Clinical trial NCT01402284
Conditions: Multiple Myeloma
Keywords: Novel Drug Combinations Protease Inhibitors Decreased Peripheral Neuropathy Auto Stem Cell Transplant Multiple Myeloma
Sponsor: National Cancer Institute (NCI)
Start date: 2011-07-21; Completion date: 2020-09-24
Enrollment: 45 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

\- Carfilzomib is an experimental anti-cancer drug that has not yet been approved for treating multiple myeloma. Lenalidomide is a drug that may stop tumor growth and help the immune system kill cancer cells. Dexamethasone is a drug that helps stop inflammation. It is sometimes used to treat (alone or with other drugs) certain types of cancer, especially multiple myeloma. This combination of drugs has not been tested in people with multiple myeloma. Researchers want to see whether it is safe and effective for this group.

Objectives:

\- To test the effectiveness of combined carfilzomib, lenalidomide, and dexamethasone in treating multiple myeloma.

Eligibility:

\- People at least 18 years of age who have multiple myeloma that has not been treated.

Design:

* Participants will be screened with a medical history and physical exam. They will also have blood and urine tests, a bone marrow sample, and molecular imaging studies.
* Participants will have eight 28-day cycles of treatment. The combined study drugs will be given as tablets and injections. Those in the study will be monitored with frequent blood tests, bone marrow samples, and molecular imaging studies. In addition to current standard measures to determine clinical responses, molecular tests will be conducted to define evidence of minimal residual disease.
* After the first four cycles of therapy, those who are eligible for a stem cell transplant will have stem cells collected and stored for use if the cancer returns.
* After stem cell collection, participants will have the second four treatment cycles.

  -, If the disease has improved or is stable at the end of eight cycles, those in the study may have another 12 cycles of low-dose (maintenance) lenalidomide alone.
* Participants will have regular follow-up visits after the end of the study chemotherapy.

Detailed description:
Background:

* Multiple myeloma (MM) is an incurable plasma cell neoplasm with a median survival of 3-4 years.
* Novel agent combinations with proteasome inhibitors demonstrate improved response rates while increasing survival in MM patients.
* A common debilitating side effect of the proteasome inhibitor bortezomib is neuropathy.
* Carfilzomib is a new proteasome inhibitor with potent anti-MM effects and decreased peripheral neuropathy

Objectives:

-Evaluate toxicity, including peripheral neuropathy, of carfilzomib, lenalidomide, and dexamethasone (CRd) in untreated MM patients

Eligibility:

* Newly diagnosed patients with histologically confirmed multiple myeloma
* Age greater than or equal to 18 years
* Creatinine Clearance (CrCl) greater than or equal to 60 ml/min. CrCl will be calculated using the Cockcroft- Gault method. If the calculated CrCl based on Cockcroft-Gault method is \<60 mL/min, patient will have a 24 hr urine collection to measure CrCl. The measured CrCl must also be greater than or equal to 60 ml/min.
* Without serious co-morbidity that would interfere with receipt of CRd
* Absolute neutrophil count (ANC) greater than or equal to 1.0 K/uL, hemoglobin greater than or equal to 8 g/dL, and platelet count greater than or equal to 75 K/uL
* Adequate hepatic function, with bilirubin less than 1.5 x the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than 3.0 x ULN

Design:

* Single arm, single stage phase II trial of combination therapy (carfilzomib, lenalidomide, and dexamethasone) for untreated multiple myeloma patients with an early stopping rule for toxicity
* 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 will undergo stem cell collection
* Patients achieving stable disease or better after 8 cycles of CRd 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
* Pre- and post-treatment bone marrow biopsies will be obtained for confirmation of diagnosis and correlative studies
* Patients will also undergo evaluation for minimal residual disease at regular interval time points, using multi-parametric flow cytometry and fludeoxyglucose 18F-positron emission tomography - computed tomography (FDG PET-CT)
* A single stage phase II design will be employed, with an early stopping rule. Unless 4 or more patients in the first 20 have Grade 3 or higher neurologic toxicity in the first 2 completed cycles, a total of 45 evaluable patients will be enrolled in this study.

Arms: arm 1: Patients will receive 8 cycles of induction combination therapy of carfilzomib, lenalidomide, and dexamethasone (CRd). Patients achieving stable disease or better after 8 cycles of CRd 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
Interventions: intervention 1: Carfilzomib intervention 2: Lenalidomide intervention 3: Dexamethasone intervention 4: Lenalidomide intervention 5: Lenalidomide
Intervention descriptions: intervention 1: Cycle 1: 20 mg/m(2) intravenous (IV) infusion over 30 minutes on days 1 and 2, then 36 mg/m(2) IV on days 8, 9, 15, and 16 Cycle 2-8: 36mg/ m(2) IV infusion over 30 minutes on days 1, 2, 8, 9, 15, and 16 intervention 2: Cycle 1: 25 mg oral days 2-21 of 28-day cycle; Cycle 2 - 8: 25 mg oral days 1-21 of 28-day cycle; After 8 cycles of combination carfilzomib, lenalidomide, and dexamethasone (CRd), patients may continue Lenalidomide for 12 cycles; After 12 cycles of extended dosing of Lenalidomide, patients may continue Lenalidomide for one year intervention 3: Cycle 1: 20 mg oral or IV on days 2, 8, 9, 15, 16, 22, and 23 Cycle 2-4: 20 mg oral or IV on days 1, 2, 8, 9, 15, 16, 22, and 23 Cycle 5-8: 10 mg oral or IV on days 1, 2, 8, 9, 15, 16, 22, and 23 intervention 4: After 8 cycles of combination carfilzomib, lenalidomide, and dexamethasone (CRd), patients may continue Lenalidomide for 12 cycles intervention 5: After 12 cycles of extended dosing of Lenalidomide, patients may continue Lenalidomide for one year

Protocol documents:
Prot_SAP_002.pdf: 
Abbreviated Title:  CRd in Newly Diagnosed MM 
Version Date:  03/27/2020 
 
1 
 Abbreviated Title:  CRd in Newly Diagnosed MM 
 
CC Protocol #:  11-C-0221 P 
 
Version Date:   03/27/2020 
 
NCT Number: NCT01402284   
 
Carfilzomib, Lenalidomide, and Dexamethasone in Newly Diagnosed Multiple Myeloma:  
Clinical and Correlative Phase II Study 
 
 
 
NCI Principal Investigator: Dickran Kazandjian, M.D. A-F 
Joint appointment: 
• Lymphoid Malignancies Branch (LYMB), CCR, NCI 
• Office of Hematology and Oncology Products, FDA 
National Institutes of Health (NIH) 
10 Center Drive, Room 4N115  
Bethesda, MD 20892 
Phone:  240-383-6311  
E-mail:  kazandjiand@mail.nih.gov  
 
 
 
Investigational Agents:     
Drug Name: 
Carfilzomib 
IND Number: 
112587 
Sponsor: 
Center for Cancer Research 
Manufacturer 
Amgen, Inc. 
 
