexamethasone- 
induced hyperglycemia, electrolyte abnormalities not clinically significant and 
require no treatment except oral repletion lasting < 72 hous, or Grade 3 
lenalidomide induced-maculopapular rash) 
• 
≥ Grade 3 nausea, vomiting, or diarrhea despite maximal antiemetic/antidiarrheal 
therapy lasting ≥ 7 days 
• 
Grade 3 Creatinine increased ≥ 3x baseline or ≥ 4.0 mg/dL lasting ≥ 7 days 
• 
≥ Grade 3 fatigue lasting for ≥ 7 days 
• 
Any non-hematologic toxicity requiring a dose reduction within Cycle 1 except for 
lenalidomide-induced maculopapular rash and dexamethasone-induced 
hyperglycemia 
• 
Major bleeding toxicity defined as : ≥ Grade 3 hematoma, ≥ Grade 3 
hemorrahage (specified organ- GI, renal, hematuria/bladder, lung, etc.) ≥ Grade 
2 Intracranial hemorrhage. 
 
Hematologic  
• 
Grade 4 neutropenia (ANC < 0.5 x 109/L) lasting for ≥ 7 days 
• 
Febrile neutropenia (ANC < 1.0 x 109/L with a fever ≥ 100.5°F) 
• 
Grade 4 thrombocytopenia (platelets < 25.0 x 109/L) lasting ≥ 7 days despite 
dose delay 
• 
Grade 3-4 thrombocytopenia associated with major bleeding 
• 
Any hematologic toxicity requiring a dose reduction within Cycle 1 
 
 
4.2.2 
Dose Escalation 
The trial will initially enroll 3 patients at the 45 mg/m2 dose of carfilzomib and escalate 
to 56 mg/m2 (Level 2) per table 4.2.2.2. Subjects need to receive all doses in first cycle 
to be eligible for next cohort dose escalation unless patient has a DLT. If excessive 
toxicity is observed at the starting dose (Level 1), the study include a further de- 
escalation dose of 36 mg/m2 (Level -1).. 
 
Table 4.2.2.1 
Dose escalation table 
 
Dose Escalation Schedule 
Dose Level 
Carfilzomib * 

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Approval date: 08-Oct-2020 
Page 13 of 64 
 
 
 
Level -1 
36 
Level 1 
45 
Level 2 
56 
* Doses are stated as mg/m2/dose; max BSA of 2.2 m2 
• 
• 
• 
• 
 
 
 
 
 
 
 
 
 
Table 4.2.2.2 Dose escalation will follow the rules outlined in the Table below. 
 
 
Number of Patients with 
DLT 
at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter up to 3 patients at the next dose level 
> 2 
Dose escalation will be stopped. This dose level will be 
declared the maximally administered dose (highest dose 
administered). Up to three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients 
were treated previously at that dose. 
1 out of 3 
Enter up to 3 more patients at this dose level. 
• 
If 0 of these 3 patients experience DLT, proceed to 
the next dose level. 
• 
If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose. UP to three (3) 
additional patients will be entered at the next lowest 
dose level if only 3 patients were treated previously at 
that dose. 
<1 out of 6 at highest dose 
level below the maximally 
administered dose 
This is the MTD and is generally the recommended phase 
2 dose. At least 6 patients must be entered at the 
recommended phase 2 dose. 

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IRB Number: 15-326 A(11) 
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5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
 
5.1 
Carfilzomib (IND# 112587) 
 5.1.1 Scientific Background 
Carfilzomib is a tetrapeptide ketoepoxide-based irreversible inhibitor developed by Amgen 
Pharmaceuticals, Inc. that forms a covalent bond with N-terminal threonine residue of the 
chymotrypsin domain. Compared to bortezomib, carfilzomib demonstrates equal potency 
but greater selectivity for the chymotrypsin activity site over the tryptic and caspase 
domains. 
 
 
Chemical Structure of Carfilzomib 
 
 
 
Carfilzomib is less reactive to non-proteasome proteases compared to bortezomib, likely 
contributing to lower levels of neuropathy and myelosuppression11-13. In vitro models 
suggest carfilzomib has activity against bortezomib resistant myeloma cell lines 12. 
Carfilzomib can also work synergistically with dexamethasone to enhance tumor cell 
death12. A number of phase I and phase II studies are currently investigating carfilzomib 
toxicity and efficacy in MM. 
5.1.2 
Formulation and Preparation of Drug 
Carfilzomib for Injection will be provided as a lyophilized powder which, when 
reconstituted, contains 2 mg/mL isotonic solution of carfilzomib Free Base in 10 mM 
sodium citrate buffer (pH 3.5) containing 10% (w/v) sulfobutylether- -cyclodextrin 
(SBE- -CD, Captisol®). Lyophilized Carfilzomib for Injection is stored in a refrigerator at 
2°C–8°C. Water for injection is the only acceptable solution for reconstitution. Vials are for 
single use. After addition of the appropriate amount of water for injection and mixing, a 
volume of carfilzomib appropriate for a patient's dose will be added to 5% dextrose 
injection (D5W) in a sufficient amount to yield a volume to administer 100 mL in a polyvinyl 
chloride or polyolefin container is administered as an IV infusion . 
 
For clinical use, Carfilzomib products will contain excess drug-containing fluid to 
compensate for product container and administration set priming volumes. 

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IRB Number: 15-326 A(11) 
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Page 15 of 64 
 
 
Before dispensing Carfilzomib products from the Pharmacy, an administration set suitable 
for a portable pump (e.g., Gemstar set 13758-28) will be attached, the administration set 
tubing will be primed with drug-containing fluid, air will be purged from the tubing (but not 
the product container), and the administration set will be capped with a Luer locking cap. 
Lyophilized Carfilzomib for Injection is an investigational therapeutic agent provided in a 
single-dose vial as a sterile, lyophilized powder in the following dosages: 
 
• 
60 mg Single-Use Glass Vial / 4 pk Carton: Each single-dose vial provides 60 mg of 
carfilzomib in a 50 mL labeled glass vial with an elastomeric stopper and Blue flip-off 
lid. The product is supplied in labeled carton(s) containing four (4) single-use 
vials/carton and is shipped and stored between 2°C - 8°C (36°F - 46°F). Remove the 
Blue flip-off lid on the vial and aseptically add 29 mL of Water for Injection, USP to the 
lyophilized drug. Gently invert the vial multiple times and let stand to yield a clear 
solution containing 2 mg/mL carfilzomib. After reconstitution as instructed, a maximum 
total of 30 mL deliverable volume containing 60 mg of carfilzomib can be withdrawn 
from the vial. 
 
5.1.2.1 
Inspection 
The reconstituted drug solution in the vial should be a clear liquid. Inspect all vials for the 
presence of any suspended particles, particulate matter, discoloration or hazy solution 
prior to administration. 
 
If the solution is not clear or particles exist in inspected vials, record the observation in the 
appropriate Drug Accountability Log and notify Amgen immediately. 
• 
DO NOT USE THE DRUG. 
• 
Place the vial(s) into a plastic bag labeled as "Quarantined" with the date. 
• 
Store labeled quarantined drug in a temperature-monitored refrigerator and ensure 
they are physically segregated from the drug that is available for use. 
• 
Amgen will instruct the clinical site on how to proceed with quarantined vial(s). 
 
5.1.2.2 
Calculation of Dose 
Each dose will consist of Carfilzomib for Injection administered on a mg/m2 basis, and 
should be based on the patient's actual calculated body surface area (BSA). 
The BSA should be calculated based upon the institution's practice and method of 
calculation should remain consistent throughout a subject's participation in the trial. 
Subjects with a BSA > 2.2 m2 will receive a dose based upon a 2.2 m2 BSA. 
Dose adjustments do not need to be made for weight gains/losses of ≤ 20%. 
5.1.2.3 
Lyophilized Drug Product 
Lyophilized Carfilzomib for Injection must be kept in the labeled drug cartons and stored at 
2°C - 8°C (36°F - 46°F) in a refrigerator. If procedures permit, the refrigerator should be 
continuously monitored and temperature records retained for review. The refrigerator 
should also be on a backup generator and alarmed for temperature deviations if available. 
Lyophilized Carfilzomib for Injection exposed at any time to temperatures exceeding 30°C 
/ 86°F must be discarded. 

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IRB Number: 15-326 A(11) 
Approval date: 08-Oct-2020 
Page 16 of 64 
 
 
 
 
 
5.1.2.4 
Reconstituted Drug Product 
Once a drug vial is reconstituted and inspected, the clear solution can be stored in a 
refrigerator (recommended) controlled from 2°C - 8°C (36°F - 46°F) or at room 
temperature from 15°C - 30°C (59°F - 86°F) until use. Once reconstituted, Carfilzomib for 
Injection must be used on the day of reconstitution or else it must be destroyed. Prior to 
administration, all reconstituted drug should be equilibrated to room temperature. DO NOT 
FREEZE LYOPHILIZED OR RECONSTITUTED DRUG. 
 
5.1.2.5 
Diluted Drug Product 
After dilution with D5W for clinical use, Carfilzomib should be stored under refrigeration. 
 
 
5.1.3 
Administration procedures: 
Carfilzomib will be administered by intravenous infusion over 10 minutes for the 20 mg/m2 
dose and over 30-minutes for the 56 mg/m2. 45 mg/m2 and 36 mg/m2 doses through a 
peripheral or central venous access device via portable (ambulatory) pump. Care should 
be taken in placing and maintaining the product container at a level physically higher than 
the pump to avoid advancing air into the administration set tubing. 
If the patient has a dedicated line for carfilzomib administration, the line must be flushed 
with a minimum of 20 mL of normal saline prior to and after drug administration. 
5.1.4 
Incompatibilities: 
In an in vitro study using human liver microsomes, carfilzomib showed modest direct and 
time-dependent inhibitory effect on human cytochrome CYP3A4/5. Given that the 
clearance of carfilzomib likely occurs extrahepatically via the activity of epoxide hydrolase 
and peptidase activities, the clinical relevance of these in vitro results is not clear. No 
clinically significant drug interactions have been noted to date in patients receiving a 
variety of agents metabolized by CYP3A4. Moreover, no dose adjustments have been 
required for any concomitant medication in patients receiving carfilzomib. However, 
caution should be exercised in administration of concomitant medications which are 
substrates of human CYP3A4. 
 
5.2 
Lenalidomide 
5.2.1 
Scientific Background 
REVLIMID® (lenalidomide), a thalidomide analogue, is an immunomodulatory agent with 
anti-angiogenic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -2H- 
isoindol-2-yl) piperidine-2,6-dione and it has the following chemical structure: 
Chemical Structure of Lenalidomide 

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IRB Number: 15-326 A(11) 
Approval date: 08-Oct-2020 
Page 17 of 64 
 
 
O 
H 
N 
O 
 
N 
O 
 
NH2 
The mechanism of action of lenalidomide remains to be fully characterized. Although the 
exact antitumor mechanism of action of lenalidomide is unknown, a number of 
mechanisms are postulated to be responsible for lenalidomide’s activity against MM. 
Lenalidomide has been shown to increase T cell proliferation, which leads to an increase 
in IL-2 and IFN-gamma secretion. The increased level of these circulating cytokines 
augment natural killer cell number and function, and enhance natural killer cell activity to 
yield an increase in MM cell lysis. In addition, lenalidomide has direct activity against MM 
and induces apoptosis or G1growth arrest in MM cell lines and in MM cells of patients 
resistant to melphalan, doxorubicin and dexamethasone. Revlimid® is approved in 
combination with dexamethasone for the treatment of patients with MM that have received 
at least one prior therapy.17,18 The drug has also been studied in newly diagnosed patients 
in combination with low-dose dexamethasone, as well as with bortezomib and 
dexamethasone as mentioned earlier.19,8 
5.2.2 
Forumulation and Preparation of Drug 
Lenalidomide will be supplied as capsules for oral administration. Celgene Inc. will provide 
lenalidomide 5, 10, 15 and 25 mg capsules for the Induction Phase of the protocol and for 
the extended dosing phase(s). 
5.2.3 
Stability and Storage: 
Lenalidomide should be stored at room temperature away from direct sunlight and 
protected from excessive heat and cold. 
5.2.4 
Administration procedures: 
Celgene Corporation will supply Revlimid® (lenalidomide) to study participants at no 
charge through the REMS® program. Bottles will contain a sufficient number of capsules 
for one cycle of dosing; no more than a one-month supply of lenalidomide may be 
dispensed at one time. 
5.2.5 
Incompatibilities: 
Results from human in vitro metabolism studies and nonclinical studies show that 
REVLIMID is neither metabolized by nor inhibits or induces the cytochrome P450 pathway 
suggesting that lenalidomide is not likely to cause or be subject to P450- based metabolic 
drug interactions in man. 
 
Digoxin 
When digoxin was co-administered with lenalidomide, the digoxin AUC was not 
significantly different; however, the digoxin Cmax was increased by 14%. Periodic 
monitoring of digoxin plasma levels, in accordance with clinical judgment and based on 

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IRB Number: 15-326 A(11) 
Approval date: 08-Oct-2020 
Page 18 of 64 
 
 
standard clinical practice in patients receiving this medication, is recommended during 
administration of lenalidomide. 
 
Warfarin 
Co-administration of multiple doses of 10 mg of lenalidomide had no effect on the single 
dose pharmacokinetics of R- and S-warfarin. Co-administration of single 25-mg dose 
warfarin had no effect on the pharmacokinetics of total lenalidomide. Expected changes in 
laboratory assessments of PT and INR were observed after warfarin administration, but 
these changes were not affected by concomitant lenalidomide administration. 
 
