Clinical trial NCT01572480
Conditions: Multiple Myeloma
Keywords: Proteasome Inhibitor Immunomodulatory Agents Combination Therapy Anti-Myeloma Activity
Sponsor: National Cancer Institute (NCI)
Start date: 2012-05-29; Completion date: 2025-02-28
Enrollment: 55 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Background:

* Multiple myeloma is a blood cancer that affects the plasma cells. These cells help produce antibodies and fight infection. Smoldering multiple myeloma (SMM) is a related condition that may develop into multiple myeloma. The current standard of care for SMM is close follow-up without treatment until multiple myeloma develops. However, researchers are studying possible treatments for SMM itself. One possible treatment involves a combination of cancer treatment drugs.
* Lenalidomide is a drug that may help reduce or prevent the growth of cancer cells. Dexamethasone is a steroid that is often given with other anti-cancer drugs. These two drugs are an approved treatment for multiple myeloma that has not responded to at least one other treatment. Carfilzomib is an experimental drug that has been effective in treating multiple myeloma. Researchers want to combine these three drugs to see if they are a safe and effective treatment for SMM.

Objectives:

\- To see if carfilzomib, lenalidomide, and dexamethasone are a safe and effective treatment for smoldering multiple myeloma.

Eligibility:

\- Individuals at least 18 years of age who have SMM that is likely to progress to multiple myeloma.

Design:

* Participants will be screened with a physical exam and medical history. They will also have blood and urine tests, and baseline bone marrow scans. Bone marrow samples will also be collected.
* Participants will have eight 28-day cycles of treatment with the three study drugs. The drugs will be given as tablets or as infusions. Treatment will be monitored with frequent blood tests and study visits.
* After the first four cycles, participants who are eligible for a stem cell transplant will have their stem cells collected and stored for future use.
* At the end of eight cycles, participants whose disease has not progressed will have up to 12 more cycles of treatment with lenalidomide tablets alone.

Detailed description:
Background:

Smoldering multiple myeloma (SMM) is a precursor condition to multiple myeloma (MM) defined by the clinical parameters of M-protein \>= 3.0 g/dL or bone marrow plasma cells \>= 10% and absence of end organ disease.

Risk of progression of high risk SMM at 5 years is 72-75% with median time to progression \< 2 years.

The current standard of care for SMM is close follow-up without treatment until symptomatic MM develops. However, International Myeloma Working Group (IMWG) states "Preventive clinical trials need to be considered for patients with high risk smoldering myeloma".

Carfilzomib is a new proteasome inhibitor with potent anti-MM effects

Objectives:

To assess the response rate of cyclophosphamide, lenalidomide, and dexamethasone (CRd) in patients with high-risk SMM, focusing on the

Minimal residual disease (MRD(-) Complete Response (CR) rate

Eligibility:

SMM according to the International Myeloma Working Group definition; i.e.:

Serum M-protein \>=3 g/dl and/or bone marrow plasma cells \>=10 % and \< 60%

Absence of anemia: Hemoglobin \>10 g/dl

Absence of renal failure: serum creatinine \< 2.0 mg/dL.

Absence of hypercalcemia: Calcium (Ca) \< 10.5 mg/dl or 2.65 mmol/L

Absence of lytic bone lesion

Involved/un-involved light chain ratio must be \< 100

Measurable disease

High-risk SMM per Mayo Clinic, Spanish Programa de Estudio y Tratamiento de las Hemopatías Malignas (PETHEMA), or the Rajkumar, Landgren, Mateos criteria

Age \>=18 years

Eastern Cooperative Oncology Group (ECOG) performance status 0-2

Adequate laboratory parameters as defined in the protocol

Design:

Single arm pilot trial of combination therapy (carfilzomib, lenalidomide, and dexamethasone) for high risk smoldering multiple myeloma

Patients will receive 8 cycles of induction combination therapy of CRd

Each cycle consists of 28-days

After 4 cycles of therapy, transplant eligible patients may choose to undergo stem cell collection

After 8 cycles of CRd, patients will receive lenalidomide extended dosing (phase I) for 12 cycles. After 12 cycles, patients will have the option to continue extended dosing (phase II) for one additional year.

Patients will have routine blood work with serum protein electrophoresis (SPEP) and free light chains monthly during the induction phase. Laboratory evaluations may be spread out to every 3 months during the maintenance and follow-up phases.

Pre-treatment, post-treatment and follow-up bone marrow biopsies will be obtained for confirmation of diagnosis, response and correlative studies

Patients will also undergo evaluation for minimal residual disease at regular interval time points, using multi-parametric flow cytometry and fluorodeoxyglucose (FDG)-positron emission tomography (PET)-computed tomography (CT)

This single arm pilot study will plan on initially enrolling 12 evaluable patients to detect a very good partial response (VGPR) from baseline. A replicate cohort of 16 evaluable patients will then be enrolled in order to more precisely define the response rate to the CRd regimen in this population. Accrual will then be extended to a total of 50 evaluable patients in order to estimate the MRD(-) CR rate with reasonable precision. To allow for a number of inevaluable patients and screen failures, the accrual ceiling will be set at 63.

Arms: arm 1: Carfilzomib (intravenous (IV), Days 1, 2, 8, 9, 15, and 16 of the 28-day cycle); Revlimid (by mouth (PO), Days 1-21 of the 28-day cycle; exception: not given on cycle 1 day 1); and Dexamethasone (PO or IV, Days 1, 2, 8, 9, 15, 16, 22, and 23 of the 28-day cycle; exception: not given on cycle 1 day 1) arm 2: Carfilzomib (intravenous (IV), Days 1, 2, 8, 9, 15, and 16 of the 28-day cycle); Revlimid (by mouth (PO), Days 1-21 of the 28-day cycle); and Dexamethasone (PO or IV, Days 1, 2, 8, 9, 15, 16, 22, and 23 of the 28-day cycle)
Interventions: intervention 1: Carfilzomib intervention 2: Revlimid intervention 3: Dexamethasone
Intervention descriptions: intervention 1: Carfilzomib intravenous (IV) 20-36 mg/m\^2 per dose on days 1, 2, 8, 9, 15, and 16 of each cycle based on arm; until disease progression or unacceptable toxicity. intervention 2: Revlimid by mouth (PO) 25 mg/day, days 1-21 every 28 days of each cycle based on arm; until disease progression or unacceptable toxicity. intervention 3: Dexamethasone by mouth (PO) 20 mg per dose on days 1, 2, 8, 9, 15, 16, 22, and 23 of each cycle based on arm; until disease progression or unacceptable toxicity.

Protocol documents:
Prot_SAP_002.pdf: 
Abbreviated Title:  CRd for Smoldering Myeloma
Version Date:  01/01/2024
1
Abbreviated Title: CRd for Smoldering Myeloma
NIH Protocol #: 12C0107 
Version Date: 01/01/2024
NCT Number: NCT01572480
Carfilzomib, Lenalidomide, and Dexamethasone in High Risk 
Smoldering Multiple Myeloma: A Clinical and Correlative Pilot Study
NCI Principal Investigator: Elizabeth Hill, M.D.
Lymphoid Malignancies Branch (LYMB)
Center for Cancer Research (CCR)
National Cancer Institute (NCI)
Building 10, Room 3B38
National Institutes of Health (NIH)
Bethesda, MD  20892
Phone:  240-889-5377
Email: elizabeth.hill@nih.gov 
Drug Name:
Carfilzomib
Lenalidomide 
REVLIMID®
Dexamethasone
IND Number:
112587
Sponsor:
Center for Cancer Research (CCR)
Manufacturer:
Amgen, Inc. 
Bristol Myers Squibb 
(BMS)
Generic
Supplier
Amgen, Inc.
BMS is providing 
commercial supply
 CC Pharmacy 
 
(BMS/Celgene tracking #:  RV-MM-NCI-0719)


Abbreviated Title:  CRd for Smoldering Myeloma
Version Date:  01/01/2024
2
PRÉCIS 
Background:

SMM is a precursor condition to MM defined by the clinical parameters of M-protein ≥ 
3.0 g/dL or bone marrow plasma cells ≥ 10% and absence of end organ disease.  

Risk of progression of high risk SMM at 5 years is 72-75% with median time to 
progression <2 years. 

The current standard of care for SMM is close follow-up without treatment until 
symptomatic MM develops.  However, IMWG states “Preventive clinical trials need to 
be considered for patients with high risk smoldering myeloma”.

Carfilzomib is a new proteasome inhibitor with potent anti-MM effects
Objectives:

To assess the response rate of CRd in patients with high-risk SMM, focusing on the 
MRD(-) CR rate
Eligibility:

SMM according to the International Myeloma Working Group definition; i.e.: 
o
Serum M-protein ≥3 g/dl and/or bone marrow plasma cells ≥10 % and <60% 
o
Absence of anemia: Hemoglobin >10 g/dl
o
Absence of renal failure: serum creatinine < 2.0 mg/dL. 
o
Absence of hypercalcemia: Ca <10.5 mg/dl or 2.65 mmol/L
o
Absence of lytic bone lesion
o
Involved/un-involved light chain ratio must be < 100

Measurable disease as defined in the protocol

“High-risk SMM” per Mayo Clinic, Spanish PETHEMA, or the Rajkumar, Landgren, 
Mateos criteria

Age >18 years

Eastern Cooperative Oncology Group (ECOG) performance status 0-2

Adequate laboratory parameters as defined in the protocol
Design:

Single arm pilot trial of combination therapy (carfilzomib, lenalidomide, and 
dexamethasone) for high risk smoldering multiple myeloma 

Patients will receive 8 cycles of induction combination therapy of CRd

Each cycle consists of 28-days

After 4 cycles of therapy, transplant eligible patients may choose to undergo stem cell 
collection 

After 8 cycles of CRd, patients will receive lenalidomide extended dosing (phase I) for 
12 cycles. After 12 cycles, patients will have the option to continue extended dosing 
(phase II) for one additional year.


Abbreviated Title:  CRd for Smoldering Myeloma
Version Date:  01/01/2024
3

Patients will have routine blood work with SPEP and free light chains monthly during the 
induction phase.  Laboratory evaluations may be spread out to every 3 months during the 
maintenance and follow-up phases. 

Pre-treatment, post-treatment and follow-up bone marrow biopsies will be obtained for 
confirmation of diagnosis, response and correlative studies

Patients will also undergo evaluation for minimal residual disease at regular interval time 
points, using multi-parametric flow cytometry and FDG PET-CT

This single arm pilot study will plan on initially enrolling 12 evaluable patients to detect 
a VGPR from baseline. A replicate cohort of 16 evaluable patients will then be enrolled 
in order to more precisely define the response rate to the CRd regimen in this population. 
Accrual will then be extended to a total of 50 evaluable patients in order to estimate the 
MRD(-) CR rate with reasonable precision. To allow for a number of inevaluable patients 
and screen failures, the accrual ceiling will be set at 63.


Abbreviated Title:  CRd for Smoldering Myeloma
Version Date:  01/01/2024
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TABLE OF CONTENTS 
PRÉCIS...........................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................4
STATEMENT OF COMPLIANCE ................................................................................................7
1
INTRODUCTION ...................................................................................................................7
1.1
Study Objectives ...............................................................................................................7
1.2
Background and Rationale................................................................................................9
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................15
2.1
Eligibility Criteria ...........................................................................................................15
2.2
Screening Evaluation ......................................................................................................18
2.3
Participant Registration and Status Update Procedures..................................................20
2.4
Treatment Assignment and Randomization/Stratification Procedures ...........................20
2.5
Baseline Evaluation.........................................................................................................21
3
STUDY IMPLEMENTATION .............................................................................................21
3.1
Study Design...................................................................................................................21
3.2
Drug Administration .......................................................................................................23
3.3
Dose Modifications.........................................................................................................26
3.4
Study Calendar................................................................................................................33
3.5
Cost and Compensation ..................................................................................................36
3.6
Criteria for Removal from Protocol Therapy and Off Study Criteria.............................36
4
CONCOMITANT MEDICATIONS/MEASURES and CONSIDERATIONS ....................37
4.1
Tumor Lysis Syndrome...................................................................................................37
4.2
Transfusions/Growth Factors..........................................................................................38
4.3
Anti-Coagulation.............................................................................................................38
4.4
HSV and VSV Prophylaxis.............................................................................................39
4.5
Antibiotic Prophylaxis ....................................................................................................39
4.6
Progressive Multifocal Leukoencephalopathy (PML)....................................................39
4.7
Hepatitis B Virus (HBV) Reactivation ...........................................................................39
5
CORRELATIVE STUDIES FOR RESEARCH ...................................................................40
5.1
Biospecimen Collection ..................................................................................................40
5.2
Samples for Genetic/Genomic Analysis .........................................................................48
5.3
Sample Storage, Tracking and Disposition.....................................................................48
6
DATA COLLECTION AND EVALUATION .....................................................................51


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6.1
Data Collection ...............................................................................................................51
6.2
Data Sharing Plan............................................................................................................52
6.3
Response Criteria ............................................................................................................52
6.4
Toxicity Criteria..............................................................................................................55
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN...55
7.1
Definitions.......................................................................................................................55
7.2
OHSRP Office of Compliance and Training / IRB Reporting........................................55
7.3
NCI Clinical Director Reporting.....................................................................................55
7.4
NIH Required Data and Safety Monitoring Plan............................................................56
8
SPONSOR SAFETY REPORTING......................................................................................56
8.1
Definitions.......................................................................................................................56
8.2
Assessment of Safety Events ..........................................................................................57
8.3
Reporting of Serious Adverse Events .............................................................................58
8.4
Waiver of expedited reporting to CCR ...........................................................................58
8.5
Safety Reporting Criteria to the Pharmaceutical Collaborators......................................58
8.6
Reporting Pregnancy.......................................................................................................61
8.7
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND...................62
8.8
Sponsor Protocol Deviation Reporting ...........................................................................62
9
CLINICAL MONITORING..................................................................................................63
10
STATISTICAL CONSIDERATIONS ..................................................................................64
10.1
Sample Size/Accrual Rate...............................................................................................64
10.2
Statistical Analysis of Secondary/Exploratory Endpoints ..............................................65
11
COLLABORATIVE AGREEMENTS..................................................................................66
11.1
Agreement Type – CRADA............................................................................................66
12
HUMAN SUBJECTS PROTECTIONS................................................................................66
12.1
Rationale For Subject Selection......................................................................................66
12.2
Participation of Children.................................................................................................66
12.3
Evaluation of Benefits and Risks/Discomforts ...............................................................66
12.4
Risks/Benefits Analysis ..................................................................................................67
12.5
Consent Process and Documentation..............................................................................68
13
REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................69
13.1
Study Discontinuation and Closure.................................................................................69
13.2
Quality Assurance and Quality Control..........................................................................69


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13.3
Conflict of Interest Policy...............................................................................................70
13.4
Confidentiality and Privacy ............................................................................................70
14
PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION...............71
14.1
CARFILZOMIB (IND # 112587)...................................................................................71
14.2
LENALIDOMIDE  ........................................................................................................73
14.3
Dexamethasone ..............................................................................................................75
15
REFERENCES ......................................................................................................................77
16
APPENDICES .......................................................................................................................82
APPENDIX A:  Performance Status Criteria ............................................................................82
APPENDIX B:  Requirements for REMS.................................................................................83
APPENDIX C:  Bone Marrow Aspirate Collection, Sorting and Storage ................................87
APPENDIX D:  Peripheral Blood and Urine Collection and Storage.......................................89


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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Council on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.
1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective
To assess the response rate of CRd in patients with high-risk SMM, focusing on the 
minimal residual disease (MRD) negative complete response rate
1.1.2
Secondary Objectives

To determine biochemical and symptomatic progression free survival (PFS) 

To determine duration of response (DOR)

To determine duration of minimal residual disease (MRD) negative complete 
response (CR), and to estimate the rate of durable MRD(-) CRs (greater than one 
year)

To evaluate toxicity of combination therapy (carfilzomib, lenalidomide, and 
dexamethasone)   

To evaluate biological activity of carfilzomib and correlate to clinical outcomes (gene 
expression profiling on pre- and post-carfilzomib exposure bone marrow samples) 
NOTE: This endpoint no longer applies as of Amendment H (version date 
06/12/2017).

To determine overall survival (OS)

To compare the MRD (-) CR rates between patients enrolled from 2012-2014 vs. 
enrolled in 2017 and later years
1.1.3
Exploratory Objectives 

MRD detection by next generation VDJ sequencing, exome sequencing, and PD-
1/PD-L1 expression in the bone marrow compartment 


Abbreviated Title:  CRd for Smoldering Myeloma
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
To evaluate FISH data on available patients enrolled following amendment L (version 
date 05/17/2018) with respect to classification into high risk vs. non-high-risk patients

To evaluate radiographic changes (FDG avidity) in bone marrow heterogeneity and 
focal infiltration by PET/CT at baseline and overtime

To evaluate radiographic changes (signal intensity) in bone marrow heterogeneity and 
focal lesions by Diffusion Weighted MRI (DW-MRI) at baseline and over time


Abbreviated Title:  CRd for Smoldering Myeloma
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1.2
BACKGROUND AND RATIONALE
1.2.1
Introduction
Multiple myeloma (MM) is a neoplasm characterized by the proliferation and 
accumulation of malignant plasma cells in the bone marrow that lead to the 
overproduction of monoclonal proteins in the serum or urine, affecting nearly 20,000 
people annually.[1]  End-organ damage resulting from this disorder includes 
hypercalcemia, renal insufficiency, anemia, and lytic bone lesions.5  Myeloma remains 
incurable, with a median survival of 3-4 years in the United States, although newer 
therapies appear to be improving survival.[2-4]  Importantly, two recent studies have 
proven that all cases of MM are preceded by a premalignant state, monoclonal 
gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma 
(SMM), although at this time the biological mechanism of this progression is not 
understood.[5, 6]  Currently, clinicians do not have access to any established biological 
markers that reliably predict progression to myeloma in patients with MGUS.  This study 
is designed to better understand these premalignant disorders and their progression to 
MM. 
MGUS is a premalignant plasma cell proliferative disorder that is characterized by 
elevated monoclonal immunoglobulin (M-protein) < 3 g/dL and bone marrow plasma 
cells < 10% in the absence of any other plasma cell disorder.[7]  Epidemiological studies 
have estimated the prevalence of MGUS as 3.2% in patients older than 50 years; these 
patients have a 1% annual risk of progression to MM.[8, 9]  However, risk factors of M-
protein ≥ 1.5 g/dL, non-IgG M-protein, and abnormal serum free-light chain ratio are 
known to confer a higher rate of progression (58% at 20 years).[10] Similar to MGUS, 
SMM is a precursor condition to MM defined by the clinical parameters of M-protein ≥ 
3.0 g/dL or bone marrow plasma cells ≥ 10%.  Its risk of progression is higher than that 
of MGUS, estimated to be an average of 10% annually.[11]  SMM can be risk stratified 
into categories using Mayo Clinic risk criteria[12] and Spanish PETHEMA[13] risk 
criteria in addition to the high-risk criteria set forward by Rajkumar, Landgren, Mateos 
[14].  At 5 years, risk of progression to MM for high risk SMM patients, using the above 
risk models is 72-76%.  Median time to progression for high risk SMM is less than 2 
years1.  
The current standard of care for SMM is close follow-up without treatment until 
symptomatic MM develops. Using melphalan-prednisone in SMM, early treatment has 
not been found to delay progression to active disease or improve overall survival [15]. 
The first randomized phase III study using novel drugs (lenalidomide/dexamethasone vs. 
surveillance) in SMM was presented by the Spanish study group in December 2009 at the 
annual ASH meeting [16]. In May 2011, an intention to treat (ITT), interim analysis 
(n=58) presented at the International Myeloma Workshop in Paris [17] showed the 
following: 7% stringent complete remission (sCR), 7% CR, 10% very good partial 
remission (VGPR) and 57% partial remission (PR). After a median of 7 (range 1-21) 
cycles of lenalidomide maintenance, the sCR increased to 13%. In the treatment arm, 15 
(25%) patients had progressive disease (median follow-up 22 months). In the surveillance 
arm, 28 (46%) patients progressed to active MM. Median time to progression (TTP) from 
inclusion was 25 months for the surveillance arm versus median not reached in the 
treatment arm (p<0.05). 


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1.2.2
Proteasomes and Bortezomib
In MM, proteasomes have been found to play a critical role in protein turnover and 
degradation, thereby affecting essential cell functions of cell cycle control, signal 
transduction, apoptosis, and stress 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 [18].  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.         
Bortezomib is a dipeptide boronate reversible inhibitor of the chymotryptic domain of the 
26S proteasome. In combination with other agents, bortezomib demonstrates a potent 
anti-myeloma effect in initial treatment of transplant and non-transplant candidates, as 
well as in relapsed/refractory disease settings [19, 20].  A recent phase I/II study shows 
promising efficacy of the novel combination: bortezomib, lenalidomide, and 
dexamethasone in newly diagnosed multiple myeloma patients, with 74% of subjects 
achieving very good partial response (VGPR) or better [21].   
Despite undisputable benefits of novel agents, bortezomib and others pose certain clinical 
challenges.  Bortezomib drug toxicity is common with side effects including neuropathy, 
GI distress (diarrhea), myelosuppression (in particular thrombocytopenia) and herpes 
zoster re-activation.  Bortezomib associated peripheral neuropathy can be experienced in 
up to 33% (Grade 1 and 2) and <18% (Grade 3 and 4) newly diagnosed multiple 
myeloma patients [22].  In the aforementioned phase I/II study, with combination 
bortezomib, lenalidomide, and dexamethasone, 80% of treated patients experienced 
sensory neuropathy all grades [21].  In addition, as increasing numbers of patients are 
treated with novel agents, drug resistance and refractoriness seems to present a significant 
dilemma.  Myeloma patients refractory or resistant to bortezomib and at least one IMID 
(lenalidomide or thalidomide) demonstrate median overall survival and event free 
survival of 6 months and 1 month, respectively [23].  
1.2.3
Investigational Drug Carfilzomib
Carfilzomib 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 myelosuppression [24-26].  In vitro models suggest 
carfilzomib has activity against bortezomib resistant myeloma cell lines [25].  
Carfilzomib can also work synergistically with dexamethasone to enhance tumor cell 
death [25].  A number of phase I and phase II studies are currently investigating 
carfilzomib toxicity and efficacy in multiple myeloma.  One such phase Ib/II trial is 
examining combination therapy with carfilzomib, lenalidomide, and low dose 
dexamethasone in refractory/relapsed multiple myeloma patients.  Based on this ongoing 
study, no MTD of carfilzomib was identified in the dose escalation portion of the study 


Abbreviated Title:  CRd for Smoldering Myeloma
Version Date:  01/01/2024
11
their highest dose cohort received. Based on data from an interim analysis including 12 
evaluable newly diagnosed MM patients (who received up to 8 cycles of carfilzomib, 
lenalidomide and dexamethasone), 83% achieved VGPR.  Among 19 patients evaluable 
for toxicity, less than 1% patients experienced grade 1 peripheral neuropathy.   
As of April 2020, carfilzomib has been examined in approximately 6,582 people in a 
research setting. It has been found that carfilzomib can cause a reactivation of hepatitis B 
virus. Additionally, there have been 4 cases of Progressive Multifocal 
Leukoencephalopathy (PML) possibly linked to Carfilzomib. 
1.2.4
Proposed Study Investigation with Correlative Studies
Given carfilzomib’s potent anti-myeloma activity and lack of peripheral neuropathy, we 
propose a pilot investigation study of combination therapy (Cycles 1-8 carfilzomib, 
lenalidomide and dexamethasone) in high-risk SMM patients followed by extended 
dosing with lenalidomide (for 12 cycles). Proposed correlative studies include gene 
expression profiling on CD 138 + pre- and post- carfilzomib plasma cells, identification 
of potential biomarkers (blood, urine, bone marrow aspirates), proteasome activity and 
ubiquination assays, and effects on downstream signaling targets.  
Patients will also undergo evaluation for minimal residual disease at regular interval time 
points, using multi-parametric flow cytometry, FDG PET-CT, Diffusion weighted MRI 
(DW-MRI) and detection of clonality using heavy and/or light chain immunoglobulin 
rearrangement. Current response criteria in MM are often limited in predicting clinical 
response and duration of response, and minimal residual disease (MRD) use in MM is 
still under current investigation.  Immunophenotyping of abnormal plasma cells using 
multi-parametric flow cytometry has prognostic value in the post-autologous stem cell 
transplantation setting, and patients achieving negative MRD flow status compared to 
those with residual positive MRD flow status had longer OS (median not reached vs. 89 
months, p = 0.002). 22   Other techniques, such as, polymerase chain reaction (PCR) of Ig 
heavy chain (IGH) rearrangements and light chain genes have also been employed in 
evaluating for MRD and found to have prognostic significance in showing prolonged PFS 
after intensive therapy.23 More recently, two important published meta-analysis data have 
suggested that MRD negative status (≤10-5 sensitivity) is an important endpoint that is 
associated with improved direct clinical benefit, both in terms of PFS and OS [27, 28]. 
Furthermore, in the updated 2015 IMWG response criteria for multiple myeloma, both 
MRD negative CR and sustained MRD negative CR at 10-6 to 10-5 sensitivity are formal 
response categories signifying “deep” responses. There is limited published data on MRD 
status as surrogate marker in the smoldering myeloma setting.
FDG-PET CT has been valuable at localizing intramedullary and extramedullary disease 
in MM.  FDG uptake is able to distinguish between active lesions and chronic disease, 
scar tissue, necrotic tissue, radiation changes, and other benign disease.  The sensitivity 
of FDG-PET in detecting myelomatous involvement is approximately 85%, and its 
specificity is approximately 90%.25  Along the lines of more advanced imaging 
techniques, DW-MRI has recently been found as a potential complementary imaging 
modality that focusses on the actual myeloma plasmacytoma disease rather than 
subsequent bone destruction. The MY-RADS group state that because skeletal survey and 
CT predominantly help to detect the destructive effects of myeloma on trabecular and 
cortical bone rather than disease within the bone marrow space, sensitivity and capability 