Commercial Agents:  Dexamethasone, Lenalidomide  


Abbreviated Title:  CRd in Newly Diagnosed MM 
Version Date:  03/27/2020 
 
2 
PRÉCIS  
Background: 
• Multiple myeloma (MM) is an incurable plasma cell neoplasm with a median survival of 
3-4 years. 
• Novel agent combinations with proteasome inhibitors demonstrate improved response 
rates while increasing survival in MM patients.   
• A common debilitating side effect of the proteasome inhibitor bortezomib is neuropathy. 
• Carfilzomib is a new proteasome inhibitor with potent anti-MM effects and decreased 
peripheral neuropathy  
Objective: 
• To evaluate toxicity, including peripheral neuropathy, of carfilzomib, lenalidomide, and 
dexamethasone (CRd) in untreated MM patients 
Eligibility: 
• Newly diagnosed patients with histologically confirmed multiple myeloma  
• Age ≥ 18 years 
• Creatinine Clearance (CrCl) ≥ 60 ml/min.  CrCl will be calculated using the Cockcroft-
Gault method.  If the calculated CrCl based on Cockcroft-Gault method is <60 mL/min, 
patient will have a 24 hr urine collection to measure CrCl. The measured CrCl must also 
be ≥ 60 ml/min. 
• Without serious co-morbidity that would interfere with receipt of CRd 
• Absolute neutrophil count (ANC) ≥ 1.0 K/uL, hemoglobin ≥ 8 g/dL, and platelet count ≥ 
75 K/uL 
• Adequate hepatic function, with bilirubin < 1.5 x the ULN, and AST and ALT < 3.0 x 
ULN 
Design: 
• Single arm, single stage phase II trial of combination therapy (carfilzomib, lenalidomide, 
and dexamethasone) for untreated multiple myeloma patients with an early stopping rule 
for toxicity 
• 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 will undergo stem cell collection  
• Patients achieving stable disease or better after 8 cycles of CRd 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 SPEP and free light chains monthly during the 
induction phase.  Laboratory evaluations may be spread out to every 3 months during the 


Abbreviated Title:  CRd in Newly Diagnosed MM 
Version Date:  03/27/2020 
 
3 
maintenance and follow-up phases. 
• Pre- and post-treatment in addition to follow-up bone marrow biopsies will be obtained 
for confirmation of diagnosis, response and durability, 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. 
• A single stage phase II design will be employed, with an early stopping rule. Unless 4 or 
more patients in the first 20 have Grade 3 or higher neurologic toxicity in the first 2 
completed cycles, a total of 45 evaluable patients will be enrolled in this study. 


Abbreviated Title:  CRd in Newly Diagnosed MM 
Version Date:  03/27/2020 
 
4 
TABLE OF CONTENTS  
PRÉCIS .................................................................................................................................. 2 
TABLE OF CONTENTS ......................................................................................................... 4 
1 
INTRODUCTION .......................................................................................................... 7 
1.1 
Study Objectives........................................................................................................ 7 
1.2 
Background and Rationale ......................................................................................... 7 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT.................................................. 14 
2.1 
Eligibility Criteria .................................................................................................... 14 
2.2 
Screening Evaluation ............................................................................................... 16 
2.3 
Registration Procedures ........................................................................................... 16 
2.4 
Baseline Evaluation ................................................................................................. 17 
3 
STUDY IMPLEMENTATION ..................................................................................... 18 
3.1 
Study Design ........................................................................................................... 18 
3.2 
Drug Administration ................................................................................................ 19 
3.3 
Dose Modifications.................................................................................................. 22 
3.4 
Study Calendar ........................................................................................................ 28 
3.5 
Criteria for Removal from Protocol Therapy and Off Study Criteria .......................... 31 
4 
CONCOMITANT MEDICATIONS/MEASURES......................................................... 31 
4.1 
Tumor lysis syndrome.............................................................................................. 31 
4.2 
Bone Disease/Extramedullary Disease ...................................................................... 32 
4.3 
Hypercalcemia......................................................................................................... 33 
4.4 
Transfusions/Growth Factors.................................................................................... 33 
4.5 
Anti-Coagulation ..................................................................................................... 33 
4.6 
HSV, VSV Prophylaxis............................................................................................ 33 
5 
BIOSPECIMEN COLLECTION................................................................................... 34 
5.1 
Correlative Samples for Research/Pharmacokinetic Studies....................................... 34 
5.2 
Sample Storage, Tracking and Disposition................................................................ 41 
5.3 
Samples for Genetic/Genomic Analysis .................................................................... 43 
6 
DATA COLLECTION AND EVALUATION ............................................................... 43 
6.1 
Data Collection........................................................................................................ 43 
6.2 
Data Sharing Plans................................................................................................... 45 
6.3 
Response Criteria..................................................................................................... 45 
6.4 
Toxicity Criteria ...................................................................................................... 47 


Abbreviated Title:  CRd in Newly Diagnosed MM 
Version Date:  03/27/2020 
 
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7 
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN .. 48 
7.1 
Definitions............................................................................................................... 48 
7.2 
OHSRP Office of Compliance and Training / IRB Reporting .................................... 48 
7.3 
NCI Clinical Director Reporting............................................................................... 48 
7.4 
NIH Required Data and Safety Monitoring Plan........................................................ 48 
8 
SPONSOR PROTOCOL/SAFETY REPORTING ......................................................... 49 
8.1 
Definitions............................................................................................................... 49 
8.2 
Assessment of Safety Events .................................................................................... 50 
8.3 
Reporting of Serious Adverse Events........................................................................ 50 
8.4 
Waiver of expedited reporting to CCR ...................................................................... 51 
8.5 
Safety Reporting Criteria to the Pharmaceutical Collaborators................................... 51 
8.6 
Reporting Pregnancy to CCR ................................................................................... 53 
8.7 
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND ................. 53 
8.8 
Sponsor Protocol Non-Adherence Reporting............................................................. 53 
9 
CLINICAL MONITORING.......................................................................................... 54 
10 
STATISTICAL CONSIDERATIONS ........................................................................... 54 
10.1 Study Design/Primary Endpoints .............................................................................. 54 
10.2 Sample Size Determination ...................................................................................... 54 
10.3 Statistical Analyses .................................................................................................. 55 
11 
COLLABORATIVE AGREEMENTS........................................................................... 55 
11.1 Agreement Type ...................................................................................................... 55 
12 
HUMAN SUBJECTS PROTECTIONS......................................................................... 56 
12.1 Rationale For Subject Selection ................................................................................ 56 
12.2 Participation of Children .......................................................................................... 56 
12.3 Participation of Subjects Unable to Give Consent ..................................................... 57 
12.4 Risks/Benefits Analysis ........................................................................................... 57 
12.5 Consent Process and Documentation ........................................................................ 57 
13 
PHARMACEUTICAL INFORMATION ...................................................................... 58 
13.1 CARFILZOMIB (IND # 112587) ............................................................................. 58 
13.2 LENALIDOMIDE ................................................................................................... 60 
13.3 Dexamethasone ....................................................................................................... 62 
14 
REFERENCES............................................................................................................. 64 
15 
APPENDICES ............................................................................................................. 67 


Abbreviated Title:  CRd in Newly Diagnosed MM 
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15.1 Appendix A:  Requirements for REMS® .................................................................. 67 
15.2 Appendix B:  Bone Marrow Aspirate Collection, Sorting and Storage ....................... 71 
15.3 Appendix C:   Research Peripheral Blood and Urine Collection and Storage .............. 73 
 