Concomitant Therapies That May Increase the Risk of Thrombosis 
Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as 
estrogen containing therapies, should be used with caution in MM patients receiving 
lenalidomide with dexamethasone 
 
 
5.3 
Dexamethasone 
5.3.1 
Preparation, Handling, Storage 
Dexamethasone is a synthetic adrenocortical steroid. Corticosteroids are naturally- 
occurring chemicals produced by the adrenal glands located above the kidneys. 
Corticosteroids affect the 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. The empirical 
formula is C22H29FO5 and the structural formula is: 
 
 
Dexamethasone is stable in air and almost insoluble in water. 
 
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. 

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IRB Number: 15-326 A(11) 
Approval date: 08-Oct-2020 
Page 19 of 64 
 
 
At the study site, all investigational study drugs will be stored in a locked, safe area to 
prevent unauthorized access. Dexamethasone should be stored at controlled room 
temperature, 68-77◦F (20-25◦C) and not frozen, and according to label requirements. 
Dexamethasone should be handled by trained pharmacy staff. The use of gloves and 
other appropriate protective clothing is recommended as necessary. 
 
Dexamethasone supply will be obtained through commercial supply. 
Dexamethasone is an oral drug, and does not require specific preparation details. 
At the end of the study, unused supplies of dexamethasone should be destroyed and 
documented according to institutional policies. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
Describe the characteristics of the patient/subject population. 
6.1 
Subject Inclusion Criteria 
• 
Newly diagnosed patients with histologically confirmed MM based on the following 
criteria: 
o Clonal plasma cells in the bone marrow 
o Measurable disease within the past 4 weeks defined by any one of the following: 
- 
Serum monoclonal protein ≥ 1.0 g/dL 
- 
Urine monoclonal protein >200 mg/24 hour 
- 
Involved serum immunoglobulin free light chain > 10 mg/dL AND abnormal 
kappa/lambda ratio 
 
• 
Evidence of underlying end organ damage and/or myeloma defining event attributed to 
underlying plasma cell proliferative disorder meeting at least one of the following: 
o Hypercalcemia: serum calcium >0.25 mmol/L (> 1 mg/dL) above upper limit of 
normal or ≥ 2.75 mmol/L (11 mg/dL) 
o Anemia: hemoglobin value <10 g/dL or > 2 g/dL below lower limit of normal 
o Bone disease: ≥ 1 lytic lesions on skeletal X-ray, CT, or PET-CT. For patients with 
1 lytic lesion, bone marrow should demonstrate ≥10% clonal plasma cells 
o Clonal bone marrow plasma cell percentage ≥60% 
o Involved/un-involved serum free light chain ratio ≥100 and involved free light chain 
>100 mg/L. 
o > 1 focal lesion on magnetic resonance imaging study (lesion must be >5 mm) in 
size 
 
• 
Creatinine Clearance ≥ 60 ml/min. CrCl can be measured or estimated using 
Cockcroft-Gault method 
 
• 
Age ≥ 18 years at the time of signing the informed consent documentation 

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Page 20 of 64 
 
 
• 
Eastern Cooperative Oncology Group (ECOG) performance status 0-2 
 
• 
Absolute neutrophil count (ANC) ≥ 1.0 K/uL, hemoglobin ≥ 8 g/dL, and platelet count ≥ 
75 K/uL, unless if cytopenias are deemed to be due disease at discretion of clinical 
investigator. Transfusions and growth factors are permissible. 
 
• 
Adequate hepatic function, with bilirubin < 1.5 x the ULN, and AST and ALT < 3.0 x 
ULN. 
 
• 
All study participants must be able to tolerate one of the following thromboprophylactic 
strategies: aspirin, low molecular weight heparin or warfarin (coumadin) or alternative 
anti-coagulant. 
 
• 
All study participants must be registered into the mandatory eREMS® program, and be 
willing and able to comply with the requirements of REMS®. 
 
• 
Females of childbearing potential (FCBP)† must have a negative serum or urine 
pregnancy test within 10 – 14 days and again within 24 hours prior to prescribing 
lenalidomide for Cycle 1 (prescriptions must be filled within 7 days) and must either 
commit to continued abstinence from heterosexual intercourse or begin TWO 
acceptable methods of birth control, one highly effective method and one additional 
effective method AT THE SAME TIME, at least 28 days before she starts taking 
lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree 
to use a latex condom during sexual contact with a FCBP even if they have had a 
successful vasectomy. 
 
†A female of childbearing potential is a sexually mature female who: 1) has not undergone 
a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal 
for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 
consecutive months). 
 
6.2 
Subject Exclusion Criteria 
• 
Patients receiving >1 cycle of prior treatment or concurrent systemic treatment for 
multiple myeloma 
o Treatment of hypercalcemia or spinal cord compression or aggressively 
progressing myeloma with current or prior corticosteroids is permitted 
o Bisphosphonates are permitted 
o Concurrent or prior treatment with corticosteroids for indications other than 
multiple myeloma is permitted 
o Prior treatment with radiotherapy is permitted 
o Prior treatment for smoldering myeloma is permitted with a washout period 
of 4 weeks from last dose. Smoldering patients previously treated with 
carfilzomib are excluded. 

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o Patients with measurable disease who received up to one cycle of any 
therapy within 60 days with a washout period of 4 weeks from last dose (on 
a trial or outside a trial) are eligible 
 
• 
Plasma cell leukemia 
 
• 
POEMS syndrome 
 
• 
Amyloidosis 
 
• 
Pregnant or lactating females. Becase there is a potential risk for adverse events 
nursing infants secondary to treatment of the mother with carfilzomib in 
combination with lenalidomide. These potential risks may also apply to other 
agents used in this study. 
 
• 
Uncontrolled hypertension or diabetes 
 
• 
Active hepatitis B or C infection 
 
• 
Known or suspected HIV or serologically positive 
 
• 
Has significant cardiovascular disease with NYHA Class III or IV symptoms, 
EF<40% or hypertrophic cardiomyopathy, or restrictive cardiomyopathy, or 
myocardial infarction within 6 months prior to enrollment, or unstable angina, or 
unstable arrhythmia as determined by history and physical examination. 
Echocardiogram will be performed during screening evaluation. 
 
• 
Moderate or severe pulmonary hypertension defined as PASP > 50mm Hg. For 
those patients where PASP is indeterminate, moderate to severe symptoms of 
pulmonary hypertension ( World Health Organization functional assessment class 
III or IV) will be used to determine exclusion criteria. 
 
• 
Has refractory GI disease with refractory nausea/vomiting, inflammatory bowel 
disease, or bowel resection that would prevent absorption of oral agents 
• 
Uncontrolled intercurrent illness including but not limited to active infection or 
psychiatric illness/social situations that would compromise compliance with study 
requirements 
• 
Significant neuropathy ≥Grade 3 or Grade 2 neuropathy with pain at baseline 
• 
Contraindication to any concomitant medication, including antivirals or 
anticoagulation. 
• 
Major surgery within 3 weeks prior to first dose 
 
 
7.0 
RECRUITMENT PLAN 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-326 A(11) 
Approval date: 08-Oct-2020 
Page 22 of 64 
 
 
This study will be conducted at MSKCC. Efforts will be made to ensure that women and 
minority groups are adequately represented in this trial. Internally, an effort will be made 
to position this protocol for patients that demonstrate high-risk prognostic features, so as 
not to conflict with other ongoing newly-diagnosed multiple myeloma studies. All patients 
will be seen by MSKCC myeloma physicians and associated MSKCC co-investigators, 
enrolled and registered at MSKCC. All co-investigators agree to follow the treatment in the 
protocol and to conduct the proposed investigation according to recognized principles of 
good clinical practice. Participation is voluntary. Each patient must be informed about the 
neoplastic nature of his/her disease and willingly consent to participation in this study. 
Every patient will be informed of the procedures to be followed, the potential benefits, side 
effects, risks, and discomforts of the trial and of potential therapeutic alternatives. All 
participants will be required to sign statements of informed consent and research 
authorization that conform to FDA, IRB and HIPAA guidelines. Informed consent will be 
documented by the use of a written consent form that has been approved by the MSKCC 
IRB. 
 
 
 
 
8.0 
PRETREATMENT EVALUATION 
• 
A complete history and physical examination with documentation of measurable 
disease and assessment of performance status using the ECOG scale must be 
performed within 4 weeks prior to study entry 
o Patients will be evaluated for baseline neuropathy. Patients with grade 2 with 
painful neuropathy or grade 3 and higher will be excluded. 
 
The following laboratory tests will be completed within 4 weeks prior to study entry 
• 
CBC with differential and reticulocyte count 
• 
Chem 14, Magnesium, and Phosphate and eGFR determination 
• 
Uric acid, LDH, and Beta-2 Microglobulin 
• 
PT, PTT 
• 
Serum protein electrophoresis (SPEP) and immunofixation to assess for presence and 
quantity of monoclonal protein (M-protein) 
• 
24 hour urine sample for protein electrophoresis (UPEP) and immunofixation to assess 
for monoclonal protein in the urine (Bence-Jones proteinuria) at baseline. 
• 
Serum free light-chain studies, determined using the FreeliteTM assay system 
• 
Quantitative immunoglobulins 
• 
Viral serologies 
o Hepatitis B surface antigen 
o Anti-Hepatitis C (HCV) antibody. If positive, will follow with HCV RNA PCR 
• 
Review of bone marrow core biopsy and aspirate. 
• 
Serum or urine pregnancy test in women of child-bearing potential. 
• 
12-lead EKG 
• 
Echocardiogram – 2D Echo or strain echo 

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Research and clinical laboratory tests to be performed within 4 weeks of study entry and prior to 
starting therapy 
• 
Bone Marrow 
o Histopathological evaluation on bone marrow aspirate and biopsy 
o Immunophenotyping of aberrant clonal plasma cells by multiparametric flow 
cytometry. 
o Immunoglobulin heavy and/or light chain rearrangement. 
o Interphase FISH/cytogenetics 
o To create a bone marrow and peripheral blood sample bank of whole BM 
lysate, CD 138+ fractions and CD 138- fractions cell sorting with subsequent 
correlatives on both fractions. These samples may be used to later evaluate 
biological activity of carfilzomib, lenalidomide, and dexamethasone. Potential 
analyses include sequencing and gene expression profiling on pre and post 
therapy bone marrow samples, identification of potential biomarkers (blood, 
urine, bone marrow aspirates), and evaluation of proteasome activity. 
 
 
• 
Peripheral Blood/Urine 
o Peripheral blood and urine samples for storage and establishing a biobank. 
o Immune cells – including, but not limited to T cells (CD4 and CD8), LGL, and 
NK cells. 
 
Imaging (FDG/PET/CT scan) within 4 weeks of study entry and prior to starting therapy 
Prior to 18F-FDG PET/CT imaging, the subject will be fasted and have not received any sugar 
containing substance (i.e. glucose, sucrose, dextrose) for 4-6 hours. Subjects will be encouraged 
to drink water during this period to reduce radiation dose to the kidneys and will be asked to void 
prior to 18F-FDG injection. Women of childbearing potential will have a documented report of 
negative pregnancy test from the CC or another accredited lab performed on the day of the scan 
or the day before the scan. 
 
18F-FDG, [18F]-fludoeoxyglucose is an FDA approved radiopharmaceutical. Immediately prior to 
injection, the subject’s blood glucose level will be evaluated via fingerstick. Non-diabetic subjects 
with fasting blood glucose levels above 150 mg/dl may be rescheduled at the discretion of the PI. 
Subjects will be asked to refrain from excessive physical exertion for the 24 hours prior to 
injection. The 18F-FDG injection procedure will be injected and be followed by a ~20 ml saline 
(sodium chloride IV infusion 0.9% w/v) flush over a period of ~20 seconds. The injection site will 
be evaluated pre- and post administration for any reaction (e.g. bleeding, hematoma, redness, or 
infection). 
 
Whole body (vertex to toes) static PET/CT imaging will be performed beginning at 1-hour, and 
again at 2-hours post injection. PET/CT standard operating procedures. The patient will be 
instructed to maintain good hydration in order to reduce the radiation dose. 

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The radiation dose from the procedure will be a maximum of 2.1 rem per year; this is within the 
RSC guidelines of 5.0 rem per year for adults. 
 
PET-CT performed within the 4 weeks at an outside institution can be acceptable as baseline 
study as long as films are forwarded to the Department of Radiology for an official MSKCC 
reading 
 
9.0 
TREATMENT/INTERVENTION PLAN 
Patients who have signed the consent form and are deemed eligible for this clinical trial will start 
therapy with carfilzomib, lenalidomide and dexamethasone (CRd) with the following schedule: 
• 
Length of cycle: 28 days. Treatment window for day 1 of start of each cycle is +/- 7 days. 
Treatment window for intra-cycle carfilzomib doses is + /- 3 days. 
• 
These cycles will consist of: 
o Carfilzomib 
▪ 
Cycle 1: 20 mg/m2 IV infusion over 10 minutes on days 1 and 2, then 45 or 
56 mg/m2 IV infusion over 30 minutes on days 8, 9, 15, and 16 depending 
on the assigned dose level 
▪ 
Cycle 2 - up to 12: 45 or 56 mg/m2 IV infusion over 30 minutes on days 1, 
2, 8, 9, 15, and 16 
o Lenalidomide 
▪ 
Cycle 1 - up to 12: 25 mg oral days 1-21 of 28-day cycle 
o Dexamethasone 
▪ 
Cycle 1-4: 20 mg oral or IV on days 1, 2, 8, 9, 15, 16, 22, and 23 
▪ 
Cycle 5 - up to 12: 10 mg oral or IV on days 1, 2, 8, 9, 15, 16, 22, and 23 
 
 
 
 
9.1 
Cycle 1 adjustments 
In Cycle 1, the following adjustments to the dosing schema will be implemented: 
• 
Per FDA label recommendations and standard dosing in previous trials, carfilzomib 
will be given at a lower dose of 20 mg/m2 on Days 1 and 2 of Cycle 1. Initiating 
carfilzomib at higher doses than 20 mg/m2 may increase risk of cytokine release- 
like syndrome. 
• 
Hydration will be administered prior and subsequent to carfilzomib dosing at the 
clinical discretion of the investigator or per MSKCC institution standard care 
practice. 
9.2 
Dose Modifications 
9.2.1 
Dose Reductions for Lenalidomide 

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Page 25 of 64 
 
 
 
Lenalidomide 
Baseline dose 
25 mg 
One level dose reduction 
20 mg 
Two level dose reduction 
15 mg 
Three level dose 
reduction 
10 mg 
Four level dose 
reduction 
5 mg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.2.2 
Dose Reductions for Carfilzomib 
 
 
Carfilzomib 
DL -1 
Carfilzomib 
DL 1 
Carfilzomib 
DL 2 
Baseline dose 
36 mg/m2 
45 mg/m2 
56 mg/m2 
One level dose 
reduction 
27 mg/m2 
36 mg/m2 
45 mg/m2 
Two level dose 
reduction 
20 mg/m2 
27 mg/m2 
36 mg/m2 

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If more than 2 dose reductions are required with Carfilzomib, study treatment will be 
discontinued and the patient will go off therapy. De-escalation of carfilzomib occurring in 
patients during first cycle (DLT window) of phase I will count as a DLT. 
 