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as a restaging tool are inherently limited. [29]  Myeloma infiltrates within bone marrow 
can be observed on CT if they lie within the marrow spaces adjacent to fatty bone 
marrow. However, in trabecular bone spaces (ie vertebral bodies), myeloma infiltrates are 
difficult to evaluate given factors including the trabeculae, degenerative changes, benign 
lesions, and osteoporosis. In contrast, MRI allows direct imaging of the bone marrow 
given its superb sensitivity, soft-tissue contrast, and early detection of focal myeloma 
lesions. Although PET/CT can also detect myeloma lesions, MRI is more sensitive 
especially with newer techniques, i.e. DW-MRI, which have shown a sensitivity of 77% 
compared to 47% for PET/CT. [30] Current whole-body MRI protocols can incorporate 
DW-MRI sequences that are sensitive to cellular density and viability and are important 
for disease detection and monitoring. Another benefit of DW-MRI sequences are that 
they are quick to perform (~30-45 minutes) and interpret. Finally, the relationship of 
apparent diffusion coefficient values with cell density has the potential to assess response 
to treatment and response heterogeneity prior to changes in lesion size. [31, 32] The 
recent MY-RADS recommendations were published in an attempt to promote 
standardization and decrease variations in the acquisition, interpretation, and reporting of 
whole-body MRI and allow better response assessments across cancer centers. MY-
RADS recommendations do require validation within clinical trials, including 
assessments of reproducibility and therefore we will be guided by the group’s 
recommendations especially in regard to MRI data acquisition and analysis protocols. 
[29]
Incorporating such techniques into prospective clinical trials may have a role in 
evaluating response to therapy.
Effective with Amendment G (version date 07/20/2015), bone marrow aspirate and 
biopsy will be obtained for research studies at the discretion of the PI.
1.2.5
Continuation of Lenalidomide
Since the initiation of the protocol new data has been published regarding the efficacy 
and safety of extended dosing with lenalidomide in multiple myeloma patients.  Three 
double blind randomized control trials were published in the same May 2012 issue of 
NEJM showing that patients receiving extended dosing with lenalidomide (10-15 mg) 
after induction type regimens have a significant progression free survival benefit in the 
lenalidomide therapy arms[33-35].  Two studies (McCarthy et al. and Attal et al.) were 
conducted after autologous HSCT and one study (Palumbo et al.) assessed transplant 
ineligible patients after induction therapy with melphalan, lenalidomide and prednisone.  
Importantly, McCarthy and colleagues showed an overall survival benefit in patients 
receiving lenalidomide compared to placebo (15% vs. 23%, p = 0.03)[34].  A small 
increased risk of secondary primary malignancies (SPM) was noted in the lenalidomide 
groups compared to the placebo groups in all three trials with a cumulative incidence of 
SPMs 7-8% in the lenalidomide arms of the three studies [36].  However, it should be 
noted that such a risk has been well known and established in multiple myeloma patients 
receiving alkylator therapy, such as melphalan[37].  All three of the aforementioned 
randomized trials used lenalidomide after melphalan exposure, a significant and notable 
difference between our trial (12-C-0107) and theirs.  Despite this increased risk of 
secondary malignancy, post ad hoc analysis for all three trials with second malignancies 
being scored as “events” still showed a significant event free survival benefit for 


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lenalidomide arms compared to placebo[33-35].
In a recent meta-analysis presented by Palumbo et al. at ASCO 2013[36] including over 
3000 patients reporting SPM cumulative incidence from randomized phase III trials 
comparing Len vs. No Len treatments, the cumulative incidence rates of hematologic 
SPMs at 36 months was 1.4% Len vs. 0.4% No Len (HR 3.8, 95% CI 1.15-12.62, p = 
0.029) and solid SPMs at 36 months was 2.6% Len vs. 2.9 % No Len (HR 1.1, 95% CI 
0.62-2.00, p = 0.72).  In a subset analysis, investigators reviewed specific treatment 
regimens.  Cumulative incidence of hematologic SPMs at 36 months were consistently 
higher in regimens following lenalidomide + melphalan 1.8% vs. lenalidomide + 
cyclophosphamide 0.3% vs. lenalidomide alone 0.3% vs. melphalan alone 0.4% (HR 
3.8, 2.11-6.86, p<0.001).  Unfortunately, the meta-analysis did not account for duration 
of lenalidomide therapy.  However, it does seem to imply there is an increased risk of 
SPM in patients exposed to both melphalan and lenalidomide agents.  Our study does 
not have melphalan exposure. Therefore, extrapolating cumulative SPM incidence (7-
8% in lenalidomide arm) from the published randomized lenalidomide maintenance 
trials[33-35] would likely be overestimating incidence in our population given the lack 
of melphalan exposure in our trial.  Recently, colleagues from the Mayo Clinic 
published long-term results of their experience with lenalidomide and dexamethasone.  
They report a SPM incidence of 6.6% in a regimen that does not include melphalan.  
Furthermore, recent data show that the risk of SPM is inherently associated with plasma 
cell disorders independent of therapy. For example, MGUS patients have an increased 
risk of AML/MDS, which is the most common SPM reported in multiple myeloma 
patients[37].  
Currently no direct study allows us to accurately estimate anticipated SPM incidence, 
however, based on prior studies, recent meta-analysis, and lack of melphalan exposure with 
lenalidomide, we would anticipate an incidence range of 5.2-8% with a median follow-up 
period of 3 years.
In accord with these recent publications, lack of alkylator exposure and a similar study 
design to the phase III Spanish PETHEMA Quiredex trial, we increased lenalidomide 10 
mg extended dosing from the initially proposed 1 year to 2 years in patients that maintain 
their current clinical response and do not show signs of progression as outlined in Section 
6.3 or reasons for removal from protocol therapy listed in Section 3.5. 
1.2.6
Patient Reported Outcome/Quality of Life:  PROMIS
Patient-Reported Outcomes Measurement Information System (PROMIS) is a health-
related patient reported outcome (PRO) quality of life measurement instrument that was 
developed by NIH/NCI to standardize patient-reported outcomes for national use by 
research clinicians. Two versions of PROMIS are available to researchers: computer-
adaptive tests (CATs) and short forms.[38-43] The short forms are brief, static 
instruments that have demonstrated similar reliability to the longer, dynamic CATs, 
which provide precise measures for studying populations with widely varied responses 
and longitudinal self-report data. Each short form includes 4 to 8 items, measures 
reported health outcomes in the past 7 days on a Likert type scale and takes less than 5 
minutes each to complete; collectively we anticipate the questionnaires chosen for this 
study to take approximately 20 minutes in total.  


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PROMIS instruments, measuring a broad range of health domains, have been validated 
for adults (>18) with a variety of health conditions. Results of PRO for patients with 
RRMM treated with the carfilzomib, lenalidomide, dexamethasone regimen have been 
published before; however, will be explored additionally in this study.[44] The most 
important difference in the prior study was the patient population was relapsed/refractory. 
In the current study, we hope to gain insight into PROs in a relatively healthy population 
who otherwise would not be treated for smoldering myeloma outside of a clinical trial. 
Given that the standard of care for smoldering MM is observation, it is imperative to 
evaluate the effect of treatment on PROs.
NOTE: As of February 1, 2021 PROMIS surveys are no longer completed.


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2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
2.1.1.1 Patients must have histologically or cytologically confirmed Smoldering Multiple 
Myeloma confirmed by the Principal Investigator in discussion with the Laboratory of 
Pathology, NCI or the Department of Laboratory Medicine, CC, as needed, and based 
on the International Myeloma Working Group Criteria[45]:

Serum M-protein ≥3 g/dl and/or bone marrow plasma cells ≥10 % and <60%

Absence of anemia: Hemoglobin >10 g/dl

Absence of renal failure: serum creatinine < 2.0 mg/dL  

Absence of hypercalcemia: Ca <10.5 mg/dl

Absence of lytic bone lesion on X-ray, CT, or PET/CT and not more than 1 lesion 
on spinal MRI (NOTE: At the discretion of the investigator, PET/CT may replace 
MRI in patients who have a contraindication to MRI.)

Involved/un-involved light chain ratio must be < 100
2.1.1.2 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 

Serum immunoglobulin free light chain >10 mg/dL AND abnormal kappa/lambda 
ratio (reference 0.26-1.65)
NOTE:  As of Amendment L (version date 05/17/2018), the primary endpoint is 
MRD(-) CR rate; therefore, per the discretion of the Principal Investigator, patients 
without measurable disease (e.g., M-spike <1) may also be enrolled. This is in line with 
the most recent IMWG MM response criteria.
2.1.1.3 Age >18 years.  Because no dosing or adverse event data are currently available on the 
use of carfilzomib in combination with lenalidomide in patients <18 years of age, 
children are excluded from this study, but may be eligible for future pediatric trials. 
2.1.1.4 ECOG performance status <2 (Karnofsky >60%, see APPENDIX A)
2.1.1.5 Patients must have normal organ and marrow function as defined below: 

absolute neutrophil count (ANC) >1.0 K/uL 
NOTE:  At the discretion of the investigator, patients with an ANC of 0.5 K/uL – 
<1.0 K/uL may also be enrolled if clinically appropriate (e.g., patients with a 
baseline neutropenia that is chronic and that does not cause complications).  

platelets >75 K/uL

hemoglobin > 8 g/dL (transfusions are permissible)

total bilirubin <1.5 X institutional upper limit of normal 

AST(SGOT)/ALT(SGPT) <3.0 X institutional upper limit of normal (ULN)

Serum creatinine ≤1.5 X institutional ULN. If serum creatinine is above 1.5 X 
ULN, Creatinine Clearance (CrCl) or eGFR (estimated glomerular filtration rate) 


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must be ≥ 50 ml/min. 
o
CrCl will be calculated by Cockcroft-Gault method.  CrCl (calculated) = 
(140 – Age) x Mass (in kilograms) x [0.85 if Female] 72 x Serum 
Creatinine (in mg/dL). 
o
eGFR will be calculated by either of the following well established 
formulas: modification of diet in renal disease (MDRD) or the chronic 
kidney disease (CKD)-epidemiology collaboration (EPI) (institutional 
standard) equations.

CrCl may also be determined by measuring a 24 hour urine collection The  
measured CrCl must be ≥ 50 ml/min.
2.1.1.6 In addition to having SMM, patients must also be classified as “high-risk SMM” per 
Mayo Clinic[12]  or Spanish PETHEMA[13]  criteria.  NOTE:  Criteria set forward by 
Rajkumar, Landgren, Mateos [14] may also be used to define high risk disease, namely 
clonal bone marrow plasma cells ≥10% and any one or more of the following:

Serum M protein ≥30g/L

IgA SMM

Immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes

Serum involved/uninvolved FLC ratio ≥8 (but <100)

Progressive increase in M protein level (evolving type of SMM; increase in serum 
M protein by ≥25% on 2 successive evaluations within a 6-month period)

Clonal BMPCs 50%-60%

Abnormal PC immunophenotype (≥95% of BMPCs are clonal) and reduction of 
≥1 uninvolved immunoglobulin isotypes

t(4;14) or del(17p) or 1q gain

Increased circulating PCs

MRI with diffuse abnormalities or 1 focal lesion

PET-CT with focal lesion with increased uptake without underlying osteolytic 
bone destruction
2.1.1.7 All study participants must be registered into the mandatory REMS® program, and be 
willing and able to comply with the requirements of REMS®.
2.1.1.8 The effects of carfilzomib on the developing human fetus are unknown.   The 
immunomodulatory agents used in this trial (i.e., lenalidomide) are known to be 
teratogenic.  Women of child-bearing potential and men must agree to use adequate 
contraception.  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 
† 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).


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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. All patients must be counseled at a minimum of every 28 days 
about pregnancy precautions and risks of fetal exposure; see APPENDIX B:  
Requirements for REMS. Should a woman become pregnant or suspect she is pregnant 
while she or her partner is participating in this study, she should inform her treating 
physician immediately. In regard to carfilzomib, FCBP and their male partners must 
agree to use at least one method of effective contraception for at least 30 days after the 
last dose of carfilzomib and males must agree to use contraception and not to donate 
sperm for at least 90 days after the last dose of carfilzomib.
2.1.1.9 Ability of subject to understand and the willingness to sign a written informed consent 
document.
2.1.2
Exclusion Criteria
2.1.2.1 Patients who are receiving any other investigational agents.
2.1.2.2 Concurrent systemic treatment or prior therapy within 4 weeks for SMM.  NOTE:  
Treatment with corticosteroids for other indications is permitted
2.1.2.3 Patients with a diagnosis of MM as defined by the 2014 IMWG diagnostic criteria[45]
2.1.2.4 Contraindication to any concomitant medication, including antivirals, anticoagulation 
prophylaxis, tumor lysis prophylaxis, or hydration given prior to therapy
2.1.2.5 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to carfilzomib or lenalidomide agents used in study, such as bortezomib or 
thalidomide, in addition to patients with known allergy to sulfobutyl ether β-
cyclodextrin (Captisol®).
2.1.2.6 Uncontrolled hypertension or diabetes  
2.1.2.7 Pregnant or lactating females.  Pregnant women are excluded from this study. The 
effects of carfilzomib on a developing human fetus are unknown.  Lenalidomide is 
teratogenic with unknown potential for abortifacient effects.  Breastfeeding women and 
women planning on breastfeeding may not participate. No studies of carfilzomib have 
been conducted on breast feeding women and it is not known if it is excreted in milk.  
Because there is an unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with Carfilzomib/Lenalidomide, breastfeeding 
should be discontinued if the mother is treated with Carfilzomib/Lenalidomide.  
2.1.2.8 Significant cardiovascular disease with NYHA Class II, III or IV symptoms, or 
hypertrophic cardiomegaly, or restrictive cardiomegaly, or myocardial infarction 
within 3 months prior to enrollment, or unstable angina, or unstable arrhythmia.
2.1.2.9 Active hepatitis B or C infection.


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2.1.2.10 Has refractory GI disease with refractory nausea/vomiting, inflammatory bowel 
disease, or bowel resection that would prevent absorption.
2.1.2.11 Significant neuropathy >Grade 2 at the time of first dose or within 14 days of 
enrollment.
2.1.2.12 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations within 2 weeks that would limit 
compliance with study requirements.  
2.1.2.13 History of other malignancy (apart from basal cell carcinoma of the skin, or in situ 
cervix carcinoma) except if the patient has been free of symptoms and without active 
therapy during at least 2 years or if, at the clinical discretion of the investigator, the 
risks of this study do not outweigh the potential benefits on a case to case basis.
2.1.2.14 Major surgery within 1 month prior to enrollment.
2.1.3
Recruitment Strategy
Participant sources will include NIH patient populations and outside physician referrals.  Of 
note, our outside physician referral network has a high representation of minorities. 
This protocol may also be abstracted into a plain language announcement and posted on NIH 
websites and on NIH social media platforms.
In addition, we will work with specialists from the NIH Clinical Center Office of Patient 
Recruitment to develop study-specific public service announcements (e.g., Twitter, Facebook, 
etc.) and informational fliers to be used for recruitment activities.  All information to be posted 
or distributed publicly will be submitted to the IRB for review and approval in advance of use. 
Investigators may also take part in online and in-person patient support groups and social media 
forums where patients gather for networking, general support and information about their 
disease. These groups and forums may also serve as indirect recruitment referral resources (e.g., 
investigators may provide information/links to publicly available resources for more information 
on clinical trials to which a patient may self-refer).
2.2
SCREENING EVALUATION
2.2.1
Screening activities performed prior to obtaining informed consent
Minimal risk activities that may be performed before the subject has signed a consent include the 
following: 

Email, written, in person or telephone communications with prospective subjects 

Review of existing medical records to include H&P, laboratory studies, etc.  

Review of existing MRI, x-ray, or CT images

Review of existing photographs or videos

Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes
A waiver of consent for these activities has been requested in section 12.5.1.


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2.2.2
Screening activities performed after a consent for screening has been signed
The following activities will be performed only after the patient has signed the screening consent 
for this study or the consent for study 01C0129 (provided the procedure is permitted on that 
study) on which screening activities may also be performed. Assessments performed at outside 
facilities or on another NIH protocol within the timeframes below may also be used to determine 
eligibility once a patient has signed the consent.
A complete history and physical examination with documentation of measurable disease and 
assessment of performance status using the ECOG scale must be performed prior to study entry.
The following studies and laboratory tests will be completed 4 weeks prior to study entry, unless 
otherwise noted:

CBC with differential and reticulocyte count 

Acute Care (sodium, potassium, chloride, CO2, glucose, BUN, creatinine), Mineral 
(serum calcium, phosphate, magnesium and albumin) and Hepatic (alkaline phosphatase, 
ALT, AST, total and direct bilirubin) Panels, and CrCl calculation 

Uric acid, LDH, and Beta-2 Microglobulin 

Serum protein electrophoresis (SPEP) and immunofixation to assess for presence and 
quantity of monoclonal protein (M-protein) 

Random urine sample for protein electrophoresis (UPEP) and immunofixation to assess 
for monoclonal protein in the urine (Bence-Jones proteinuria). Collect a 24 hour urine 
sample if necessary for confirmation of Smoldering Multiple Myeloma diagnosis [i.e. if 
patient’s serum monoclonal protein is not measurable (< 1.0 g/dl)].  

Serum free light-chain studies

Quantitative immunoglobulins

Viral serologies:  Hepatitis B surface antigen and Anti Hepatitis C (HCV) antibody. If 
Anti HCV is positive, will follow with HCV RNA PCR 

If the patient does not meet Mayo Clinic criteria or the criteria set forth by Rajkumar, 
Landgren, Mateos for high-risk SMM, but he/she has evidence of immunoparesis, the 
patient will have to undergo a bone marrow core biopsy and/or aspirate with flow 
cytometry to determine high-risk disease as defined by the PETHEMA criteria. If a bone 
marrow aspirate is done at screening, then the sample can be processed for baseline 
assays (see APPENDIX C:  Bone Marrow Aspirate Collection, Sorting and Storage) to 
minimize the number of bone marrow biopsies

Serum or urine pregnancy test in women of child-bearing potential. 

12-lead EKG

A skeletal survey of the axial and appendicular skeleton will be performed.  (NOTE:  A 
skeletal survey does not have to be repeated if performed at the NIH within 3 months of 
screening.) 

A spinal MRI (cervical/thoracic/lumbar) is required prior to study entry to exclude ≥ 2 
lytic lesions; if patient has had an MRI performed at an outside facility, one performed at 


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NIH is not required but may be performed for research purposes. (NOTE:  At the 
discretion of the Principal Investigator, PET/CT may replace MRI in patients who have a 
contraindication to MRI.)  (NOTE:  An MRI does not have to be repeated if performed at 
the NIH within 3 months of screening.)
2.3
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
2.3.1
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE).
Individuals who do not meet the criteria for participation in this trial (screen failure) will not be 
rescreened.
2.4
TREATMENT ASSIGNMENT AND RANDOMIZATION/STRATIFICATION PROCEDURES
2.4.1
Cohorts
Number
Name
Description
1
Multiple 
myeloma 
Smoldering multiple myeloma patients with high-risk disease
2.4.2
Arms
Designation
Name
Description
A
Experimental:  
Treatment 
(Carfilzomib, 
Revlimid and 
Dexamethasone)
Carfilzomib (IV, Days 1, 2, 8, 9, 15, and 16 of the 28-day cycle); 
Revlimid (PO, Days 1-21 of the 28-day cycle; exception: not given 
on cycle 1 day 1); and, Dexamethasone (PO or IV, Days 1, 2, 8, 9, 
15, 16, 22, and 23 of the 28-day cycle; exception: not given on 
cycle 1 day 1)  
(NOTE:  Closed upon activation of Amendment H version date 
06/12/2017.)
B
Experimental:  
Treatment 
(Carfilzomib, 
Revlimid and 
Dexamethasone)
Carfilzomib (IV, Days 1, 2, 8, 9, 15, and 16 of the 28-day cycle); 
Revlimid (PO, Days 1-21 of the 28-day cycle); and, 
Dexamethasone (PO or IV, Days 1, 2, 8, 9, 15, 16, 22, and 23 of 
the 28-day cycle)
(NOTE:  Opened effective with Amendment H. version date 
06/12/2017)
2.4.3
Treatment Assignment and Randomization/Stratification
Single arm/group assignment; open-label and non-randomized.


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2.5
BASELINE EVALUATION
Research and clinical laboratory tests to be performed prior to starting therapy.  Refer to Section 
5 for details on biospecimen collection and correlative studies.      
2.5.1
Echocardiogram, Pro Brain-type natriuretic peptide (BNP) PT, PTT, and Troponin   
2.5.2
Bone Marrow 

Histopathological evaluation on bone marrow aspirate and biopsy

Immunophenotyping of aberrant clonal plasma cells by multiparametric flow cytometry.   

Interphase FISH/cytogenetics (If previously done, repeat not necessary)

CD 138+ fractions and CD 138- fractions cell sorting with subsequent correlatives on 
both fractions to be done in the Young Lab.   

Proteasome activity and quantification (peripheral blood and bone marrow).   

Immunoglobulin heavy and/or light chain rearrangement.
2.5.3
Peripheral Blood, Urine, and Imaging

Peripheral blood and urine samples for storage and establishing a biobank.  (See 
APPENDIX DAPPENDIX D:  Peripheral Blood and Urine Collection and Storage)

Subunit profiling and activity of circulating proteasomes by enzyme-like immunosorbent 
assay (optional). 

Apoptosis assays to identify necrotic or late stage apoptotic cells.  

Immunolocalization studies.  

Peripheral blood flow cytometry assessing for circulating plasma cells under the direction 
of Hao-Wei Wang, MD

Peripheral blood will be assessed for immune cell populations including, but not limited 
to T cells (CD4 and CD8), LGL, and NK cells using flow cytometry. 

FDG PET/CT scan within 4 weeks of study entry and prior to starting therapy.  NOTE:  
See additional information in Section 5.1.3 

Diffusion Weighted Whole Body (DW-MRI) (exception: patients with a contra-
indication or inability to perform due to administrative or logistical reasons
2.5.4
Questionnaires/Patient-Reported Outcomes (PROs)
NOTE:  See Section 5 
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
Patients with high risk SMM will be enrolled on the pilot study and treated with 3-drug 
combination (Cycles 1-8 carfilzomib 20/36 mg/m2, lenalidomide 25 mg, dexamethasone 20 mg 
cycles 1-4 and 10 mg cycles 5-8) followed by extended lenalidomide dosing.
All ongoing testing and procedures will take place per the Study Calendar, Section 3.4.  NOTE:  
Treatment is planned to be administered on an outpatient basis.  At the investigator’s discretion 
(e.g., for additional monitoring, patient social reasons, etc.), patients may be treated on an 


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inpatient basis.  Any cases of planned hospitalization are not considered reportable serious 
adverse events per Section 8.4. 
3.1.1
Cycles 1-4 and 5-8

Cycle 1 ONLY: Carfilzomib 20 mg/m2 per dose, days 1 and 2; Carfilzomib 36 mg/m2 per 
dose, days 8, 9, 15, and 16

Cycles 2-8: Carfilzomib 36 mg/m2 per dose, days 1, 2, 8, 9, 15, and 16

Cycles 1-8: 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

For patients who choose to undergo stem cell harvest, the next cycle may be delayed for 
up to 5 weeks.

Cycles 5-8: Dexamethasone 10 mg/dose, days 1, 2, 8, 9, 15, 16, 22 and 23 followed by 
extended lenalidomide
After receiving first 4 cycles, patients who are considered to be eligible for subsequent high 
dose therapy/autologous stem cell transplant (ASCT) will be encouraged to undergo 
autologous stem cell harvesting for potential use in the future. In accord with current clinical 
standards, the decision whether a given patient is eligible for subsequent high dose 
therapy/ASCT, or not, will be based on a clinical assessment conducted by the transplant 
center that evaluates the patient.  
3.1.2
Maintenance and Ongoing Treatment or Follow-Up
After 8 cycles, patients will proceed to extended dosing phase I of lenalidomide (Days 1-21 of 28 
day cycle) for 12 cycles. After 12 cycles of extended dosing of lenalidomide, patients who 
maintain their current clinical response and do not meet criteria of PD as defined in Section 6.3 
will have the option to continue lenalidomide as clinically indicated for an additional year on 
extended dosing phase II.
After 2 years of maintenance, patients will be followed by clinical and laboratory examination 
every 3-6 months until disease progression requiring treatment. If patients progress, they may be 
contacted by phone or email to gather survival information. (Note: patients who have not 
progressed after 2 years of maintenance therapy, but decide to continue lenalidomide 
maintenance at an outside facility, may also be followed on this protocol as above for long term 
follow-up at the discretion of the investigator. This follow up will consist of clinic and laboratory 
examination, however, if the patient is undergoing these investigations at an outside facility, 
follow-up can be limited to NIH investigator-patient or NIH investigator-outside physician 
communication of test results.) 
Of note: On October 19, 2015, the study was closed to accrual for administrative reasons. 
Eighteen patients had enrolled at that time. Effective with Amendment H (version date 
06/12/17), the study status will change to “Open-Recruiting” to allow for enrollment of the 
remaining 10-12 patients as per the statistical analysis plan of this protocol.


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23
3.2
DRUG ADMINISTRATION
3.2.1
Induction Phase:  Cycles 1-8 with 28 day cycles
3.2.2
Agents  
3.2.2.1 Carfilzomib

Cycle 1:  20 mg/m2 IV infusion over 30 minutes on days 1 and 2, then 36 mg/m2 IV 
on days 8, 9, 15, and 16

Cycle 2-8:  36 mg/ m2 IV infusion over 30 minutes on days 1, 2, 8, 9, 15, and 16

See Section 14.1.3 for drug formulation and preparation instructions
3.2.2.2 Lenalidomide

Cycle 1-8:  25 mg oral days 1-21 of 28-day cycle

Lenalidomide capsules should be swallowed whole, and should not be broken, 
chewed or opened.   

If a dose of lenalidomide is missed, it should be taken as soon as possible on the same 
day.  If it is missed for the entire day, it should not be made up.

Patients who take more than the prescribed dose of lenalidomide should be instructed 
to seek emergency medical care if needed and contact study staff immediately.  

Lenalidomide (Revlimid®) will be provided to research subjects for the duration of 
their participation in this trial at no charge to them or their insurance providers (unless 
they continue lenalidomide maintenance at an outside facility).  Lenalidomide will be 
provided in accordance with the REMS® program of Celgene/BMS Corporation.  Per 
standard REMS® requirements all physicians who prescribe lenalidomide for 
research subjects enrolled into this trial, and all research subjects enrolled into this 


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24
trial, must be registered in and must comply with all requirements of the REMS® 
program.  Prescriptions must be filled within 7 days.  Only enough lenalidomide for 
one cycle of therapy will be supplied to the patient each cycle.
3.2.2.3 Dexamethasone

Cycles 1-4:  20 mg oral or IV on days 1, 2, 8, 9, 15, 16, 22, and 23

Cycles 5-8:  10 mg oral or IV on days 1, 2, 8, 9, 15, 16, 22, and 23
In Cycle 1, the following supportive care measures will be implemented:  

Hydration will be administered prior and subsequent to carfilzomib dosing. 
o
Oral hydration:  All subjects must be well hydrated (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.  
o
IV hydration:  500 mL (250 mL before & 250 mL after carfilzomib) OR 1000 mL 
(500 mL before & after carfilzomib) of normal saline or other appropriate IV fluid 
formulation must be given before and after each carfilzomib dose during Cycle 1.  
Total volume will be determined at the discretion of clinician and volume status 
of patient.