Abbreviated Title:  CRd in Newly Diagnosed MM 
Version Date:  03/27/2020 
 
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1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective 
To evaluate toxicity, including peripheral neuropathy, of carfilzomib, lenalidomide, and 
dexamethasone (CRd) in untreated MM patients 
1.1.2 Secondary Objectives 
• To determine best response rates according to International Myeloma Working Group 
criteria after 8 cycles of CRd combination therapy 
• To determine progression free survival (PFS) 
• To determine duration of response (DOR) 
• To determine overall survival (OS)  
• To evaluate biological activity of carfilzomib and correlate to clinical outcomes, 
including gene expression profiling on pre- and post-carfilzomib exposure bone marrow 
samples 
• To assess the impact of minimal residual disease by flow cytometry and PET/CT in 
relation to outcome 
1.1.3 Exploratory Objectives 
• To assess MRD detection by next generation VDJ sequencing, exome sequencing, and 
PD-1/PD-L1 expression in the bone marrow compartment 
• To evaluate radiographic changes (signal intensity) in bone marrow heterogeneity and 
focal lesions by Diffusion Weighted MRI (DW-MRI) over time. 
• To evaluate radiographic changes (FDG avidity) in bone marrow heterogeneity and focal 
infiltration by PET/CT overtime. 
1.2 
BACKGROUND AND RATIONALE 
1.2.1 Introduction 
Multiple myeloma (MM) is characterized by clonal proliferation of malignant plasma cells in the 
bone marrow, affecting an estimated 20,000 people annually(1).  Disease hallmarks include 
presence of monoclonal protein in serum or urine and features of end organ damage, including 
hypercalcemia, renal insufficiency, anemia, and bone lytic lesions(2).  MM remains incurable 
with an estimated median survival of 3-4 years with conventional therapies and longer with 
newer agents(3, 4). 
1.2.2 Proteasomes and Bortezomib 
Proteasomes 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(5).  
Inhibiting proteasomes in malignant cells leads to buildup of ubiquinated proteins, resulting in 
eventual cell death.  Such inhibitor effects likely extend beyond just a simple overaccumulation 
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. 


Abbreviated Title:  CRd in Newly Diagnosed MM 
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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(6, 7).  A recent phase I/II study shows promising efficacy of 
the novel combination: bortezomib, lenalidomide, and dexamethasone in newly diagnosed MM 
patients, with 74% of subjects achieving very good partial response (VGPR) or better(8).  
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, thrombocytopenia and herpes zoster re-activation.  
Bortezomib associated peripheral neuropathy can be experienced in up to 33% (Grade 1 and 2) 
and up to 18% (Grade 3 and 4) of newly diagnosed MM patients(9).  In the aforementioned 
phase I/II study, with combination bortezomib, lenalidomide, and dexamethasone, 80% of 
treated patients experienced sensory neuropathy all grades(8).  In addition, as increasing numbers 
of patients are treated with novel agents, drug resistance and refractoriness seem 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(10). 
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.  
Chemical Structure of Carfilzomib 
 
Carfilzomib is less reactive to non-proteasome proteases compared to bortezomib, likely 
contributing to lower levels of neuropathy and myelosuppression(11-13).  In vitro models 
suggest carfilzomib has activity against bortezomib resistant myeloma cell lines(12).  
Carfilzomib can also work synergistically with dexamethasone to enhance tumor cell death (12).  
A number of phase I and phase II studies are currently investigating carfilzomib toxicity and 
efficacy in MM.   
As of July 2019, carfilzomib has been examined in approximately 11,000 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. 


Abbreviated Title:  CRd in Newly Diagnosed MM 
Version Date:  03/27/2020 
 
9 
1.2.3.1 Phase I Carfilzomib Monotherapy 
A Phase 1 clinical trial, PX-171-002, testing carfilzomib in subjects with relapsed/refractory 
hematologic malignancies, is being completed(14).  During the dose escalation portion of the 
trial, 36 subjects received carfilzomib on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle.  20 
subjects with MM were enrolled on the study.   
No dose limiting toxicities (DLTs) were observed in the initial seven cohorts (doses ranged from 
1.2 to 15 mg/m2) of three subjects each.  At the 20 mg/m2 dose level, one of eight patients had a 
Grade 3 renal failure at Cycle 1, Day 2 which was considered possibly related to study drug and 
lasted for six days.  The patient continued on study for the remainder of Cycle 1 before having 
disease progression.   At the 27 mg/m2 dose level, one of six subjects experienced a DLT during 
Cycle 1, consisting of severe hypoxia with pulmonary infiltrates following Day 2 of dosing.  In 
subjects where the 27 mg/m2 dose was efficacious, a “first dose effect” was seen that included a 
constellation of findings that appeared to be the clinical sequelae of rapid tumor lysis syndrome 
(TLS) and/or cytokine release.  This effect was notable for fever, chills, and/or rigors occurring 
during the evening following the first day of infusion.  On the second day, three of five subjects 
with MM experienced an increase in creatinine to Grade 2 including the subject with the DLT.  
This elevation was rapidly reversible and all three subjects were rechallenged with carfilzomib 
without recurrence of the events.  Interestingly, all three subjects had a rapid decline in serum 
and/or urine M-protein levels.  There were no consistent changes in potassium, calcium, 
phosphorous, or uric acid levels although some increases in LDH and other markers of tumor 
lysis were noted.  Because of the possible TLS and reversible creatinine elevations, hydration 
and very-low dose dexamethasone prophylaxis were instituted in subsequent studies and have 
essentially eliminated clinically significant TLS/creatinine elevations and the other “first-dose” 
effects.   
Four of the twenty MM patients achieved a partial response (PR), one of two at the 15 mg/m2 
dose, one of six at the 20 mg/m2 dose, and two of five at the 27 mg/m2 dose.   
1.2.3.2 Phase II Carfilzomib Monotherapy  
Two Phase 2 clinical studies are ongoing with carfilzomib in MM patients, PX-171-003-A0 
(N=46) in relapsed and refractory MM and PX-171-004 (N=39) in relapsed MM.(15, 16) In both 
studies, patients were dosed with 20 mg/m2 on Days 1, 2, 8, 9, 15, and 16 on a 28 day schedule.  
In these studies there were four cases of suspected or documented TLS prior to institution of the 
prophylaxis guidelines.  Since these guidelines were implemented, no further cases of TLS have 
been reported including in >350 additional patients with relapsed or refractory MM treated in 
ongoing Phase II studies.   
A “stepped up” dosing schedule, referred to as 20/27 mg/m2, has subsequently been incorporated 
into the PX-171-003 study (referred to as PX-171-003-A1) in order to maximize the clinical 
benefit of carfilzomib.  Patients receive 20 mg/m2 for the first cycle and 27 mg/m2 thereafter.  
The study completed enrolment of 266 patients by the end of 2009 and formed the basis for 
NDA filing in beginning of 2011.   
No cases of TLS were observed and rates of BUN and creatinine elevation dropped sharply, with 
Grade 3/4 renal impairment dropping to 2.2% in A1(from 15% in A0), most likely due to 
hydration and very low dose dexamethasone.  The other most common adverse events were 
similar to the A0 portion of the study.  Treatment-emergent peripheral neuropathy remains low 
on this portion of the study with 15% Grade 1/2 and one (0.7%) Grade 3/4 event reported to date 


Abbreviated Title:  CRd in Newly Diagnosed MM 
Version Date:  03/27/2020 
 
10 
on PX-171-003-A1(15).  In addition, anemia rates in the PX-171-003-A1 (higher dose) were 
lower than those reported in the PX-171-003–A0 portion of the study, possibly indicating that 
the higher dose of carfilzomib is achieving better clearing of neoplastic cells in the bone marrow 
allowing superior normal marrow reconstitution.  Rates of thrombocytopenia and neutropenia 
were similar in the two cohorts, with Grade 3 neutropenia in ~5% without any Grade 4 
neutropenia to date.(15)  
1.2.4 Investigational Drug Lenalidomide 
REVLIMID® (lenalidomide), a thalidomide analogue, is an immunomodulatory agent with anti-
angiogenic properties.  The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -2H-isoindol-2-yl) 
piperidine-2,6-dione and it has the following chemical structure:  
Chemical Structure of Lenalidomide 
 