 
9.2.3 
Dose Reductions for Dexamethasone 
 
 
Dexamethasone 
Cycles 1-4 
Dexamethasone 
Cycles 5-10 
Baseline dose 
20 mg 
10 mg 
One level dose reduction 
10 mg 
4 mg 
Two level dose reduction 
4 mg 
0 mg 
Three level dose 
reduction 
0 mg 
 
9.3. 
Hematologic Toxicity 
9.3.1 
On day 1 of each new cycle, patients must meet the following criteria: 
• 
ANC ≥ 1.0 x 109 /L 
• 
AST and ALT < 5 x ULN 
• 
Platelet count ≥ 50 x 109 /L 
9.3.2 
If these conditions are not met on Day 1 of a new cycle: 
• 
The next cycle of treatment will not be initiated until the above conditions 
(section 9.3.1) are met. If ANC and platelet counts do not satisfy the 
requirements above after 2 weeks of withholding treatment, the subject will 
go off therapy. Transfusions and growth factors are permissible after cycle 
1. 
• 
For patients not meeting day 1 criteria (section 9.3.1) for two cycles (non- 
consecutive), the study drug dose(s) will be modified for the next cycle 
based on dose reduction tables of section 9.2. 
9.3.3 
If a patient develops thrombocytopenia or neutropenia during the cycle, 
then the following actions would take place (see 
Thrombocytopenia/Neutropenia table below). 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-326 A(11) 
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Page 27 of 64 
 
 
 
Thrombocytopenia 
Lenalidomide 
Carfilzomib 
Fall to < 25 x 109/L 
Hold both Lenalidomide and Carfilzomib, follow CBC at least weekly or 
more frequently if clinically indicated. Hold prophylactic anti-coagulation. 
Return to ≥ 25 x 
109/L 
Resume lenalidomide at next dose 
reduction 
Resume carfilzomib at full 
dose.* 
Subsequent fall to < 
25 x 109/L 
Hold both Lenalidomide and Carfilzomib, follow CBC at least weekly or 
more frequently if clinically indicated. Hold prophylactic anti-coagulation. 
Return to ≥ 25 x 
109/L 
Resume lenalidomide at next dose level 
reduction 
Resume carfilzomib at full 
dose.* 
*Carfilzomib may be dose reduced at the clinical discretion of investigator. 
 
 
 
Neutropenia (Absolute 
Neutrophil Count) 
Lenalidomide 
Carfilzomib 
Falls to < 0.5 x 109/L or to 
< 1.0 x 109/L with fever 
Hold Lenalidomide and Carfilzomib. Add filgrastim if Grade 3 
with fever (single temperature of 38.3ºC or sustained 
temperature of 38ºC for > 1 hour) or Grade 4. Follow CBC at 
least weekly or more frequently if clinically indicated. 
Returns to ≥ 1.0 x 109/L 
Resume Lenalidomide at 
next dose reduction. 
Resume Carfilzomib at full 
dose.* 
Subsequent drop to < 0.5 x 
109/L or to < 1.0 x 109/L with 
fever 
Hold Lenalidomide and Carfilzomib. Add filgrastim if Grade 3 
with fever or Grade 4. Follow CBC at least weekly or more 
frequently if clinically indicated. 
Returns to ≥ 1.0 x 109/L 
Resume Lenalidomide at 
next dose reduction. 
Resume Carfilzomib at full 
dose.* 
*Carfilzomib may be dose reduced at the clinical discretion of investigator. 
 
 
9.4 
Non-Hematologic Toxicities Requiring Dosing Modifications 
9.4.1 
Any ≥Grade 3 toxicity require appropriate study drug to be held until 
resolved to Grade 1 or baseline (unless specified below in tables 9.4.4) 
prior to resuming therapy or initiating next cycle. Investigator will determine 
which drug will be held based on side effect profile and clinical judgment. If 
therapy has been held for more than 2 weeks due to non-hematologic 
toxicity, the patient will be removed from protocol therapy. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-326 A(11) 
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Page 28 of 64 
 
 
9.4.2 
Protocol therapy will be withheld for patients who require treatment of 
Grade 3 infection. If therapy has been held for more than 3 weeks due to 
treating a grade 3 infection, the patient will be removed from protocol 
therapy. 
9.4.3 
For patients experiencing ≥grade 3 toxicity (unless specified below in tables 
9.4.4), subsequent doses will be reduced at next dose level (according to 
the tables in section 9.2) if the adverse event was deemed to beattributed 
to study drugs. If the adverse event was deemed to be unrelated to study 
drugs, the patient may continue the full dose. 
 
9.4.4 
Electrolyte or metabolic abnormalities that are reversible with electrolyte 
replacement within 72 hours or < grade 3 infections that can be controlled 
by appropriate therapy are exempt from holding treatment or dose 
modifications. 
 
 
Lenalidomide Toxicities 
Specific Dosing Modifications 
Blistering Rash (Any Grade) 
Discontinue lenalidomide and remove patient from therapy 
Venous thrombosis/embolism 
Hold lenalidomide and start therapeutic anticoagulation. 
Restart lenalidomide at investigator’s discretion at current 
dose level. 
Renal Dysfunction 
CrCl based on Cockcroft-Gault 
formula: CrCl = (140 – Age) x 
Mass (in kilograms) x [0.85 if 
Female] 72 x Serum Creatinine 
(in mg/dL) 
• 
CrCl 31-60 ml/min – Dose reduce lenalidomide to 10 
mg daily from Days 1-21 
• 
CrCl ≤30 mL/min (not requiring dialysis) – Dose reduce 
Lenalidomide to 15 mg every 48 hours 
• 
CrCl ≤30 mL/min (requiring dialysis) – Decrease 
Lenalidomide to 5 mg daily and on dialysis days 
give lenalidomide dose after dialysis. 
Infection (≥Grade 3) 
Hold therapy, treat underlying infection. 
Remove patient from therapy if treatment of grade 3 
infection persists for more than 3 weeks. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-326 A(11) 
Approval date: 08-Oct-2020 
Page 29 of 64 
 
 
 
Carfilzomib Toxicities 
Specific Dosing Modifications 
Allergic Reaction/Hypersensitivity 
• 
Grade 2: Hold carfilzomib until ≤ Grade 1 and resume 
at full carfilzomib dose 
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 carfilzomib until all abnormalities in serum chemistries 
have resolved. Resume at full dose 
Herpes zoster or simplex of any 
grade 
Hold carfilzomib until lesions are dry. Resume at full dose 
Neuropathy 
Grade 2 treatment emergent neuropathy with pain: Hold 
carfilzomib until resolved to ≤ Gr 1 without pain. Then 
restart at next dose level reduction. 
Congestive Heart Failure 
Any subject with symptoms of congestive heart failure, 
whether or not drug related, must have the dose held until 
resolution, clinically controllable (see below) or return to 
baseline. 
In patients with preserved EF, if symptoms are controllable 
by fluid management measures, patients may continue at 
current carfilzomib dose level. In patients with preserved 
EF but symptoms are not controllable by fluid management 
measures, carfilzomib should be dose reduced at next 
dose level. 
Any patient with symptomatic Class III or IV Heart failure 
and ejection fraction decrease from baseline, will stop 
therapy and go off protocol. 
Hypertension (uncontrollable by 
medications, hypertension 
emergencies, or >3 episodes of 
hypertension urgencies) 
Hypertension uncontrollable by medications or >3 episodes 
of hypertension urgencies – hold carfilzomib and decrease 
to next dose level. 
Hypertension emergecy – stop therapy and go off protocol 
Myocardial infarction 
Any patient experiencing myocardial infarction will stop 
therapy and go off protocol 

Memorial Sloan Kettering Cancer Center 
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Page 30 of 64 
 
 
9.5 
Monitoring 
 
9.5.1 
Routine labs (CBC, chemistry panel 14, LDH, magnesium, uric acid, phosphate) 
will be performed on Day 1, 2, 8, 15, and 22 of cycle 1, Day 1 of each cycle 
thereafter, end of therapy, and 1-year and 3-year after end of therapy. Myeloma 
tests include serum protein electrophoresis, serum immunofixation, beta-2 
microglobulin, quantitative immunoglobulins and serum free light chains assay will 
be performed at baseline, Day 1 of each cycle, end of therapy, and 1-year and 3- 
year after end of therapy. Serum Lymphocyte subsets will be performed at 
baseline, Day 1 of cycle 4, and end of treatment. Routine labs, myeloma labs, and 
lymphocyte subsets can be performed 24 hrs in advance. 
9.5.2 
For patients with intial baseline 24-hr UPEP samples demonstrating ≥100 mg/24 
hrs, patients with continue to have 24-hr UPEP samples day 1 of each cycle. 
Once 24-hr UPEP is <100 mg/24 hrs, patient can have random UPEP with IFE 
until achieving negativity. If initial baseline 24-hr UPEP sample is IFE positive 
and/or <100 mg/24, patients can have random UPEP samples with IFE until 
achieving negativity. Once random UPEP and IFE is negative, no further urine 
samples are needed (unless patient’s disease is primarily measurable by 24 hr 
urines i.e. oligosecretory/hyposecretory) 
9.5.3 
Patients will have clinic visits with H&P or standard progress notes assessing for 
toxicity/side effects on Day 1 of each cycle, end of therapy, 1-month after end of 
therapy, 1-year after end of therapy and 3-year after end of therapy. Treatment 
window for day 1 of start of each cycle is +/- 7 days. Treatment window for intra- 
cycle carfilzomib doses is +/- 3 days. 
9.5.4 
At CR/sCR or end of therapy, routine labs (CBC, chemistry panel 14, LDH, 
magnesium, uric acid, phosphate), myeloma specific tests - serum protein 
electrophoresis, serum immunofixation, beta-2 microglobulin, quantitative 
immunoglobulins and serum free light chains assay, lymphocyte subsets, 24-hr 
urine sample for protein electrophoresis (UPEP) and immunofixation to assess for 
monoclonal protein in the urine (Bence-Jones proteinuria). A bone marrow aspirate 
will also be performed to assess the status of minimal residual disease by flow 
cytometry (Sample sent will be the first bone marrow “pull”). Patient will have clinic 
visit (relevant clinical laboratorie and H&P) 1 month after completing combination 
therapy to undergo assessment of toxicities/adverse events. 
 
9.5.5 
Patients will have an EKG and echocardiogram (2-D or strain scho) performed at 
baseline and after completion of 4 cycles of therapy. Outside echocardiograms 
are permissable 
9.5.6 
Patients will have FDG-PET-CT at baseline, end of therapy or upon suspicion of 
progressive disease as clinically indicated. 
9.5.7 
PFS and OS data will be collected for patients. 
 
9.6 
After Protocol Therapy 
 
9.6.1 
Upon completion of protocol therapy, patients will be encouraged to proceed onto 
maintenance therapy or high dose therapy with stem cell rescue under a separate 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-326 A(11) 
Approval date: 08-Oct-2020 
Page 31 of 64 
 
 
treatment protocol or standard of care. If clinically indicated, patients may need 
additional alternative therapy. 
 
9.6.2 
After completion of protocol therapy, patients will remain on study for an additional 
3 years for survival analysis. 
 
CONCOMITANT MEDICATIONS/MEASURES 
TUMOR LYSIS SYNDROME 
Hydration and Fluid Monitoring 
a) Oral hydration: For patients deemed at risk for TLS or dehydration, oral hydration 
may be considered (i.e., volume replete). Begin oral hydration equal to 
approximately 30 mL/kg/day (~6–8 cups of liquid per day), starting 48 hours prior 
to the planned first dose of carfilzomib. Compliance must be reviewed with the 
subject and documented by the site personnel prior to initiating treatment with 
carfilzomib; treatment is to be delayed or withheld if oral hydration is not deemed to 
be satisfactory. 
b) IV hydration: IV hydration will be administered per MSKCC institutional standards 
and can be adjusted at the clinical discretion of the investigator. 
 
Laboratory Monitoring 
1) Appropriate basic metabolic panel chemistries, including creatinine for day 1 of each cycle 
and days 1, 8, and 15 of cycle 1, and complete blood counts (CBC) with platelet count 
should be obtained. Labs may be drawn 24 hrs prior to receiving treatment. 
2) Subjects with laboratory abnormalities consistent with lysis of tumor cells -fold increase, 
(e.g., serum creatinine ≥ 50% increase, 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 
Clinical Monitoring 
1) Signs and symptoms indicative of TLS, such as fevers, chills/rigors, dyspnea, nausea, 
vomiting, muscle tetany, weakness, or cramping, seizures, and decreased urine output. 
Management 
1) If TLS occurs, cardiac rhythm, fluid, and serial laboratory monitoring should be instituted. 
Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer 
therapeutic and supportive care, including dialysis, as clinically indicated. 
 