In subjects considered to be still at risk for TLS at completion of Cycle 1, hydration 
should be continued into subsequent cycles if clinically indicated.
3.2.3
Harvesting Stem Cells

After receiving first 4 cycles, patients who are considered to be eligible for 
subsequent high dose therapy/autologous stem cell transplant (ASCT) will be given 
the option to undergo autologous stem cell harvesting (not as part of this protocol) for 
potential use in the future. 

Collection and delivery can be conducted at outside institutions.  In accord with 
current clinical standards, the decision whether a given patient is eligible for 
subsequent high dose therapy/ASCT, or not, will be based on a clinical assessment 
conducted by the transplant center that evaluates the patient.  

If harvesting and delivery of high dose therapy/autologous stem cell transplant is 
conducted at NIH Clinical Center, it will be conducted under a separate protocol.

Transplant eligible patients will be defined as age <75 years with no significant 
disease co-morbidities and ECOG ≤2.  

For patients who choose to undergo stem cell harvest, next cycle may be delayed for 
up to 5 weeks.
3.2.4
Extended Dosing Phase I:  Cycles 9-20

Patients will go on to receive extended dosing with oral lenalidomide 10 mg/dose, 
given daily for 21 days of a 28 day cycle, for 12 cycles.

Lenalidomide ordered in the extended dosing phase of the study will be prescribed by 
NIH Clinical Center physicians in one month increments for all patients. Upon 
completion of phone counseling per the REMS® program, the NIH Clinical Center 


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physician will prescribe a 28 day supply of lenalidomide to be sent to the patient by 
express delivery.

For FCBP patients in the extended dosing phase of the study, lenalidomide will be 
prescribed by NIH Clinical Center physicians in one month increments. FCBP 
patients will still be required to have medically supervised pregnancy testing as 
outlined in APPENDIX BAPPENDIX B:  Requirements for REMS; and may have 
the pregnancy test performed by local treating physician. In these cases, the local 
physician will submit the results to NIH Clinical Center for review. Upon receipt of 
negative pregnancy test result and completion of phone counseling per the REMS® 
program, NIH Clinical physician will prescribe a 28-day supply of lenalidomide to be 
sent to the patient by express delivery.
3.2.5
Extended Dosing Phase II (optional): Cycles 21through 32 (effective with Amendment C 
version date 07/11/2013):

After 12 cycles of extended dosing of lenalidomids (phase I), patients who maintain 
their current clinical response and do not meet criteria of PD as defined in Section 6.2 
will have the option to continue lenalidomide 10 mg/dose as clinically indicated for 
one additional year. For those patients who are ready to begin extended dosing phase 
II, treatment may be delayed until amendment C (version date 07/11/2013) is 
approved by the IRB.

Lenalidomide will be ordered in extended dosing phase II will be prescribed by NIH 
Clinical Center physicians in one month increments for all patients. Upon completion 
of phone counseling per the REMS® program, the NIH Clinical Center physician will 
prescribe a 28 day supply of lenalidomide to be sent to the patient by express 
delivery.

For FCBP patients in the extended dosing phase of the study, lenalidomide will be 
prescribed by NIH Clinical Center physicians in one month increments. FCBP 
patients will still be required to have medically supervised pregnancy testing as 
outlined in APPENDIX B; and may have the pregnancy test performed by local 
treating physician. In these cases, the local physician will submit the results to NIH 
Clinical Center for review. Upon receipt of negative pregnancy test result and 
completion of phone counseling per the REMS® program, NIH Clinical physician 
will prescribe a 28 day supply of lenalidomide to be sent to the patient by express 
delivery.

The duration for extended dosing was determined based on the study design from the 
Phase III trial Quiredex trial of lenalidomide/dexamethasone followed by 
lenalidomide maintenance vs. observation in high-risk SMM patients conducted by 
the Spanish PETHEMA study group.  In this study, the treatment arm received 9 
cycles of induction therapy with lenalidomide and dexamethasone followed by 
lenalidomide maintenance.  In August of 2011, the Quiredex protocol was amended 
to stop lenalidomide maintenance treatment after 2 years.  In addition, the three 
largest randomized phase III trials investigating lenalidomide maintenance were 
published in 2012 with median follow-up periods ranging from 30 months to 45 
months.  Two out of three of these studies continue lenalidomide maintenance until 
progression with no planned end date for lenalidomide maintenance29,30.


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26
3.3
DOSE MODIFICATIONS
NOTE:  If patients require lenalidomide dose reductions and experience delays in drug 
administration (e.g., due to pharmacy not having the correct dosage form and/or time 
required to get the correct/adjusted dose supply to the patient), these administrative delays 
will not be considered a reportable protocol deviation.  Furthermore, appointments and 
treatments missed by patients due to logistical reasons including weather and 
transportation problems will not be considered a reportable protocol deviation. Patients 
may miss up to 15% of lenalidomide doses. All efforts will be made to attaining and 
delivering medications to the patient expeditiously.
3.3.1
Dose Reductions: Induction Phase
Dexamethasone
Lenalidomide
Carfilzomib
Cycles 1-4
Cycles 5-8
Baseline dose
25 mg daily on Days 
1-21 of 28 day cycle
36 mg/m2
20 mg
10 mg
One level dose 
reduction
20 mg daily on Days 
1-21 of 28 day cycle
27 mg/m2
10 mg
4 mg
Two level 
dose reduction
15 mg daily on Days 
1-21 of 28 day cycle
20 mg/m2
4 mg
0 mg
Three level 
dose reduction 
10 mg daily on Days 
1-21 of 28 day cycle
0 mg
Four level 
dose reduction
5 mg daily on Days 
1-21 of 28 day cycle
3.3.1.1 Lenalidomide and Carfilzomib dosages are not modified in concert; i.e., lenalidomide 
and carfilzomib dosage reductions are implemented separately.  If more than 2 dose 
reductions are required with Carfilzomib, study treatment will be discontinued and the 
patient will go off therapy. 
3.3.1.2 If there is no resolution of toxicity after 2 weeks of withholding treatment or up to 3 
weeks for infection related treatment, the subject will go off therapy
3.3.2
Hematologic Toxicity:  Induction Phase
3.3.2.1 Due to the nature of the disease originating in the bone marrow, events occurring within 
the first two cycles of treatment and deemed to be due to disease burden will be 
exempt from dose reductions at the discretion of the investigator.
3.3.2.2 On day 1 of each new cycle (or day 1 of every third cycle during extension phase), 
patients must meet the following criteria or dose modify based on dose reductions in 
table 3.3.1:

ANC ≥ 1.0 x 109 /L

Platelet count ≥ 75 x 109 /L during cycles 1-8; Platelet count >50 x 109/L during 
cycles 9 and beyond
If these conditions are not met on Day 1 of a new cycle, a new cycle of treatment will 
not be initiated until the toxicity has resolved.  If there is no resolution after 2 weeks of 
withholding treatment or up to 3 weeks for infection related treatment, the subject will 
go off therapy.  


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27
If the investigator chooses to dose reduce according to table 3.3.1, the investigator will 
determine which drug will be modified based on side effect profile and clinical 
judgment.
3.3.2.3 If a patient develops thrombocytopenia or neutropenia during the cycle, then the 
following actions would take place (see Thrombocytopenia/Neutropenia table below).  
Thrombocytopenia
Lenalidomide
Carfilzomib
Fall to < 25 x 109/L
Hold both Lenalidomide and Carfilzomib, follow CBC weekly.  
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 weekly.  
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 weekly
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 weekly
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.
3.3.3
Non-Hematologic Toxicity: Induction Phase
3.3.3.1 Toxicity ≥ grade 3 will require appropriate study drug to be held until resolved to ≤ 
Grade 1 unless specified below.  Investigator will determine which drug will be held 
based on side effect profile and clinical judgment.
3.3.3.2 Once toxicity has resolved ≤ grade 1, subsequent doses will be reduced at next dose 
level (according to table in section 3.3.1) if the adverse event was deemed to be 
treatment related by the PI.  If the adverse event was deemed to be unrelated to 
treatment, the patient may continue the full dose.    
3.3.3.3 Readily reversible electrolyte and metabolic abnormalities, infections or diarrhea 
controlled by appropriate therapy are exempt. 
3.3.3.4 Patients with Grade 3 or higher peripheral neuropathy, Grade 3 or higher non-blistering 
rash or blistering rash of any grade, grade 3 or higher hypersensitivity reactions will be 
removed from protocol therapy.


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Lenalidomide Toxicities
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. 
(Alternatively, MDRD or CKD-
epi formulas may be used to 
estimate eGFR as more accurate 
indictors of renal dysfunction than 
CrCl in discrepant cases)
CrCl 31-50 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. 
Carfilzomib Toxicities
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 or return to baseline.  After which, treatment 
may continue at reduced dose or patient may be withdrawn 
from therapy.
Renal Toxicity:
Serum creatinine ≥ 2 × baseline, or 
Creatinine clearance less than 15 
mL/min, or creatinine clearance 
decreases to less than or equal to 50% of 
baseline, or need for hemodialysis
Withhold dose and continue monitoring renal function 
(serum creatinine or creatinine clearance).
If attributable to carfilzomib, resume when renal function 
has recovered to within 25% of baseline; start at 1 dose 
level reduction.  If not attributable to carfilzomib, dosing 
may be resumed at the discretion of the physician. For 
patients on hemodialysis receiving carfilzomib, the dose is 
to be administered after the hemodialysis procedure. 
If Posterior Reversible Encephalopathy 
Syndrome (PRES) is suspected
If PRES is suspected, hold carfilzomib. Consider 
evaluation with neuroradiological imaging, specifically 
MRI, for onset of visual or neurological symptoms 
suggestive of PRES. If PRES is confirmed, permanently 
discontinue carfilzomib. If the diagnosis of PRES is 
excluded, carfilzomib administration may resume at 
same dose, if clinically appropriate.


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Carfilzomib Toxicities
Dosing Modifications
If thrombotic microangiopathy 
(TTP/HUS) is suspected
Hold carfilzomib and manage per standard of care 
including plasma exchange as clinically appropriate. 
If TMA is confirmed and related to carfilzomib, 
permanently discontinue carfilzomib. If the diagnosis is 
excluded, carfilzomib can be restarted at the previous dose. 
If the condition recurs, permanently discontinue 
carfilzomib.
Hepatic Impairment: 
Mild to moderate liver dysfunction: 
defined as 2 consecutive values, at least 
28 days apart, of: 
(1) total bilirubin (> 33% direct) > 1x 
ULN to < 3x ULN OR 
(2) an elevation of AST and/or ALT 
with normal bilirubin Grade 3 elevation 
in ALT and/or AST (> 5x ULN) 
Grade 3 elevation in total bilirubin 
Drug-induced hepatotoxicity 
(attributable to carfilzomib)
25% dose reduction. Dose may be re-escalated if liver 
function tests return to normal and drug-induced 
hepatotoxicity is excluded. 
Hold carfilzomib until resolution to baseline. 
Monitor any abnormality weekly. Resume carfilzomib with 
a 25% dose reduction if drug-induced hepatotoxicity is 
excluded. 
Hold carfilzomib until resolution to baseline. Monitor total 
bilirubin and direct bilirubin weekly. 
Upon resolution of total bilirubin to normal, resume 
carfilzomib dosing with a 25% dose reduction if drug-
induced hepatotoxicity is excluded. 
Discontinue carfilzomib
Thrombotic Microangiopathy (TMA)
If the diagnosis is suspected, hold carfilzomib and manage 
per standard of care including plasma exchange as 
clinically appropriate. If TMA is confirmed, permanently 
discontinue carfilzomib. If the diagnosis is excluded, 
carfilzomib can be restarted.
3.3.4
Dose Reductions: Extended Dosing Phases I and II
Lenalidomide
Baseline dose
10 mg daily on Days 1-21 of 28 day cycle
One level dose reduction
5 mg daily on Days 1-21 of 28 day cycle
3.3.5
Hematologic Toxicity: Extended Dosing Phases I and II
3.3.5.1 On day 1 (or within 7 days prior to day 1) of every third cycle during extension phase, 
patients must meet the following criteria or dose modify based on dose reductions in 
table 3.3.4:

ANC ≥ 1.0 x 109 /L


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
Platelet count >50 x 109/L during cycles 9 and beyond
If these conditions are not met on Day 1 of every third cycle, treatment will not be 
initiated until the toxicity has resolved or returned to baseline. If there is no resolution 
after 2 weeks of withholding treatment or up to 3 weeks for infection related 
treatment, the subject will go off therapy.  
3.3.5.2 If a patient develops thrombocytopenia or neutropenia during the cycle, then the 
following actions would take place (see Thrombocytopenia/Neutropenia table below).  
Thrombocytopenia
Lenalidomide
Fall to < 25 x 109/L
Hold Lenalidomide, follow CBC weekly.  Hold prophylactic anti-
coagulation.
Return to ≥ 25 x 109/L
Resume lenalidomide at next dose reduction if deemed drug 
related
Subsequent fall to < 25 x 109/L
Hold Lenalidomide.  Hold prophylactic anti-coagulation
Return to ≥ 25 x 109/L
Patient will go off therapy if deemed drug related
Neutropenia 
(Absolute Neutrophil Count)
Lenalidomide
Falls to < 0.5 x 109/L or to 
< 1.0 x 109/L with fever
Hold Lenalidomide.  Add filgrastim if Grade 3 with fever 
(single temperature of 38.3o or sustained temperature of 38o 
for > 1 hour) or Grade 4.  Follow CBC weekly
Returns to ≥ 1.0 x 109/L
Resume Lenalidomide at next dose reduction.  
Subsequent drop to < 0.5 x 109/L or 
to < 1.0 x 109/L with fever
Hold Lenalidomide.  Add filgrastim if Grade 3 with fever or 
Grade 4.  Follow CBC weekly
Returns to ≥ 1.0 x 109/L
Patient will go off therapy if deemed drug related 
3.3.6
Non-Hematologic Toxicity- Extended Dosing Phase
3.3.6.1 Toxicity ≥ grade 3 will require study drug to be held until resolved to ≤ Grade 1 or 
baseline unless specified below.  
3.3.6.2 Once toxicity has resolved ≤ grade 1 or baseline, subsequent doses will be reduced at 
next dose level (according to table in Section 3.3.4) if the adverse event was deemed to 
be treatment related by the PI.  If the adverse event was deemed to be unrelated to 
treatment, the patient may continue the full dose.  In the case of renally adjusted doses, 
dosing modifications are made according to table below. 
3.3.6.3 Readily reversible electrolyte and metabolic abnormalities or infections controlled by 
appropriate therapy are exempt. 


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31
Common Lenalidomide 
Toxicities
Dosing Modifications
Non-Blistering Rash
If Grade 3, hold lenalidomide dose and restart at next dose 
reduction once rash improves to ≤ Grade 1
If Grade 4, discontinue lenalidomide and remove patient from 
therapy
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. 
(NOTE:  Alternatively, MDRD 
or CKD-epi formulas may be 
used to estimate eGFR as more 
accurate indictors of renal 
dysfunction than CrCl in 
discrepant cases.)
CrCl 31-50 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 and see carfilzomib 
dosing below.
CrCl ≤30 mL/min (requiring dialysis) – Decrease Lenalidomide 
to 5 mg daily and on dialysis days dose lenalidomide after 
dialysis. 
3.3.7
Monitoring
3.3.7.1 Patients may be observed in the hospital for administration of cycle 1 Days 1 and 2 of 
therapy (at the discretion of the investigator).
3.3.7.2 Routine labs (cbc w/differential, acute care, mineral, hepatic panels, uric acid and LDH) 
will be performed on Day 1, 2, 8, 15, and 22 of cycle 1 and Day 1 of each cycle during 
cycles 2-8 and on Day 1 (or within 7 days prior to day 1) of every third cycle during 
extension phases I and II.
3.3.7.3 Myeloma tests include serum protein electrophoresis, serum immunofixation, serum 
free light chains, quantitative immunoglobulins, beta-2 microglobulin and will be 
performed at baseline and Day 1 of each cycle and on Day 1 (or within 7 days prior to 
day 1) of every third cycle during extension phase I and II.  Subsequent serum 
immunofixation will only be performed on those patients clinically indicated.
3.3.7.4 Random urine sample for protein electrophoresis (UPEP) and immunofixation to assess 
for monoclonal protein in the urine (Bence-Jones proteinuria) to be performed at 
baseline, day 1 of each cycle 1-8, and day 1(or within 7 days prior to day 1) of every 
third cycle during extension phase I and II.  In patients whose measurable disease is 
best determined by measuring Bence- Jones protein quantification, a 24-hour UPEP 
will be performed at baseline, day 1 of each cycle 1-8, and day 1 (or within 7 days 
prior to day 1) of every third cycle during extension phase I and II. Otherwise, 24-hr 
UPEP Bence-Jones quantification will be estimated from random UPEP specimens 
performed at baseline, day 1 of each cycle 1-8, and day 1 (or within 7 days prior to day 
1) of every third cycle during extension phase [46]. 
3.3.7.5 Patients will have clinic visits with H&P or standard progress notes assessing for 
toxicity/side effects on Day 1, 2, 8, 15, and 22 of cycle 1 and Day 1 (or within 7 days 
prior to day 1) of each cycle during cycles 2-8 and on Day 1 (or within 7 days prior to 
day 1) of every third cycle during extension phases I and II. May be delayed up to 7 
days per PI discretion for clinical or logistical reasons.


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3.3.7.6 Additional laboratory studies and clinic visits will be performed if clinically indicated.
3.3.7.7 FDG-PET scan and/or DW-MRI will be performed on patients at baseline, during 
cycles 1-8 if patient obtains CR or at the end of cycle 8 if no CR is achieved, during 
cycles 9-20 if patient obtains CR or at the end of cycle 20 if no CR is achieved, and 
during cycle 21 and beyond if patient obtains CR or at treatment termination.  During 
extension phase lenalidomide, FDG-PET scans and/or DW-MRIs are optional for those 
patients that are MRD negative at the end of cycle 8 regardless of response. At PI 
discretion, patient may be asked to have an additional PET-CT and/or DW-MRI at 
progression. 
3.3.7.8 During lenalidomide extension phases I and II, FCBP patients will still be required to 
have pregnancy testing as outlined in APPENDIX B.  Local treating physicians will be 
required to submit results to NIH clinical center for review.  


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3.4
STUDY CALENDAR
Induction Treatment q
Cycle 1
Cycle 2-8
Extended Treatment
(Phases I and II)q
End of 
Treatmentr 
and 
Follow-Up 
Test/Procedure
Screening 
Baseline
Day 
1
Day 
8
Day 
15
Day 
22
Day 
1  
CR 
Achieved/
End of 
Cycle 
8l, m, n
Day 1 of 
every third 
cycle from 
cycle 9 and 
beyond p
Phase I-CR Achieved (Cycle 9-20)/ 
End of Cycle 20 and Phase II-CR 
achieved (Cycle 21-32)/ 
Treatment termination l, m, n, p
Every 3-6 
monthsj, m, q
Disease 
Progression 
at any Time 
Pointk
Medical Record Review
x
x
H&P/Clinic Visit
x
x
x
x
x
x
x
ECOG
x
x
x
Informed Consent
x
Routine Labsa
x
x
x
x
x
x
x
x
Urine for UPEP and IFE l
xl
x
xl
xl
xl
xl
Viral Studiesb
x
Register for RevAssist
x
Pregnancy Testc
xc
xd
xe
xe
xe
xc
xc,e
xe
xe
Myeloma testsf
x
x
x
xo
x
Research Blood/Urine *
x
x
x
x
x
x
x
x
x
Bone Marrow/Aspirate
xg
xi, n
xi, n
xi
x
Skeletal Survey
x
FDG PET-CT
x
xm
xm
x
x
MRI of spine
xs
Diffusion Weighted MRI
x
xm
xm
xm
xm
Echocardiogram, BNP 
and Troponin
x
Adverse Events
x
12 lead EKG
x
NOTE:  All assessments are pre-dose on the day indicated, unless otherwise described below.  After initiation of treatment, variations of +/- 3-14 days of 
scheduled visits are permitted, as noted (see also footnote q).   For patients who choose to undergo stem cell harvest, next cycle may be delayed for up to 5 
weeks.  Refer to Section 5.1 for specific details on research samples and imaging correlates to be collected. *See Section 5, Correlative Studies for Research, for 
additional information on the research blood, urine, and bone marrow sampling. Note, that any missed research blood/urine tests or surveys will not be 
considered protocol deviations.


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a.
Routine tests include CBC with differential, reticulocyte count, Acute Care (sodium, potassium, chloride, CO2, glucose, BUN, creatinine), 
Mineral (serum calcium, phosphate, magnesium and albumin) and Hepatic (alkaline phosphatase, ALT, AST, total and direct bilirubin) 
Panels, uric acid, eGFR determination, and LDH.  NOTE:  PT and PTT will only be performed at baseline.
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 
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). During extension phase, FCBP patients will 
have pregnancy tests per footnote “e”. Local treating physicians will be required to submit results to NIH Clinical Center for review.
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 B).
f.
Myeloma tests include serum protein electrophoresis, serum immunofixation, urine electrophoresis, urine immunofixation, serum free light 
chains, quantitative immunoglobulins, beta-2 microglobulin and will be performed at baseline and Day 1 of each cycle.  Subsequent serum 
immunofixation, urine immunofixation, and urine electrophoresis will only be performed on those patients clinically indicated.   
g.
Baseline bone marrow aspiration and biopsy will be sent to Dept. of Pathology, flow cytometry, FISH/cytogenetics, CD 138 
sorting/GEP/storage (Young Lab) and heavy/light chain immunoglobulin rearrangement (optional) and/or NRAS/KRAS mutations in 
Molecular Pathology (optional). For screening eligibility purposes, an outside bone marrow may be used in which case a baseline at the NIH 
will also be performed. Note: As of February 6, 2023, all participants have completed the maintainance phase (C32) thus bone marrow and 
peripheral blood research samples will be sent to Ryan Young’s lab on a case to case basis.
h.
FOOTNOTE NO LONGER APPLIES/DELETED IN AMENDMENT M (version date 07/20/2018).  PREVIOUS TEXT:  Optional Cycle 1 
Day 2 bone marrow aspirate alone sent for CD138 sorting (GEP studies and microenvironment studies).  NOTE:  This no longer in effect 
with Amendment H (version date 06/30/2017).  
i.
Bone marrow aspirate and biopsy can be performed +/- 21 days of intended cycle day.  Bone marrow aspirate and biopsy will be sent to 
Hematology Section, Department of Lab Medicine (DLM), flow cytometry (bone marrow immunophenotyping of plasma cells), CD 138 
sorting/GEP/storage, and +/- heavy/light chain immunoglobulin rearrangement and/or NRAS/KRAS mutations in Molecular Pathology 
(optional). In follow up period, PET/CTs will be done approximately annually.
j.
At minimum, follow-up will be every 3-6 months until progression of disease, or death.  Patients may be followed at more frequent time 
intervals if clinically indicated, i.e. following post-therapy toxicity.  Patients who have progressive disease while on study will be followed 
with restaging scans and laboratory tests as clinically indicated. Patients who are taken off treatment will continue to be followed for survival 
by phone or clinic visit. Patients who finish all 32 cycles of treatment will be followed at least every 6 months by clinic visit with laboratory 
evaluation and by bone marrow biopsy yearly at the discretion of the investigator. Of note, patients who do not progress, but decide to 


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continue or resume therapy at an outside facility, may be followed by clinical and laboratory examination every 3-6 months. Alternatively, 
this data may be captured by investigator-patient or investigator-physician phone or email communication if the required examinations have 
been performed at the outside facility.
k.
At disease progression, marrow and FDG-PET/CT are optional.
l.
Urine for protein electrophoresis (UPEP) and immunofixation to assess for monoclonal protein in the urine (Bence-Jones proteinuria) at 
screening, day 1 of each cycle during cycles 1-8, day 1 of (or within 7 days prior to day 1) every third cycle during cycles 9-32, and at 
treatment termination. In patients whose measurable disease is best determined by measuring Bence- Jones protein quantification, a 24 hour 
UPEP will be performed at baseline, day 1 of each cycle 1-8, and day 1 (or within 7 days prior to day 1) of every third cycle during extension 
phase I and II. Otherwise, 24-hr UPEP Bence-Jones quantification will be estimated from random UPEP specimens performed at baseline, 
day 1 of each cycle 1-8, and day 1 (or within 7 days prior to day 1) of every third cycle during extension phase[46].  
m. FDG-PET scan will be performed on patients at baseline, during cycles 1-8 if patient achieves CR and/or at the end of cycle 8 if no CR is 
achieved, during cycles 9-20 (extended dosing phase I) if patient achieves CR and/or at the end of cycle 20 if no CR is achieved, and during 
cycles 21-32 (extended dosing phase II) if CR is achieved or at treatment termination. FDG-PET scan can be performed +/- 21 days of 
intended cycle day.  For patients who are on extended dosing with lenalidomide and are found to be negative by immunohistochemistry and 
flow cytometry of the bone marrow (MRD negative), clearance of abnormal protein in blood and/or urine does not mandate a repeated bone 
marrow and the results will be interpreted as complete response.  However, a bone marrow will be repeated at the discretion of investigator. 
Diffusion weighted MRI (DW-MRI) will also be performed at the discretion of the PI. DW-MRI will be performed by standard techniques in 
the NCI Molecular Imaging Program. In follow up, PET/CTs and DW-MRIs will be done approximately annually, if feasible (i.e., missed 
scans will not be considered protocol deviations).  Note:  DW-MRIs are optional after Cycle 8.
n.
Bone marrow biopsy and aspirate will be performed on patients at baseline, during cycles 1-8 if patient achieves CR or at the end of cycle 8 
if no CR is achieved, during cycles 9-20 (extended dosing phase I) if patient achieves CR or at the end of cycle 20 if no CR is achieved, and 
during cycles 21-32 (extended dosing phase II) if CR is not achieved or at treatment termination. Bone marrow aspirate and biopsy can be 
performed +/- 21 days of intended cycle day.
o.
Repeat myeloma tests at treatment termination.
p.
Within 7 days prior to D1 of each cycle. 
q.
After initiation of treatment, visits may be adjusted per PI discretion for logistical or administrative reasons (e.g. holidays, bad weather, etc.); 
this may include skipped doses of lenalidomide.  For cycles 2-8, the preferred adjustment is -1/+3-day with no more than 2 missed doses of 
lenalidomide.  For cycles 9-forward, the preferred adjustment is -1/+7 days. For follow-up period may be adjusted from every 3-6 months to 
up to 6 months (+6 months) at the discretion of the PI 
r.
End of treatment visit will occur approximately 30 days (+/- 7 days) after the last dose of study drug. If the patient cannot return to the 
Clinical Center for this visit, a request will be made to collect required clinical labs (specify as needed) from a local physician or laboratory.  
If this is not possible, patients may be assessed by telephone for symptoms. 
s.
At the discretion of the Principal Investigator, PET/CT may replace MRI in patients who have a contraindication to MRI.