The mechanism of action of lenalidomide remains to be fully characterized. Although the exact 
antitumor mechanism of action of lenalidomide is unknown, a number of mechanisms are 
postulated to be responsible for lenalidomide’s activity against MM.  Lenalidomide has been 
shown to increase T cell proliferation, which leads to an increase in IL-2 and IFN-gamma 
secretion.  The increased level of these circulating cytokines augment natural killer cell number 
and function, and enhance natural killer cell activity to yield an increase in MM cell lysis.  In 
addition, lenalidomide has direct activity against MM and induces apoptosis or G1growth arrest 
in MM cell lines and in MM cells of patients resistant to melphalan, doxorubicin and 
dexamethasone.  Revlimid® is approved in combination with dexamethasone for the treatment of 
patients with MM that have received at least one prior therapy.(17, 18) The drug has also been 
studied in newly diagnosed patients in combination with low-dose dexamethasone, as well as with 
bortezomib and dexamethasone as mentioned earlier.(8, 19)   
1.2.5 Phase I Combination Therapy Carfilzomib, Lenalidomide, and Dexamethasone in 
Refractory/Relapsed MM  
PX-171-006 is an ongoing Phase 1b study in patients with relapsed MM in which carfilzomib is 
administered in combination with lenalidomide (Revlimid®) and dexamethasone.(20) “Low-
dose” dexamethasone 40 mg/day is given on Days 1, 8, 15, and 22 in all cases.  Carfilzomib is 
administered IV on Days 1, 2, 7, 8, 15, and 16; lenalidomide is administered PO on Days 1 
through 21.  Enrollment has closed in this study, and no MTD was reached.  The maximum per 
protocol doses of carfilzomib (20/27mg/m2) with lenalidomide 25mg and low dose 
dexamethasone are being used.  After 8 patients tolerated these doses well, an additional 44 
patients were enrolled in an “expansion” cohort at this level.  To date, 40 patients were treated in 
cohorts 1-6 and 44 in the cohort 6 expansion. 27/32 patients in cohorts 1–5 are evaluable for 
safety and 29/32 for response. No dose-limiting toxicities or deaths attributed to study treatment 
have been observed. No treatment emergent fatigue, neuropathy, or thrombotic events ≥ Grade 
(G) 3 were observed. Hematological AEs ≥G3 (thrombocytopenia [n=6], anemia [n=4], and 
neutropenia [n=6]) were reversible. 4 patients had drug-related SAEs as follows: transient G3 
N
N
H
O
O
O
NH2


Abbreviated Title:  CRd in Newly Diagnosed MM 
Version Date:  03/27/2020 
 
11 
sinus bradycardia, G3 upper respiratory tract infection, febrile neutropenia, and G3 diarrhea + G3 
urinary infection. ORR and CBR for the 29 evaluable patients are 59% and 72%, respectively. 
Response data is shown in the table below.  
 
CRd: Cohorts 1–5 
(CFZ: 15 to 20 mg/m2; LEN: 10 to 25 mg)  
Response 
Relapsed (n=16) 
Refractory 
(n=13) 
Overall  
(n=29) 
   ≥ CR/nCR 
5 (31) 
1 (8) 
6 (21) 
   ≥ VGPR 
7 (44) 
4 (31) 
11 (38) 
   ≥ PR 
9 (56) 
8 (62) 
17 (59) 
   ≥ MR 
11 (67) 
10 (77) 
21 (72) 
1.2.6 Phase I Combination Therapy Carfilzomib, Lenalidomide, and Dexamethasone in Newly 
Diagnosed MM 
Results of a phase I/II study in newly diagnosed MM patients was recently published evaluating 
carfilzomib, lenalidomide, and dexamethasone.(21)   Carfilzomib was the only escalating agent, 
ranging from 20 mg/m2 (dose level 1), 27 mg/m2 (dose level 2), to a recently amended dose of 
36 mg/m2 (dose level 3) based on recent toxicity assessments.  Lenalidomide was administered 
at 25 mg PO (days 1-21) while dexamethasone was given at 40/20 (cycles 1-4/5-8) mg PO 
weekly. 
The study enrolled 53 patients, 4 patients at 20 mg/m2, 13 at 27 mg/m2, 18 at 36 mg/m2 and 
additional 18 in the expanded phase 2 cohort at 36 mg/m2.  One patient had a DLT at dose level 
27 mg/m2 with an episode of non-febrile neutropenia.  Two patients experienced DLT at 36 
mg/m2 dose level with episodes of dyspnea and pulmonary edema.  Data indicated a dose 
dependent trend of increasing DLTs, however, the DLT probability was estimated to be less than 
20% set for the MTD using the TITE-CRM algorithm.  The MPD of 36 mg/m2 was selected as 
the expansion dose for phase II. Hematological AEs ≥G3 (were thrombocytopenia 17%, anemia 
21%, and neutropenia 17%).  Non-hematologic AEs ≥G3 include hypophosphatemia 25%, 
hyperglycemia 23%, DVT/PE 9%, rash 8%, and elevated liver function test 8%.  Peripheral 
neuropathy was experienced by 23% and limited in severity to Grade 1(17%) and 2 (6%).  There 
was no Grade 3 or 4 peripheral neuropathy reported.  After a median of 12 cycles of treatment, 
62% achieved at least near CR and 42% achieved a stringent CR. 
1.2.7 Minimal Residual Disease (MRD) in MM 
Current response criteria, which are defined by M-spike, plasma cell burden, and abnormal free 
light chains, are often limited in predicting clinical response and duration of response.  MRD 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.(22) At day 100 post auto-transplant, 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).  Other techniques, such as, polymerase chain reaction 
(PCR) of Ig heavy chain (IGH) rearrangements and light chain genes have also been employed in 


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12 
evaluating for MRD and found to have prognostic significance in showing prolonged PFS after 
intensive therapy.(23)  
FDG-PET CT has been valuable at localizing intramedullary and extramedullary disease in 
multiple myeloma.  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%.(24)   
Incorporating such techniques into prospective clinical trials may have a role in evaluating 
response to therapy.       
1.2.8 Proposed Study Investigation with Correlative Studies 
Given carfilzomib’s potent anti-myeloma activity and lack of peripheral neuropathy, we propose 
a phase II investigation of combination therapy (Cycles 1-8 carfilzomib, lenalidomide, 
dexamethasone) in newly diagnosed MM patients followed by extended dosing with 
lenalidomide (days 1-21 of 28 day cycle) for 12 cycles.  Patients will be enrolled on study to 
determine if the CRd 3 drug-combination demonstrates a rate of grade 3 or worse neurologic 
toxicity lower than 10% in the first two completed cycles.  After 4 cycles, transplant eligible 
patients will undergo autologous stem cell harvesting.  After 8 cycles, patients achieving SD or 
better will proceed to extended dosing with lenalidomide.  Patients not achieving SD will be off 
treatment.  Response criteria is outlined in Section 5.3.  Proposed correlative studies include 
gene expression profiling on purified CD 138 + pre- and post- carfilzomib plasma cells, 
identification of potential biomarkers (blood, urine, bone marrow aspirates), proteasome 
quantification and activity, 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, and detection of clonality using heavy 
and/or light chain immunoglobulin rearrangement.  Effective with Amendment L (version date 
07/15/2015), bone marrow aspirate and biopsy will be obtained for research studies at the 
discretion of the PI. 
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%.  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 as a restaging tool are 
inherently limited. 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 (i.e. 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. 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 is that they are quick to perform (~45 minutes) and interpret. Finally, 


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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. 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 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. 
 