Optional medication for high-risk TLS patients 
1) Allopurinol is optional and will be prescribed at the Investigator’s discretion. These 
subjects may receive allopurinol 300 mg PO BID (Cycle 1 Day -2, Day -1), continuing for 2 
days after Cycle 1 Day 1 (total of 4 days), then reduce dose to 300 mg PO QD, continuing 
through Day 17 of Cycle 1. Allopurinol dose should be adjusted according to the package 
insert. At this point, the investigators do not anticipate the need for using rasburicase. 
Subjects who do not tolerate allopurinol should be discussed with the Lead Principal 
Investigator. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-326 A(11) 
Approval date: 08-Oct-2020 
Page 32 of 64 
 
 
BONE DISEASE/EXTRAMEDULLARY DISEASE 
1) Radiation therapy: Subjects may receive limited local radiation for treatment of 
uncontrolled pain, cord compression, vertebral instability/impending fracture, etc. 
2) Kyphoplasty/Vertebroplasty: Subjects may receive kyphoplasty/vertebroplasty for 
symptomatic vertebral compression fractures. 
3) Bisphophonate therapy: Approved bisphophonate therapy ( zoledronic acid or 
pamidronate) is allowed. Patients will be monitored for renal function and osteonecrosis of 
the jaw. Patients may require prior evaluation from dental specialist before instituting 
bisphosphonates. 
HYPERCALCEMIA 
Patients may receive treatment for hypercalcemia including hydration, bisphophonates, 
furosemide, steroids, calcitonin, etc. 
TRANSFUSIONS/GROWTH FACTORS 
1) Subjects may receive RBC or platelet transfusions if clinically indicated. 
2) Subjects may receive supportive care with erythropoietin or darbopoetin. 
3) Colony-stimulating factors may be used if neutropenia occurs. 
4) Growth factors and transfusions should not be administered prophylactically during cycle 1 
unless clinically indicated. 
ANTI-COAGULATION 
Oral Aspirin 81 mg or 325 mg or suitable alternative anti-coagulation for thrombotic prophylaxis 
every day for the duration of their participation in the study. 
HSV, VSV, PCP PROPHYLAXIS 
Oral Valacyclovir of 500 mg daily or suitable alternative of Acyclovir throughout all cycles in which 
carfilzomib is given. 
If CD4 count </= 200 /uL, PCP Prophylaxis with Bactrim/Pentamidine/Dapsone or suitable 
alternative should be considered by investigator unless there is a contraindication. 
ANTI-EMETIC PROPHYLAXIS 
Palonosetron 250 mg should beadministered on day 1, 8, and 15 but can be held at the discretion 
of the treating investigator. 
 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 

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IRB Number: 15-326 A(11) 
Approval date: 08-Oct-2020 
Page 33 of 64 
 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
Study 
Pre- 
Treatme 
nt 
Induction Treatment 
End of 
therapyi 
Follow 
-up 
Cycle 1 
Cycles 2- up to 12 
1 
month 
after 
end of 
therap 
y i,l 
1-year 
and 3- 
year 
after 
end of 
therap 
y 
Day 
1 
Day 2 
Day 
8 
Day 
15 
Day 
22 
After 
completing 
4 cycles 
Day 1l 
CR/sC 
R 
reache 
d 
Medical Record 
Review 
x 
x 
x 
x 
H&P with blood 
pressure 
x 
x 
x 
x 
xm 
Echo + EKG 
x 
xn 
ECOG 
x 
x 
x 
Informed Consent 
x 
Viral Studiesb 
x 
Register for RevAssist 
x 
Routine Labsa 
x 
x 
x 
x 
x 
x 
x 
x 
xm 
Lymphocyte subsets 
x 
xa 
(only 
C4D1) 
x 
Myeloma testsf,j 
xf,j 
xf,j 
xf,j 
xm 
Urine for UPEP and 
IFE j 
xj 
xj 
xj 
xm 
Pregnancy Testc 
xc, d 
xd 
xd 
xe 
xe 
xe 
xc 
xe 
Research Blood/Urine 
x 
x 
x 
x 
x 
x 
x 
x 
xm 
Bone Marrow/Aspirate 
xg 
xh 
xh 
xm 
FDG PET-CTk 
x 
x 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-326 A(11) 
Approval date: 08-Oct-2020 
Page 34 of 64 
 
 
 
Adverse 
Events/Toxicity 
x 
x 
x 
x 
 
a. Routine tests include CBC, reticulocyte count, Chem 14, magnesium, phosphate, uric acid, eGFR determination and LDH. Reticulocyte count will 
only be performed at baseline, day 1 of every cycle, and end of therapy. PT and PTT will only be performed at baseline. Peripheral blood 
lymphocyte subsets at baseline, C4D1, and end of therapy. In addition, a CBC must be performed on days 8 and 15 of every cycle. Labs can be 
performed 24 hrs in advance. 
b. Viral studies include Hep B surface antigen and Hep C antibody. If Hep C antibody positive, Hep C RNA PCR will be performed 
c. Pregnancy tests (urine or serum) for females of childbearing potential. A female of childbearing potential (FCBP) is a sexually mature female who: 
1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 co nsecutive months 
(i.e., has had menses at any time in the preceding 24 consecutive months) 
d. Pregnancy tests (urine or serum) must occur within 10 – 14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 
(prescriptions must be filled within 7 days). 
e. FCBP with regular or no menstruation must have a pregnancy test (serum or urine) weekly for the first 28 days and then every 28 days while on 
therapy (including breaks in therapy); at discontinuation of lenalidomide and at Day 28 post the last dose of lenalidomide. Females with irregular 
menstruation must have a pregnancy test (serum or urine) weekly for the first 28 days and then every 14 days while on therapy (including breaks 
in therapy), at discontinuation of lenalidomide and at Day 14 and Day 28 post the last dose of lenalidomide (see Appendix A: Risks of Fetal 
Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods). 
f. 
Myeloma tests include serum protein electrophoresis, serum immunofixation, 24 -hr urine electrophoresis, urine immunofixation, serum free light 
chains, quantitative immunoglobulins, beta-2 microglobulin. Labs can be performed 24 hrs in advance. 
g. Bone marrow aspiration and biopsy will be sent for histopathology, flow cytometry, FISH/cytogenetics, heavy/light chain immun oglobulin 
rearrangement,. Aspirate lysate will also be sent for cell sorting into CD 138 - and + fractions and whole bone marrow lysate for HOTB storage so 
molecular profiling with GEP and DNA-based sequencing at baseline can be performed as correlative work. 
h. Bone marrow aspirate and biopsy can be performed +/- 21 days of intended cycle day or achievement of CR/sCR. The first pull bone marrow 
aspirate will be sent for MRD testing for Multiparametric flow cytometry. Bone marrow aspirate and biopsy will be sent to evaluate for 
histopathology, flow cytometry (bone marrow immunophenotyping of plasma cells), heavy/light chain immunoglobulin rearrangemen t. Aspirate 
lysate will also be sent for cell sorting into CD 138- and + fractions and whole bone marrow lysate for HOTB storage so molecular profiling with 
GEP and DNA-based sequencing at baseline can be performed as correlative work. For patients, reaching CR/sCR MRD negative timepoint 
earlier where MRD negative status is confirmed at earlier bone marrow evaluation, bone marrow aspiration and biopsy at end of study will be 
optional. Otherwise, all other bone marrow biopsies are mandatory. 
i. 
After study therapy ends, follow-up will be 1 month after study end date. Patients may be followed at more frequent time intervals, and thereafter if 
clinically indicated. Patients who have progressive disease while on therapy will be followed with restaging scans and labor atory tests as clinically 
indicated. At disease progression, marrow and FDG-PET/CT are optional but recommended. 
j. 
For patients with intial baseline 24-hr UPEP samples demonstrating ≥100 mg/24 hrs, patients with continue to have 24 -hr UPEP samples day 1 of 
each cycle. Once 24-hr UPEP is <100 mg/24 hrs, patient can have random UPEP with IFE until achieving negativit y. If initial baseline 24-hr 
UPEP sample is IFE positive and/or <100 mg/24, patients can have random UPEP samples with IFE until achieving negativity. On ce random 
UPEP and IFE is negative, no further urine samples are needed (unless patient’s disease is primarily measurable by 24 hr urines) 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-326 A(11) 
Approval date: 08-Oct-2020 
Page 35 of 64 
 
 
k. FDG-PET scan will be performed on patients at baseline, end of therapy or upon suspicion of progressive disease as clinically indicated. End of 
therapy FDG-PET scan can be performed +/- 21 days. 
l. 
Treatment window for day 1 of start of each cycle is +/- 7 days. Treatment window for intra-cycle carfilzomib doses is + 2 days. . 
m. After 1- and 3-year from completing therapy, PFS and OS data will be collected on patients. Patients will option of having formal evaluatio n with 
H&P, clinical labs, myeloma labs and bone marrow evaluating for MRD status. PFS and OS data may be collected over the phone along with 
review of medical records. Survival, PFS, and time to next line of treatment data may be collected on subsequent pr otocols that patients have 
consented for (maintenance protocols/bio-banking or storage protocols). 
n. Patients will have an EKG and echocardiogram (2-D or strain) performed at baseline and after completion of 4 cycles of therapy. Outside 
echocardiograms are permissible 

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Clinical and Correlative Studies - To create a bone marrow (clinical pathology, 
whole BM lysate, CD 138+ fractions and CD 138- fractions cell sorting with 
subsequent correlatives on both fractions ), peripheral blood, and urine sample 
bank. These samples may be used to later to evaluate biological activity of 
carfilzomib, lenalidomide, and dexamethasone. Timepoints and potential 
analyses are listed below: 
Bone Marrow 
Sampling Time Points of Bone Marrow correlative studies 
a) Baseline 
b) CR/sCR during cycles 2-and up to 12 
c) End of therapy 
d) 1 and 3 year timepoints after completing therapy (optional) 
 
Baseline 
During Cycles 
2-12 if reaches CR/sCR 
End of study 
therapy 
1 and 3 year 
timepoints 
after 
completing 
therapy 
Pathology/IHC 
x 
x 
x 
x 
Multiparametric Flow 
Cytometry 
x 
X* 
X* 
x 
FISH/Cytogenetics 
x 
Molecular Pathology 
for light or heavy chain 
immunoglobulin 
rearrangement 
x 
x 
x 
x 
Storage (sorted and 
whole cell lysate) 
x 
X 
X 
X 
*Patients undergoing MRD evaluation or End of study evaluation, the first pulled sample will be sent 
for Multiparametric flow cytometry. For those patients that are MRD negative by flow cytometry 
during their routine pre-stem cell collection bone marrow assessments, the result will count towards 
their MRD evaluation. 
• 
Potential studies on the stored bone marrow samples may include but are not limited to the 
following: 
 
Bone Marrow Aspirate/Biopsy 
Pathology/Immunohistochemistry 
Immunohistochemical staining will be assessed using immunohistochemistry markers such as CD 
138, light chains, CD56 etc. Microenvironment interactions will also be assessed using various 
immunohistochemistry markers for osteoblasts, osteoclasts, stromal cells and proteasome 
components. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-326 A(11) 
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Page 37 of 64 
 
 
Minimal Residual Disease 
Flow cytometry: Immunophenotyping of aberrant plasma cells by flow cytometry currently involves, 
but is not limited to, the use of the following reagents: CD138, CD19, CD45, CD38, and CD56. 
Characteristic changes in immunophenotypically abnormal plasma cells (CD38 bright and/or CD138 
positive) include but are not limited to decreased or absent CD19 and CD45, decreased CD38, 
increased CD56, decreased CD27, decreased CD81, increased CD117. For patients with non- 
evaluable samples at MRD assessment, patients can opt for repeat MRD assessment or continue to 
receive a total of 8 cycles of CRd. For those patients that are MRD negative by flow cytometry 
during their routine pre-stem cell collection bone marrow assessments, the result will count towards 
their MRD evaluation. The first pulled bone marrow sample will be sent for multi-parametric flow 
cytometry as a priority. Samples will undergo MRD testing per MSK institutional practice, see 
section 12.0 for further methodology practice. 
 