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3.5
COST AND COMPENSATION 
3.5.1
Costs
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center.  If some tests and procedures performed 
outside the NIH Clinical Center, participants may have to pay for these costs if they are not 
covered by insurance company. Medicines that are not part of the study treatment will not be 
provided or paid for by the NIH Clinical Center.    
3.5.2
Compensation
Participants will not be compensated on this study.
3.5.3
Reimbursement 
The NCI will cover the costs of some expenses associated with protocol participation. Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate. The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy. 
3.6
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 30 days (+/- 7 days) following the last dose of study therapy. 
3.6.1
Criteria for removal from protocol therapy

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 require more than 2 dose reductions of carfilzomib.

Toxicity has not resolved after 2 weeks of withholding treatment or up to 3 weeks for 
infection related treatment

Grade 3 non-blistering rash or blistering rash of any grade 

Grade 3 neuropathy

Grade 3 hypersensitivity reaction

Diagnosis of posterior reversible encephalopathy (PRES) or thrombotic 
microangiopathy (TMA)

Patient completes the protocol (as outlined in Section 3.2)

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. 
3.6.2
Off-Study Criteria

Patient requests to be withdrawn from study


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
Death

Physician’s determination that withdrawal is in the patient’s best interest. 

Patients who receive non-protocol therapy for progression to symptomatic myeloma 
may remain on study for evaluation (by phone, email, or clinic visit) of survival per 
study schedule at the discretion of the investigator. 

Patients who have not progressed but choose to continue lenalidomide maintenance 
beyond 32 cycles at an outside facility may stay on study at the discretion of the 
investigator.

Permanent loss of capacity to give consent

Screen failure

Lost to follow up
3.6.3
Lost to Follow-Up
A participant will be considered lost to follow-up if he or she fails to return for three (3) 
consecutive scheduled visits and is unable to be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site will attempt to contact the participant and reschedule the missed visit within five 
(5) business days and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain if the participant wishes to and/or should continue in 
the study.

Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, an IRB approved certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented in 
the participant’s medical record or study file. 

Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
4
CONCOMITANT MEDICATIONS/MEASURES AND CONSIDERATIONS
4.1
TUMOR LYSIS SYNDROME
4.1.1
Hydration and Fluid Monitoring Guidelines
a.
Oral hydration:  All subjects must be well hydrated (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. 
b. IV hydration:  Adequate hydration is required prior to dosing in Cycle 1, especially for 
patients at high risk of tumor lysis syndrome or renal toxicity. The recommended 
hydration includes both oral fluids (30 ml per kg at least 48 hours before Cycle 1, Day 1) 
and intravenous fluids (250 ml to 500 ml of appropriate intravenous fluid prior to each 
dose in Cycle 1). If needed, given an additional 250 to 500ml following carfilzomib 
administration. Continue oral and/or intravenous hydration, as needed, in subsequent 
cycles. Monitor patients for evidence of volume overload and adjust hydration to 


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individual patient needs, especially in patients with or at risk for cardiac failure.  Total 
volume will be determined at the discretion of clinician and volume status of patient. 
c.
In subjects considered to be still at risk for TLS at completion of Cycle 1, hydration 
should be continued into subsequent cycles if clinically indicated.  
4.1.2
Laboratory Monitoring
a.
Appropriate chemistries, including creatinine, and complete blood counts (CBC) with 
platelet count should be obtained and reviewed prior to carfilzomib dosing.  Results of 
laboratory studies must be reviewed and deemed acceptable prior to administering the 
carfilzomib dose.  
b. Subjects with laboratory abnormalities consistent with lysis of tumor cells (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
4.1.3
Clinical Monitoring  
a.
Signs and symptoms indicative of TLS, such as fevers, chills/rigors, dyspnea, nausea, 
vomiting, muscle tetany, weakness, or cramping, seizures, and decreased urine output.
b. Patients will be admitted to the inpatient hospital and observed while receiving Cycle 1 
Days 1 and 2 of therapy.
4.1.4
Management
a.
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.
b. All cases of TLS must be reported to Amgen as a Serious Adverse Event (SAE) through 
the normal process within 24 hours of the clinical site becoming aware of the event.
4.1.5
Optional medication for high risk TLS patients:
a.
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.  Subjects who do not tolerate allopurinol should be discussed with the 
Lead Principal Investigator.
4.2
TRANSFUSIONS/GROWTH FACTORS
Subjects may receive RBC or platelet transfusions if clinically indicated.  
Colony-stimulating factors may be used if neutropenia occurs but should not be given 
prophylactically.  
4.3
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. Anti-Xa levels will need to be 
followed in those patients with eGFR<30 ml/min and receiving enoxaparin. In general, 


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temporarily holding of prophylactic or treatment doses (for venous thrombo-embolism) anti-
coagulation with either aspirin or enoxaparin peri-procedurally (e.g., for bone marrow biopsies) 
is not required. However, in rare cases, the clinician may hold when clinically indicated.
4.4
HSV AND VSV PROPHYLAXIS
Oral Valacyclovir of 500 mg daily or oral Acyclovir of 800 mg BID throughout all cycles in 
which carfilzomib is given.  
4.5
ANTIBIOTIC PROPHYLAXIS
Patients at risk for developing infections will be offered antibiotic prophylaxis.  Risk assessment 
will be performed by clinical investigator.  For instance, diabetic patients or patients taking 
chronic steroids will be offered Bactrim prophylaxis (or similar agents) to avoid risk of PCP 
infection.     
4.6
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)
Patients on this study will be monitored for any new or worsening neurologic, cognitive or 
behavioral signs and symptoms that may be suggestive of PML as part of the differential 
diagnosis of central nervous system disorders. If PML is suspected, withhold administration of 
carfilzomib; subjects should be promptly referred to a specialist and appropriate diagnostic 
testing should be initiated. Carfilzomib should be discontinued if PML diagnosis is confirmed.
4.7
HEPATITIS B VIRUS (HBV) REACTIVATION
Active HBV is an exclusion criterion for this study. However, some patients who are carriers for 
HBV will be allowed on study. For subjects who are carriers of HBV, prophylaxis with antivirals 
should be considered. Carriers of HBV who require treatment with carfilzomib should be closely 
monitored for signs and symptoms of active HBV infection throughout and following the end of 
treatment with carfilzomib. For subjects with active HBV reactivation, carfilzomib should be 
withheld until infection is adequately controlled.


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5
CORRELATIVE STUDIES FOR RESEARCH 
5.1
BIOSPECIMEN COLLECTION
Baseline
During Cycle 2-8 or 
End of Cycle 8* 
During Extended Dosing Phases of 
Cycles 9-20/ End of Cycle 20 OR 
Cycles 21-32/End of Cycle 32/
End of Treatment#
Follow-Up Period after 32 cycles of 
maintenance every 3-6 months^
Disease Progression
Pathology/IHC
X
X
X
X
X
Multiparametric Flow Cytometry
X
X
X
X
X
FISH/Cytogenetics 
X
X
Molecular pathology for light or heavy chain 
immunoglobulin rearrangement and/or KRas 
and NRas mutation analysis (NOTE: Not to 
be performed as of Amendment H (version 
date 06/30/2017))
X
X 
(optional)
X
(optional)
X
CD138+ sorting/Gene expression profiling/ 
microenvironment 
X
X
X
X
X
Other research lab as below, including Next 
Generation Sequencing
X
X
X
X
X
Storage
X
X
X
X
X
*During Cycle 2-8 if CR achieved or End of Cycle 8 if no CR is achieved
#During Extended Dosing Phases (Phase I and II) if CR achieved during cycles 9-20/ End of cycle 20 and if 
CR achieved during cycles 21-32/End of Cycle 32 (or end of treatment).
^ During the Follow-Up Period, any missed research blood/urine tests or surveys will not be considered 
protocol deviations.
Note: Biospecimen collection directly from participants is completed; analyses are undergoing.
5.1.1
Bone Marrow and peripheral blood
Sampling Time Points of Bone Marrow correlative studies 
Although specified types of tubes are listed below, based on availability and investigator discretion, tube 
types may be substituted for any of the assays to be performed.
Effective with Amendment G (version date 07/20/2015), bone marrow aspirate and biopsy will be 
obtained for research studies at the discretion of the PI.


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a. During extension phase lenalidomide, bone marrow biopsy and aspirates are optional for 
those patients that are MRD negative at the end of cycle 8 regardless of response.
b. Patients may be asked to undergo bone marrow procedure with aspiration and core 
biopsy at progression of disease at the discretion of the PI.
c. Collection of bone marrow, sorting of bone marrow and storage of bone marrow samples 
is outlined in APPENDIX C and Section 5.2.1.
d. Correlative studies associated with bone marrow specimen will be performed and related 
to clinical outcome if the results of the study indicate a clinical or translational rationale 
for analyzing the samples.  Such studies may include but are not limited to the following:  
i.
Pathology/Immunohistochemistry:  Bone marrow biopsy and aspirate will be sent to 
Clinical Center Department of Laboratory Medicine, Hematology Section for 
morphological evaluation by Irina Maric, MD and Clinical Center Hematology Staff. 
Immunohistochemical staining will be performed under the direction of Irina Maric, 
MD.  Plasma cell burden will be assessed using immunohistochemistry markers such 
as CD 138, light chains, CD56 etc.  Plasma cells and microenvironment interactions 
will also be assessed using various immunohistochemistry markers for osteoblasts, 
osteoclasts, stromal cells and proteasomes.
ii. 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 (CD138 positive) include but 
are not limited to absent CD19 and CD45, decreased CD38, and increased 
CD56.  These studies will be performed under the direction of Hao-Wei Wang 
of the flow cytometry unit in the NCI Laboratory of Pathology.
iii.
FISH and cytogenetics:  Interphase FISH/cytogenetics had been performed on 
patients enrolled in this protocol in the NCI Laboratory of Pathology Clinical 
Cytogenetics Unit. As of amendment H (version date 06/30/2017), 
FISH/cytogenetic information may be derived from the patient’s outside records 
or performed on baseline bone marrow samples at a third-party testing laboratory 
per the CC DLM clinical laboratory protocol/procedure which currently is done at 
the Mayo laboratories, Test ID: PCPDF, Plasma Cell Proliferative Disorder 
(PCPD).  
iv.
Cell Sorting, GEP profiling, whole exome sequencing, microRNA analysis and 
microenvironment interactions - Marrow aspirate will be sent to the lab of the Dr. 
Ryan Young (Building 10/4N106) in the Department of Laboratory Medicine and 
sorted into CD 138 + and CD 138 – fractions. Dr. Young and staff will also 
perform the below assays for unsorted bone marrow aspirate for VDJ sequencing 
and assessment of MRD negativity.  Note: As of February 6, 2023, all 
participants have completed the maintainance phase (C32) thus bone marrow and 
peripheral blood research samples will be sent to Ryan Young’s lab on a case to 
case basis.


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
GEP profiling targeted exome sequencing, and VDJ sequencing for MRD 
assessment: Bone marrow aspirates will be collected and sent to the Young 
Lab after 8 cycles of induction or CR, after 20 and 32 cycles of treatment 
and at annual follow-up milestones where BM aspirates are collected (if the 
samples were collected from the patients.)  At baseline: CD138+ plasma 
cells will be purified from bone marrow aspirates harvested. Baseline 
CD138+ cells will be sent for VDJ sequencing and to University of Miami 
(Dr. Ola Landgren) for targeted/whole exome sequencing and molecular 
expression analyses (depending on resources) in a coded, linked manner.  At 
subsequent time points, once patient is in CR, plasma cells will not be 
purified and aspirates will be viably frozen.  Samples will be sent out in 
batches. Of note, some samples may be sent to FDA/OHOP for next 
generation sequencing, see below. 

Bone marrow, blood and urine samples, and associated clinical lab data will 
be sent to Adaptive Biotechnologies Corp. for deep sequencing of the VDJ 
sequence. Samples and data will be submitted to Adaptive Biotechnologies 
Corp. without any personal identifiers.

CD 138- fractions from baseline samples will be analyzed for 
microenvironment interactions such as cytokine profiling, miRNAs, etc. in 
the Young Lab. A fraction of CD138- cells will also be cultured to isolate 
bone marrow stromal cells for further analyses. At the same time points, one 
6 ml EDTA tube of peripheral blood will be collected for parallel analysis. 

Both fractions will be collected, batched, and entered into a biobank.  See 
Section 5.3 for storage of bone marrow biobank. As of Amendment H 
(version date 06/30/2017), As of Amendment version date 01/12/21, aspirate 
samples will be stored in DLM under Dr. Young. 

Aspirate samples may also undergo identification of downstream signaling 
targets, proteasome activity, and ubiquitination pathways on cell lysate or 
marrow aspirate.
v. 
Additional molecular profiling including DNA-, RNA- and protein-based assays 
in bone marrow, blood, and urine samples will be performed. The purpose of 
these assays will be to further characterize underlying biology and correlate with 
clinical outcomes in an exploratory manner. These are not limited to, but include 
the following.

Next Generation Sequencing (NGS) collaboration with Office of 
Hematology and Oncology Products (OHOP) FDA
This study will be involved in the multi-protocol CCR collaborations with 
OHOP/FDA in terms of the translational and correlative aspects utilizing OHOP’s 
“wet lab” to perform NGS assays on various human samples enrolled on a variety 
of CCR clinical trials. The transfer of samples will be performed under a CCR 
“umbrella” MTA. The samples will be locally biobanked in the BPC (Figg Lab) 


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and batched at the NIH until time for shipment, at which time, the samples will be 
sent to:
ATTN: Elliot Rosen, Ph.D.
DBRR III/OBP/OPQ/CDER
Food and Drug Administration
10903 New Hampshire Ave,
Bldg. 52/72, Room 2248,
Silver Spring, MD 20993
Tel: 240-402-7353
Email: Elliot.Rosen@fda.hhs.gov
The correlative NGS assays to be performed will be dependent on final agreement 
in investigating mutually important questions of interest with our collaborators.  
These include but are not limited to all or some of the following but are all 
optional:
1.
T-cell receptor repertoire (immunoseq): More recently research in the 
literature has shown that patients most likely to benefit from immunotherapies 
are those who are found to have anti-tumor T cell clonality. Lenalidomide is 
an immunomodulatory and therefore it is important to analyze this along with 
immune subsets below in SMM. NGS DNAseq will be used to analyze the 
VDJ sequence of T-cells to determine clonality. Input source may be PBMC 
or whole blood and approximately 2 ug of input gDNA will be needed which 
will amount to a whole blood collection of two 10 ml EDTA tubes. Collection 
time points include the following milestones, baseline, C8 or CR, 1 year and 2 
years.
2.
Germline single nucleotide polymorphisms (SNP) and copy number variations 
(CNV) DNAseq: Whole exome or genome sequencing will be performed on 
peripheral blood to determine baseline germline SNPs and CNVs. Whole 
blood (one 10 mL EDTA tube) sample will be collected at baseline for 
germline DNA extraction. This DNA will be used to analyze and compare 
germline vs. somatic/tumor genetic alterations based on sequence data. 
Furthermore, germline normal polymorphic variation will be analyzed as 
genome-wide association study (GWAS) to determine whether certain normal 
variations predispose patients with treated SMM to progress to biochemical or 
overt symptomatic disease. Additionally, these germline variations may be 
analyzed for association with treatment related adverse events.
3.
ctDNA: Targeted DNAseq will be performed on ctDNA for assessment of 
minimal residual disease (MRD). In addition to the VDJ targeted commercial 
assay to determine presence of the malignant clone, the library will also 
include other known recurrent genetic aberrations. Approximately 45% of 
myeloma patients have hyperdiploidy of one of the odd numbered 
chromosomes, the other 45% have specific translocations/deletions, well 
characterized, including translocations of 6;14, 11;14, 4;14, 14;16, 16;18, 17p 
del, and cMYC.  Therefore, the assay will focus on both VDJ as with other 
hematologic malignancies and recurrent genetic alterations similar to the 


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approach used in solid malignancies. Blood collection will involve two 10 mL 
EDTA tubes, alternatively, Streck tubes may be used if processing of the 
sample will be delayed by more than 2 hours.
4.
Gene expression profiling: RNAseq will be performed on CD138+ myeloma 
cells and correlated with DNAseq results. Additionally, peripheral 
blood/PBMC will analyzed for immune related signatures. One 10 mL EDTA 
tube will be used for this purpose.
vi. 
Immune subset analysis
Bone marrow and PBMCs will be processed, stored, and assessed by the 
Developmental Therapeutics Branch (DTB) Lab using multiparameter flow 
cytometry for immune subsets including but not necessarily limited to Tregs, 
MDSC subsets, monocyte subsets, CD8+ T-cells and CD4+Foxp3- T-cells. 
Assessment will include functional markers, i.e. PD-1, Tim-3, CTLA-4 and/or 
CD40. 

PBMC collection of specimen(s): Two 8-10 ml EDTA (purple top) or BD 
Vacutainer Cell Preparation Tubes (CPB; blue and black tiger top) will be 
collected from each patient. Immediately after collection, mix the blood 
sample by gentle inversion several times. The date and exact time of each 
blood draw should be recorded on the tube.

Bone marrow collection of specimens: 1 ml of bone marrow will be collected 
from each patient
Collection Time points

Blood: Baseline, C3D1pre, post C8 or CR, post 1 year and post 2 years

Bone marrow: Baseline, post C8 or CR, post 1 year and post 2 years
Notification and Handling: 
As soon as possible after the patient is scheduled please send email notification to 
DTB lab (Sunmin Lee at leesun@mail.nih.gov and/or Min-Jung Lee at 
leemin@mail.nih.gov) and call the lab at 240-760-6330 when the sample is drawn 
and a lab member will come for immediate pick up.
5.1.2
Research Blood/Serum and Urine
5.1.2.1 At any given time, up to 100cc of peripheral blood will be collected.  The amount of 
blood collected will be dictated by the number of experiments to be performed, and by 
the patient’s peripheral blood count.  Typical time points include: 

Baseline

Days 8 and 15 of Cycle 1

Day 1 of every cycle during cycles 2-8; and if patient achieves CR or at the 
end of cycle 8 if no CR is achieved

Day 1(or within 7 days prior to day 1) of every third cycle during cycles 9 and 
beyond during extended dosing phases (I and II), if patient achieves CR or at 


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the end of cycle 20 if no CR is achieved, during cycles 21-32 if CR is 
achieved or at treatment termination. 

Every 3-6 months during the post-maintenance follow-up period

Disease Progression: at any time point if the patient has progression of disease
5.1.2.2 The standard number of peripheral blood research tubes drawn for collection and 
storage at each of the above time points may include but are not limited to the 
following:  one 8 mL serum separator tube (SST), one 10 mL sodium heparin tube 
(GTT), and one 10 mL EDTA lavender top tube for storage in the Blood Processing 
Core (BPC) in 10/5A09 (Figg Lab) for biobanking. Additionally, up to six 10 ml 
EDTA tubes may be collected for various experiments to be performed with FDA 
collaborators, see below and one 6 mL EDTA lavender top tube for analysis and 
storage in the Young Lab.
5.1.2.3 At any given time, approximately 45 mL of urine will be collected into a standard urine 
collection cup and sent for analysis and storage at each of the above time points.  
Typical time points include: 

Baseline

Day 8 and 15 of Cycle 1

Day 1 of every cycle during cycles 2-8

Day 1 (or within 7 days prior to day 1) of every third cycle during cycles 9 
and beyond during extended dosing phases (I and II) if patient achieves CR or 
at the end of cycle 20 if no CR is achieved, during cycles 21-32 if CR is 
achieved or at treatment termination. 

Disease Progression: at any time point if the patient has progression of 
disease. 
NOTE:  The amount of urine collected will be dictated by the number of 
experiments to be performed.       
5.1.2.4 Collection and storage of peripheral blood and urine outlined in APPENDIX D.  
Sample Requirements and Handling:  The date and exact time of each blood draw 
should be recorded on the sample tube. Serum samples should be kept at room 
temperature for 30-60min prior to being refrigerated.  
5.1.2.5 Peripheral blood and/or urine samples from patients will be analyzed for potential 
serum or urine biomarkers as well as drug concentrations, and correlated to clinical 
outcomes if the results of the study indicate a clinical or translational rationale for 
analyzing the samples.  Such biomarkers may include but are not limited to:

Peripheral blood flow cytometry assessing for circulating plasma cells under 
the direction of Hao-Wei Wang, MD.  

Subunit profiling and activity of circulating proteasomes by enzyme-like 
immunosorbent assay 

Apoptosis assays pre- and post-carfilzomib to identify necrotic or late stage 
apoptotic cells 

Immunolocalization studies  


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
Markers of bone turnover and disease activity

Peripheral blood will be assessed for immune cell populations including, but 
not limited to T cells (CD4 and CD8), LGL, and NK cells using flow 
cytometry.

Blood and urine samples and associated clinical lab data will be sent to 
Adaptive Biotechnologies Corp for deep sequencing of the VDJ sequence.
5.1.3
Imaging – FDG-PET/CT
5.1.3.1 Schedule
FDG-PET scan will be performed on patients at baseline, during cycles 1-8 if patient obtains CR 
or at the end of cycle 8 if no CR obtained, during cycles 9-20 if patient obtains CR or at the end 
of cycle 20 if no CR obtained, during cycles 21-32 if patient obtains CR or at treatment 
termination.  During extension phase lenalidomide, FDG-PET scans are optional for those 
patients that are MRD negative at the end of cycle 8 regardless of response. At PI discretion, 
patient may be asked to have an additional PET-CT at progression. 
5.1.3.2 Procedures
Prior to 18F-FDG PET/CT imaging, the subject will have fasted and 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]-fluorodeoxyglucose is an FDA approved radiopharmaceutical.  Immediately 
prior to injection, the subject’s blood glucose level will be evaluated via finger stick.  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.  
Patients will report to the NCI clinic on the day of the F-18 PET/CT scan and peripheral venous 
access will be obtained (most commonly via IV in the antecubital fossa).  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 
approximately 1-hour post injection per PET/CT standard operating procedures.  The patient will 
be instructed to maintain good hydration in order to reduce the radiation dose. 
5.1.3.3 Location of Scanners to be used for imaging 
5.1.4
 Patients may be imaged either in the Molecular Imaging Program (MIP) or Nuclear 
Medicine to allow flexibility in scheduling; whenever possible, the same scanner used at 
baseline should be used in follow-up.  Imaging – DW-MRI
5.1.4.1 Schedule


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For newly enrolled patients, whole body DW-MRI scans will be performed on patients at 
baseline, cycle 4 and if and when patient reaches a PR, CR, and/or PD, and at the end of 
treatment. During follow-up period, scans may be done at any time point at the discretion of the 
investigator.  We plan to obtain DW-MRI scans on current patients, for whom we may not have 
a baseline DW-MRI scan, at the same timepoints, as applicable. 
5.1.4.2 Procedures
DW-MRI exploits differences in the diffusion of water in various tissues to internal physiology. 
The image contrast in reflects the difference in rate of diffusion between tissues. All attempts 
will be made to perform the DW-MRI scans on the same day as PET/CTs, but is not mandatory. 
For DW-MRI, no external contrast will be used and fasting is not required. Standard clinical 
operating procedures will be used for image collection. DW-MRI evaluations will be considered 
purely exploratory.
5.1.4.3 Results
Patients will be given the results of the DW-MRI scans.  But given the exploratory and research 
nature of the scans, these results will not be used for clinical decision-making purposes.
5.1.5
Patient Reported Outcomes
The PROMIS Patient Reported Outcome Measurement Information System (PROMIS®) QoL 
instrument was administered to all consenting patients who speak English or Spanish until 
February 1, 2021. This instrument was administered at baseline; at the start of every cycle 
(cycles 2-8 only); the start of every 3rd cycle (cycles 9-32 only); every 3-6 months thereafter 
during the follow-up phase; and at the time a patient was taken off treatment. Since the measures 
have not been validated in other languages, participation in this portion of the study was limited 
to subjects who speak either English or Spanish. Further, although patients were not given the 
option to “opt out” of completing PROs, it was not considered a reportable deviation when PROs 
were not completed or were missed for any reason as this is an exploratory endpoint. 
PROMIS is funded by the National Institutes of Health and provides clinicians and researchers 
access to efficient, precise, valid, and responsive measures of health and well–being in clinical 
trial patients. The short forms that were implemented in this study involved questions in the 
domains of physical function, anxiety, depression, fatigue, sleep disturbance, ability to 
participate in social roles and activities, pain interference, pain intensity, and cognitive function. 
A computer tablet-based application also exists which can utilize computer adaptive tests (CAT) 
which can lower patient burden; that is, adapting the template 37 questions presented on the 
paper short forms based on patient response. The questionnaires took no more than 20 minutes to 
complete.  
As feasible, the PROMIS data may be captured based on this CAT PROMIS tablet application; 
alternatively, the paper short forms presented in the appendix will be used. Data was secured on 
the tablet based on 2 passwords. When results are ready for analysis, they will be exported in 
excel format and submitted for storage in C3D or Labmatrix, as appropriate. 
 NOTE: As of February 1, 2021 PROMIS surveys are no longer completed.


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5.2
SAMPLES FOR GENETIC/GENOMIC ANALYSIS
5.2.1
Description of the scope of genetic/genomic analysis
Genomic testing will be done as described in Section 0. 
5.2.2
Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized
Confidentiality for genetic samples will be maintained as described in Sections 5.3.1 and 5.3.2.  
In addition, a Certificate of Confidentiality has been obtained for this study.
5.2.3
Management of Results
We plan to contact participantsif a clinically actionable gene variant is discovered. Clinically 
actionable findings for the purpose of this study are defined as disorders appearing in the 
American College of Medical Genetics and Genomics recommendations for the return of 
secondary findings that is current at the time of primary analysis. (A list of current guidelines is 
maintained on the CCR intranet: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists).  
Subjects will be contacted at this time with a request to provide a sample to be sent to a CLIA 
certified laboratory within the NIH or as a send-out test to another CLIA certified lab.   
This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis.
5.2.4
Genetic Counseling
If the research findings are verified in the CLIA certified lab, the subject will be referred to a 
genetic healthcare provider within the NIH for the disclosure of the results. These activities will 
be funded by the Center for Cancer Research.   
5.3
SAMPLE STORAGE, TRACKING AND DISPOSITION
5.3.1
Procedures for Collecting, Processing, and Storage of Bone Marrow biopsies

See APPENDIX C 

Orders for bone marrow biopsies should be placed in the Clinical Research Information 
System (Clinical Research Center, NIH, Bethesda, MD).