1.2.9 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(24-26).  
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)(26).  A small increased risk of secondary primary malignancies was noted in the 
lenalidomide groups compared to the placebo groups in all three trials.  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(27, 28).  All three of the aforementioned 
randomized trials used lenalidomide after melphalan exposure, a significant and notable 
difference between our trial (11-C-0221) 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 lenalidomide arms compared to 
placebo(24-26, 29). 
In accord with these recent publications and lack of alkylator exposure in our protocol using 
CRd, 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. 
1.2.10 Updated Interim Analysis- ASH 2012 
In an interim analysis presented at ASH 2012, we updated results on the first 20/45 patients.  
Among the first 20 patients, none developed ≥ grade 3 neuropathy.  Best responses with a 
median of 7 cycles showed 15/20(75%) nCR/sCR, 2/20(10%) VGPR, 2/20 (10%) PR, and 1/20 
(5%) SD. Patients demonstrating ORR (PR or higher) was 19/20 (95%).  Patients with ≥ grade 3 
non-hematologic toxicities include: LFT elevation (20%), fatigue (15%), rash/pruritus (15%), 
dyspnea (10%), CHF (10%), general disorders and administration site conditions (5%), mood 
alterations (5%), and electrolyte disturbances (5%).  Patients with ≥ grade 3 hematologic 
toxicities include:  lymphopenia (60%), and anemia (5%).    


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2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
2.1.1.1 Newly diagnosed patients with histologically confirmed Multiple Myeloma (MM based 
on the following criteria: 
a) Clonal plasma cells in the bone marrow  
b) 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 
c) Evidence of underlying end organ damage attributed to underlying plasma cell 
proliferative disorder meeting at least one of the following: 
• Hypercalcemia:  serum calcium ≥ 2.65 mmol/L 
• Renal Insufficiency:  serum creatinine > 2.0 mg/dL   
• Anemia: hemoglobin value <10 g/dL or 2 g/dL < normal reference 
• Bone disease:  lytic lesions, severe osteopenia or pathological fractures 
2.1.1.2 Creatinine Clearance ≥ 60 ml/min.  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).  If calculated CrCl based on Cockcroft-Gault method is <60 
mL/min, patient will have a 24 hr urine collection to measure CrCl. The measured CrCl 
must also be ≥ 60 ml/min.   
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 will be eligible for future pediatric trials. 
2.1.1.4 Eastern Cooperative Oncology Group (ECOG) performance status 0-2 
• Absolute neutrophil count (ANC) ≥ 1.0 K/uL, hemoglobin ≥ 8 g/dL (transfusions are 
permissible), and platelet count ≥ 75 K/uL 
• Adequate hepatic function, with bilirubin < 1.5 x the ULN, and AST and ALT < 3.0 x 
ULN.  
2.1.1.5 All study participants must be able to tolerate one of the following thromboprophylactic 
strategies: aspirin, low molecular weight heparin or warfarin (coumadin).  
2.1.1.6 All study participants must be registered into the mandatory eREMS® program, and be 
willing and able to comply with the requirements of REMS®. 
2.1.1.7 Females of childbearing potential (FCBP)† must have a negative serum or urine 
 
† 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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pregnancy test within 10 – 14 days and again within 24 hours prior to prescribing 
lenalidomide for Cycle 1 (prescriptions must be filled within 7 days) and must either 
commit to continued abstinence from heterosexual intercourse or begin TWO 
acceptable methods of birth control, one highly effective method and one additional 
effective method AT THE SAME TIME, at least 28 days before she starts taking 
lenalidomide.  FCBP must also agree to ongoing pregnancy testing.  Men must agree to 
use a latex condom during sexual contact with a FCBP even if they have had a 
successful vasectomy.     
2.1.1.8 Subjects must be able to give informed consent 
2.1.2 Exclusion Criteria 
2.1.2.1 Prior or concurrent systemic treatment for MM.   
• Treatment of hypercalcemia or spinal cord compression or aggressively progressing 
myeloma with corticosteroids is permitted.   
• Bisphosphonates are permitted.  
• Treatment with corticosteroids for indications other than MM is permitted.   
• Radiotherapy is permitted. 
• Treatment for smoldering myeloma is permitted. 
2.1.2.2 Plasma cell leukemia 
2.1.2.3 Pregnant or lactating females.  Because there is a potential risk for adverse events in 
nursing infants secondary to treatment of the mother with carfilzomib in combination 
with lenalidomide, breastfeeding should be discontinued if the mother is treated with 
carfilzomib and lenalidomide.  These potential risks may also apply to other agents 
used in this study. 
2.1.2.4 Uncontrolled hypertension or diabetes 
2.1.2.5 Active hepatitis B or C infection 
2.1.2.6 Has significant cardiovascular disease with NYHA Class III or IV symptoms, or 
hypertrophic cardiomyopathy, or restrictive cardiomyopathy, or myocardial infarction 
within 3 months prior to enrollment, or unstable angina, or unstable arrhythmia as 
determined by history and physical examination.  Echocardiogram will be performed if 
clinically warranted.   
2.1.2.7 Has refractory GI disease with refractory nausea/vomiting, inflammatory bowel 
disease, or bowel resection that would prevent absorption  
2.1.2.8 Uncontrolled intercurrent illness including but not limited to active infection or 
psychiatric illness/social situations that would compromise compliance with study 
requirements 
2.1.2.9 Significant neuropathy ≥Grade 3 at baseline 
2.1.2.10 Contraindication to any concomitant medication, including antivirals, anticoagulation 
prophylaxis, tumor lysis prophylaxis, or hydration given prior to therapy 
2.1.2.11 Major surgery within 1 month prior to enrollment 


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2.1.3 Recruitment Strategies 
Participant sources will be from outside physician referrals and from standard websites such as 
clinicaltrials.gov and the NCI CCR website. 
2.2 
SCREENING EVALUATION 
2.2.1 Clinical Evaluation 
2.2.1.1 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. 
a) Patients will be evaluated for baseline neuropathy.  Patients with grade 3 or higher 
will be excluded.   
2.2.1.2 The following laboratory tests will be completed 4 weeks prior to study entry: 
a) CBC with differential and reticulocyte count 
b) 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 eGFR determination 
c) Uric acid, LDH, and Beta-2 Microglobulin 
d) PT, PTT 
e) Serum protein electrophoresis (SPEP) and immunofixation to assess for presence 
and quantity of monoclonal protein (M-protein) 
f) 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 Multiple Myeloma diagnosis.  
g) Serum free light-chain studies, determined using the FreeliteTM assay system 
h) Quantitative immunoglobulins 
i) Viral serologies 
1) Hepatitis B surface antigen 
2) Anti-Hepatitis C (HCV) antibody. If positive, will follow with HCV RNA PCR  
j) Review of bone marrow core biopsy and aspirate.  
k) Serum or urine pregnancy test in women of child-bearing potential. 
l) 12-lead EKG 
2.2.1.3 A skeletal survey of the axial and appendicular skeleton will be performed.  Exception 
may be made if skeletal survey has been performed within the past 3 months and was 
found to be positive. In this case, films will be forwarded to the Clinical Center for an 
additional reading by the Department of Radiology. 
2.3 
REGISTRATION PROCEDURES 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 
encrypted email to: NCI Central Registration Office ncicentralregistration-l@mail.nih.gov.  
After confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to 
advise them of the acceptance of the patient on the protocol prior to the release of any 
investigational agents.  Verification of Registration will be forwarded electronically via e-mail to 