Molecular pathology: For MRD samples utilizing the NGS LymphoSIGHT™ (Sequenta, Inc., South 
San Francisco, CA) platform, immunoglobulin heavy and kappa chain variable, diversity, and joining 
gene segments from genomic DNA obtained from CD138+ bone marrow (BM) cell lysate or cell-free 
supernatant BM aspirate were amplified using universal primer sets as described elsewhere21. An 
MM clonotype was defined as an immunoglobulin rearrangement identified by NGS at a frequency of 
≥5%. 
Mass spectrometry based proteomics for minimal residual disease assessment: Serial urine and 
serum samples will be analyzed to detect clonotypic peptides representing patient’s monoclonal 
immunoglobulin heavy and light chains using high resolution mass-spectrometry-based proteomics. 
FISH and cytogenetics 
Interphase FISH/cytogenetics will be performed on patients enrolled in this protocol. 
DNA-based target mutations 
Bone marrow aspirate samples will be analyzed for somatic mutations by exome-sequencing of 
targeted genes using FoundationOne Heme platform (or equivalent i.e. MSK Impact Heme). After 
therapy, perform if response is <PR or evidence of gross residual disease on SPEP/UPEP 
Cell Sorting and Bone marrow cell lysate 
Bone marrow aspirate storage samples will be sorted into CD 138 + and CD 138 – fractions and 
whole bone marrow cell lysate per HOTB SOP. 
Research Blood/Serum and Urine 
a) One 7-8 mL serum tube will be collected at baseline, Day 2, Day 8, Day 15, and Day 22 of 
Cycle 1, Day 1 of every cycle during cycles 2-up to 12, during Cycles 2-12 if CR/sCR is 
achieved, at the end of therapy, and at any time point if the patient has progression of 
disease. One 7-8 mL EDTA tube will be collected at baseline Day 1 of every cycle during 
cycles 2-up to 12, during Cycles 2-12 if CR/sCR is achieved, at the end of therapy, and at any 
time point if the patient has progression of disease. 
b) Urine (random samples of 10 mL) will be collected into a standard urine collection cup and 
sent for analysis and storage at each of the above timepoints. Time points include: baseline, 
Day 2, Day 8, Day 15 and Day 22 of Cycle 1, Day 1 of every cycle during cycles 2-up to 12, 
during Cycles 2- up to 12 if CR/sCR is achieved, at the end of therapy, , and at any time point 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-326 A(11) 
Approval date: 08-Oct-2020 
Page 38 of 64 
 
 
if the patient has progression of disease. 
c) Peripheral blood and/or urine samples from patients will be analyzed for potential serum or 
urine biomarkers as well as drug concentrations, and describe the association with clinical 
outcomes if the results of the study indicate a clinical or translational rationale for analyzing 
the samples. 
 
 
Assessment/Evaluation Plan 
The protocol consent form asks participants for permission for re-contact to discuss research 
findings if an incidental research finding is made that may be critical to their health or preventive 
care, or that of their issue. If a participant agrees to be re-contacted, he/she will not be told the 
specific results of the research test, but will be informed that his/her samples were used in a project 
and a potential risk was discovered. If the participant is interested in further discussion of the 
research findings, he/she will be asked to contact MSKCC Clinical Genetics Service for counseling 
and specific genetic testing. 
The below schema will be followed by MSKCC investigators who identify a potentially actionable 
incidental finding in the course of research conducted on samples collected under this protocol: 
 
In the event an investigator's research identifies a finding that he or she believes should be 
communicated to the subject (and/or family designee), the investigator shall communicate this to the 
OCR-IRB. The finding will be reviewed by a group convened by the IRB to determine whether the 
incidental finding should be discussed with the subject. In the event that group determines that the 
finding should be discussed with the subject, and the subject has consented to be re-contacted, then 
the treating/consenting physician shall be contacted by the OCR-IRB representative and asked to 
refer the subject to the Clinical Genetics Service for further discussion of the research finding. After 
appropriate counseling and consent, the Clinical Genetics Service will request permission to confirm 
the result in a New York DOH-approved laboratory prior to communication of the specific result. If 
the patient is not available (e.g. deceased), then the surrogate designated on the consent will be 
contacted and the above will occur. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-326 A(11) 
Approval date: 08-Oct-2020 
Page 39 of 64 
 
 
 
 
 
 
The IRB and Clinical Genetics Service, as per above flow chart, will be notified when a 
participant’s samples uncover a potentially reportable incidental finding(s). The following 
information must be provided to OCR-IRB representative and Clinical Genetics: 
 
• 
Participant Name/MRN # 
• 
Type of Biospecimen (tissue, blood, etc) 
• 
Incidental Finding 
• 
Project # (Waiver or Biospecimen Protocol #) that this analysis occurred under 
• 
Collection Protocol # 
Contact: ocrgapirb@mskcc.org 
 
11.0 
TOXICITIES/SIDE EFFECTS 
11.1 
Carfilzomib 
Likely Side Effects: those occurring in more than 20% or more than 20 out of 100 persons who 
receive carfilzomib: 
• 
Fatigue (tiredness) 
• 
Fever 
• 
Headache 
• 
Cough 

Memorial Sloan Kettering Cancer Center 
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• 
Shortness of breath (at rest or with exertion) which in rare cases may be life-threatening or 
resulting in death 
• 
Nausea 
• 
Vomiting 
• 
Diarrhea 
• 
Constipation 
• 
Decreased red blood cell count which may lead to feeling tired 
• 
Decreased platelet counts which may lead to increase bleeding or bruising 
• 
Decreased white blood cell count which may decrease your ability to fight infection 
• 
Upper respiratory tract infection 
• 
Mild decreases in kidney function which are generally reversible 
• 
Swelling of the arms or legs 
• 
Back pain 
• 
Inflammation of the liver (mild, reversible changes in liver function tests) 
 
 
Less Likely Side Effects: those occurring in 5-20% or 5 to 20 out of 100 persons who receive 
carfilzomib: 
• Flu-like symptoms such as fever, chills, or shaking that may occur at any time but are more likely 
to occur on the day of or the day after carfilzomib infusion 
• 
Decreased or worsening of heart function including chest pain, abnormal heart rhythm, heart 
attack, and heart failure. This can be serious, potentially life threatening event. 
• Loss of or decreased appetite which may lead to weight loss 
• Insomnia (difficulty sleeping) 
• Dizziness 
• High blood pressure 
• Abnormal physical weakness or lack of energy 
• Blurred or double vision 
• Numbness, tingling, painful or decreased sensation in hands and/or feet 
• Blood chemistry and electrolyte alterations 
• Rash and/or itching, or dry skin 
• Pneumonia 
• Pain, burning, or irritation at the infusion site 
• Generalized pain 
• Pain in the bones or joint pain or extremities 
• Muscle spasm, pain, or weakness 
 
Rare and/or Potentially Serious Side Effects: these have occurred in less than 5% or in less than 5 
out of 100 persons who receive carfilzomib: 
• Herpes zoster reactivation 
• Liver failure 
• Acute kidney failure 
• Increase in the blood pressure in the arteries of the lungs (Pulmonary Hypertension) 
• Infusion reactions (which can occur during or shortly after carfilzomib infusion) including flushing or 
feeling hot, fever, shakes, nausea, vomiting, weakness, shortness of breath, swelling of the face, 
pain in the muscles or joints, tightness or pain in the chest, and low blood pressure 
• Allergic reaction including total blood rash, hives, and difficulty breathing 
• Tumor Lysis Syndrome: Caused by rapid killing of tumor cells during dosing. When the tumor cells 
die, they release their contents into the bloodstream. If cell killing is very rapid, this can affect 

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blood chemistries and the kidneys. In severe cases, this can lead to shutdown of kidney function 
requiring dialysis 
• Posterior reversible encephalopathy syndrome (PRES): A rare condition that causes swelling of 
the brain and affects how it functions. A person with PRES may experience headaches, confusion, 
loss or decreased level of consciousness, blurred vision or blindness, seizures, and possibly 
death. If caught early and treated, PRES may be reversed. 
 
 
11.2 
Lenalidomide 
Likely Side Effects: those occurring in more than 20% or more than 20 out of 100 persons who 
receive lenalidomide: 
• 
Low number of white blood cells (with or without fever) 
• 
Anemia (lowered red blood cells) 
• 
Decrease in cells that help your blood clot (lowered platelets) 
• 
Swelling in legs and/or extremities 
• 
Diarrhea 
• 
Constipation 
• 
Nausea 
• 
Feeling weak and unwell, fatigue 
• 
Fever 
• 
Chills 
• 
Rash 
• 
Pain including muscles, joints, back, and non-cardiac chest pain 
• 
Dizziness 
• 
Shaking or tremor 
• 
Shortness of breath 
• 
Upper respiratory tract infection 
 
Less Likely Side Effects: those occurring in 5-20% or 5 to 20 out of 100 persons who receive 
lenalidomide: 
 
• 
Vision Blurred 
• 
Altered sense of taste 
• 
Pain or decreased sensation of touch 
• 
Pneumonia 
• 
Urinary tract infection 
• 
Increased sweating 
• 
Dry skin 
• 
Itching 
• 
Decreased appetite 
• 
Weight loss 
• 
Vomiting 
• 
Abdominal pain 
• 
Dry mouth 
• 
Electrolyte imbalance in blood 
• 
Blood clot in lower or upper extremities 
• 
Lowered level of consciousness with drowsiness, listlessness, and apathy 

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Approval date: 08-Oct-2020 
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• 
Abnormal liver lab tests 
• 
Loss of fluid 
• 
Muscle weakness 
• 
Tingling of skin 
• 
High or low blood pressure 
 
 
Rare and/or Potentially Serious Side Effects: these have occurred in less than 5% or in less than 5 
out of 100 persons who receive lenalidomide: 
• Lowered white blood cells with fever 
• Blood clot to lung 
• Irregular heart beat 
• Congestive heart failure – abnormal functioning of heart leading to fluid in lungs and extremities 
• Stroke 
• Immune destruction of red blood cells (autoimmune hemolytic anemia) 
• Slow heart rate or fast heart rate 
• Heart attack 
• Blindness 
• Mood swings, hallucinations 
• Gastrointestinal bleed 
• Severe skin allergic reactions: lining of the nose, mouth, stomach and intestines or rash leading to 
the separation of the top layer of skin, swelling under the skin 
• Rapid death of cancer cells where the accumulating contents of dying cancer cells cause an 
imbalance in the chemistry of the body which can lead to kidney damage. 
• Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental 
monkey 
study similar to birth defects caused by thalidomide in humans. If lenalidomide is used during 
pregnancy, it may cause birth defects or death to a developing baby. 
• Second primary cancers 
 
 
 
11.3 
Dexamethasone 
Likely Side Effects: those occurring in more than 20% or more than 20 out of 100 persons who 
receive lenalidomide: 

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• 
Increase in appetite 
• 
Weight gain 
• 
Fatigue 
• 
Fluid retention, which can lead to swelling in the legs, arms and within the face 
• 
High blood pressure 
• 
Rise in the blood sugar 
• 
Problems with low levels of potassium in the blood 
• 
Menstrual cycle disturbances 
• 
Depression or Mood swings or changes in personality 
• 
Trouble with sleeping 
• 
Dizziness 
• 
Headache 
• 
Slow wound healing 
• 
Thin, fragile skin, black and blue marks 
• 
Increased sweating and/or flushing 
• 
Increase in body hair 
• 
Bone thinning, which can lead to spinal fracture or destruction or fracture of the long bones 
(thigh/hip and upper arm/shoulder) 
• 
Hormonal disturbances during times of stress or illness 
• 
Hiccups 
• 
Nausea 
Rash – mild acne 
• 
Increased risk of infections. This can be a serious, potentially life threatening event. 
• 
Yeast infections 
 
Less Likely Side Effects: those occurring in 5-20% or 5 to 20 out of 100 persons who receive 
lenalidomide: 
• 
Stomach ulcers or worsening or irritation or existing ulcers. This can be serious, potentially life 
threatening event. 
• 
Muscle weakness or loss of muscle mass 
• 
Inflammation of the pancreas 
• 
Cataract formation 
• 
Glaucoma 
• 
Rupture of tendons 
• 
Vein blood clots in the veins of the legs or lungs. This can be a serious potentially life threatening 
event. 
 
Rare and/or Potentially Serious Side Effects: these have occurred in less than 5% or in less than 5 
out of 100 persons who receive lenalidomide: 
• 
Severe allergic reactions (including facial redness, shortness of breath, profuse perspiration, 
abdominal cramps, fast heart beat, and low blood pressure - severe allergic reactions). 
• 
Brain swelling. 
• 
Convulsions. 
• 
Formation of a hole in the small and/or large bowel particularly in people with preexisting bowel 
problems. This can be a serious, potentially life threatening event. 
• 
Irritation and bleeding of the esophagus (the tube from the mouth of the stomach) 
• 
If you are more prone to heart disease, you may experience heart failure 
• 
Aseptic necrosis (bone death) of the hip 

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12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
Disease Parameters 
a) A "measurable" serum M-protein is ≥ 1 g/dL or a "measurable" urine M-spike is ≥ 200 mg/24 
hours or “measurable light chains” are either a serum kappa or lambda FREE light chain of 
>10 mg/dL along with an abnormal kappa to lambda free light chain ratio, patient is 
considered to have "measurable" disease. 
b) The serum free light chain (FLC) assay is of particular use in monitoring response to therapy 
in patients who have light-chain disease. When using this assay, it is important to note that 
the FLC levels vary considerably with changes in renal function and do not solely represent 
monoclonal elevations. Thus both the level of the involved and the uninvolved FLC isotype 
(i.e., the involved/uninvolved ratio or involved-uninvolved difference) should be considered in 
assessing response. The serum FLC assay should be used in assessing response if the 
baseline level of the involved FLC is >10mg/dL and abnormal kappa/lambda ratio (when 
primary determinant of response). 
c) For patients with intial baseline 24-hr UPEP samples demonstrating ≥100 mg/24 hrs, patients 
with continue to have 24-hr UPEP samples day 1 of each cycle. Once 24-hr UPEP is <100 
mg/24 hrs, patient can have random UPEP with IFE until achieving negativity. If initial 
baseline 24-hr UPEP sample is IFE positive and/or <100 mg/24, patients can have random 
UPEP samples with IFE until achieving negativity. Once random UPEP and IFE is negative, 
no further urine samples are needed (unless primary determinant of response) 
d) In order to be classified as a response, confirmation of serum monoclonal protein, serum 
immunoglobulin free light chain (when primary determinant of response) and urine 
monoclonal protein (when primary determinant of response) results must be made by 
verification on two consecutive determinations at different timepoints. 
e) Compression fracture does not exclude continued response and may not indicate 
progression; findings of worsening compression fracture will be subject to interpretation of 
the clinical investigator. 
Minimal Residual Disease 
For patients undergoing MRD or end of study assessment, the first pulled bone marrow sample will 
be sent for multi-parametric flow cytometry as a priority. Flow cytometry based assay to rule out 
MRD (defined as less than 20 abnormal plasma cells) in bone marrow aspirates of CR/sCR patients. 
For patients with samples demonstrating between 10-20 abnormal plasma cells, cases will be 
reviewed with hematopathologist and clinical investigator on a case by case basis to determine 
whether sample is considered MRD positive. Patients with <CR/sCR are considered MRD positive. 
We will use the MSKCC flow cytometry MRD method which is based on 10-colors in a single tube.16. 
The test demonstrates highly similar results when compared to the current Euroflow approach. This 
test is validated and already in clinical use at MSK. Immunophenotyping of aberrant plasma cells by 
flow cytometry currently involves, but is not limited to, the use of the following reagents: CD138, 
CD19, CD45, CD38, and CD56. Characteristic changes in immunophenotypically abnormal plasma 
cells (CD38 bright and/or CD138 positive) include but are not limited to decreased or absent CD19 
and CD45, decreased CD38, increased CD56, decreased CD27, decreased CD81, increased 
CD117. For patients with non-evaluable samples at MRD assessment, patients can opt for repeat 
MRD assessment or continue to receive a total of 12 cycles of CRd. For those patients that are MRD 
negative by flow cytometry during their routine pre-stem cell collection bone marrow assessments, 

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the result will count towards their MRD evaluation. 
 