Materials for research studies will be documented on form NIH 2803-1.  Samples will not 
be sent outside NIH without appropriate approvals and/or agreements, if required. 

Bone marrow biopsies will be submitted in native condition to the NIH Clinical Center 
Department of Laboratory Medicine and handled according to routine procedures for 
diagnosis.  Bone marrow core biopsies will be fixed and paraffin embedded for 
histological and immunohistochemical analysis and long-term storage.  Bone marrow 
aspirates will be prepared according to routine procedures.  Five to ten air-dried aspirate 
smears will be stored long-term. 

Initial processing of bone marrow aspirates for research will depend on the size of the 
aspirate.  CD138 positive plasma cells will be isolated from a subset of these samples and 
stored in Young Lab). 

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cataloged.  Prior to Amendment H (version date 06/12/2017), these research samples 
were stored in the laboratory of the Lymphoid Malignancies Branch or in a temperature 
controlled, alarm secured nitrogen tank in the NCI Department of Hematopathology. As 
of Amendment H (version date 06/12/2017), these samples will be stored in a 
temperature controlled, alarm secured nitrogen tank/deep freezer in the NIH Department 
of Laboratory Medicine. For information regarding these samples, please contact Mark 
Roschewski, M.D. at 240-760-6183 or Ryan Young  at240-858-3513. 

Frozen specimens will be wrapped in aluminum foil labeled with the patient’s name and 
accession number, put into a resealable polyethylene freezer bag, and stored in a liquid 
nitrogen freezer.  The liquid nitrogen freezers are monitored daily for temperature 
variations.  A FileMaker Pro database called HP Patient Information and Specimen 
Inventory is used for tracking the samples.

The PI will record any loss or unanticipated destruction of samples as a deviation. 
Reporting will be per the requirements of section 7.2.
5.3.2
Procedures for stored serum, peripheral blood, and urine specimens in the Blood 
Processing Core:
See APPENDIX D for processing of samples  
Please e-mail Blood Processing Core (BPC) (Dr. Figg’s Lab) at  NCIBloodcore@mail.nih.gov 
at least 24 hours before transporting samples (the Friday before is preferred).
For sample pickup, page 102-11964.  Samples are to be delivered to the Figg Lab (4B11).
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number).
For questions regarding sample processing, contact BPC by e-mail at 
NCIBloodcore@mail.nih.gov.

All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered 
and stored in the Labmatrix utilized by the BPC. This is a secure program, with access to 
Labmatrix limited to defined BPC personnel, who are issued individual user accounts. 
Installation of Labmatrix is limited to computers specified by Dr. Figg. These computers 
all have a password restricted login screen. 

Labmatrix creates a unique barcode ID for every sample and sample box, which cannot 
be traced back to patients without Labmatrix access. The data recorded for each sample 
includes the patient ID, name, trial name/protocol number, time drawn, cycle time point, 
dose, material type, as well as box and freezer location. Patient demographics associated 
with the clinical center patient number are provided in the system. For each sample, there 
are notes associated with the processing method (delay in sample processing, storage 
conditions on the ward, etc.).

Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80C 
according to stability requirements.  These freezers are located onsite in the BPC and 
offsite at NCI Frederick Central Repository Services in Frederick, MD. Visitors to the 
laboratory are required to be accompanied by laboratory staff at all times. 

Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in Labmatrix . 


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All researchers are required to sign a form stating that the samples are only to be used for 
research purposes associated with this trial (as per the IRB approved protocol) and that 
any unused samples must be returned to the BPC. It is the responsibility of the NCI 
Principal Investigator to ensure that the samples requested are being used in a manner 
consistent with IRB approval.

Following completion of this study, samples will remain in storage as detailed above. 
Access to these samples will only be granted following IRB approval of an additional 
protocol, granting the rights to use the material. 

If, at any time, a patient withdraws from the study and does not wish for their existing 
samples to be utilized, the individual must provide a written request. Following receipt of 
this request, the samples will be destroyed (or returned to the patient, if so requested). 
The PI will record any loss or unanticipated destruction of samples as a deviation. 
Reporting will be per the requirements of section 7.2.

Sample barcodes are linked to patient demographics and limited clinical information. 
This information will only be provided to investigators listed on this protocol, via 
registered use of Labmatrix. It is critical that the sample remains linked to patient 
information such as race, age, dates of diagnosis and death, and histological information 
about the tumor, in order to correlate genotype with these variables.
5.3.3
Samples processing in the Department of Laboratory Medicine and NCI Laboratory of 
Pathology.

Biopsy, bone marrow or peripheral blood samples will be obtained from the 
Hematopathology Section of the NCI Laboratory of Pathology (LP) or the Hematology 
Section (HS) of the DLM, CC. 

Samples are coded by the LP HS, DLM HS or Young Lab.  Tissue sections, or peripheral 
blood samples will be obtained and stored in the Young lab or LP Proteomics Core lab 
without any personal identifiers and will be labeled with the anonymous LP HS or DLM 
HS sample accession ID number. 

The relationship between the accession ID number and the patient clinical information 
will be stored in a secure database that is maintained and regularly backed up by Drs. 
Ryan Young, Elaine Jaffe, or Dr. David Levens. 

The Young laboratory or LP Proteomics Core Lab will prepare tissue lysates, RNA and 
DNA from each sample.  Samples, lysates and derived biologic molecules will be stored 
in Eppendorf tubes marked with the sample accession ID number in locked -80° C 
freezers in the Young laboratory or LP Proteomics Core Lab.
5.3.4
Protocol Completion & Sample Destruction
Any specimens that are remaining at the completion of the protocol will be stored in the 
conditions described above.
The principal investigator will record the following: 

Destroyed samples which become unsalvageable because of environmental factors (ex. a 
broken freezer or lack of dry ice in a shipping container) or if a patient withdraws 
consent.  

Samples lost in transit between facilities or misplaced by a researcher.  


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
All other problems associated with samples.
6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant data 
capture system provided by the NCI CCR and ensuring data accuracy, consistency and 
timeliness. The principal investigator, associate investigators/research nurses and/or a contracted 
data manager will assist with the data management efforts. Primary and final analyzed data will 
have identifiers so that research data can be attributed to an individual human subject participant.
All adverse events (AEs), including clinically significant abnormal findings on laboratory 
evaluations, regardless of severity, will be followed until return to baseline or stabilization of the 
event.  
Document AEs from the first study intervention from Study Day 1 through 30 days after the last 
dose of study drug. Beyond 30 days after the last intervention, only adverse events which are 
serious and related to the study intervention need to be recorded. 
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following:

Results in discontinuation from the study

Is associated with clinical signs or symptoms 

Requires treatment or any other therapeutic intervention

Is associated with death or another serious adverse event, including hospitalization. 

Is judged by the Investigator to be of significant clinical impact

If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome.
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule as applicable. 
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1.
6.1.1
Long-term follow-up data collection
When patients enter the long-term follow-up period, the following data will be collected:

adverse events related to Carfilzomib

survival status which will be collected by phone or clinic visit

additional cancer therapy received
6.1.2
Record Keeping
Complete records must be maintained on each patient; these records will consist of the hospital 
chart as well as any other outside information obtained from outside laboratories, radiology 
reports, or physician’s records. The primary source documentation will include patient eligibility 


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data, patient history, flow sheets (including specialty forms for pathology, radiology, or surgery), 
an off-study summary sheet, and a final assessment by the treating physician.
6.1.3
Forwarding of Patient Data from Other Institutions
Either due to extenuating medical circumstances or for convenience, some patients may elect to 
have certain routine laboratory studies or protein marker analyses performed at an outside 
institution between scheduled interval visits to the CRC for this protocol. These results will be 
forwarded to the Myeloma Research Nurse; the data will be entered into the study database and 
filed in the medical record. Additional blood or tissue samples drawn on patients enrolled in this 
protocol between scheduled visits may be forwarded and entered into the database as indicated.
6.2
DATA SHARING PLAN
6.2.1
Genomic Data Sharing Plan
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy.
6.3
RESPONSE CRITERIA
Response assessments will be performed Day 1 of every cycle during Cycles 1-8 and every third 
cycle during Cycles 9-20: Cycles 9, 12, 15, 18 and every third cycle during Cycles 21-32:  
Cycles 21, 24, 27, 30 and end of 32.  During the follow-up period, response assessments will be 
done every 3-6 months, unless being primarily followed at outside facility at which time all 
effort will be made to receive response data at least yearly.
6.3.1
Disease Parameters

Measurable is defined as any of the following: serum M-protein is ≥ 1 g/dL or 
"measurable" urine M-spike is ≥ 200 mg/24 hours or serum kappa or lambda FREE light 
chain of 10 mg/dL along with an abnormal kappa to lambda free light chain ratio.

The serum free light chain (FLC) assay is of particular use in monitoring response to 
therapy in patients who have oligo-secretory 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 only if the baseline serum and/or urine M proteins 
are not “measurable” by traditional criteria (serum M protein ≥ 1gm/dL and/or urine M 
protein ≥ 200 mg/24), and the baseline level of the involved FLC is ≥ 10mg/dL and 
clonal (abnormal ratio). Patients included on the study on the basis of FLC alone (i.e., no 
measurable serum/urine) should be the only ones who are evaluated using FLC response 
criteria. The others should follow usual criteria and ignore FLC results.

In order to be classified as a hematologic 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.

Caution must be exercised to avoid rating progression or relapse on the basis of variation 
of radiological technique alone. Compression fracture does not exclude continued 


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response and may not indicate progression. When progression is based on skeletal disease 
alone, it should be discussed with the PI before removing the patient from the study.

Appearance of monoclonal or oligoclonal bands that are different from original isotype 
may not be defined as “relapse from CR”. Oftentimes, 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 clinician 
before being labeled as “relapse”[47, 48].

Random urine specimens will be performed day 1 of each cycle (cycles 1-8) and day 1 
(or within 7 days prior to day 1) of every third cycle (cycles 9-32).  24-hr UPEPs will be 
performed to confirm and document “CR” response (once serum and random have 
become negative for monoclonal protein and immunofixation).  In patients whose 
measurable disease is best determined by measuring Bence Jones protein quantification, a 
24 hr UPEP will be performed at baseline, day 1 of each cycle 1-8, and day 1 (or within 7 
days prior to day 1) of every third cycle during extension phase I and II.  Otherwise, 24-
hr UPEP Bence-Jones quantification will be estimated from random UPEP specimens 
performed at baseline, day 1 of each cycle 1-8, and day 1 (or within 7 days prior to day 1) 
of every third cycle during extension phase[46].

As of amendment L (version date 05/17/2018), primary endpoint will be MRD (-) CR 
rate, therefore per the discretion of the investigator, patients without measurable disease 
may also be enrolled.
6.3.2
Response Criteria adapted from International Myeloma Working Group Criteria for 
Multiple Myeloma[49] and addition of nCR category[21, 50] 
6.3.2.1  Evaluation of Response Criteria

MRD(-) CR 
Complete Response as defined below plus:
Absence of phenotypically aberrant clonal plasma cells by flow cytometry on bone 
marrow aspirates using the eight-color two-tube approach developed and validated by 
LP Flow cytometry lab for MRD detection in multiple myeloma with a minimum 
sensitivity of 1 in 10⁵ nucleated cells or higher.

Stringent Complete Response (sCR) 
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. 

Complete Response (CR) 
Negative immunofixation on the serum and urine and disappearance of any soft tissue 
plasmacytomas and ≤5% plasma cells in bone marrow 

Near Complete Response (nCR) 
Defined as absence of myeloma protein on electrophoresis, independent of 
immunofixation status[50]

Very Good Partial Response (VGPR) 


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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.

Partial Response (PR) 
≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by 
≥90% or to <200mg per 24h.  If the serum and urine M-protein are unmeasurable, a 
≥50% decrease in the difference between involved and uninvolved FLC levels is 
required in place of the M-protein criteria 

Stable Disease (SD) 
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. 

Progressive disease (PD) 
Requires any one or more of the following: 
Increase of ≥25% from lowest response value in the following on 2 consecutive 
measurements: 
o
Serum M-component and/or (the absolute increase must be ≥0.5g/dl). The 
serum M-component increases of ≥1 gm/dl are sufficient to define relapse if 
starting M-component is ≥5g/dl. 
o
Urine M-component and/or (the absolute increase must be ≥200mg/24h 
o
Only in patients without measurable serum and urine M-protein levels: the 
difference between involved and uninvolved FLC levels. The absolute 
increase must be >10mg/dl. 
o
Bone marrow plasma cell percentage: the absolute % must be ≥10% 
o
Definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in size of existing bone lesions or soft tissue plasmacytomas 
o
Development of hypercalcemia that can be attributed solely to the plasma cell 
proliferative disorder.

Relapse from CR
Any one or more of the following:
o
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”. 
Oftentimes, 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 clinician before 
being labeled as “relapse”.
o
Development of ≥ 5% plasma cells in the bone marrow


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o
Appearance of any other sign of progression (i.e., new plasmacytoma, lytic 
bone lesion, hypercalcemia.
6.3.3
Progression-Free Survival
PFS is defined as time of start of treatment to time of progression or death, whichever occurs 
first.
6.3.4
Duration of Best Response
The duration of overall response is measured from the time measurement criteria are met for best 
response until the first date that recurrent or progressive disease is objectively documented.   
6.4
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). 
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING
7.2.1
Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. Note: Only IND Safety 
Reports that meet the definition of an unanticipated problem will need to be reported per these 
policies.
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
7.3
NCI CLINICAL DIRECTOR REPORTING 
Problems expeditiously reviewed by the OHSRP in the NIH eIRB system will also be reported to 
the NCI Clinical Director/designee; therefore, a separate submission for these reports is not 
necessary. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email unless they are due to progressive disease.  


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To report these deaths, please send an email describing the circumstances of the death to 
NCICCRQA@mail.nih.gov within one business day of learning of the death.
7.4
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.4.1
Principal Investigator/Research Team 
The clinical research team will meet approximately weekly when patients are being actively 
treated on the trial to discuss each patient. Decisions about dose level enrollment and dose 
escalation if applicable will be made based on the toxicity data from prior patients. 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in 
section 7.2.1 will be submitted within the appropriate timelines.
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
8
SPONSOR SAFETY REPORTING
8.1
DEFINITIONS
8.1.1
Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product (ICH E6 (R2)).
8.1.2
Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:

Death,

A life-threatening adverse event (see section 8.1.3)

Inpatient hospitalization or prolongation of existing hospitalization 
o
A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event.
o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient or subject convenience) is not considered a serious adverse 
event. 


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o
Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria.

Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions.

A congenital anomaly/birth defect

Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.
8.1.3
Life-threatening 
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32)
8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 4.0.
8.1.5
Relationship to Study Product
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.  

Related – There is a reasonable possibility that the study product caused the adverse 
event. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event.

Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event.
8.2
ASSESSMENT OF SAFETY EVENTS
AE information collected will include event description, date of onset, assessment of severity 
and relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship.  AEs will be followed through resolution.
SAEs will be:

Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator.


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
Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database.

Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor with the exception of any listed in section 8.4. 
8.3
REPORTING OF SERIOUS ADVERSE EVENTS
Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety using the CCR SAE report form.  Any exceptions to the 
expedited reporting requirements are found in section 8.4.
All SAE reporting must include the elements described in section 8.2.
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report form 
and instructions can be found at: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions
Following the assessment of the SAE by OSRO, other supporting documentation of the event 
may be requested by the OSRO Safety and should be provided as soon as possible.
8.4
WAIVER OF EXPEDITED REPORTING TO CCR 
As death and hospitalization due to disease progression are part of the study objectives, and 
captured as an endpoint in this study, they will not be reported in expedited manner to the 
sponsor. However, if there is evidence suggesting a causal relationship between the study drug 
and the event, report the event in an expedited manner according to section 8.3. 
8.5
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS
All events listed below must be reported in the defined timelines to OSROSafety@mail.nih.gov. 
The CCR Office of Regulatory Affairs will send all reports to the manufacturers as described 
below. 
Note: All agreements with all manufacturers are no longer active, thus the the below sections are 
retained only for historical purposes. 
8.5.1
SAE Reporting to Amgen
All SAEs, except for TLS, occurring after the subject has signed the informed consent form 
(ICF) until 30 days after the last dose of any study treatment must be fully documented and 
reported to Amgen Global Safety as soon as possible but no later than 7 calendar days of initial 
receipt of the information.  All cases of TLS must be reported to Amgen as a Serious Adverse 
Event (SAE) through the normal process within 24 hours of the clinical site becoming 
aware of the event
The SAE report forms and the SAE Supplemental Form or MedWatch Form 3500a should be 


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faxed/emailed together to Amgen Global Safety: 
Toll-free U.S. Fax Number: 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 
8.5.2
Reporting Pregnancy to Amgen
8.5.2.1 Contraception/Female
Females of childbearing potential should be advised to avoid becoming pregnant while being 
treated with carfilzomib. Given that carfilzomib was clastogenic in the in vitro chromosomal 
aberration test in peripheral blood lymphocytes, as a precaution, females of childbearing 
potential and/or their male partners should use effective contraception methods or abstain from 
sexual activity during and for 30 days after treatment with carfilzomib. If pregnancy occurs 
during this time, patients should be apprised of the potential hazard to the fetus. 
Based on its mechanism of action and findings in animals, carfilzomib can cause fetal harm 
when administered to a pregnant woman. Carfilzomib caused embryo-fetal toxicity in pregnant 
rabbits at doses that were lower than in subjects receiving the recommended dose. carfilzomib 
administered to pregnant rats and rabbits during the period of organogenesis was not teratogenic 
at doses up to 2 mg/kg/day in rats or up to 0.8 mg/kg/day in rabbits. 
If carfilzomib is used during pregnancy, or if the subject becomes pregnant while taking this 
drug, she should inform the investigator or study staff immediately. The investigator should 
notify Amgen of the pregnancy and discuss follow-up with the subject. It is not known if 
carfilzomib will reduce the efficacy of oral contraceptives. Due to an increased risk of venous 
thrombosis associated with carfilzomib, subjects currently using oral contraceptives or a 
hormonal method of contraception associated with a risk of thrombosis should consider an 
alternative method of effective contraception. 
The length of time contraception should be used and acceptable contraceptive methods will be 
discussed with all subjects at the time of enrollment and during participation.
8.5.2.2 Contraception/Male:
Males of reproductive potential should be advised to avoid fathering a child while being treated 
with carfilzomib. The potential for carfilzomib to be transferred via semen and its effect on 
sperm are unknown. Male subjects treated with carfilzomib and/ or their female partners (if of 
childbearing potential) should use effective contraceptive methods or abstain from sexual 
activity while treated with carfilzomib for 90 days after treatment. If pregnancy occurs during 
this time, patients should be apprised of the potential hazard to the fetus.
Male subjects should be advised to inform the investigator or study staff immediately in the 
event that their female partner becomes pregnant during the study. Upon receipt of this 
information, the investigator should notify Amgen of the pregnancy and discuss follow-up 
regarding the pregnancy outcome with the subject.
The length of time contraception should be used and acceptable contraceptive methods will be 
discussed with all subjects at the time of enrollment and during participation.
8.5.2.3 Breast Feeding


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No studies of carfilzomib have been conducted in breastfeeding women. Carfilzomib should not 
be used during breast feeding. Breastfeeding women and women planning on breastfeeding may 
not participate in clinical trials with carfilzomib. It is not known whether carfilzomib is present 
in human breast milk. Due to the potential for adverse effects in nursing infants from 
carfilzomib, a decision should be made whether to discontinue nursing or to discontinue 
carfilzomib, taking into account the potential benefit of carfilzomib to the mother.   If a woman 
breastfeeds during the study, she must inform the investigator or study staff immediately. The 
investigator should notify Amgen that the subject has breastfed the infant and discuss follow up 
with the subject.
8.5.2.4 SAE Reporting to BMS
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 BMS as described below.
Serious adverse events (SAE) are defined above. The investigator must inform BMS in writing 
using a 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 should be noted on the report.  The written 
report must be completed and supplied to BMS 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/BMS tracking number (RV-MM-NCI-0719) and the institutional protocol number 
should be included on SAE reports (or on the fax cover letter) sent to BMS.  A copy of the fax 
transmission confirmation of the SAE report to BMS should be attached to the SAE and retained 
with the patient records. 
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: 
mailto:drugsafety@celgene.com
8.5.2.5 Reporting Pregnancy to BMS 
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 BMS 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 


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reproductive toxicity for further evaluation and counseling.
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify BMS 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  BMS 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 BMS 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.
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.
BMS 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 
Reporting will be per the collaborative agreement. 
8.6
REPORTING PREGNANCY 
All required pregnancy reports/follow-up to OSRO will be submitted to: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. Forms and instructions 
can be found here: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions
8.6.1
Maternal exposure
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the Pregnancy becomes known,
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (section 8.1.2) should be reported as 
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The outcome of all pregnancies should be followed up and documented.
8.6.2
Paternal exposure
Male patients should refrain from fathering a child or donating sperm during the study treatment 
and for at least 28 days after last dose of lenalidomide and 90 days after the last dose of 
carfilzomib.
Pregnancy of the patient’s partner is not considered to be an AE. the outcome of all pregnancies 
occurring from the date of the first dose until 28 days after last dose of lenalidomide and 90 days 
after the last dose of carfilzomib should, if possible, be followed up and documented. Pregnant 
partners may be offered the opportunity to participate in an institutional pregnancy registry 
protocol (e.g., the NIH IRP pregnancy registry study) to provide data about the outcome of the 
pregnancy for safety reporting purposes.
8.7
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected.  CCR will report an AE as a suspected 
adverse reaction only if there is evidence to suggest a causal relationship between the study 
product and the adverse event.  CCR will notify FDA and all participating investigators (i.e., all 
investigators to whom the sponsor is providing drug under its INDs or under any investigator’s 
IND) in an IND safety report of potential serious risks from clinical trials or any other source, as 
soon as possible, in accordance to 21 CFR Part 312.32. 
All serious events will be reported to the FDA at least annually in a summary format.
8.8
SPONSOR PROTOCOL DEVIATION REPORTING
A Protocol Deviation is defined as any non-compliance with the clinical trial Protocol, Manual 
of Operational Procedures (MOP) and other Sponsor approved study related documents, GCP, or 
protocol-specific procedural requirements on the part of the participant, the Investigator, or the 
study site staff inclusive of site personnel performing procedures or providing services in support 
of the clinical trial.
It is the responsibility of the study staff to document any protocol deviation identified by the 
Staff or the site Monitor in the CCR Protocol Deviation Tracking System (PDTS) online 
application. The entries into the PDTS online application should be timely, complete, and 
maintained per CCR PDTS user requirements. 
In addition, any deviation to the protocol should be documented in the participant’s source 
records and reported to the reviewing IRB per their guidelines. OSRO required protocol 
deviation reporting is consistent with E6(R2) GCP: Integrated Addendum to ICH E6(R1): 4.5 
Compliance with Protocol; 5.18.3 (a), and 5.20 Noncompliance; and ICH E3 16.2.2 Protocol 
deviations.
9
CLINICAL MONITORING
Clinical site monitoring is conducted to ensure:

that the rights of the participants are protected; 

that the study is implemented per the approved protocol, Good Clinical Practice and 
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
the quality and integrity of study data and data collection methods are maintained.  
Monitoring for this study will be performed by NCI CCR Office of Sponsor and Regulatory 
Oversight (OSRO) Sponsor and Regulatory Oversight Support (SROS) Services contractor. 
Clinical site monitoring activities will be based on OSRO standards, FDA Guidance E6(R2) 
Good Clinical Practice: Integrated Addendum to ICH E6(R1) March 2018, and applicable 
regulatory requirements.
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) 
developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address human 
subject protections and integrity of the study data. OSRO will determine the intensity and 
frequency of monitoring based on several factors, including study type, phase, risk, complexity, 
expected enrollment rate, and any unique attributes of the study and the site. The Sponsor will 
conduct a periodic review of the CMP to confirm the plan's continued appropriateness. A change 
to the protocol, significant or pervasive non-compliance with GCP, or the protocol may trigger 
CMP updates.
OSRO SROS Monitoring visits and related activities will be conducted throughout the life cycle 
of each protocol. The first activity is before the study starts to conduct a Site Assessment Visit 
(SAV) (as warranted), followed by a Site Initiation Visit (SIV), Interim Monitoring Visit(s) 
(IMVs), and a study Close-Out Visit (COV).
Some monitoring activities may be performed remotely, while others will occur at the study site(s). 
Monitoring visit reports will describe visit activities, observations, and associated action items or 
follow-up required for resolution of any issues, discrepancies, or deviations. Monitoring reports 
will be distributed to the study PI, NCI CCR QA, CCR Protocol Support Office, and the Sponsor 
regulatory file.
The site Monitor will inform the study team of any deviations observed during monitoring visits. 
If unresolved, the Monitor will request that the site Staff enter the deviations in the CCR Protocol 
Deviation Tracking System (PDTS) for deviation reporting to the Sponsor and as applicable per 
institutional and IRB guidance.
10 STATISTICAL CONSIDERATIONS
10.1 SAMPLE SIZE/ACCRUAL RATE
The primary objective of this trial is to determine whether use of CRd is associated with a 
substantial fraction of patients with high-risk SMM who exhibit at least a VGPR from baseline 
until the end of 8 cycles of treatment. 
The study will initially enroll 12 evaluable patients and determine M-spike levels on each patient 
pre-treatment as well as after each cycle of treatment. The percent decline from baseline will be 
determined for each patient. If 12 evaluable patients are enrolled and if 5 or more patients exhibit 
a VGPR, then the probability of this occurring is 7.3% if the true probability of a VGPR decline 
is 20%. The probability of 5 or more with a 50% decline is 80.6% if the true probability of a 
VGPR decline is 50%. Thus, obtaining 5 or more patients out of 12 with a VGPR would provide 
strong evidence that the true probability of a VGPR was consistent with 50% or more as opposed 
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In order to allow for a small number of inevaluable patients, the initial accrual ceiling will be set 
at 14.
If 1-2 patients per month can be enrolled on this trial, it expected that accrual could be completed 
in 6 to 12 months.
Amendment C (version date 07/11/2013) will permit enrollment to a replicate cohort in order to 
more precisely define the response rate to the CRd regimen in this population.  Based on 
preliminary results from the first 8 evaluable patients on the initial pilot cohort, 7 patients have 
experienced a VGPR or better response (87.5%).  Amendment C (version date 07/11/2013) will 
allow enrollment of a replicate cohort of 16 evaluable patients in order to estimate the response 
rate in this cohort independently from the initial cohort of 12 evaluable patients. With 16 
evaluable patients, a two-sided 90% confidence interval for the proportion of patients with a 
VGPR or greater will extend +/- 14% from the observed proportion if the expected proportion is 
87%. 
Thus, 16 newly enrolled patients will be evaluated for response separately from the initial 12 
patients. If the proportions with a VGPR are sufficiently similar (approximately p>0.35 by a 
Fisher’s exact test), then in addition to reporting the results separately, an additional result will 
be the combined proportion of VGPR or greater along with a two-sided 90% confidence interval 
about this observed proportion. If there are 28 total patients which can be combined in an 
evaluation, a simple two-sided 90% confidence interval for the proportion of patients with VGPR 
or greater will extend approximately +/- 11% from the observed proportion if the expected 
proportion is 86% (24 of 28 responses, for example).
Enrolling additional patients to this replicate cohort will allow the secondary endpoints of 
duration of response and PFS to be determined with greater precision; it will also allow us to 
conduct stratified analysis by molecular subtypes (hyperdiploid vs. non-hyperdiploid); and it will 
provide greater safety data than that available from the pilot cohort of 12 patients.
All 18 patients enrolled on the trial during 2012-2014 exhibited VGPR or better responses, 
including 17 with some variation of a CR and 16 who were MRD(-). Beginning with 
Amendment L (version date 05/17/2018), the primary objective of the trial is revised to increase 
the precision of the estimate of the MRD (-) CR rate. The trial will be extended to enroll a total 
of 50 evaluable patients to do so. With a total of 50 evaluable patients, the 95% two-sided 
confidence interval width about a conservative estimate of the MRD (-) CR rate of 70% would 
be +/- 12.7%. If the MRD (-) CR rate were 85%, 50 patients would permit the estimate to be 
determined with a 95% two-sided confidence interval of +/- 9.9%.
As of January 2018, a total of 21 patients have been enrolled on the trial and it is anticipated that 
1-2 patients per month will continue to be accrued. Thus, it is expected that the remaining 29 
patients can be enrolled in approximately 2 years. To allow for a number of inevaluable patients 
and screen failures, the accrual ceiling will be set at 63.
10.2 STATISTICAL ANALYSIS OF SECONDARY/EXPLORATORY ENDPOINTS
Secondary endpoints are duration of response and progression free survival (both biochemical 
progression and progression to overt symptomatic multiple myeloma).  Duration of response is 
defined as time from response to disease progression or death.  Progression free survival is 
defined as time of study entry to progression or death.  Duration of response and progression free 