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the research team. A recorder is available during non-working hours.  
Note:  As indicated in Section 12.3, all subjects will be offered the opportunity to complete an 
NIH advanced directives form.  This should be done preferably at baseline but can be done at 
any time during the study as long as the capacity to do so is retained.  The completion of the 
form is strongly recommended, but is not required. 
2.4 
BASELINE EVALUATION 
2.4.1 Research and clinical laboratory tests to be performed within 4 weeks of study entry and 
prior to starting therapy.  Refer to Section 5 for details on biospecimen collection and 
correlative studies.       
2.4.1.1  Bone Marrow (see Section 5) 
a) Immunophenotyping of aberrant clonal plasma cells by multiparametric flow 
cytometry    
b) Interphase FISH/cytogenetics  
c) CD 138+ fractions and CD 138- fractions cell sorting with subsequent correlatives 
on both fractions    
d) Proteasome activity and quantification    
e) Markers for autophagy of myeloma plasma cells on pre and post exposure of 
carfilzomib 
f) Histopathological evaluation on bone marrow aspirate and biopsy 
1) Immunoglobulin heavy and/or light chain rearrangement 
2.4.1.2 Peripheral Blood/Urine 
a) Peripheral blood and urine samples for storage and establishing a biobank.  
(Appendix C) 
b) Samples for pharmacokinetics 
c) Subunit profiling and activity of circulating proteasomes by enzyme-like 
immunosorbent assay   
d) Apoptosis assays to identify necrotic or late stage apoptotic cells   
e) Immunolocalization studies.   
f) Flow cytometry 
1) Peripheral blood for circulating plasma cells 
2) Immune cells – including, but not limited to T cells (CD4 and CD8), LGL, and 
NK cells 
3) Autophagy   
2.4.2 Novel imaging studies (FDG PET/CT scan) within 4 weeks of study entry and prior to 
starting therapy 
Prior to 18F-FDG PET/CT imaging, the subject will be fasted and have not received any 
sugar containing substance (i.e. glucose, sucrose, dextrose) for 4-6 hours.  Subjects will 
be encouraged to drink water during this period to reduce radiation dose to the kidneys 
and will be asked to void prior to 18F-FDG injection.  Women of childbearing potential 
will have a documented report of negative pregnancy test from the CC or another 
accredited lab performed on the day of the scan or the day before the scan.   
18F-FDG, [18F]-fludoeoxyglucose is an FDA approved radiopharmaceutical.  


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Immediately prior to injection, the subject’s blood glucose level will be evaluated via 
fingerstick.  Non-diabetic subjects with fasting blood glucose levels above 150 mg/dl 
may be rescheduled at the discretion of the PI.  Subjects will be asked to refrain from 
excessive physical exertion for the 24 hours prior to injection.  Patients will report to the 
NCI Molecular Imaging Clinic (MIC) on the day of their 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 1-
hour, and again at 2-hours post injection.  PET/CT standard operating procedures.  The 
patient will be instructed to maintain good hydration in order to reduce the radiation dose.  
The radiation dose from the procedure will be a maximum of 2.1 rem per year; this is 
within the RSC guidelines of 5.0 rem per year for adults. 
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
• Patients with newly diagnosed MM will be enrolled on the Phase II study and treated 
with 3 drug combination (Cycles 1-8 carfilzomib, lenalidomide, dexamethasone) 
followed by extended lenalidomide dosing. 
• After receiving first 4 cycles, patients who are considered to be eligible for subsequent 
high dose therapy/autologous stem cell transplant (ASCT) will undergo autologous stem 
cell harvesting for potential use in the future. 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. 
• For patients who choose to undergo stem cell harvest, next cycle may be delayed for up 
to 5 weeks. 
• After 8 cycles, patients achieving SD or better 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. 
• Patients not achieving SD will be off treatment. 
• Patients will be enrolled on study to determine if the CRd 3 drug-combination 
demonstrates a rate of grade 3 or worse neurologic toxicity of 10% or lower in the first 
two completed cycles.  A rate greater than 10% will be considered excessive. 


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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:  36mg/ m2 IV infusion over 30 minutes on days 1, 2, 8, 9, 15, and 16 
3.2.2.2 Lenalidomide 
• Cycle 1:  25 mg oral days 2-21 of 28-day cycle 
• Cycle 2-8:  25 mg oral days 1-21 of 28-day cycle  
• Lenalidomide capsules should be swallowed whole, and should not be broken, 
chewed or opened.    
 


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• 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.  
Lenalidomide will be provided in accordance with the REMS® program of 
Celgene Corporation.  Per standard REMS® requirements all physicians who 
prescribe lenalidomide for research subjects enrolled into this trial, and all research 
subjects enrolled into this trial, must be registered in and must comply with all 
requirements of the 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 
• Cycle 1:  20 mg oral or IV on days 2, 8, 9, 15, 16, 22, and 23 
• Cycle 2-4:  20 mg oral or IV on days 1, 2, 8, 9, 15, 16, 22, and 23 
• Cycle 5-8:  10 mg oral or IV on days 1, 2, 8, 9, 15, 16, 22, and 23 
3.2.3 In Cycle 1, the following adjustments to the dosing schema will be implemented: 
• Cycle 1 Day 1, carfilzomib will be adminstered alone. 
• Patients will be admitted and observed as an inpatient while receiving Cycle 1 Day 1 
and 2 therapy.   
• Carfilzomib will be given at a lower dose of 20 mg/m2 on Days 1 and 2 of Cycle 1.   
• Lenalidomide and Dexamethasone will not be given on day 1 
• Bone marrow biopsy with aspirtation will be performed at baseline and Cycle 1 Day 
2   
• Hydration will be administered prior and subsequent to carfilzomib dosing.  
1) 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.  Compliance 
must be reviewed with the subject and documented by the site personnel prior to 
initiating treatment with carfilzomib; treatment is to be delayed or withheld if 
oral hydration is not deemed to be satisfactory. 
2) 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 D1 and D2.  Total volume will be determined at the discretion of 
clinician and volume status of patient.  If lactate dehydrogenase (LDH) or uric 
acid is elevated at Cycle 2, Day 1, then the recommended IV hydration should be 
repeated for Cycle 2.  The goal of the hydration program is to maintain robust 
urine output, (e.g., ≥ 2 L/day).  Subjects should be monitored periodically during 
this period for evidence of fluid overload. 
3) 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 


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3.2.4 Harvesting Stem Cells 
• After 4 cycles of induction combination therapy, patients who are clinically 
considered to be transplant eligible and who do not opt out from that procedure will 
be sent for evaluation of harvesting autologous stem cells at a transplant center. 
• Transplant eligible patients will be defined as age <75 years of age with no 
significant disease co-morbidities and ECOG ≤2.  Individual transplant centers will 
evaluate patient eligibility based on their own criteria.        
• For patients who choose to undergo stem cell harvest, next cycle may be delayed for 
up to 5 weeks. 
3.2.5 Extended Dosing Phase I:  Cycles 9-20 
• Patients that achieve a SD or better after 8 cycles of therapy will go on to receive 
extended dosing with oral lenalidomide 10 mg, 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 
monthly by NIH Clinical Center physicians. 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.  
• Females of childbearing potential (FCBP) patients will be required to have 
pregnancy testing as outlined in Appendix A:  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. 
3.2.6 Extended Dosing Phase II (optional): Cycles 21through 32 (effective with Amendment H 
version date: 05/17/2013): 
• After 12 cycles of extended dosing of lenalidomide (phase I), 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 one 
additional year. For those patients who are ready to begin extended dosing phase II, 
treatment may be delayed until amendment H is approved by the IRB. 
• Lenalidomide ordered in extended dosing phase II will be prescribed monthly by 
NIH Clinical Center physicians. 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.   
• FCBP patients will be required to have pregnancy testing as outlined in Appendix 
A; 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. 


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3.3 
DOSE MODIFICATIONS 
3.3.1  Dose Reductions: Induction Phase 
 
Lenalidomide 
Carfilzomib 
Dexamethasone 
Cycles 1-4 
Dexamethasone 
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 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 
3.3.2.3 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.   
3.3.2.4 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.  
3.3.2.5 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. 