Traditional Response Criteria from International Myeloma Working Group Criteria for Multiple 
Myeloma22 
Evaluation of Response Criteria 
a) Stringent Complete Response (sCR) 
o Complete Response as defined below plus: Normal FLC ratio and absence of clonal 
cells in bone marrow by immunohistochemistry or immunofluorescence (presence/ 
absence of clonal cells is based on the kappa/ lambda ratio. 
b) Complete Response (CR) 
o Negative immunofixation on the serum and urine and disappearance of any soft 
tissue plasmacytomas and <= 5% plasma cells in bone marrow 
c) Very Good Partial Response (VGPR) 
o Serum and urine M-protein detectable by immunofixation but not on electrophoresis 
or 90% or greater reduction in serum M-protein plus urine M- protein level <100mg 
per 24h. If the serum and urine M-protein are unmeasurable, a ≥ 90% decrease in the 
difference between involved and uninvolved FLC levels is required in place of the M- 
protein criteria. 
d) Partial Response (PR) 
o ≥ 50% reduction in M protein and reduction in 24-h urinary M-protein by ≥ 90% or to < 
200 mg per 24h . If the serum and urine M-protein are unmeasurable, a ≥ 90% 
difference between involved and uninvolved FLC levels is required in place of the M- 
protein criteria 
e) Stable Disease (SD) 
o Not meeting criteria for CR, VGPR, PR or progressive disease. All categories also 
require no known evidence of progressive or new bone lesions if radiographic studies 
were performed. Radiographic studies are not required to satisfy these response 
requirements. 
f) Progressive disease (PD) 
o Requires any one or more of the following: 
▪ 
Increase of ≥ 25% of nadir in: 
▪ 
Serum M-component and/or (absolute increase must be ≥ 0.5 g/dl. The 
serum M-component increases of ≥ 1gm/dl are sufficient to define relapse if 
starting M-component is ≥ 5 gm/dl. 
▪ 
Urine M-component and/or (the absolute increase must be ≥ 200 mg/24h 
▪ 
Only in patients without measureable serum and urine M-protein levels: the 
difference between involved and uninvolved FLC levels. The absolute 
increase must be >10mg/dl. 
▪ 
Bone marrow plasma cell percentage: the absolute % must be ≥ 10% 
▪ 
Definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in size of existing bone lesions or soft tissue 
plasmacytomas 
▪ 
Development of that can be attributed solely to the plasma cell proliferative 
disorder 

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g) Relapse from CR 
o Any one or more of the following: 
▪ 
Reappearance of serum or urine M-protein by immunofixation or 
electrophoresis. (Appearance of monoclonal or oligoclonal bands that are 
different from original isotype may not be defined as “relapse from CR”. 
Often times, such bands may indicate fluctuations in immunological 
parameters that are not reflective of MM disease. In these situations, 
immunofixation and electrophoresis will be interpreted by the clinican before 
being labeled as “relapse”23,24. 
▪ 
Development of ≥ 5% plasma cells in the bone marrow 
▪ 
Appearance of any other sign of progression (ie, new plasmacytoma, lytic 
bone lesion, hypercalcemia 
Progression-Free Survival 
PFS is defined as time of start of treatment to time of progression or death, whichever occurs first. 
 
Overall Survival 
Overall survival is defined as the time of start of treatment to death from any cause. 
Toxicity Criteria 
The following adverse event management guidelines are intended to ensure the safety of 
each patient while on the study. The descriptions and grading scales found in the revised 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized 
for AE reporting. All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP 
web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40). 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
Off-therapy Criteria 
Patients with medically concerning grade 3 or 4 adverse events related to drug therapy may be 
taken off therapy at the discretion of the principal investigator. 
• 
Patients who require more than 2 dose reductions of carfilzomib 
• 
Hematologic toxicity has not completely resolved or resolved to < grade 1 or baseline after 2 
weeks of withholding treatment 
• 
Therapy has been held for more than 3 weeks due to treating a grade 3 infection 
• 
Grade 4 non-blistering rash or blistering rash of any grade 
• 
Grade 4 neuropathy 
• 
Grade 4 hypersensitivity reaction 
• 
Patient experiencing significant cardiac event as outlined in section 9.5 

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Table Dose Escalation/Toxicity Risk 
• 
Patient completes the protocol treatment 
• 
Progression of disease 
• 
Patient chooses to go off therapy 
• 
The principal investigator may remove patient from protocol therapy if deemed necessary 
due to medical conditions, compliance, etc. 
• 
Patient becomes pregnant. 
Off-Study Criteria 
• 
Patient requests to be withdrawn from study 
• 
Death 
• 
Physician’s determination that withdrawal is in the patient’s best interest. 
Patient has completed 1- and 3-year evaluation from end of therapy 
14.0 
BIOSTATISTICS 
Phase I: 
The goal of the phase I trial is to find the maximum tolerated dose (MTD) of carfilzomib when used in 
combination with lenalidomide and dexamethason. The trial design is a standard 3 by 3 dose 
escalation design. The three carfilzomib dose levels that will be explored are listed in Section 4.2.2 
and the DLT evaluation window is the first cycle of therapy. The DLT definition is provided in Section 
4.2.1. 
1. A cohort of three patients will be enrolled at the first dose level (45/mg/m2). If no DLTs 
are observed in the cohort, the next dose level will be explored. 
2. If one DLT is observed in the initial cohort of three, an additional three patients will be 
treated at the same dose level. If no additional patients have a DLT, the next dose level 
will be explored. 
3. If at any point two or more patients have a DLT at a given dose level, the MTD will have 
been exceeded and the previous dose level will need to be investigated. 
4. If three patients are treated at a potential MTD, the dose cohort will be expanded to six 
for confirmation. 
 
Using this dose escalation scheme, escalation to the next treatment level is probable if the risk of DLT 
is low, and the likelihood of escalations decreases as the risk of DLT increases, as demonstrated in 
table below: 
 
 
 
 
True risk of Toxicity 
.10 
.20 
.30 
.40 
.50 
.60 
Probability of Escalation 
.91 
.71 
.49 
.31 
.17 
.08 
 
 
 
The minimum and maximum sample size for the phase I trial is 4 and 18, respectively. It is 
anticipated that 1-2 patients per month may enroll on this trial; thus, approximately one year or less 
is anticipated as the accrual period for the phase I study. 

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Phase II: 
The phase II component of this trial will explore the efficacy of the combination therapy using the 
carfilzomib dose selected in the phase I trial. The primary endpoint is CR/sCR MRD negativity 
(MRD-) rate by flow cytometry upon or prior to completion of 12 cycles of therapy. Patients with 
<CR/sCR are considered MRD positive. Based on previous research an CR/sCR MRD- rate by flow 
cytometry of 45% would be promising enough to warrant further investigation, while a rate of 20% 
would not be promising for further investigation. Using a Simon’s optimal two-stage design, the first 
stage of the trial will enroll 14 patients. This includes the three-six patients treated at the MTD in the 
phase I trial. If three patients or fewer are CR/sCR MRD- by flow cytometry, the trial will stop due to 
a lack of efficacy; otherwise, an additional 11 will enroll to a total sample size of 25 at end of phase 
II. If at least eight patients are MRD- (at the MTD), the intervention will be considered promising for 
further research. The type 1 error is set at 0.10 and the type II error is set at 0.10. If the true MRD- 
rate is 20%, the probability of early termination is 70%. For patients that come off trial prior to 
completion of 4 cycles of therapy, due to reasons unrelated to disease progression or toxicities, 
patients can be replaced (max 3) for MRD evaluation as part of the phase II assessment. 
 
It is anticipated that 1-2 patients per month may enroll on this trial; thus, approximately one year is 
anticipated as the accrual period for the phase II study. The total maximum possible projected 
sample size for the study is 37 patients. 
 
Secondary endpoints for both Phase I and II: 
 
1. To estimate the overall response rate (ORR) according to International Myeloma Working 
Group criteria at each cycle and as the best response during the treatment of up to 12 
cycles. In addition to ORR, the rates of VGPR+CR and CR alone will also be estimated and 
reported. The exact 95% confidence intervals will also be included. 
2. Kaplan-Meier methodology will be used to estimate progression-free survival and overall 
survival . Estimates of survival along be with 95% confidence intervals will be provided for 
select time points. 
3. To explore the concordance of different MRD methodologies. MRD status by multiparametric 
flow cytometry will be compared to next-generation sequencing and to mass spectrometry 
based proteomics methodologies. The concordance across the different technologies will be 
reported along with an exact 95% confidence interval. 
4. To create a bone marrow and peripheral blood sample bank. These samples may be used to 
later evaluate the biological activity of carfilzomib, lenalidomide, and dexamethasone. 
Potential analyses include sequencing and gene expression profiling on pre and post 
therapy bone marrow samples, identification of potential biomarkers (blood, urine, bone 
marrow aspirates), and evaluation of proteasome activity. 
 
Exploratory Studies: 
 
1. The gene panel HemePACT (or alternative equivalent platform) will explore whether any 
mutations appear to be associated with response to therapy or toxicity associated with 
therapy. This descriptive aim will combine patients across all dose levels. This analysis is 
for hypothesis-generation, and all results will be cautiously interpreted. Fisher’s exact test 

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may be used to assess any potential association. The variant allele frequency (VAF) will be 
summarized for each mutation. 
 
2. HemePACT (or alternative equivalent platform) will also be evaluated using samples at the 
time of progression of disease or during an ongoing response and will be compared to the 
pre-treatment baseline samples to explore whether pathways leading to emergence of 
resistance to the drug regimen can be identified. Similar to the previous objective, this aim is 
for hypothesis generation, and all results will be cautiously interpreted. Changes in the VAF 
from baseline will be summarized for patients with an ongoing response and for patients 
who have progression of disease. A paired t-test may be used to further describe this 
association. This aim will combine patients across all explored dose levels. 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
15.1 
Research Participant Registration 
 
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain 
informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. During the registration process registering individuals will be required to 
complete a protocol specific Eligibility Checklist. The individual signing the Eligibility 
Checklist is confirming whether or not the participant is eligible to enroll in the study. 
Study staff are responsible for ensuring that all institutional requirements necessary to 
enroll a participant to the study have been completed. See related Clinical Research 
Policy and Procedure #401 (Protocol Participant Registration). 
 
 
15.2 
Randomization 
 
This study will not include randomization. 
16.0 
DATA MANAGEMENT ISSUES 
All patients will be enrolled on protocol at Memorial Sloan-Kettering Cancer Center. We 
expect to be able to enroll the necessary 34 patients into this study in 2 years. 
The data manager (Clinical Research Coordinator/CRC) will be responsible for confirming 
eligibility and assisting the MD with the registration process. All study data will be collected 
by an assigned CRC who will enter this information into the Clinical Research Database 
(CRDB). This database will be utilized for data collection and storage and for reporting 
protocol specific events such as accrual demographics, toxicities and adverse events to the 
IRB, and the sponsor. 
The CRC will collect toxicity and concomitant medication information and patient interviews. 
Adverse events, including all toxic effects of treatment will be tabulated individually according 
to severity or toxicity grade. The data manager will also monitor laboratory testing throughout 

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the study. Laboratory data will be tabulated and summarized by descriptive statistics, as well 
as on the basis of MSKCC specified normal ranges. 
 
 
16.1 
Quality Assurance 
Monthly registration reports will be generated to monitor patient accruals and completeness 
of registration data. Routine data quality reports will be generated to assess missing data 
and inconsistencies. Accrual rates, extent and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study period and potential problems will be brought to 
the attention of the study team for discussion and action. 
Random sample data quality and protocol compliance audits will be conducted by the study 
team, at a minimum of two times per year, more frequently if indicated. 
16.2 
Data and Safety Monitoring 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research. The MSKCC Data and 
Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://mskweb2.mskcc.org/irb/index.htm 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research QA) and departmental procedures for quality control, plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the Center’s Research Council and Institutional Review Board. 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed 
and the monitoring procedures will be established at the time of protocol activation. 
 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
Participation in this trial is voluntary. All patients will be required to sign a statement of 
informed consent, which must conform to MSKCC and collaborating centers IRB guidelines. 