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survival will be estimated using the Kaplan-Meier and log-rank methods. Secondary endpoints 
will also include rate and duration of MRD-negative CR and OS.
A number of correlative studies will be performed in order to assess carfilzomib in vitro 
biological activity and investigate minimal residual disease in SMM.  Minimal residual disease 
will be further explored using multi-parametric flow cytometry, PCR-based techniques, and 
advanced imaging.
Beginning with Amendment L (version date 05/17/2018), the secondary objectives will also 
include:
1. To estimate the durable MRD (-) CR rate, estimating the fraction of patients who have an 
MRD (-) CR for 1 year as a minimum. This fraction will be estimated along with a 95% 
two-sided confidence interval. 
2. To compare the outcomes among the 18 patients enrolled in 2014 or earlier to the 32 
enrolled in 2017 or later because the diagnostic criteria for SMM vs. MM were revised in 
2014 after the 18th patient was enrolled. The MRD (-) CR rates will be compared between 
these two cohorts of patients using a two-tailed Fisher’s exact test. All other comparisons 
of outcomes between the two cohorts will be interpreted as exploratory and will be done 
using appropriate non-parametric statistical tests without adjustment for multiple 
comparisons.
3. To obtain and report safety data on all enrolled evaluable patients to fully characterize the 
safety of the regimen in a modestly large number of subjects treated on one protocol.
An exploratory objective is also added to evaluate FISH data on available patients enrolled 
following amendment L (version date 05/17/2018) with respect to classification into high risk vs. 
non-high-risk patients. Known high risk FISH markers in multiple myeloma literature will be 
evaluated, namely, 4;14, 14;16, 14;20, del 17p, and 8;14. When available outside lab results will 
be confirmed either by results from the NCI Laboratory of Pathology or by the Mayo Laboratory 
results (Test ID: PCPDF, Plasma Cell Proliferative Disorder (PCPD)) and mutual results will be 
used for the analysis. 
11 COLLABORATIVE AGREEMENTS 
11.1 AGREEMENT TYPE – CRADA 
Note: All agreements with all manufacturers are no longer active, thus the the below text is 
retained only for historical purposes. 
The following CRADAs are associated with this protocol:  Amgen, Inc. (formerly directly with 
Onyx Pharmaceuticals), Inc. for Carfilzomib (#02695); Celgene Corporation for Lenalidomide 
(#02696).   
12 HUMAN SUBJECTS PROTECTIONS 
12.1 RATIONALE FOR SUBJECT SELECTION
MM is an almost always incurable plasma cell neoplasm that comprises approximately 10%


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of all hematologic malignancies, affecting 20,000 patients annually[51].  Recent studies have 
shown that MM is preceded by MGUS and SMM.[5]  Rate of progression at 5 years from high 
risk SMM to MM is 72-76% at 5 years with a median TTP of < 2 years [12, 13].  MM affects all 
genders and races.  Incidence rates of myeloma is higher among Blacks compared to Caucasians, 
affecting 14.3 black males per 100, 000 males and 10.0 black females per 100,000 females 
compared to 6.7 white males per 100, 000 males and 4.1 white females per 100, 000 women.  
The median age at death for myeloma is 75 years of age[51].  As such, we expect that the 
majority of patients enrolled in this trial will be older adults of either gender or race. MM 
patients enrolled on this study will consist of patients referred to and screened at the NIH 
Clinical Center. There will be no subject selection bias with regard to gender, ethnicity, or race. 
This protocol excludes lactating and pregnant women from receiving this investigational drug to 
avoid any possible risks to the fetus or newborn.  
12.2 PARTICIPATION OF CHILDREN
Pediatric patients with SMM are extremely rare. Patients under the age of 18 are excluded from 
this study because inclusion of a rare younger patient will not provide adequate generalizable 
information to justify their inclusion in this study.
12.3 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
Currently, MM is an incurable malignancy with frequent complications of skeletal fractures, 
anemia, renal failure and hypercalcemia.  Conventional radiographs reveal that 79% of patients 
will have observed skeletal abnormalities at time of diagnosis[52].  Treatment of high risk SMM 
patients may reduce skeletal related events from occurring and prevent morbidity from 
irreversible bone damage seen with MM.  In addition, treating SMM with potent anti-MM 
therapeutics before disease biology becomes aggressive in later disease states may also increase 
the potential for a cure or prolong progression free survival or overall survival.  The added 
benefit of searching for minimal residual disease markers using FDG-PET CT, flow cytometry, 
and PCR techniques will allow us to probe depth of response beyond standard insufficient 
clinical markers.
Risks of the study include exposing asymptomatic patients without clinical MM to 
chemotherapeutic agents.  However, it must be noted that carfilzomib, a new-generation 
proteasome inhibitor, has been tested in phase 1 trials in combination with lenalidomide and 
dexamethasone with minimal toxicity and favorable side effect profiles.  The most recent phase 1 
trial in newly diagnosed MM patients has shown >83% VGPR rates after a median of 8 cycles in 
12 patients with <1% neuropathy.[53] Procedures required for obtaining samples/data for 
experimental purposes (venipuncture, urine collection, PET/CT scan, DW-MRI and bone 
marrow biopsy) are of limited risk to the patient.  Although patients will suffer some additional 
pain or discomfort from the PET/CT scans and annual bone marrow biopsies, clinical experience 
has shown that the medical risk is limited. 
The genetic testing performed on the study carries with it a potential loss of privacy in case of 
database compromise, as well as psychological distress to participant and possibly family 
members in the event that incidental findings are disclosed.   
12.3.1 Known Potential Risks
12.3.1.1 Radiation Exposure


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On this study, patients will receive approximately three FDG PET/CT scans (as indicated in 
section 5.1.3.1). The procedures for performing FDG PET/CT scans will follow clinical policies, 
no special procedures apply to these assessments for research purposes.  
The total radiation dose for research purposes will be approximately 3.6 rem.
12.3.1.2 Blood draws
Pain and bruising in the area where the blood was drawn, lightheadedness, fainting due to 
transient lowering of blood pressure, and infection at the blood-drawing site.
12.3.1.3 Questionnaires
Emotional discomfort associated with answering potentially uncomfortable questions.
12.3.1.4 Intravenous Catheter
Pain, bleeding, infection, and collapsed lung. The long-term risks of the catheter include 
infection and clotting of veins. 
12.3.1.5 Bone marrow aspiration and biopsy 
Local bleeding, pain at the site, infection, allergy to the local anesthetic, and soreness at site.
12.3.1.6 PET/CT and DW-MRI scans
PET/CT may cause physical discomfort during the placement of an intravenous line and the 
necessity to remain still on back for 30 minutes. The DW-MRI may cause physical discomfort 
due to necessity to remain still on back for about 1½ hours. 
12.3.1.7 Psychological or Social Risks Associated with Return of Incidental or Secondary 
Findings
Learning of genetic risks for another disease or disability may cause emotional distress.
12.4 RISKS/BENEFITS ANALYSIS
Given the high rates of progression specific to the high risk SMM populations and low toxicity 
profile of combination therapy, risk of exposure does not seem to outweigh the clinical benefit 
that patients may derive from therapy.  More importantly, much of patient morbidity in MM is 
associated with pain from irreversible skeletal related events.  Such a trial would aim to treat or 
cure the disease before irreversible bone damage occurs or before aggressive clinical MM 
occurs.  Discomfort from venipuncture, bone marrow biopsy, PET/CT scan and DW-MRI is 
minimal and of limited risk compared to the knowledge gained by depth of response from 
disease monitoring.
12.5 CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document to the 
participant or consent designee(s) as applicable for review prior to consenting.  A designated 
study investigator will carefully explain the procedures and tests involved in this study, and the 
associated risks, discomforts and benefits. In order to minimize potential coercion, as much time 
as is needed to review the document will be given, including an opportunity to discuss it with 
friends, family members and/or other advisors, and to ask questions of any designated study 
investigator. A signed informed consent document will be obtained prior to entry onto the study.


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The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
policy, including HRPP Policy 303) per discretion of the designated study investigator and with 
the agreement of the participant/consent designee(s).  Whether in person or remote, the privacy 
of the subject will be maintained. Consenting investigators (and participant/consent designee, 
when in person) will be located in a private area (e.g., clinic consult room). When consent is 
conducted remotely, the participant/consent designee will be informed of the private nature of 
the discussion and will be encouraged to relocate to a more private setting if needed.
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or as described below, with a manual 
(non-electronic) signature on the electronic document.  When required, witness signature will be 
obtained similarly as described for the investigator and participant.  
Consent for the optional biopsies performed on this study will be obtained at the time of the 
procedure. If the patient refuses the optional biopsy at that time, the refusal will be documented 
in the medical record and in the research record.
Manual (non-electronic) signature on electronic document:
When a manual signature on an electronic document is used for the documentation of consent at 
the NIH Clinical Center, this study will use the following to obtain the required signatures. 

Adobe platform (which is not 21 CFR Part 11 compliant); or,  

iMedConsent platform (which is 21 CFR Part 11 compliant)
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the same 
screen may be used when in the same location, but is not required.  
Both the investigator and the participant will sign the document using a finger, stylus or mouse. 
NOTE: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent 
Process for additional information (e.g., verification of participant identity when obtaining 
consent remotely) found at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
12.5.1 Request for Waiver of Consent of Consent for Screening Activities 
Prior to the subject signing the consent for this study pre-screening activities listed in section 
2.2.1 may be performed. 
We request a waiver of consent for these activities as they involve only minimal risk to the 
subjects.  A waiver will not adversely affect the rights and welfare of the subjects given that the 
activities are only intended to determine suitability for screening for participation in research 
protocols.  These activities could not practicably be carried out without the wavier as central 
recruiting services, utilized in the NIH Clinical Center, perform pre-screening activities for 
multiple studies and obtaining consent for each one is beyond their resources.  The subjects will 
be provided with additional pertinent information after participation as they will be informed 
whether or not they are eligible to sign a consent for additional screening.


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13 REGULATORY AND OPERATIONAL CONSIDERATIONS 
13.1 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, IND 
sponsor and regulatory authorities. If the study is prematurely terminated or suspended, the 
Principal Investigator (PI) will promptly inform study participants, the Institutional Review 
Board (IRB), and sponsor and will provide the reason(s) for the termination or suspension.  
Study participants will be contacted, as applicable, and be informed of changes to study visit 
schedule.
Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants

Demonstration of efficacy that would warrant stopping   

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met

Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).
13.2 QUALITY ASSURANCE AND QUALITY CONTROL
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management 
plan will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Council on 
Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities.
13.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 


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design and conduct of this trial.  The study leadership in conjunction with the National Cancer 
Institute has established policies and procedures for all study group members to disclose all 
conflicts of interest and will establish a mechanism for the management of all reported dualities 
of interest.
13.4 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor. This confidentiality is extended to cover testing of biological samples 
and genetic tests in addition to the clinical information relating to participants. Therefore, the 
study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records.
The study participant’s contact information will be securely stored at the clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements.
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the NCI CCR. This will not include the 
participant’s contact or identifying information. Rather, individual participants and their research 
data will be identified by a unique study identification number. The study data entry and study 
management systems used by the clinical site and by the NCI CCR research staff will be secured 
and password protected. At the end of the study, all study databases will be archived at the NIH 
Clinical Center.
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants.
14 PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION  
14.1 CARFILZOMIB (IND # 112587)
14.1.1 Source 
Carfilzomib is provided to investigator by Amgen, Inc. 


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14.1.2 Toxicity 
A comprehensive listing of all toxicities (i.e., very common, common, etc.) are listed in the 
informed consent document.  The approved USPI may also be referenced for current information 
related to this agent. See below information regarding most significant toxicities:    
Fetal Risk 
Do not use Carfilzomib during pregnancy. If Carfilzomib is used during pregnancy, it may cause 
birth defects or death to a developing baby. Women of childbearing potential must use 2 forms 
of contraception or continuously abstain from heterosexual sex during and for 4 weeks after 
Carflizomib treatment.
Tumor Lysis Syndrome:
Fatal instances of tumor lysis syndrome have been reported during treatment with lenalidomide. 
The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. 
These patients should be monitored closely and appropriate precautions taken.
Most common adverse reactions: 
Fatigue, vomiting/nausea, fever, respiratory infection, hypertension, diarrhea, loss or decrease of 
appetite, insomnia, neutropenia, peripheral edema
Very rare and serious adverse reactions:
Cytomegalovirus, progressive multifocal leukoencephalopathy (PLM), pericarditis, pancreatitis, 
posterior reversible encephalopathy syndrome (PRES), cholestasis, hepatitis B virus reactivation, 
thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS)  
14.1.3 Formulation and preparation 
14.1.3.1 Formulation
Carfilzomib for injection is a sterile, white to off-white lyophilized powder and is available as a 
single-use 60 mg vial. Each 60 mg vial contains 60 mg of carfilzomib, 3000 mg sulfobutylether 
beta-cyclodextrin, 57.7 mg citric acid, and sodium hydroxide for pH adjustment (target pH 3.5).
14.1.3.2 Preparation
Vials will be reconstituted with Sterile Water for Injection to a concentration of 2 mg/mL by 
adding 29 mL to the 60 mg vial. The calculated dose will be withdrawn from the vial and further 
diluted into a 100 mL intravenous bag of 5% Dextrose Injection, USP. Refer to the FDA-
approved labeling for detailed reconstitution and dilution instructions.
14.1.3.3 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.


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
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).
14.1.3.4 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.
14.1.4 Stability and Storage  
14.1.4.1 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
14.1.4.2 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 is stable for a total of 
24 hours. DO NOT FREEZE LYOPHILIZED OR RECONSTITUTED DRUG.
14.1.4.3 Diluted Drug Product 
After dilution with 5% Dextrose Injection for clinical use, Carfilzomib should preferably be 
stored under refrigeration unless plan for administration immediately following preparation. 
Diluted Carfilzomib is stable for 24 hours in the refrigerator or 4 hours at room temperature 
from the time of vial reconstitution.  If refrigerated, the infusion solution should be equilibrated 
to room temperature prior to administration.
14.1.5 Administration procedures 
Carfilzomib will be administered by intravenous infusion over 30 minutes through a peripheral 
or central venous access device as a secondary infusion into a primary line containing 5% 
Dextrose Injection. Infusions can be stopped or slowed down if patient is experiencing infusion 
reactions. 
Do not mix carfilzomib with or administer as an infusion simultaneously with other drugs.
Flush line AFTER drug administration with a minimum of 50 mL of 0.9% Normal Saline or 5% 
Dextrose Injection (particularly for infusions through a peripheral line to minimize phlebitis 
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14.1.6 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.
14.2 LENALIDOMIDE  
14.2.1 Source 
REVLIMID® (lenalidomide) is provided to investigator by Celgene Inc. under Cooperative 
Research and Development Agreement (CRADA).
14.2.2 Toxicity 
A comprehensive listing of all toxicities (i.e., very common, common, etc.) are listed in the 
informed consent document.  The approved USPI may also be referenced for current information 
related to this agent.  See below information regarding most significant toxicities:  
Fetal Risk 
Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused 
limb abnormalities in a developmental monkey study. Thalidomide is a known human 
teratogen that causes severe life-threatening human birth defects.  If lenalidomide is used 
during pregnancy, it may cause birth defects or death to a developing baby. In women of 
childbearing potential, obtain 2 negative pregnancy tests before starting REVLIMID® 
treatment. Women of childbearing potential must use 2 forms of contraception or 
continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID 
treatment.
Hematologic Toxicity
REVLIMID can cause significant neutropenia and thrombocytopenia. In the pooled MM 
studies Grade 3 and 4 hematologic toxicities were more frequent in patients treated with the 
combination of REVLIMID and dexamethasone than in patients treated with dexamethasone 
alone.
Deep Vein Thrombosis and Pulmonary Embolism
Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary 
embolism) have occurred in patients with MM treated with lenalidomide combination 
therapy.  A significantly increased risk of DVT and PE was observed in patients with MM 
who were treated with REVLIMID and dexamethasone therapy in a clinical trial. 
Allergic Reactions
Angioedema, anaphylaxis, and serious dermatologic reactions including Stevens-Johnson 
syndrome
(SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. 
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receive REVLIMID. REVLIMID interruption or discontinuation should be considered for 
Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, 
exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed 
following discontinuation for these reactions.
Tumor Lysis Syndrome
Fatal instances of tumor lysis syndrome have been reported during treatment with 
lenalidomide. The patients at risk of tumor lysis syndrome are those with high tumor burden 
prior to treatment. These patients should be monitored closely and appropriate precautions 
taken.
Most common adverse reactions (≥20%) 
Fatigue, neutropenia, constipation, diarrhea, muscle cramp, anemia, pyrexia, peripheral 
edema, nausea, back pain, upper respiratory tract infection, dyspnea, dizziness, 
thrombocytopenia, tremor and rash.
Rare and Serious adverse reactions
Myocardial infarction, myocardial ischemia, cardiac failure, gastrointestinal hemorrhage, 
intestinal obstruction; meningitis, infections of the skin, joints, and kidney; abnormal levels 
of blood sugars and electrolytes, hypoxia, hepatocellular injury.
14.2.3 Formulation and preparation 
Lenalidomide will be supplied as capsules for oral administration. Bristol Myers Squibb (BMS) 
will provide lenalidomide 5, 10, 15 and 25 mg capsules for the Induction Phase of the protocol 
and for the extended dosing phase(s). 
14.2.4  Stability and Storage 
Lenalidomide should be stored at room temperature away from direct sunlight and protected 
from excessive heat and cold.
14.2.5 Administration procedures 
Bristol Myers Squibb (BMS) will supply Revlimid® (lenalidomide) to the Clinical Center 
Pharmacy to be dispensed to study participants at no charge through the REMS® program.  
Lenalidomide will be shipped directly to patients or picked up directly from the Clinical Center 
pharmacy.   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.   
11.2.6 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


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different; however, the digoxin Cmax was increased by 14%. Periodic monitoring of digoxin 
plasma levels, in accordance with clinical judgment and based on 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. 
14.3 DEXAMETHASONE 
14.3.1 Source
Dexamethasone will be provided from commercial sources by the NIH Clinical Center Pharmacy 
Department. 
14.3.2 Toxicity
Common  
Cardiovascular: Hypertension 
Dermatologic: Atrophic condition of skin, Finding of skin healing, Impaired 
Endocrine metabolic: Cushing's syndrome, Decreased body growth 
Gastrointestinal: Disorders of gastrointestinal tract 
Immunologic: At risk for infection 
Musculoskeletal: Osteoporosis 
Ophthalmic: Cataract (5%), Raised intraocular pressure (25%) 
Psychiatric: Depression, Euphoria 
Respiratory: Pulmonary tuberculosis
Serious  
Endocrine metabolic: Hyperglycemia, Primary adrenocortical insufficiency 
Ophthalmic: Conjunctival hemorrhage (22%), Glaucoma, Vitreous detachment (2%)
14.3.3 Formulation and preparation
Oral Tablet (Scored): 4 mg
Injection, solution, as sodium phosphate:  4 mg/mL (1 mL, 5 mL, 30 mL) 
14.3.4 Administration procedures
Oral: Administer with meals to decrease GI upset. 


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I.V.: Administer intravenously over 10 minutes. 
14.3.5 Incompatibilities
Contraindicated:  Praziquantel (theoretical), Rotavirus Vaccine, Live (established)
Major:  Aldesleukin (theoretical), Bupropion (theoretical), Darunavir (theoretical), Dasatinib 
(theoretical), Etravirine (theoretical), Fosamprenavir (theoretical), Imatinib (theoretical), 
Ixabepilone (theoretical), Lapatinib (theoretical), Nilotinib (theoretical), Quetiapine (probable), 
Romidepsin (theoretical), Sunitinib (theoretical), Temsirolimus (theoretical), Thalidomide 
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16 APPENDICES
APPENDIX A:  PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no 
evidence of disease.
0
Normal activity.  Fully active, 
able to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
80
Normal activity with effort; 
some signs or symptoms of 
disease.
1
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active 
work.
60
Requires occasional assistance, 
but is able to care for most of 
his/her needs.
2
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and 
about more than 50% of waking 
hours.
50
Requires considerable assistance 
and frequent medical care.
40
Disabled, requires special care 
and assistance.
3
In bed >50% of the time.  
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours.
30
Severely disabled, 
hospitalization indicated.  Death 
not imminent.
20
Very sick, hospitalization 
indicated. Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.


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APPENDIX B:  REQUIREMENTS FOR REMS
Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control 
Methods
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 BMS 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.

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®.


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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 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.


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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:  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.  


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
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.


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APPENDIX C:  BONE MARROW ASPIRATE COLLECTION, SORTING AND STORAGE
Collection of Bone Marrow
NOTE:  Refer to Section 5.1 for correlative study bone marrow time points and Study Calendar 
(Section 3.4).

Orders for bone marrow biopsies should be placed in the Clinical Research Information 
System (Clinical Research Center, NIH, Bethesda, MD).

Notify the CCR Hematology lab that flow immunophenotyping is being performed
(301-496-4473).  The hematology BM collection tech will bring a 10 mL tube sodium 
heparin Vacutainer tube to the specimen collection site and prepare an extra smear for the 
Flow Cytometry Laboratory.

Get sterile heparin suitable for injection from the nurse’s station.  Rinse syringe and 
needle with sterile heparin, leaving no less than 0.5 mL in syringe.

Bone marrow samples will be collected as bone marrow core biopsies and aspirates for 
analyses. Aspirate first 2 cc of marrow for morphology first and give specimen to 
Hematology lab technician to be given to Hematology Section, Department of Lab 
Medicine (1 mL will go to Hematopathology and 1 mL (optionally) will be delivered to 
Irina Maric, MD for research assessing proteasomes).  Reposition needle and, for cellular 
specimens, aspirate 5-8 mL of bone marrow for flow cytometry and cell sorting in 
heparin containing syringe.  

Bone marrow core biopsies and one fraction of marrow aspirates will be fixed and 
paraffin-embedded for histological/immunohistochemical analysis and long term storage. 
One fraction of marrow aspirates will be stored as air-dried aspirate smears and the rest 
will be frozen. 

After processing in the pathology department, clot sections will be sent to the Molecular 
Diagnostics Core Laboratory, LP, NCI under the direction of Mark Raffeld, MD for 
determination immunoglobulin heavy and/or light chain rearrangement, and 
KRAS/NRAS mutations (No longer being done, as of Amendment H (version date 
06/12/2017).

For aspirate specified for flow cytometry under the direction of Hao-Wei Wang, 
immediately discharge 1 mL of aspirated marrow syringe into a 10mL sodium heparin 
Vacutainer, cap tube tightly and mix by gentle inversion 5-6 times. Label tube with 
patient name, unique identifier number and date.  Deliver immediately to the Flow 
Cytometry Laboratory 3S240 (specimens containing hematopoietic neoplasms have a 
tendency to clot and must be processed immediately). Call for STAT Escort pickup and 
delivery if you cannot deliver the specimen yourself (301-496-9295).  Aspirate from 
marrows at baseline, end of cycle 8/or CR reached between cycles 1-8, end of cycle 20/or 
CR reached between cycles 9-20 and during treatment termination/or CR reached 
between cycles 21 and beyond will be sent for plasma cell flow cytometry 
immunophenotyping at Hao-Wei Wang’s lab.  

For aspirate designated for CD138 sorting, VDJ sequencing, exome sequencing, and 
microenvironment studies, send remaining aspirate sample to the Young Laboratory 
(Building 10/4N106) Place aspirate sample in EDTA syringe immediately on ice.  
Transfer within 30 minutes of sampling to the lab for processing. For baseline samples, 
cells will be sorted in CD138+ and – fractions.  CD138+ plasma cells will be viably 
frozen and batched to be sent to Adaptive Technologies for VDJ sequencing and to 


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MSKCC for exome sequencing.  CD138- fractions will be studied by Dr.’s Wang and 
Young.  At subsequent time points, CD138+ sorting will not be done if the patient is in 
remission. Note: As of February 6, 2023, all participants have completed the 
maintainance phase (C32) thus bone marrow and peripheral blood research samples will 
be sent to Ryan Young’s lab on a case to case basis.