Abbreviated Title:  CRd in Newly Diagnosed MM 
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23 
Thrombocytopenia 
Lenalidomide 
Carfilzomib 
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 38.3o 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.   
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 or infections controlled by 
appropriate therapy are exempt.  
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 


Abbreviated Title:  CRd in Newly Diagnosed MM 
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24 
Common Lenalidomide 
Toxicities 
Dosing Modifications 
Venous thrombosis/embolism 
Hold lenalidomide and start therapeutic anticoagulation.  Restart 
lenalidomide at investigator’s discretion at current dose level.   
Renal Dysfunction  
CrCl based on Cockcroft-Gault  
formula: CrCl = (140 – Age) x 
Mass (in kilograms) x [0.85 if 
Female] 72 x Serum Creatinine (in 
mg/dL) 
• 
CrCl 31-60 ml/min – Dose reduce lenalidomide to 10 mg 
daily from Days 1-21 
• 
CrCl ≤30 mL/min (not requiring dialysis) – Dose reduce 
Lenalidomide to 15 mg every 48 hours 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.  
 
Common Carfilzomib Toxicities 
Dosing Modifications 
Allergic Reaction/Hypersensitivity 
 
• 
Grade 2-3.  Hold carfilzomib until ≤ Grade 1 and resume at 
full carfilzomib dose 
• 
Grade 4.  Discontinue protocol therapy 
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 or Grade 
3 neuropathy.   Continue to dose.  If neuropathy persists for 
more than two weeks hold carfilzomib until resolved to ≤ 
Gr 2 without pain. Then restart at next dose level reduction. 
• 
Grade 4 neuropathy.   Discontinue protocol therapy 
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. 
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 


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25 
table 3.3.4: 
• ANC ≥ 1.0 x 109 /L 
• 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. 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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26 
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  
formula: CrCl = (140 – Age) x 
Mass (in kilograms) x [0.85 if 
Female] 72 x Serum Creatinine 
(in mg/dL) 
• 
CrCl 31-60 ml/min – Dose reduce lenalidomide to 10 mg 
daily from Days 1-21 
• 
CrCl ≤30 mL/min (not requiring dialysis) – Dose reduce 
Lenalidomide to 15 mg every 48 hours 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 will be observed in the hospital for administration of cycle 1 Days 1 and 2 of 
therapy. 
3.3.7.2 Routine labs (cbc, chemistry panel 14, LDH, magnesium, uric acid, phosphate) will be 
performed on Day 1, 2, 8, 15, and 22 of cycle 1 and Day 1 (or within 2 days prior to 
day 1) of each cycle during cycles 1-8 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 (or within 2 days prior to day 1) of each cycle in the 
induction phase 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 (or within 2 days prior to day 1) of each cycle during cycles 1-8, and 
day 1 (or within 7 days prior to day 1) of every third cycle during extension phase I and 
II. If patient obtains CR, then a 24 hour UPEP will be performed to confirm CR status. 
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 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 of every third cycle during 
extension phase.       
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 of each cycle 
during cycles 1-8 and on Day 1 of every third cycle during extension phases I and II. 


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27 
(This can be delayed up to one week per PI discretion for clinical and/or logistical 
reasons). 
3.3.7.6 Additional laboratory studies and clinic visits will be performed if clinically indicated. 
3.3.7.7 FDG-PET scan will be performed on patients in the Molecular Imaging Department 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 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 scan and/or DW-MRI at 
progression. The radiation dose from the procedure will be a maximum of 2.1 rem per 
year; this is within the RSC guidelines of 5.0 rem per year for adults. 
3.3.7.8 With amendment P, patients who remain on study will be asked to undergo DW-MRI 
on an annual basis, however, these will not be mandatory.  
3.3.7.9 During lenalidomide extension phases I and II, FCBP patients will still be required to 
have pregnancy testing as outlined in Appendix A.  Local treating physicians will be 
required to submit results to NIH clinical center for review.   
 


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28 
3.4 
STUDY CALENDAR 
Study 
Pre-
treatment 
Induction Treatment 
Extended Treatment 
End of 
Treatment 
and 
Follow-Up 
Disease 
Progression 
at any Time 
Pointl, p 
Cycle 1 
Cycle 2-8 
Extended Dosing Phase (Phases I and II) 
Every 
3-6 months 
(j,p,r,s,t) or 
annual (u) 
Day 
1 
Day 
2 
Day 
8 
Day 
15 
Day 
22 
Day 
1p 
CR 
Achieved/
End of 
Cycle 
8m,n,o,p 
Day 1 of 
Cycles 9, 
12, 15, 18, 
21, 24, 27, 
30c,e,r,s 
Day 1 
Cycles 9, 
12, 15, 
18p,r,s 
Day 1 
Cycles 
9-32r,s 
Phase I-CR Achieved 
(Cycle 9-20)/ End of 
Cycle 20 and Phase II-
CR achieved (Cycle 21-
32)/ Treatment 
termination m,n,o,p,r,s 
Medical Record 
Review 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
H&P 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
 
 
 
 
ECOG 
x 
 
 
 
 
 
x 
 
x 
 
 
 
 
 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Routine Labsa 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
 
 
x 
x 
Urine for UPEP 
and IFE m 
x 
xm 
 
 
 
 
xm 
xm 
xm 
 
 
xm 
x 
x 
Viral Studiesb 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Register for 
REMS® 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testc 
xc 
xd 
xd 
xe 
xe 
xe 
xc 
 
xc,e 
 
xc.e 
xe 
xe 
 
Myeloma Testsf 
x 
 
 
 
 
 
x 
 
x 
 
 
xq 
x 
x 
Pharmacokinetic 
Studies 
 
xk 
 
 
 
 
x 
 
 
x 
 
 
 
 
Research 
Blood/Urine 
x 
 
x 
x 
x 
 
x 
x 
x 
 
 
xr 
x 
x 
Bone 
Marrow/Aspirate 
xg 
 
xh 
 
 
 
 
xi, o 
 
 
 
xi, o 
xi 
x 
Skeletal Survey 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
FDG PET-CT  
x 
 
 
 
 
 
 
xn 
 
 
 
xn 
xn 
x 
DW-MRI 
 
 
 
 
 
 
 
 
 
 
 
 
xu 
 


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29 
Adverse 
Events/Toxicity 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
a. Routine tests include CBC, 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.  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 A: Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods). 
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.  Subsequent serum immunofixation and urine immunofixation 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 13 8 sorting/GEP/storage and 
heavy/light chain immunoglobulin rearrangement and/or NRAS/KRAS mutations in Molecular Pathology 
h. Cycle 1 Day 2 bone marrow require aspirate alone sent for CD138 sorting (GEP studies and microenvironment studies), flow cytometry for proteasomes and 
(optional) autophagy markers.   
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, DLM, flow cytometry (bone marrow immunophenotyping of plasma cells, autophagy of plasma cells, and +/- optional assessment of proteasomes), 
CD 138 sorting/GEP/storage, and +/- heavy/light chain immunoglobulin rearrangement and/or NRAS/KRAS mutations in Molecular Pathology (optional). 
During the follow up phase, BM biopsy and aspirate studies along with peripheral blood flow cytometry will be done on a yearly basis at the discretion of 
the PI. 
j. 
At minimum, follow-up will be every 3-6 months plus or minus 6 months until progression of disease, institution of alternative therapy (if patients decide to 
receive lenalidomide to continue maintenance therapy from an outside institution, they are allowed to stay on study), or death.  Patients may be followed at 
more frequent time intervals if clinically indicated, i.e. following post-therapy toxicity.   
i. 
Patients who finish all 32 cycles of treatment and who do not continue therapy outside of this study and who have not progressed 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 continue or resume therapy at an outside facility, may be followed by clinical an d 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.   
ii. 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 or who have subsequently progressed may continue to be followed for survival by phone or clinic visit at the discretion of 