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Patients will be eligible for this trial regardless of gender or racial/ethnic background. All 
patients must follow the guidelines for pregnancy testing birth control and counseling related 
to the risk of fetal exposure to lenalidomide and bortezomib. 
The protocol for this study has been designed in accordance with the general ethical 
principles outlined in the Declaration of Helsinki. The review of this protocol by the IRB and 
the performance of all aspects of the study, including the methods used for obtaining 
informed consent, must also be in accordance with principles enunciated in the declaration, 
as well as ICH Guidelines, Title 21 of the Code of Federal Regulations (CFR), Part 50 
Protection of Human Subjects and Part 56 Institutional Review Boards. 
17.1 
Privacy 
MSK’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
The consent also indicates that samples and genetic information collected may be shared 
with other qualified researchers. Such information will not include identifying information such 
as name. It is also stated in the consent and Research Authorization that research data (e.g. 
genomic sequence) may be placed into databases monitored by the National Institutes of 
Health, and may be made accessible to investigators approved by the U.S. government. 
Consent for re-contact 
Patients are asked in a series of check boxes at the end of the consent if 1) if they consent to 
be contacted to discuss research findings which may derive from their sample; and 2) if not 
available (e.g. deceased), if they wish to have their designated representative on the consent 
to be contacted. 
Use of identifiable information for genetic studies 
 
It will be explained to participants that future research may also be done to identify changes 
in genes that predict risk for cancer or other diseases; if such germline genetic research is 
perfomed, then to be in compliance with New York State law (see section 3.5), it will not be 
possible to provide results of research tests not performed in a New York State Department 
of Health approved clinical laboratory. It is stated in the consent that participants will be told 
that they will not receive any specific results from potential research tests. The consent will 
tell participants that if they wish to have genetic testing done for personal reasons than they 
should make an appointment with the MSKCC Clinical Genetics Service. 
 
If in the course of this research a research finding is obtained that may be critical to the 
preventive care of the participant or their family, as determined by procedures overseen by 
the IRB, those participants, if they consent to checklist questions 1, 2, will be referred to the 
Clinical Genetics Service for a consulation. At that time, genetic counseling can be offered in 
accordance with New York State requirements, and appropriate clinical testing offered in an 

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approved laboratory. Please see flow chart and requirements for reporting under section 
10.0. 
 
Patients will be informed that future research may also identify changes in genes that predict 
risks for cancer or other diseases. Procedures for informing patients or their designees, 
confirmation by a New York State approved laboratory, and followup assessments and 
counseling are already detailed in Section 10.0 above. 
 
For tumor (somatic) genetic studies, germline studies of genetic variants of unknown 
significance (e.g. for example, in pharmacogenetics studies), gene discovery studies, and 
cellular, immunologic, or other studies using banked correlative tissues, the name and 
personal identifiers may be removed from the sample, but a coded link will be maintained. 
 
Research analysis of tumor genomes may inadvertently reveal, or require some knowledge 
of the germline genome. Such research studies could be performed on samples not 
identifiable to the researcher but with identifying links maintained by the TPS, HOTB or 
similar, and approved via IRB mechanisms. See section 10.0 for instructions on how to 
report incidental findings on research samples. 
Future use of samples 
 
Researchers at MSKCC may either keep indefinitely or dispose of any specimen(s) collected 
under this protocol including DNA that the samples contain. Specimens will be stored with 
identifiers in secure banks. Samples could be lost or ruined because of mechanical failure, 
and MSKCC cannot guarantee that samples will be stored indefinitely. The samples will be 
stored for as long as deemed useful for research purposes. 
Risks of research participation 
 
Risks are those of the procedure to obtain the specimen and are considered minimal. 
Another risk is release of information from health or research records in a way that violates 
privacy rights. MSKCC protects records so that name, address, phone number, and any 
other information that identifies the participant will be kept private and confidential, along with 
all personal health information. 
Benefits of research participation 
 
It is unlikely that the research using biospecimens will be of any medical benefit to 
participants. Neither the patient nor the treating physician will necessarily be told of the 
results of any research tests on the samples, except an incidental finding that may be critical 
to the preventive care of the subject or his/her issue. Research using biospecimens 
collected in this study could lead to medical and scientific products that could improve 
prevention, diagnosis, and treatment of disease; but those benefits are unlikely to accrue to 
the participants. 
Occasionally, however, there are tests conducted in research labs, the results of which might 
contribute toward treatment decisions. These studies would not yet have been reduced to 
clinical practice, but patients may be informed of such results and how they may affect 
diagnosis and treatment. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-326 A(11) 
Approval date: 08-Oct-2020 
Page 53 of 64 
 
 
Costs/compensation 
 
There is no cost to enroll or participate in this research. Biospecimens obtained under this 
research protocol may be used to make secondary products, and such products may be 
patented or licensed with commercial value. Participants are not financially compensated for 
use of their human biological specimens or secondary products, tests, and discoveries that 
derive from their biospecimens. 
 
 
17.2 
Serious Adverse Event (SAE) Reporting 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the patient of participant and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease is not considered an SAE. 
SAE reporting is required as soon as the participant starts investigational treatment/ 
intervention. SAE reporting is required for 30-days after the participant’s last investigational 
treatment/intervention. Any event that occur after the 30-day period that is unexpected and at 
least possibly related to protocol treatment must be reported. 
 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention 
and is related to a screening test of procedure (i.e., a screening biopsy) must be reported. 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office per 
IRB SOP RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be submitted 
within 5 calendar days of the event. All other SAEs must be submitted within 30 calendar 
days of the event. 
 
The report should contain the following information: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment(s) 
• 
If the adverse event was expected 
• 
Detailed text that includes the following 
o An explanation of how the adverse event was handled 
o A description of the participant’s condition 
o Indication if the participant remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-326 A(11) 
Approval date: 08-Oct-2020 
Page 54 of 64 
 
 
 
 
17.2.1  
SAE Reporting by Investigator-sponsor to Amgen 
The Investigator-sponsor must be notified of the occurrence of any SAE within 24 hours of 
the investigator, designee, or site personnel’s knowledge of the event. The Investigator- 
sponsor is responsible for notifying the appropriate health authorities (HAs), ethics 
committees (ECs), and investigators, of any expedited, annual, or other periodic safety 
reports in accordance with applicable regulations. Any safety report submission will cross 
reference the Amgen investigational new drug (IND) or clinical trial approval (CTA) number. 
The Investigator is also responsible for notifying the local ECs in accordance with local 
regulations. 
The Investigator-sponsor must inform Amgen in writing by e-mail or fax at the contact 
information listed below for all SUSARs that are judged as reasonably related to the Amgen 
study drug. Site will transmit the final CIOMS of that event to Amgen within twenty-four (24) 
hours of submitting the report to the applicable regulatory authority. 
For regulatory reporting purposes, an event of “Death, Cause Unknown” from the study shall 
be processed as a SUSAR. All forms must be completed and provided to Amgen in English. 
The Individual Case Safety Report (ICSR) may be referred to as an individual safety report or 
SAE Report, including Pregnancy Exposure Reports and Follow up Reports. The ICSR must 
be as complete as possible, at a minimum including event reference number, protocol name 
and number, investigator contact information, specific patient identifiers (e.g., initials, patient 
number, date of birth or age, or gender), the name of the suspect Study Drug, the date and 
dosage(s) of exposure, event, the date(s) of event, country of event, “Serious” Criteria, 
Relationship/causality of Study Drug, Hospitalization history for the event, Event 
status/outcome, Relevant history (including diagnostics, laboratory values, radiographs, 
concomitant medications, and event treatment, and narrative summary. 
Sponsor shall be responsible for collecting all SAEs and Pregnancy and Lactation Exposure 
Reports and will exercise commercially reasonable due diligence to obtain follow-up 
information on incomplete SAE or Pregnancy and Lactation Exposure Reports. In the event 
that the Company requires clarification or further information on individual SAE or Pregnancy 
and Lactation Exposure Reports, Company will not contact non-party investigators directly, 
but will route all such inquiries through Site for forwarding to such investigator(s). Site will be 
responsible to ensure such inquiries are completed and timely provided to Company. 
Information not available at the time of the initial report (e.g., an end date for the SAE, 
discharge summaries, lot numbers, relevant laboratory values, scan data and autopsy 
reports) which are received after the initial report must be documented on a follow-up form, 
and submitted to Amgen in the same timelines as outlined above. Sponsor shall be 
responsible for obtaining follow-up information for the SAEs and demonstrate diligence in 
attempting to obtain such information by, among other things, maintaining written records of 
such attempts. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-326 A(11) 
Approval date: 08-Oct-2020 
Page 55 of 64 
 
 
Other aggregate analysis including reports containing safety data generated during the 
course of the study is to be submitted to Amgen at the time the sponsor ISS submits to 
anybody governing research conduct i.e. RA, IRB etc. Final study report including unblinding 
data when applicable and reports of unauthorized use of a marketed product to be submitted 
to Amgen at the time the sponsor ISS submits to anybody governing research conduct i.e. 
RA, IRB etc. but not later than one calendar year of study completion. 
Sponsor will provide an annual IND report to Amgen. Reports containing safety data 
generated during the course of the study is to be submitted to Amgen at the time the sponsor 
submits to anybody governing research conduct, i.e. regulatory authorities and IRBs. 
Sponsor will support reconciliation of all ICSRs at the end of the study at a minimum. 
 
 
Reporting Pregnancy to Amgen 
 
Pregnancy Reporting by Investigator-sponsor to Amgen 
Report Pregnancy and potential infant exposure including Lactation, within ten (10) calendar 
days of Sponsor awareness. Provide to Amgen the SAE reports associated with pregnancy. 
SUSARs are to be reported within twenty-four (24) hours of submitting the report to the 
applicable regulatory authority. 
 
 
Amgen Global Safety Contact Information 
• 
Toll-free #:1-888-814-8653 
• 
For countries where the U.S. toll-free # cannot be used: +44-20-7136-1046 
• 
Email (Only for sponsors with a secure email connection with Amgen): svc-ags-in- 
us@amgen.com 
 
 
 
 
 
 
SAE Reporting to Celgene 
All adverse experience reports must include the patient number, age, sex, weight, severity of 
reaction (e.g. mild, moderate, severe), relationship to drug (e.g. probably related, unknown 
relationship, definitely not related), date and time of administration of test medications and all 
concomitant medications, and medical treatment provided. The investigator is responsible 
for evaluating all adverse events to determine whether criteria for “serious” and as defined 
above are present. The investigator is responsible for reporting adverse events to Celgene 
as described below. 
Serious adverse events (SAE) are defined above. The investigator must inform Celgene in 
writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE as soon as 
possible or at least within 24 hours of being aware of the event. The date of awareness 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-326 A(11) 
Approval date: 08-Oct-2020 
Page 56 of 64 
 
 
should be noted on the report. The written report must be completed and supplied to 
Celgene by facsimile within 24 hours/1 business day at the latest on the following working 
day. The initial report must be as complete as possible, including an assessment of the 
causal relationship between the event and the investigational product(s), if available. 
Information not available at the time of the initial report (e.g., an end date for the adverse 
event or laboratory values received after the report) must be documented on a follow-up 
report. A final report to document resolution of the SAE is required. The Celgene tracking 
number and the institutional protocol number should be included on SAE reports (or on the 
fax cover letter) sent to Celgene. A copy of the fax transmission confirmation of the SAE 
report to Celgene should be attached to the SAE and retained with the patient records. 
Celgene Corporation 
Global Drug Safety and Risk Management 
Connell Corporate Park 
300 Connell Dr. Suite 6000 
Berkeley Heights, NJ 07922 
Fax: (908) 673-9115 
E-mail: drugsafety@celgene.comdrugsafety@celgene.com 
 
Reporting Pregnancy to Celgene 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of 
age or disease state) of a female subject occurring while the subject is on lenalidomide, or 
within 28 days of the subject’s last dose of lenalidomide, are considered immediately 
reportable events. Lenalidomide is to be discontinued immediately. The pregnancy, 
suspected pregnancy, or positive pregnancy test must be reported to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, using the Pregnancy Initial Report 
Form, or approved equivalent form. The female subject should be referred to an obstetrician- 
gynecologist, preferably one experienced in reproductive toxicity for further evaluation and 
counseling. 
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal 
or abnormal outcome) using the Pregnancy Follow-up Report Form, or approved equivalent 
form. If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic 
abortion), the Investigator should report the abnormal outcome as an AE. If the abnormal 
outcome meets any of the serious criteria, it must be reported as an SAE to Celgene Drug 
Safety immediately by facsimile, or other appropriate method, within 24 hours of the 
Investigator’s knowledge of the event using the SAE Report Form, or approved equivalent 
form. 
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 lenalidomide should also be reported to Celgene Drug 
Safety immediately by facsimile, or other appropriate method, within 24 hours of the 
Investigator’s knowledge of the event using the SAE Report Form, or approved equivalent 
form. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-326 A(11) 
Approval date: 08-Oct-2020 
Page 57 of 64 
 
 
Male Subjects 
 
If a female partner of a male subject taking lenalidomide becomes pregnant, the male subject 
taking lenalidomide should notify the Investigator, and the pregnant female partner should be 
advised to call her healthcare provider immediately. 
 
Celgene Drug Safety Contact Information: 
Celgene Corporation 
Drug Safety 
86 Morris Avenue 
Summit, N.J. 07901 
Toll Free: 
(800)-640-7854 
Phone: 
(908) 673-9667 
Fax: 
(908) 673-9115 
E-mail: 
drugsafety@celgene.com 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will explain 
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information. In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-326 A(11) 
Approval date: 08-Oct-2020 
Page 58 of 64 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19.0 
REFERENCES 
 
1. 
Korde N, Roschewski M, Zingon, et al. Treatment With Carfilzomib-Lenalidomide- 
Dexamethasone With Lenalidomide Extension in Patients With Smoldering or Newly 
Diagnosed Multiple Myeloma. JAMA Oncol. 2015 Jul 2.. 
2. 
Criteria for the classification of monoclonal gammopathies, multiple myeloma and related 
disorders: a report of the International Myeloma Working Group. Br J Haematol. Jun 
2003;121(5):749-757. 