For aspirate specified for cytogenetics/FISH, aspirate, as of amendment H (version date 
06/12/2017), FISH/cytogenetic information may be derived from the patient’s outside 
records or performed on baseline bone marrow samples at a third-party testing laboratory 
per the CC DLM clinical laboratory protocol/procedure which currently is the Mayo 
Laboratory Test ID: PCPDF, Plasma Cell Proliferative Disorder (PCPD).   

For aspirate specified assessing proteasomes:  1 mL will be delivered to Irina Maric, MD 
for research assessing proteasomes. After Amendment H (version date 06/12/2017), this 
is optional.


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APPENDIX D:  PERIPHERAL BLOOD AND URINE COLLECTION AND STORAGE
Blood Processing Core 
Refer to Sections 3.4 (Study Calendar) and 5.1 for research blood and urine collection time 
points.
Venipuncture

Up to 100 mL of peripheral blood will be collected into serum separator tubes (SST), 
sodium heparin tubes (GTT) or EDTA tubes.  The amount of blood collected will be 
dictated by the number of experiments to be performed, and by the patient’s peripheral 
blood count. 

Serum 
o
Collect 7-10 mL blood in a serum separator tube (SST).
o
Allow the blood to clot by standing at room temperature for 30 minutes.
o
Separate serum from cells by centrifuging at 4 degrees C for 5 minutes at 1200xg.  
o
Pipette 2 aliquots of 1.5mLs each into two 2mL cryovials.
o
Freeze immediately at -20 or lower
o
Maintain in -80 freezer for storage until shipment

Plasma
o
Collect 7 mL blood in a sodium heparin tube (green top).
o
Place immediately on wet ice and refrigerate until time of processing.
o
Separate plasma from cells by centrifuging at 4 degrees C for 5 minutes at 1200xg.
o
Pipette 2 aliquots of 1.5mLs each into two 2mL cryovials.
o
Freeze and store in -80C freezer.

Complete blood count
o
A venous blood sample for a CBC will be collected in a 10ml EDTA lavender top (BD 
EDTA 366643) tube.  Keep at room temperature until processing begins.  
Urine Sample Collection

Approximately 45 mL of urine will be collected into a standard urine collection cup for 
further analysis.  The amount of urine collected will be dictated by the number of 
experiments to be performed.  

Transfer to a screw-cap conical tube

Freeze immediately at -20 or lower

Maintain in -80 freezer for storage until shipment
Labeling of Samples
All specimens are to be labeled per the local site’s standard procedures. The following 
information, if not provided on the specimen label, must be linked to the specimen label and 
provided on the inventory sheet: 
-
patient study ID # 


Abbreviated Title:  CRd for Smoldering Myeloma
Version Date:  01/01/2024
90
-
sample type
-
date/time of draw (DD/MMM/YY 24:00)
-
time point (ex. C1D1 pre, C1D1 24hr post)
-
any collection issues (short draw, delayed processing, etc.)
-
protocol title/number
-
institute name
-
contact information

Do not include the patient name, medical record number, or initials.

ICF_003.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 07/18/2022
Page 1 of 29
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR: Elizabeth Hill, M.D.
STUDY TITLE:
Carfilzomib, Lenalidomide, and Dexamethasone in High 
Risk Smoldering Multiple Myeloma: A Clinical and 
Correlative Pilot Study
STUDY SITE:  
NIH Clinical Center
Cohort:                                              Standard 
Consent Version:                               07/18/2022
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator:
Elizabeth Hill, M.D.
Phone:  240-760-6183
Email:  elizabeth.hill@nih.gov
This consent form describes a research study and is designed to help you decide if you would like 
to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
Members of the study team will talk with you about the information described in this document. 
Some people have personal, religious, or ethical beliefs that may limit the kinds of medical or 
research treatments they would want to receive (such as blood transfusions). Take the time needed 
to ask any questions and discuss this study with NIH staff, and with your family, friends, and 
personal health care providers. Taking part in research at the NIH is your choice.
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
The purpose of this study is to see what effects, good and/or bad, the combination of carfilzomib, 
lenalidomide, and dexamethasone has on you and your smoldering multiple myeloma (SMM).
Carfilzomib (Kyprolis) is approved by the U.S. Food and Drug Administration (FDA) to be used 
only in certain U.S. patients with relapsed and refractory multiple myeloma that have tried and 
failed other therapies. It has not been approved to be used for any other disease or condition. In 
this study, carfilzomib is an experimental study drug because it is not approved for use in all 
patients in the United States, and it is not approved by some regulatory authorities (the agencies 
that are responsible for approving the use of a medicine in a country such as the European 
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 07/18/2022
Page 2 of 29
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Medicines Agency and Health Canada). "Experimental" means that the drug is still being studied 
and that research doctors are trying to find out more about it.
Lenalidomide is a drug that alters the immune system and it may also interfere with the 
development of tiny blood vessels that help support tumor growth.  Therefore, in theory, it may 
reduce or prevent the growth of cancer cells.  Lenalidomide is approved by the Food and Drug 
Administration (FDA) for the treatment of specific types of myelodysplastic syndrome (MDS) 
and in combination with dexamethasone for patients with multiple myeloma (MM) who have 
received at least 1 prior therapy.  MDS and MM are cancers of the blood.  It is currently being 
tested in a variety of cancer conditions. In this case, it is considered experimental.
Dexamethasone is a steroid that prevents the release of substances in the body that cause 
inflammation. Dexamethasone is sometimes used as a direct chemotherapy agent in certain types 
of cancer, especially in the treatment of multiple myeloma, in which dexamethasone is given 
alone or in combination with other chemotherapeutic drugs.
WHY ARE YOU BEING ASKED TO TAKE PART IN THIS STUDY?
You are being asked to participate in this study because you have high risk smoldering multiple 
myeloma.  
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
Up to 63 patients will be enrolled in this study.
DESCRIPTION OF RESEARCH STUDY
As a person with high risk smoldering multiple myeloma, you will receive a total of 8 cycles of 
combination therapy of carfilzomib, lenalidomide, and dexamethasone.  Each cycle is 28 days.  
After the first four cycles of therapy, if you are eligible for stem cell transplant, you will be given 
the option to have stem cells collected and stored for a future autologous (with your own cells) 
stem cell transplantation if clinically indicated.  After stem cell collection, you will receive 4 
additional cycles of combination therapy with carfilzomib, lenalidomide, and dexamethasone.  
At the end of 8 cycles, if your disease has improved or has been stable on therapy you will 
receive an additional 12 cycles of lenalidomide extended dosing (part 1). After receiving 
lenalidomide extended dosing part 1, you will have the option to receive an additional 12 cycles 
of lenalidomide extended dosing (part 2).
WHAT WILL HAPPEN IF YOU TAKE PART IN THIS RESEARCH STUDY?  
Before you begin the study
Before you begin the study, if you decide to take part, some procedures and tests will need to be 
performed to determine if you qualify for the study. Appointments for these tests will be made 
by your doctor. These tests are part of regular cancer care and may be done even if you do not 
join the study. If you have had some of them recently, they may not need to be repeated. This 
will be up to your study doctor. 
You will have:

History and physical examination

Routine Blood work (about 3 tablespoons)
IRB NUMBER: 12C0107
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 07/18/2022
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

Urine laboratory tests

A bone marrow procedure to obtain aspirate and core biopsy is required for the diagnosis 
of SMM and can provide important additional information.  We will request that you 
undergo such a biopsy. 

EKG

Tests for Hepatitis B and C

Urine or blood Pregnancy test
You will also be asked if you would like to provide extra research samples that may include 
blood, urine and bone marrow biopsy and aspirate. These studies are optional and will be used to 
learn more about smoldering myeloma. Whenever possible, if you have given permission, these 
samples will be collected at the same time as the routine cancer care testing. 
During the study
If the exams, tests and procedures show that you can be in the study, and you choose to take part, 
then you will need the following tests and procedures as part of regular cancer care.

Physical exam

Routine Blood work (about 2 – 3 tablespoons)

Urine collection

Bone marrow biopsy and aspirate to assess the status of your smoldering myeloma

Urine or blood pregnancy tests in women of child-bearing potential

Echocardiogram and tests to check the function of your heart

PET/CT Scans  

The following procedures will also be done for research purposes:    
Research blood samples (about 7 tablespoons)
Research urine samples (about 2 ounces) 
Research bone marrow aspirate (about 2 teaspoons) 

DW-MRI (diffusion weighted whole body magnetic resonance imaging scans) is a scan 
that looks at the whole body.  Although it is a test that can be done routinely in the clinic, 
it is used right now as a research test for your disease.  Standard clinical operating 
procedures will be used for the test and image collection, and you and your doctors will 
receive the result of these imaging tests.  

Lenalidomide – Revlimid REMSTM Program Participation 
You have been informed of the risk of birth defects.  If you are female, you agree not to 
become pregnant while taking lenalidomide.  For this reason, lenalidomide is provided to 
patients under a special distribution program called REMS®.
In order to participate in this study, you must register into and follow the requirements of 
the REMS® program of Celgene Corporation.  This program provides education and 
counseling on the risks of fetal exposure, blood clots and reduced blood counts.  You will 
IRB NUMBER: 12C0107
IRB APPROVAL DATE: 08/10/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 07/18/2022
Page 4 of 29
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
be required to receive counseling every 28 days during treatment with lenalidomide, 
follow the pregnancy testing and birth control requirements of the program that are 
appropriate for you and take telephone surveys regarding your compliance with the 
program.
In order to obtain lenalidomide free of charge from Celgene, your name, address, phone, 
date of birth and the fact that you are participating in this trial will be disclosed to 
Celgene and its agents or vendors that supply lenalidomide and administer the REMS® 
program.  By signing this consent form you agree to this disclosure.
The study staff will provide you with more information about this program.  It is required 
of all patient who receive lenalidomide whether on or off a study.
The research blood, bone marrow aspirate, and urine samples are not mandatory. If you agree to 
donate extra blood, urine and bone marrow aspirate samples, you will be asked to give the 
additional following amounts at the time points listed in the Study Chart. The samples will be 
used for research purposes only unless otherwise noted.
The treatment consists of three drugs (carfilzomib, lenalidomide, and dexamethasone) for the 
first 8 cycles.  Each cycle lasts 28 days.  

Carfilzomib will be given through an IV (a tube inserted in your vein) for up to 30-
minutes on Days 1, 2, 8, 9, 15, and 16 of the 28-day cycle.  If you experience any adverse 
reactions while receiving Carfilzomib, the IV can be stopped. 

IV fluids will be administered with the carfilzomib treatment.  

Dexamethasone tablets or IV will be given on Days 1, 2, 8, 9, 15, 16, 22, and 23 of the 
28-day cycle.  

Lenalidomide oral tablets will be given from Days 1-21 of the 28-day cycle.  
After 4 cycles, if you are eligible for a transplant, you will be referred to a transplant center for 
collection of stem cells.  
After the completion of 8 cycles, if you achieve “stable disease” or better, you will continue on 
the extended dosing phase (part 1) for cycles 9-20.  During cycles 9-20, you will be given 
lenalidomide oral tablets days 1-21 of every 28-day cycle. If you choose to participate in part 2 
of the extended dosing phase, you will be given lenalidomide on days 1-21 of a 28-day cycle for 
cycles 21-32 (an additional 12 cycles of treatment). If you continue without progression after 32 
cycles and wish to continue “maintenance dosing” at an outside facility, this may be an option 
after discussion with your doctor.  If you do this, we may continue to follow you to see how you 
are doing for the study.  
You will be required to take aspirin or other medication to prevent blood clots while taking 
lenalidomide.  You will be required to take valacyclovir or acyclovir while taking carfilzomib to 
prevent infection by certain viruses.
Samples collected for research
The required and optional samples collected during this study may be used to help scientists 
understand how the study treatments work, or why they may cause side effects. These samples 
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Consent to Participate in a Clinical Research Study
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File in Section 4: Protocol Consent (1)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
may also help scientists to better understand your disease, and people may respond differently to 
treatment.
The results of tests done in these samples are only for research. They will not be used for your 
medical care.  They will not be used to make a diagnosis about your health. Therefore, these 
results will not be given to you or your study doctor.
What other tests will be done on my samples?
Your tissue (tumor and normal tissue) and blood that is collected will be used to look for specific 
changes in the DNA in tumors that could be used to develop new ways of diagnosing and 
treating cancer.   DNA (also called deoxyribonucleic acid) are the molecules inside cells that 
carry genetic information and pass it from one generation of cells to the next – like an instruction 
manual. Normal tissue contains the DNA (instructions) that you were born with, DNA in tumor 
cells has changed – or mutated – and we think that change in the DNA is what causes tumors to 
form and to grow.  In order to determine which parts of the DNA have mutated, we will compare 
the DNA in your tumor cells to DNA from your normal cells.  We will then analyze all of the 
results from similar tumors to see if there are any changes in the DNA that are common to a 
particular type of tumor.  In order to examine the tumor and normal tissue we may use several 
different techniques depending on the type of tissue we collect.  These could include growing 
cell lines (cells which keep dividing and growing in the laboratory, sometimes for years allowing 
us to continually study those cells) and looking in great detail at the parts of the genes that 
produce specific proteins.  When we are examining these pieces of your DNA, it is possible that 
we could identify possible changes in other parts of your DNA that are not related to this 
research.  These are known as “incidental medical findings”. 
These include: 

Changes in genes that are related to diseases other than cancer 

Changes in genes that are not known to cause any disease. These are known as normal 
variations. 

Changes in genes that are new and of uncertain clinical importance. This means that we 
do not know if they could cause or contribute to a disease or if they are normal variations. 
However, the analyses that we perform in our laboratory are for research purposes only; they are 
not nearly as sensitive as the tests that are performed in a laboratory that is certified to perform 
genetic testing. Changes that we observe unrelated to our research may or may not be valid.  
Therefore, we do not plan to inform you of the results of testing on your tissue and blood that is 
performed in our research lab.  However, in the unlikely event that we discover a finding 
believed to be clinically important based on medical standards at the time we first analyze your 
results, we will contact you. This could be many years in the future.   . If you want this to be 
done, we will draw an additional blood sample and send it for confirmatory testing. Once the 
results are available, if you would like to receive your results, we will offer to have you come to 
NIH (at our expense) to have genetic education and counseling to explain this result. If you do 
not want to come to NIH, we will help you find a local genetic healthcare provider who can 
explain it to you (at your expense).
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
If you are not contacted, you should not assume that you do not have any gene variants that 
might be related to a disease.
Who else besides the investigators on this study will know the results of my sample testing?
Once we obtain any of the samples listed above, the investigators take all your personal 
information off those samples and label them with a study code number.  Only the investigators 
on this study know who the sample came from.  The key linking your personal information with 
the code number is kept in a secure computer data base, with access only to the few research 
staff who will be discussing this study with you.  Once the sample has been labeled with a code, 
it is sent to a variety of NIH laboratories for storage and testing.  No one testing your samples 
will be able to link the results to you personally.  Specimens obtained during your participation 
in this study may be sent for testing to investigators outside of NCI or the NIH.  All samples will 
be coded to protect your privacy and no personal information will be included.  Other 
investigators on this study will have access to limited clinical and biologic data such as age, 
gender and disease status.
How long will your samples be stored?
The samples collected during this study will be stored for as long as the study is open.  When this 
study is closed, we will keep the samples for future research.
When you are finished taking the drugs (treatment)
After you complete the treatment portion of the study, you will return to the Clinical Center for 
follow-up visits about 30 days after the last dose (this may be done by phone if you cannot return 
to clinic, this visit is to check for symptoms and toxicities only) and then every 3-6 months as 
long as you are participating in the study. Follow-up visits will consist of routine labs and clinic 
visit with history and physical exam.  If your disease comes back or worsens, we may ask you to 
have optional research bone marrow biopsy and/or FDG-PET. 
You may have follow-up visits at more frequent intervals if your doctors and the study team feel 
it is needed.
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
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File in Section 4: Protocol Consent (1)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Study Chart
Before Starting Treatment
Completed 4 
weeks prior to 
starting 
treatment unless 
specified
Sign informed consent
Physical exam
Blood work (including research blood work if you choose to donate)
Urine collection (including urine research sample if you choose to donate)
24 hour-urine sample may be required (you will be notified if this applies to 
you)
Bone marrow biopsy and aspirate to assess the status of your smoldering 
myeloma
Echocardiogram (to check the function of your heart)
Register for the REMS Program
Urine or blood pregnancy tests in women of child bearing potential 
(performed 10-14 days prior to receiving prescription for lenalidomide)
Bone series (X-rays of all of your bones) and MRI (if needed)
Research FDG-PET and/or DW-MRI (if you choose to participate)

Cycle 1
Day 1 and 2
Receive infusion of intravenous fluid and Day 1 and Day 2 carfilzomib
Begin oral lenalidomide and continue from day 1-21
Routine blood work 
Receive oral/IV dexamethasone
Urine or blood pregnancy test in women of child bearing potential 
(performed within 24 hours of receiving prescription for lenalidomide)
Day 8 and 9 
Receive infusion of optional intravenous fluid and Day 8 and 9 carfilzomib
Receive oral/IV dexamethasone
Routine blood work and on Day 8: optional research blood and urine if you 
choose to donate
Day 15 and 16
Receive infusion of optional intravenous fluid and Day 15 and 16 
carfilzomib
Receive oral/IV dexamethasone
Routine blood work and on day 15: optional research blood and urine if you 
choose to donate
Day 21
Stop lenalidomide after taking Day 21 dose
Day 22 and 23
Receive oral/IV dexamethasone
Routine blood work
Day 28
Finish cycle 1
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Cycles 2-8 
Day 1 and 2
Receive infusion of optional intravenous fluid and carfilzomib
Receive oral/IV dexamethasone
Begin oral lenalidomide and continue from day 1-21
Routine blood work and optional research blood if you choose to donate 
(Day 1 only)
Routine and optional research urine if you choose to donate (Day 1 only)
Urine or blood pregnancy test in women of child bearing potential (Day 
1 only)

Day 8 and 9 
Receive infusion of optional intravenous fluid and Day 8 and 9 
carfilzomib
Receive oral/IV dexamethasone
Day 15 and 16
Receive infusion of optional intravenous fluid and Day 15 and 16 
carfilzomib
Receive oral/IV dexamethasone
Day 21
Stop lenalidomide after taking Day 21 dose
Day 22 and 23
Receive oral/IV dexamethasone
Day 28
Finish cycle 
After 4 cycles
Transplant eligible participants will undergo evaluation at transplant 
center for stem cell collection
Any point that 
complete remission 
is achieved or at the 
end of 8 cycles
Optional research blood, urine and bone marrow biopsy and aspirate if 
you choose to donate
Optional FDG-PET and/or DW-MRI will be performed on whole body 
imaging if you choose to participate
Cycles 9 and beyond 
Day 1 of every 
third cycle
Routine and optional research blood work if you choose to donate
Routine and optional research urine if you choose to donate 
Urine or blood pregnancy test in women of child bearing potential
Start lenalidomide and continue days 1-21
Optional research blood and urine work if you choose to donate

Day 21 
Stop lenalidomide after taking Day 21 dose
Day 28 
Finish cycle
Any point that 
complete 
remission is 
achieved or at 
the end of cycle 
20/ cycle 32 if 
participating in 
Optional research blood, urine and bone marrow biopsy and aspirate if you 
choose to donate
Optional FDG-PET and/or DW-MRI will be performed on whole body if 
you choose to participate
If at any point you stop treatment, we may also try to complete an in-person 
clinic visit about 30 days after stopping drug to check for symptoms and side 
effects.
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File in Section 4: Protocol Consent (1)
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extended 
dosing part 2, 
and beyond 32 
cycles
Additionally, we will continue these same optional research tests and 
assessments about every 3-6 months during follow-up if you continue 
without progression beyond 32 cycles; these will then be repeated if you 
experience progression of your disease.
What does this study involve?
Pregnancy Risk
Lenalidomide is related to thalidomide.  Thalidomide is known to cause severe life-threatening 
human birth defects.  Preliminary findings from a monkey study appear to indicate that 
lenalidomide caused birth defects in the offspring of female monkeys who received the drug 
during pregnancy.  If lenalidomide is taken during pregnancy, it may cause birth defects or death 
to an unborn baby.  The effects of carfilzomib are unknown.  
Females must not become pregnant while taking lenalidomide or carfilzomib.  If you are female, 
you agree not to become pregnant while taking lenalidomide or carfilzomib.  The study drugs 
may also be present in the semen of men.  Men must agree not to father a child while taking 
lenalidomide or carfilzomib.  Because of the risk of birth defects, all patients taking lenalidomide 
and/or carfilzomib must read the following statements that apply to them according to gender 
and menopausal status.
Pregnancy Risk – Females:
If you are a female of childbearing potential*, you will be required to have negative pregnancy 
tests throughout treatment: the first test within 10-14 days before lenalidomide is prescribed, the 
second test within 24 hours before lenalidomide is prescribed and then every 14-28 days while 
receiving lenalidomide treatment. 
*For the purposes of this study, a female of childbearing potential is a sexually mature 
female who: 1) has not undergone a hysterectomy (the surgical removal of the uterus) or 
bilateral oophorectomy (the surgical removal of both ovaries) or 2) has not been naturally 
postmenopausal for at least 24 consecutive months (i.e., has had menses at any time during 
the preceding 24 consecutive months).
You will be required to use TWO reliable forms of birth control, one highly effective method 
and one additional effective method at the same time or 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) while participating in this study; and 3) for at least 28 days 
the last dose of lenalidomide or 30 days after the last dose of carfilzomib (whichever is later).   
The following are the acceptable birth control methods:
Highly Effective Methods

Intrauterine device (IUD) 

Hormonal (birth control pills, injections, implants)

Tubal ligation 

Partner’s vasectomy
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File in Section 4: Protocol Consent (1)
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Additional Effective Methods

Latex condom

Diaphragm

Cervical Cap
You must not breastfeed a baby while you are participating in this study treatment and for at 
least 28 days after you have been discontinued from the study. 
If you have any reason to suspect you are pregnant, you must IMMEDIATELY stop taking 
lenalidomide and tell your doctor.  
Pregnancy Risk – Males: 
Lenalidomide is detected in trace quantities in human semen according to a study.  The risk to 
the fetus in females of child bearing potential whose male partner is receiving lenalidomide or 
carfilzomib is unknown at this time.  For these reasons male patients receiving lenalidomide 
and/or carfilzomib must use a latex condom during any sexual contact with a pregnant female or 
with a female of childbearing potential while you are participating in this study treatment and for 
at least 28 days after the last dose of lenalidomide or 90 days after the last dose of carfilzomib 
(whichever is later), even if you have had a successful vasectomy.  You must NEVER donate 
blood, sperm, or semen while you are participating in this study treatment and for at least 28 
days after the last dose of lenalidomide or 90 days after the last dose of carfilzomib (whichever is 
later).
IMPORTANT – All patients receiving lenalidomide:
You must NEVER share lenalidomide (or other study drugs) with someone else. You must 
NEVER donate blood while you are participating in this study treatment and for at least 28 days 
after you have been discontinued from the study.  You must receive counseling and complete 
phone surveys as required by the REMS® program.
Once it is determined that you are eligible for the study and you agree to receive treatment, you 
will begin therapy as described below:

Swallow lenalidomide capsules whole with water at the same time each day.  Do not 
break, chew or open the capsules.  

If you miss a dose of lenalidomide, take it as soon as you remember on the same day. 

If you miss taking your dose for the entire day, take your regular dose the next 
scheduled day (do NOT take double your regular dose to make up for the missed 
dose).  

If you take more than the prescribed dose of lenalidomide you should seek 
emergency medical care if needed and contact study staff immediately.
Females of childbearing potential that might be caring for you should not touch the lenalidomide 
capsules or bottles unless they are wearing gloves.
Any unused Revlimid® (lenalidomide) should be returned as instructed through the REMS® 
program.
IRB NUMBER: 12C0107
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RISKS OR DISCOMFORTS OF PARTICIPATION
What side effects or risks can I expect from being in this study?
Everyone taking part in the study will be watched carefully for any side effects. You should talk 
to your study doctor about any side effects that you have while taking part in the study. 
Carfilzomib
Carfilzomib (Kyprolis) is approved by the U.S. Food and Drug Administration (FDA) to be used 
only in certain U.S. patients with relapsed and refractory multiple myeloma that have tried and 
failed other therapies. It has not been approved to be used for any other disease or condition. In 
this study, carfilzomib is an investigational study drug because it is not approved for use in all 
patients in the United States, and it is not approved by some regulatory authorities (the agencies 
that are responsible for approving the use of a medicine in a country such as the European 
Medicines Agency and Health Canada). You will be told about the known risks, which are the 
side effects reported previously by others who took carfilzomib. However, your doctors do not 
know all the side effects that you may experience. As with all investigational drugs, all risks may 
not have been identified at this time. There may be serious unexpected or unforeseen risks while 
taking carfilzomib, including death. It is known that nearly everyone who takes carfilzomib will 
have some side effects while on the drug. Many of these side effects may be mild but some side 
effects can be serious and even fatal. 
Everyone taking part in the study will be watched carefully for any side effects. You should talk 
to your study doctor about any side effects that you have while taking part in the study. 
If side effects occur, your health care team may give you medicines to help lessen side effects. 
Your doctor may have you stop taking carfilzomib or take a lower dose of carfilzomib because of 
the side effects, or the side effects may go away on their own even if you continue to take 
carfilzomib. 
As of April 2020, approximately 6,582 people have received carfilzomib in research studies. 
Since it was approved for sale, approximately 128,000 people have been prescribed Carfilzomib 
(Kyprolis) for treatment. 
Before you take carfilzomib, your doctor needs to know if you have any:

Heart problems, including a history of chest pain (angina), heart attack, heart failure, high 
blood pressure, irregular heartbeat, or if you have ever taken a medicine for your heart

Lung problems, including a history of shortness of breath (dyspnea) at rest or with 
activity 

Kidney problems, including kidney failure or if you have ever received dialysis

Liver problems, including a history of hepatitis; particularly previous hepatitis B virus 
infection, fatty liver, or if you have ever been told your liver is not working properly

Unusual bleeding, including easy bruising or bleeding from an injury, such as a cut that 
does not stop bleeding in a normal amount of time, which can indicate you have low 
platelets

Blood clots in your veins
IRB NUMBER: 12C0107
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
Any other major disease for which you were hospitalized or received medication
Talk to your doctor or nurse if any of these apply to you before using carfilzomib.  You may 
need extra tests to check that your heart, kidneys and liver are working properly.
Very Common (may affect more than 1 in 10 people who receive carfilzomib):

Anemia (decreased red blood cell count which may lead to feeling tired)

Neutropenia (decreased white blood cell counts which may lead to a decreased ability to 
fight infection

Shortness of breath (at rest or with exertion) which in rare cases may be life-threatening or 
resulting in death 

Cough, including cough with phlegm

Diarrhea

Nausea

Constipation

Vomiting 

Fatigue (tiredness)

Fever 

Swelling of hands, feet or ankles

General weakness (lack of energy or strength)

Respiratory tract infection

Pneumonia 

Bronchitis

Inflammation of the nose and throat

Loss or decrease in appetite

Back pain and/or joint pain

Pain in limbs, hands or feet

Muscle spasms

Headache

Dizziness

Numbness

Insomnia (difficulty sleeping)

Changes to blood tests (decreased blood levels of potassium, increased blood levels of 
sugar and/or creatinine)

Hypertension (high blood pressure)
IRB NUMBER: 12C0107
IRB APPROVAL DATE: 08/10/2022


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Common (may affect up to 1 in 10 people who receive carfilzomib):

Fever associated with low white blood cell count

Heart failure and heart problems including arrhythmias

Heart attack

Blood clot in the lungs

Increased levels of blood sugar  

Fluid in the lungs 

Nose bleed 

Change in voice or hoarseness

Pain in throat

Wheezing

Pulmonary hypertension (see ‘Conditions you need to look out for’)

Blurred or double vision

Cataract 

Stomach pain

Indigestion

Toothache

Chills or feeling too hot, increased sweating

Generalized pain 

Feeling unwell

Liver problems including an increase in your liver enzyme in the blood

Abdominal pain, discomfort, or swelling 

Sore throat 

Runny nose or nasal congestions

Urinary tract infection 

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. 