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IRB Number: 15-326 A(11) 
Approval date: 08-Oct-2020 
Page 59 of 64 
 
 
3. 
Kristinsson SY, Landgren O, Dickman PW, Derolf AR, Bjorkholm M. Patterns of survival in 
multiple myeloma: a population-based study of patients diagnosed in Sweden from 1973 to 
2003. J Clin Oncol. May 20 2007;25(15):1993-1999. 
4. 
Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the 
impact of novel therapies. Blood. 2008;111(5):2516-2520. 
5. 
Groll M, Ditzel L, Lowe J, et al. Structure of 20S proteasome from yeast at 2.4 A resolution. 
Nature. Apr 3 1997;386(6624):463-471. 
6. 
Demo SD, Kirk CJ, Aujay MA, et al. Antitumor activity of PR-171, a novel irreversible inhibitor 
of the proteasome. Cancer research. Jul 1 2007;67(13):6383-6391. 
7. 
Kuhn DJ, Chen Q, Voorhees PM, et al. Potent activity of carfilzomib, a novel, irreversible 
inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple 
myeloma. Blood. Nov 1 2007;110(9):3281-3290. 
8. 
Parlati F, Lee SJ, Aujay M, et al. Carfilzomib can induce tumor cell death through selective 
inhibition of the chymotrypsin-like activity of the proteasome. Blood. Oct 15 
2009;114(16):3439-3447. 
9. 
Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171- 
003-A1) in patients with relapsed and refractory multiple myeloma. Blood. Oct 4 
2012;120(14):2817-2825. 
10. 
Singhal S, Siegel D, Martin T. Integrated safey from phase 2 studies of monotherapy 
carfilzomib in patients with relapsed and refractory multiple myeloma: an updated analysis 
(abstract). Blood. 2011;118(21). 
11. 
Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination 
with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple 
myeloma. Blood. Aug 30 2012;120(9):1801-1809. 
12. 
Korde N, Zingone A, Kwok M, et al. Phase II Clinical and Correlative Study Of Carfilzomib, 
Lenalidomide, and Dexamethasone Followed By Lenalidomide Extended Dosing (CRD-R) 
Induces High Rates Of MRD Negativity In Newly Diagnosed Multiple Myeloma (MM) 
Patients. 2013. 
13. 
Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone 
combination therapy in patients with newly diagnosed multiple myeloma. Blood. 
2010;116(5):679-686. 
14. 
Rawstron AC, Child JA, de Tute RM, et al. Minimal residual disease assessed by 
multiparameter flow cytometry in multiple myeloma: impact on outcome in the Medical 
Research Council Myeloma IX Study. J Clin Oncol. Jul 10 2013;31(20):2540-2547. 
15. 
Ludwig H, Viterbo L, Greil R, et al. Randomized phase II study of bortezomib, thalidomide, 
and dexamethasone with or without cyclophosphamide as induction therapy in previously 
untreated multiple myeloma. J Clin Oncol. Jan 10 2013;31(2):247-255. 
16. 
Flanders A, Stetler-Stevenson M, Landgren O. Minimal residual disease testing in multiple 
myeloma by flow cytometry: major heterogeneity. Blood. Aug 8 2013;122(6):1088-1089. 
17. 
Papadopoulos KP, Siegel DS, Vesole DH, et al. Phase I Study of 30-Minute Infusion of 
Carfilzomib As Single Agent or in Combination With Low-Dose Dexamethasone in Patients 
With Relapsed and/or Refractory Multiple Myeloma. J Clin Oncol. Sep 15 2014. 
18. 
Wang M, Martin T, Bensinger W, et al. Phase 2 dose-expansion study (PX-171-006) of 
carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive multiple 
myeloma. Blood. Oct 31 2013;122(18):3122-3128. 
19. 
P S, S M, Siegel D, Vij R, S R, ME B. Multivariate modeling reveals evidence of a dose- 
response relationship in phase 2 studies of single-agent carfilzomib. Blood (ASH Annual 
Meeting Abstracts). 2011;118(21):2930. 
20. 
Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform 
reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. 
Blood. May 5 2011;117(18):4691-4695. 

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IRB Number: 15-326 A(11) 
Approval date: 08-Oct-2020 
Page 60 of 64 
 
 
21. 
Martinez-Lopez J, Lahuerta JJ, Pepin F, et al. Prognostic value of deep sequencing method 
for minimal residual disease detection in multiple myeloma. Blood. May 15 
2014;123(20):3073-3079. 
22. 
Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform 
reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. 
Blood. May 5 2011;117(18):4691-4695. 
23. 
Mark T, Jayabalan D, Coleman M, et al. Atypical serum immunofixation patterns frequently 
emerge in immunomodulatory therapy and are associated with a high degree of response in 
multiple myeloma. Br J Haematol. Dec 2008;143(5):654-660. 
24. 
Guimaraes C, Bergantim R, Ramalho R, Couto N, Guimaraes JT, Trigo F. Prognostic value 
of unrelated atypical serum immunofixation patterns during multiple myeloma therapy. J 
Hematol Oncol. 2012;5:33. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
20.0 
APPENDICES 
 
Appendix A: Requirements for REMS® 
Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-326 A(11) 
Approval date: 08-Oct-2020 
Page 61 of 64 
 
 
Requirements for REMS® 
• 
Patients should be instructed never to give lenalidomide to another person. 
• 
Patients will be asked to take part in a mandatory confidential survey prior to initiation of 
lenalidomide. To take the survey, they will be instructed to call the Celgene Customer Care 
Center at 1-888-423-5436. Male patients will be asked to take the survey monthly. Female 
patients will be asked to take survey periodically (monthly if females of childbearing potential 
and every 6 months if females of not childbearing potential). 
• 
Female patients should not donate blood during therapy and for at least 28 days following 
discontinuation of lenalidomide. 
• 
Male patients should not donate blood, semen or sperm during therapy or for at least 28 
days following discontinuation of lenalidomide. 
• 
Only enough lenalidomide for one cycle of therapy may be prescribed with each cycle of 
therapy. Monthly phone counseling is required per the REMS® program in order to prescribe 
a one-month supply of lenalidomide. 
• 
All patients will be required to sign the REVLIMID, Patient-Physician Agreement Form. 
• 
Males must practice complete abstinence or use a condom during sexual contact with 
pregnant females or females of childbearing potential throughout the entire duration of 
lenalidomide treatment, during dose interruptions and for at least 28 days following 
lenalidomide discontinuation, even if he has undergone a successful vasectomy. See below 
for further details 
• 
Females of childbearing potential must agree to use two reliable forms of contraception 
simultaneously or to practice complete abstinence from heterosexual intercourse during the 
following time periods related to this study: 1) for at least 28 days before starting 
lenalidomide; 2) throughout the entire duration of lenalidomide treatment; 3) during dose 
interruptions; and 4) for at least 28 days after lenalidomide discontinuation. See below for 
further details. 
Females not of childbearing potential must sign the REVLIMID, Patient-Physician Agreement Form 
that says you are presently not pregnant and do not have the ability to have children. 
Risks Associated with Pregnancy 
The use of lenalidomide in pregnant females and nursing mothers has not been studied nor has the 
effect of the lenalidomide on human eggs and sperm. Lenalidomide is structurally related to 
thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life- 
threatening birth defects. An embryofetal development study in animals indicates that lenalidomide 
produced malformations in the offspring of female monkeys who received the drug during 
pregnancy. The teratogenic effect of lenalidomide in humans cannot be ruled out. Therefore, a risk 
minimization plan to prevent pregnancy must be observed. 
All study participants must be registered into the mandatory REMS® program, and be willing and able 
to comply with the requirements of REMS®. 
 
 
 
Criteria for females of childbearing potential (FCBP) 
This protocol defines a female of childbearing potential as a sexually mature female who: 1) has not 
undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal 

Memorial Sloan Kettering Cancer Center 
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Page 62 of 64 
 
 
for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 
consecutive months). 
The investigator must ensure that: 
• 
Females of childbearing potential comply with the conditions for pregnancy risk minimization, 
including confirmation that she has an adequate level of understanding 
• 
Females NOT of childbearing potential acknowledge that she understands the hazards and 
necessary precautions associated with the use of lenalidomide 
• 
Male patients taking lenalidomide acknowledge that he understands that traces of lenalidomide 
have been found in semen, that he understands the potential teratogenic risk if engaged in 
sexual activity with a female of childbearing potential, and that he understands the need for 
the use of a condom even if he has had a vasectomy, if engaged in sexual activity with a female 
of childbearing potential. 
Contraception 
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two reliable forms 
of contraception simultaneously or to practice complete abstinence from heterosexual intercourse 
during the following time periods related to this study: 1) for at least 28 days before starting 
lenalidomide; 2) throughout the entire duration of lenalidomide treatment; 3) during dose interruptions; 
and 4) for at least 28 days after lenalidomide discontinuation. 
The two methods of reliable contraception must include one highly effective method and one additional 
effective (barrier) method. FCBP must be referred to a qualified provider of contraceptive methods if 
needed. The following are examples of highly effective and additional effective methods of 
contraception: 
o Highly effective methods: 
▪ 
Intrauterine device (IUD) 
▪ 
Hormonal (birth control pills, injections, implants) 
▪ 
Tubal ligation 
▪ 
Partner’s vasectomy 
o Additional effective methods: 
▪ 
Male condom 
▪ 
Diaphragm 
▪ 
Cervical Cap 
Because of the increased risk of venous thromboembolism in patients with multiple myeloma taking 
lenalidomide and dexamethasone, combined oral contraceptive pills are not recommended. If a patient 
is currently using combined oral contraception the patient should switch to one of the effective method 
listed above. The risk of venous thromboembolism continues for 4−6 weeks after discontinuing 
combined oral contraception. The efficacy of contraceptive steroids may be reduced during co- 
treatment with dexamethasone. 
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of 
infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be 
considered particularly in patients with neutropenia. 
Pregnancy testing 
Medically supervised pregnancy tests with a minimum sensitivity of 50 mIU/mL must be performed for 
females of childbearing potential, including females of childbearing potential who commit to complete 
abstinence, as outlined below. 
Before starting lenalidomide 
Female Patients: 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-326 A(11) 
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Page 63 of 64 
 
 
FCBP must have two negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to prescribing 
lenalidomide. The first pregnancy test must be performed within 10-14 days prior to prescribing 
lenalidomide and the second pregnancy test must be performed within 24 hours prior to prescribing 
lenalidomide. The patient may not receive lenalidomide until the Investigator has verified that the 
results of these pregnancy tests are negative. 
Male Patients: 
Must agree to practice complete abstinence or agree to use a condom during sexual contact with 
pregnant females or females of childbearing potential throughout the entire duration of lenalidomide 
treatment, during dose interruptions and for at least 28 days following lenalidomide discontinuation, 
even if he has undergone a successful vasectomy. 
 
 
During study participation and for 28 days following lenalidomide discontinuation 
Female Patients: 
• 
FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for the 
first 28 days of lenalidomide treatment, including dose interruptions and then every 28 days 
throughout the remaining duration of lenalidomide treatment, including dose interruptions, at 
lenalidomide discontinuation, and at Day 28 following lenalidomide discontinuation. If 
menstrual cycles are irregular, the pregnancy testing must occur weekly for the first 28 days 
of lenalidomide treatment, including dose interruptions, and then every 14 days throughout the 
remaining duration of lenalidomide treatment, including dose interruptions, at lenalidomide 
discontinuation, and at Day 14 and Day 28 following lenalidomide discontinuation. 
• 
At each visit, the Investigator must confirm with the FCBP that she is continuing to use two 
reliable methods of birth control at each visit during the time that birth control is required. 
• 
If pregnancy or a positive pregnancy test does occur in a study patient, lenalidomide must be 
immediately discontinued. 
• 
Pregnancy testing and counseling must be performed if a patient misses her period or if her 
pregnancy test or her menstrual bleeding is abnormal. Lenalidomide treatment must be 
temporarily discontinued during this evaluation. 
• 
Females must agree to abstain from breastfeeding during study participation and for at least 
28 days after lenalidomide discontinuation. 
Male Patients: 
• 
Must practice complete abstinence or use a condom during sexual contact with pregnant 
females or females of childbearing potential throughout the entire duration of lenalidomide 
treatment, during dose interruptions and for at least 28 days following lenalidomide 
discontinuation, even if he has undergone a successful vasectomy. 
If pregnancy or a positive pregnancy test does occur in the partner of a male study patient 
during study participation, the investigator must be notified immediately. 
 
 
APPENDIX B 
To characterize bone marrow aspirate specimens for somatic base mutations and copy 
number alterations in key cancer-associated genes, we will perform a custom, targeted deep- 
sequencing assay on matched tumor and normal pairs. The assay, termed HEMEPACT 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-326 A(11) 
Approval date: 08-Oct-2020 
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involves massively parallel sequencing, coupled with solution-phase exon capture. Exon 
capture will be performed on barcoded pools of sequence libraries by hybridization 
(Nimblegen SeqCap Target Enrichment) using custom oligonucleotides to capture all exons 
and select introns of 585 cancer genes, including all genes significantly mutated in 
hematologic malignancies. Barcoded pools will subsequently be sequenced on an Illumina 
HiSeq 2500 to 500-1000x coverage per sample in order to maximize sensitivity for detecting 
low-abundance alterations. Through many iterations of the design of the capture probe set, 
we have maximized the coverage uniformity across all exons in our panel, thus reducing the 
number of poorly-covered exons. As a result, for a sample sequenced by HEMEPACT to 
1000x coverage, >98% of target exons are covered at >500x. The platform includes all 
genes that are druggable by approved therapies or are targets of experimental therapies 
being investigated in clinical trials at MSKCC. Custom probes have been designed to capture 
translocations involving recurrently rearranged genes.