Serious infection in the blood (sepsis)

Viral infection

Infection and/or irritation of your stomach and bowels 

Lung infection

Dehydration

Pain in the bones and muscles 

Chest pain

Muscle weakness
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
Muscle aching

Abnormal sensation, such as tingling or decreased sensation in hands and/or feet

Anxiety 

Kidney problems, including decreased ability to make urine, increased creatinine in the 
blood, and kidney failure which can lead to dialysis 

Rash and/or itching of the skin, redness of the skin

Changes to blood tests (decreased blood levels of sodium, magnesium, protein, calcium or 
phosphate, increased blood levels of calcium, uric acid, bilirubin, or c-reactive protein)

Hypotension (low blood pressure)

Blood clots in the veins

Flushing

Ringing in the ears (tinnitus)

Infusion reactions (see ‘Conditions you need to look out for’)
Uncommon and rare (may affect less than 1 in 100 people who receive carfilzomib):

Thrombotic microangiopathy (TMA):  damage to the smallest blood vessels inside many 
organs, most commonly the kidneys and brain. 

Thrombocytopenia (decreased platelet count which may lead to bleeding or 
bruising)Sudden loss of heart function

Reduced blood flow to the heart

Abnormal amount of fluid between the heart and the lining around the heart

Heart muscle disease which may cause shortness of breath and tiredness

Lung Problems (see ‘Conditions you need to look out for’)

Bleeding in the lungs

Bleeding in the stomach and bowels

Multi-organ failure 

Worsening liver function up to and including liver failure

Cholestasis, including itchy skin, yellow skin, very dark urine, and very pale stools which 
may be caused by a blockage in the flow of bile from the liver

Severe infection of the blood causing low blood pressure and low blood flow to the 
different organs

Hepatitis B Virus (HBV) Reactivation: the reappearance or rise of HBV in patients who 
previously had the virus (see ‘Conditions you need to look out for’)

Tumor lysis syndrome (TLS) (see ‘Conditions you need to look out for’)

Bleeding in the brain 

Posterior reversible encephalopathy syndrome (PRES):  serious disorder of the brain which 
often includes symptoms of headache, confusion, seizures, visual loss, and high blood 
pressure (hypertension)
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
Allergy to carfilzomib

Stroke

Bleeding

Extremely high blood pressure (see ‘Conditions you need to look out for’)

Inflammation of the pancreas gland (see ‘Conditions you need to look out for’)

Blockage of the intestines
Very rare (may affect up to 1 in 1000 people who receive carfilzomib):

Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/HUS): 
serious disorders that involve the formation of small blood clots throughout the body that 
block the flow of blood to vital organs such as the brain, heart, and kidneys 

Swelling and irritation of the lining around the heart 

Swelling of the throat

Hole in the stomach, large intestine, or large bowel 

Infection of the back of the eye (cytomegalovirus)

Progressive Multifocal Leukoencephalopathy (PML): inflammation of the brain.
The following side effects have been seen in people who received carfilzomib.  It is unknown if 
they were caused by carfilzomib, you may or may not experience these side effects:

Tiredness, infection, and easy bruising or bleeding which may be symptoms of a blood 
condition known as Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML).

Tenderness of pain in the abdomen that gets more intense with motion or touch, 
abdominal bloating or distention, nausea and vomiting, diarrhea, constipation or the 
inability to pass gas which may be symptoms of swelling of the thin tissue that lines the 
inner wall of the abdomen and covers most of the abdominal organs.
You should seek medical care immediately if you develop any of the following symptoms: 
severe shortness of breath, chest pain, fevers, chills, shaking with fever, vomiting, muscle 
weakness or cramping, seizures, fainting and/or significantly decreased urine output. 
Additional side effects of carfilzomib:

Driving and Using Machines:  You may experience fatigue, dizziness, fainting, and/or a 
drop in blood pressure after treatment with carfilzomib.  This may impair your ability to 
drive or operate machinery.  If you have these symptoms, you should not drive a car or 
operate machinery.

Hydration Risks (Prevention of TLS):  There may be risks associated with over 
hydrating (having too much fluid in your body) so it is important to follow your doctor’s 
instructions regarding how much water or other fluids you should drink. Over hydration 
may negatively affect the heart, lungs, and kidneys. 
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Conditions you need to look out for:
You must look out for certain symptoms while you are taking carfilzomib to reduce the risk of 
problems. Carfilzomib can make some conditions worse or cause serious side effects. 
Carfilzomib may cause all, some, or none of the side effects listed below.  There may also be 
unknown side effects from taking carfilzomib alone or with other drugs you may be taking. Tell 
your doctor or nurse as soon as possible if you get any of these:

Chest pains, shortness of breath, or if there is swelling of your ankles and feet, which 
may be symptoms of heart problems

Difficulty breathing, including shortness of breath (dyspnea) at rest or with activity or a 
cough, rapid breathing, feeling like you can't breathe in enough air, wheezing, or cough, 
which can be signs of lung problems

Extremely high blood pressure, severe chest pain, severe headache, confusion, blurred 
vision, nausea and vomiting, or severe anxiety, which may be signs of a condition known 
as hypertensive crisis

Shortness of breath with everyday activities or at rest, irregular heartbeat, racing pulse, 
tiredness, dizziness, and fainting spells, which can be signs of a condition known as 
pulmonary hypertension  

Swollen ankles, feet or hands, loss of appetite, passing less urine, or abnormal blood test 
results, which may be symptoms of kidney problems or kidney failure

Irregular heartbeat, kidney failure or abnormal blood test results which may be associated 
with Tumor Lysis Syndrome, which can be caused by the rapid breakdown of tumor 
cells.

A reaction to carfilzomib infusion, which can include the following symptoms: fever, 
chills or shaking, joint pain, muscle pain, facial flushing or swelling, swelling of the 
throat, weakness, shortness of breath, low blood pressure, fainting, chest tightness, or 
chest pain

Unusual bruising or bleeding, such as a cut that does not stop bleeding in a normal 
amount of time

Leg pain (which could be a symptom of blood clots in the deep veins of the leg), chest 
pain or shortness of breath (which may be a symptom of blood clots in the lungs)

Yellowing of your skin and eyes (jaundice), abdominal pain or swelling, nausea or 
vomiting, which could be signs of liver problems, including liver failure.

Bleeding, bruising, weakness, confusion, fever, nausea, vomiting and diarrhea, and acute 
kidney failure, which may be signs of blood conditions known as Thrombotic 
Microangiopathy or TMA (including Thrombotic Thrombocytopenic Purpura/Hemolytic 
Uremic Syndrome (TTP/HUS). 

Headaches, confusion, seizures, blindness, and high blood pressure (hypertension), which 
may be symptoms of a neurologic condition known as Posterior Reversible 
Encephalopathy Syndrome (PRES).
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
Blurred or double vision, vision loss, difficulty speaking, weakness in an arm or a leg, a 
change in the way you walk, problems with your balance, persistent numbness, decreased 
sensation or loss of sensation, decreased alertness, memory loss or confusion which may 
be symptoms of a central nervous system infection known as Progressive Multifocal 
Leukoencephalopathy (PML).

Persistent upper abdominal pain, fever, rapid pulse, nausea, vomiting, and tenderness 
when touching your abdomen (Acute Pancreatitis).
Lenalidomide
Lenalidomide has been studied in healthy volunteers and in patients with cancer of the blood and 
other organs of the body and in patients with other diseases.  As with any other experimental 
treatment there may be side effects or risks associated with lenalidomide, some of which are not 
yet known.  Everyone taking part in the study will be watched carefully for any side effects.  
Listed below are the side effects reported by approximately 11,552 patients who have 
participated in previous and ongoing clinical studies involving lenalidomide (as of December 26, 
2019).  These events were considered by the study doctors to be related to lenalidomide.  Side 
effects may be mild to very severe.  Side effects listed below are grouped as follows:  side effects 
of any grade which occurred in 10% or more of patients and serious side effects that occurred in 
1% or more of patients.  Serious is defined as side effects that; require in-patient hospitalization, 
cause persistent or significant disability, are life-threatening or in some cases fatal, or important 
medical events.

Likely (occurring in ≥ 10% of patients):

Fatigue or feeling tired 

Anemia or a decrease in red blood cells that can cause tiredness

Neutropenia (decreased white blood cell counts which may lead to a decreased ability to 
fight infection) 

Neutropenia associated with a fever

Leukopenia or a low white blood cell count 

Thrombocytopenia or a decrease in platelets which can cause you to bruise or bleed easily

Cataract 

Blurred vision 

Abdominal pain

Constipation or difficulty moving your bowels 

Diarrhea or loose/frequent bowel movements 

Dry mouth

Indigestion

Nausea 

Vomiting 

Chills 
IRB NUMBER: 12C0107
IRB APPROVAL DATE: 08/10/2022


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
Decreased or loss of appetite 

Weight loss 

Dehydration

Back pain 

Bone and joint pain 

Muscle pain, cramps, spasms, and weakness 

Tumor flare (inflammation of the tumor)

Swelling of the arms and legs 

Problems falling asleep or staying asleep 

Fever 

Abnormal liver function tests 

Bronchitis

Gastroenteritis or inflammation of the stomach and bowels

Influenza 

Cough 

Inflammation of the mouth, nose, throat and sinuses  

Nosebleed

Pneumonia or an infection of the lungs

Shortness of breath or difficulty catching your breath

Upper respiratory infection 

Urinary tract infection 

Rash

Itching and dry skin

General weakness (lack of energy or strength) 

Dizziness

Headache

Altered sense of taste

High or low blood pressure

Numbness, tingling, burning or prickling sensation  

Lymphopenia (decreased white blood cells that fight infection) 

Abnormal blood lab values such as high or low sugar, low calcium, low potassium, and/or 
low sodium 

Tremors

Changes in mood 

Kidney failure
IRB NUMBER: 12C0107
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
Pulmonary embolism (PE; blood clot in or around the lungs) 

Deep vein thrombosis (DVT; blood clot in a large blood vessel)
Less Likely (occurring in ≥ 1% of patients):

Hemolytic anemia: a disorder in which red blood cells are destroyed faster than they can 
be made

Heart failure and heart problems including rapid or irregular heartbeat 

Heart attack

Decreased oxygen to the heart muscle 

Atrial fibrillation 

Bleeding in the stomach and bowels 

Bowel obstruction 

Toothache

Chest pain 

Gall bladder blockage

Liver damage 

Infections and inflammations

Herpes or shingles 

Meningitis

Progression of the disease being studied 

Sepsis or an infection of the blood

Confusion

Falling 

Diabetes mellitus 

Gout

Abnormal blood levels such as high calcium, high uric acid, low phosphate, and/or low 
magnesium 

Iron overload

Tumor lysis syndrome: a metabolic complication that can occur during or without 
treatment of cancer. These complications are caused by the break-down products of dying 
cancer cells and include high potassium, high phosphorus, high uric acid in blood and urine, 
low calcium, and consequent kidney damage.

Fainting 

Night sweats

Bruising 
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Rare (occurring in < 1% of patients):

Delayed reaction causing severe rash, fever, facial swelling, or enlarged lymph nodes

High or low thyroid hormone  

Angioedema or an allergic skin disease characterized by patches of swelling involving the 
skin and/or the lining of your nose, mouth, and gastrointestinal tract

Stevens-Johnson syndrome and toxic epidermal necrolysis: serious allergic skin reactions 
that begin as a rash in one area and later cover more of the body leading to detachment of 
the top layer of skin (could be body-wide). 

Progressive Multifocal Leukoencephalopathy (PML): inflammation of the brain

Hepatitis B Reactivation 

Rhabdomyolysis: a serious condition involving destruction of skeletal muscle that can lead 
to kidney failure.  Signs and symptoms include dark, red or cola colored urine, muscle 
tenderness and stiffness, aching (myalgia) or weakness.
Other Risks related to Lenalidomide

Digoxin levels:  Lenalidomide has been shown to increase the level of digoxin in the 
blood in some patients.  Please tell your doctor if you are taking digoxin.

Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE):  Lenalidomide has 
demonstrated an increased risk of deep vein thrombosis (blood clots in larger blood 
vessels) and pulmonary embolism (a blood clot in or around the lungs) in some people 
with certain medical conditions.  The study staff will ask you about any health conditions 
you may have that may increase your chance of developing blood clots.  The risk of 
blood clots may also be increased when lenalidomide is combined with other drugs 
known to cause blood clots such as steroids, other forms of cancer drugs, hormone 
replacement therapy, birth control pills and erythropoietin (a drug given to help increase 
the red cell count).  You should let your doctor know if you take birth control pills or 
hormone replacement therapy.  You may be asked to take a blood thinner such as aspirin 
if your doctor feels that you are at increased risk for blood clots.  If your platelet count 
becomes low, the blood thinners may need to be stopped temporarily.  You will be 
instructed on the signs and symptoms of DVT and PE, including shortness of breath, 
chest pain or swelling of the arm and or leg, and if symptoms of DVT or PE occur you 
should contact your study doctor, healthcare provider or get emergency medical care 
promptly.

Second Primary Malignancies (SPM):  Higher incidences of SPM were observed in 
controlled trials of patients with multiple myeloma receiving lenalidomide.  Patients with 
multiple myeloma treated with lenalidomide in studies including melphalan and stem cell 
transplantation had a 5.2-8% higher incidence of second primary malignancies, 
particularly acute myelogenous leukemia (AML) and Hodgkin lymphoma, compared to 
patients in the control arms who received similar therapy but did not receive 
lenalidomide. However, the risk of SPM following treatment with extended lenalidomide 
(and without melphalan) is unknown. Your doctor will monitor for the development of 
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second malignancies. You and your doctor should take into account both the potential 
benefit of lenalidomide and the risk of second primary malignancies when considering 
treatment with lenalidomide.
Dexamethasone
Likely:

High blood pressure

High blood glucose

Stomach upset

Burning in stomach from excess stomach acid

Increased risk of infection

Increased appetite 

Weight gain

Thinning of bones 

Increase pressure in eyes

Personality changes, e.g., irritability, euphoria, mania

Feelings of depression

Pulmonary tuberculosis

Vision problems

Acne, allergic dermatitis, dry scaly skin
Other risks associated with this study:

Blood draws: Side effects of drawing blood include pain and bruising in the area where 
the blood was drawn, lightheadedness, or rarely fainting due to transient lowering of 
blood pressure. If you feel dizzy, you should lie down for a few minutes to avoid hurting 
yourself if you fall. Infection at the blood-drawing site could also occur. 

Intravenous Catheter: In order to receive this treatment, you may need to have a central 
venous catheter.  This catheter is placed under the skin of the chest wall and enters a 
major vein in the chest.  There are several types of catheters including those which must 
be removed after each cycle of chemotherapy (temporary type) and those which may be 
kept for the duration of therapy (permanent type).  These options will be discussed with 
you.  The risks associated with placing some catheters include pain, bleeding, infection 
and collapsed lung.  The long-term risks of the catheter include infection, and clotting of 
your veins.  If these occur, it may be necessary to remove the catheter.  These risks will 
be explained to you in more detail at the time of insertion.

Bone marrow aspiration and biopsy: Bone marrow biopsy procedure entails having an 
area in the back of your hip numbed with a local anesthetic, and a large bone marrow 
needle inserted into the hipbone. Bone marrow aspirate is obtained, and a core biopsy is 
obtained.  You may feel a pressure sensation when the needle is being inserted and a 
pulling sensation and brief discomfort as the marrow is withdrawn. The amount of 
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marrow taken is very small and will not change your body's ability to form blood cells. 
Potential complications of this procedure are local bleeding, pain at the site, infection, 
and allergy to the local anesthetic. Bleeding can be stopped by applying local pressure 
and an infection can be treated with antibiotics.  You may have some soreness at the site 
for a day or so after the procedure.

PET/CT and DW-MRI scans:  The discomfort involved with this study is related to the 
PET/CT and/ or DW-MRI scans.  The PET/CT examination discomforts include the 
placement of an intravenous line and the necessity to remain still on your back for 30 
minutes.  The DW-MRI scan requires you to remain still on your back for about 1½ 
hours.  Even though adverse side effects are not anticipated, you should tell the doctors or 
nurses supervising the scan of any discomfort you experience during the scans.

Radiation Exposure: During your participation in this research study, you will be exposed 
to radiation from three FDG PET/CT scans.  The amount of radiation exposure you will 
receive from these procedures is equal to approximately 3.6 rem. A rem is a unit of 
absorbed radiation.  
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them.  The average person in the United States receives a radiation 
exposure of 0.3 rem per year from these sources.  This type of radiation is called 
“background radiation.”  No one knows for sure whether exposure to these low amounts 
of radiation is harmful to your body. 
The FDG PET/CT scans that you get in this study will expose you to the roughly the same 
amount of radiation as 12 years’ worth of background radiation.  Most of the time, this 
amount of extra radiation is not harmful to you.  However, scientists believe that being 
exposed to too much radiation can cause harmful side effects.  This could include getting 
a new cancer.  We estimate that this could happen in about 1 out of every 1000 people who 
get a very large amount of extra radiation. 
o
Radiation risk associated with pregnancy: You may not participate in this study 
if you are pregnant. If you are able to become pregnant, we will perform a 
pregnancy test before exposing you to radiation. You must tell us if you may have 
become pregnant within the previous 14 days because the pregnancy test is 
unreliable during that time.
PSYCHOLOGICAL OR SOCIAL RISKS ASSOCIATED WITH LOSS OF PRIVACY 
Privacy Risks Associated with Genetic Testing
It may be possible that genetic information from you could be used by law enforcement agencies 
or other entities to identify you or your blood relatives.
Psychological or Social Risks Associated with Return of Incidental or Secondary Findings
As part of the research study, it is possible that you could learn that you have genetic risks for 
another disease or disability. This may be upsetting and, depending on what you learn, might create 
a need to make challenging decisions about how to respond. 
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Although your genomic information is unique to you, you share some genomic similarities with 
your children, parents, brothers, sisters, and other blood relatives. Therefore, learning your 
research results could mean something about your family members and might cause you or your 
family distress. Before joining the study, it may be beneficial to talk with your family members 
about whether and how they want you to share your results with them. 
Protections against misuse of genetic information 
This study involves genetic testing on samples.  Some genetic information can help predict future 
health problems of you and your family and this information might be of interest to your employers 
or insurers. The Genetic Information Nondiscrimination Act (GINA) is a federal law that prohibits 
plans and health insurers from requesting genetic information or using genetic information. It also 
prohibits employment discrimination based on your health information. However, GINA does not 
address discrimination by companies that sell life insurance, disability insurance, or long-term care 
insurance. GINA also does not protect you against discrimination based on an already-diagnosed 
condition or disease that has a genetic component. 
POTENTIAL BENEFITS OF PARTICIPATION
Are there benefits to taking part in this study? 
The aim of this study is to see if this experimental combination of carfilzomib, lenalidomide, and 
dexamethasone will cause your tumors to shrink. We do not know if you will receive personal, 
medical benefit from taking part in this study. These potential benefits could include shrinking of 
your tumor or lessening of your symptoms, such as pain, that are caused by the cancer.  Because 
there is not much information about the drug’s effect on your cancer, we do not know if you will 
benefit from taking part in this study, although the knowledge gained from this study may help 
others in the future who have cancer.
ALTERNATIVE APPROACHES OR TREATMENTS
What other choices do I have if I do not take part in this study? 
Instead of being in this study, you have these options:

Getting treatment or care for your cancer without being in a study

Taking part in another study

Being followed closely by your doctor for signs and symptoms of progression to multiple 
myeloma. If/when that happens, you could begin treatment for your myeloma

Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat 
the cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible.
Please talk to your doctor about these and other options.
STOPPING THERAPY 
Your doctor may decide to stop your therapy for the following reasons:

if he/she believes that it is in your best interest
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
if your disease worsens or comes back during treatment

if you have side effects from the treatment that your doctor thinks are too severe

if new information shows that another treatment would be better for you
In any case, you will be informed of the reason therapy is being stopped.
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to Celgene Corporation and 
Amgen, Inc. or designated representatives. If you withdraw your consent and leave the trial, 
any samples of yours that have been obtained for the study and stored at the NCI can be 
destroyed upon request. However, any samples and data generated from the samples that have 
already been distributed to other researchers or placed in the research databases cannot be 
recalled and destroyed.
CONFLICT OF INTEREST (COI)
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a COI Guide. You may ask your research team for a copy 
of the Protocol Review Guide or for more information. Members of the research team who do 
not work for NIH are expected to follow these guidelines but they do not need to report their 
personal finances to the NIH.
The National Institutes of Health and the research team for this study are using Carfilzomib 
developed by Amgen, Inc. and Lenalidomide developed by Celgene Inc., through a joint study 
with your researchers and the company.  The companies also provide financial support for this 
study.
OPTIONAL BIOPSY AND RESEARCH SAMPLES
You do not have to give the optional research samples in order to participate in this trial. The 
samples may include blood, urine, and bone marrow aspirate and/or biopsy samples.  Although 
samples for your regular care may be taken at the same time and you will receive those results, 
the results from any samples taken or analyzed exclusively for research purposes will not benefit 
you.  They might help other people in the future.  Even if you agree to provide the optional 
samples now, you can change your mind at any time.  The decision to participate in this part of 
the research is optional, and no matter what you decide to do, it will not affect your care. 
The study staff will ask you about your willingness to give the optional research samples, and 
will document your decision in the medical record.  If you agree to have the optional biopsies, 
you will be asked to sign a separate procedure consent document prior to the biopsy.  
USE OF SPECIMENS AND DATA FOR FUTURE RESEARCH 
To advance science, it is helpful for researchers to share information they get from studying human 
samples.  They do this by putting it into one or more scientific databases, where it is stored along 
with information from other studies. A researcher who wants to study the information must apply 
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to the database and be approved.  Researchers use specimens and data stored in scientific databases 
to advance science and learn about health and disease.  
We plan to keep some of your specimens and data that we collect and use them for future research 
and share them with other researchers. We will not contact you to ask about each of these future 
uses.  These specimens and data will be stripped of identifiers such as name, address or account 
number, so that they may be used for future research on any topic and shared broadly for research 
purposes. Your specimens and data will be used for research purposes only and will not benefit 
you.  It is also possible that the stored specimens and data may never be used.  Results of research 
done on your specimens and data will not be available to you or your doctor.  It might help people 
who have cancer and other diseases in the future.  
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data. Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers.
Genomic Data Sharing
As part of this research study, we will put your genomic data in a large database for broad sharing 
with the research community. These databases are commonly called data repositories. The 
information in this database will include but is not limited to genetic information, race and 
ethnicity, and sex.  If your individual data are placed in one of these repositories, they will be 
labeled with a code and not with your name or other information that could be used to easily 
identify you, and only qualified researchers will be able to access them. These researchers must 
receive prior approval from individuals or committees with authority to determine whether these 
researchers can access the data.
Summary information about all of the participants included in this study (including you) is being 
placed in a database and will be available through open access. That means that researchers and 
non-researchers will be able to access summary information about all the participants included in 
the study, or summary information combined from multiple studies, without applying for 
permission. The risk of anyone identifying you with this information is very low.
NIH policies require that genomic data be placed in a repository for sharing. Therefore, we cannot 
offer you a choice of whether your data will be shared.  If you do not wish to have your data placed 
in a repository, you should not enroll in this study.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines.
You will not receive any compensation as a part of this study. 
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Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
On this study, the NCI will cover the cost for some of your expenses.  Some of these costs may 
be paid directly by the NIH and some may be reimbursed after you have paid.  Someone will 
work with you to provide more information.
If your travel to the NIH Clinical Center (e.g. flight, hotel) is arranged and paid for by the NIH, 
the agency making the reservations and their representatives will have access to your identifiable 
information.
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 

If some tests and procedures are performed outside the NIH Clinical Center, you may have 
to pay for these costs if they are not covered by your insurance company.

Medicines that are not part of the study treatment will not be provided or paid for by the 
NIH Clinical Center.

Once you have completed taking part in the study, medical care will no longer be provided 
by the NIH Clinical Center.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

The study Sponsor Center for Cancer Research or their agent(s)

Qualified representatives from Amgen Inc., the pharmaceutical company who produces 
Carfilzomib.

Qualified representatives from Celgene, the pharmaceutical company that produces 
Lenalidomide. 
When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release any 
information about your research involvement without your written permission.  However, if you 
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sign a release of information form, for example, for an insurance company, the NIH will give the 
insurance company information from your medical record.  This information might affect (either 
favorably or unfavorably) the willingness of the insurance company to sell you insurance.
If we share your specimens or data with other researchers, in most circumstances we will remove 
your identifiers before sharing your specimens or data. You should be aware that there is a slight 
possibility that someone could figure out the information is about you. 
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy Act 
allows release of information from your medical record without your permission, for example, if 
it is requested by Congress. Information may also be released for certain research purposes with 
due consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
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POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Elizabeth Hill, 
M.D, Telephone: 240-760-6183. You may also call the NIH Clinical Center Patient Representative 
at 301-496-2626, or the NIH Office of IRB Operations at 301-402-3713, if you have a research-
related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
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Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness should sign below if either: 
1. A short form consent process has been used to enroll a non-English speaking subject or
2. An oral presentation of the full consent has been used to enroll a blind or illiterate subject
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 12C0107
IRB APPROVAL DATE: 08/10/2022