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30 
the PI. In certain circumstances (at the discretion of the patient and PI), patients who are being followed by an outside oncologist and institution 
may continue to stay on study without a formal NIH visit, but by investigator-patient or investigator-physician phone or email communication to 
capture clinical and laboratory data. During the follow up phase, research blood/urine collection is optional and at the discretion of the PI.  
k. Pharmacokinetic studies Cycle 1 Day 1 will be collected at the following time points: pre-dose, end of infusion, 5, 15, and 30 minutes and 1, 1.5, 2, 4, 6, and 
24 hours post administration for carfilzomib.   
l. 
At disease progression, marrow and FDG-PET/CT are optional. 
m. Urine for protein electrophoresis (UPEP) and immunofixation to assess for monoclonal protein in the urine (Bence-Jones proteinuria) at baseline, day 1 of 
each cycle during cycles 1-8, day 1 of every third cycle during cycles 9-32, and at treatment termination. If patient achieves CR, a 24 hour UPEP will be 
performed to confirm CR status. 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 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 of every third cycle during 
extension phase.  
n. FDG-PET scan will be performed on patients in the Molecular Imaging Program 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.  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. During the follow up phase, PET scans will be done on a yearly basis at the discretion of the PI.  
o. 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. 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.  
p. Variations of +/- 3-14 days of scheduled visits are permitted. For patients who choose to undergo stem cell harvest, next cycle may be delayed for up to 5 
weeks. In the follow up phase, patients may be allowed to “skip” appointment visits at the discretion of the PI.  
q. Repeat myeloma tests at treatment termination. 
r. 
Within 7 days prior to D1 of each cycle 
s. 
May be delayed up to 7 days per PI discretion for clinical or logistical reasons 
t. 
Every attempt should be made to have all subjects complete a safety visit approximately 30 days following the last dose of study therapy.  If subjects cannot 
return to clinic, this may be done by phone.  
u. With amendment P, patients will be offered DW-MRI on an annual basis; these are optional. 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 Branch.   


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31 
 
3.5 
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 following the last dose of study therapy. 
3.5.1 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 4 non-blistering rash or blistering rash of any grade  
• Grade 4 neuropathy 
• Grade 4 hypersensitivity reaction 
• 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. 
3.5.2 Off-Study Criteria 
• Patient requests to be withdrawn from study 
• Death 
• Physician’s determination that withdrawal is in the patient’s best interest.  
• Non-protocol therapy for myeloma; however, patients who have not progressed but 
choose to continue or resume lenalidomide maintenance beyond 32 cycles at an outside 
facility may stay on study at the discretion of the investigator. 
3.5.3 Off Protocol Therapy and Off-Study Procedure 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off-study. A Participant Status Updates Form from 
the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to:  NCI Central Registration Office 
ncicentralregistration-l@mail.nih.gov. 
4 CONCOMITANT MEDICATIONS/MEASURES 
4.1 
TUMOR LYSIS SYNDROME 
4.1.1 Hydration and Fluid Monitoring: 
• 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.  Compliance must be reviewed 
with the subject and documented by the site personnel prior to initiating treatment with 
carfilzomib; treatment is to be delayed or withheld if oral hydration is not deemed to be 
satisfactory. 


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• IV hydration:  500 mL (250 mL before & 250 mL after carfilzomib) OR 1000 mL (500 
mL before & 500 mL after carfilzomib) of normal saline or other appropriate IV fluid 
formulation must be given before and after each carfilzomib dose during Cycle 1 D1 
and D2.  Total volume will be determined at the discretion of clinician and volume 
status of patient.  If lactate dehydrogenase (LDH) or uric acid is elevated at Cycle 2, 
Day 1, then the recommended IV hydration should be repeated for Cycle 2.  The goal 
of the hydration program is to maintain robust urine output, (e.g., ≥ 2 L/day).  Subjects 
should be monitored periodically during this period for evidence of fluid overload. 
• 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: 
• 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.   
• 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:   
• Signs and symptoms indicative of TLS, such as fevers, chills/rigors, dyspnea, nausea, 
vomiting, muscle tetany, weakness, or cramping, seizures, and decreased urine output. 
• Patients will be admitted to the inpatient hospital and observed while receiving Cycle 1 
Days 1 and 2 of therapy. 
4.1.4 Management: 
• 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. 
• 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: 
• 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 
BONE DISEASE/EXTRAMEDULLARY DISEASE  
4.2.1 Radiation Therapy 
Subjects may receive radiation for treatment of uncontrolled pain, cord compression, vertebral 
instability/impending fracture, etc. 


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33 
4.2.2 Kyphoplasty/Vertebroplasty 
Subjects may receive kyphoplasty/vertebroplasty for symptomatic vertebral compression 
fractures.    
4.2.3 Bisphosphonate Therapy 
Approved bisphosphonate therapy (zoledronic acid or pamidronate) is allowed.  Patients will be 
monitored for renal function and osteonecrosis of the jaw.  Patients may require prior evaluation 
from dental specialist before instituting bisphosphonates.   
4.3 
HYPERCALCEMIA 
Patients may receive treatment for hypercalcemia including hydration, bisphosphonates, 
furosemide, steroids, calcitonin, etc.  
4.4 
TRANSFUSIONS/GROWTH FACTORS 
• Subjects may receive RBC or platelet transfusions if clinically indicated.   
• Subjects may receive supportive care with erythropoietin or darbopoetin.   
• Colony-stimulating factors may be used if neutropenia occurs but should not be given 
prophylactically.   
4.5 
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. 
4.6 
HSV, VSV PROPHYLAXIS 
Oral Valacyclovir of 500 mg daily or oral Acyclovir of 800 mg BID throughout all cycles in 
which carfilzomib is given.   
 
 
 
 
 


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34 
5 
BIOSPECIMEN COLLECTION 
5.1 
 CORRELATIVE SAMPLES FOR RESEARCH/PHARMACOKINETIC STUDIES 
NOTE:  Effective with Amendment L (version date 07/15/2015), bone marrow aspirate and 
biopsy will be obtained for research studies at the discretion of the PI.  Effective with 
Amendment N (version date 07/25/2017), samples for next generation sequencing (NGS) were 
added.   
Correlate 
Baseline 
Day 2 
Post 24 Hour Infusion 
During Cycles 2-8 If CR 
achieved or End of Cycle 8 
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/treatment 
termination 
Progression of disease 
Pathology/IHC 
X 
 
X 
X 
X 
Multiparametric Flow 
Cytometry 
X 
 
X 
X 
X 
FISH/Cytogenetics 
(optional) 
X 
 
 
 
X 
Molecular pathology for light or 
heavy chain immunoglobulin 
rearrangement and/or KRas and 
NRas mutation analysis 
 
X 
 
 
 
X (optional) 
 
X (optional) 
 
X 
CD138+ Sorting/GEP 
Profiling/Microenvironment  
 
X 
 
X 
 
X 
 
X 
 
X 
Flow cytometry for proteasomes 
X 
X 
X (optional) 
X (optional) 
X 
Flow cytometry for autophagy 
X 
X 
X 
X 
X 
Other research labs as below 
including Next Generation 
Sequencing (NGS) 
(Added with Amendment N; subjects 
beyond this cycle) 
X 
X 
Storage 
X 
X 
X 
X 
X 
5.1.1 Bone Marrow and Peripheral Blood 
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 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 


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35 
outlined in Appendix B 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 Katherine Calvo, MD, PhD. 
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 Maryalice Stetler-Stevenson 
of the flow cytometry unit in the NCI Laboratory of Pathology 
iii. FISH and cytogenetics:  Interphase FISH/cytogenetics will be performed on patients 
enrolled in this protocol under the direction of Diane Arthur of the Molecular 
Diagnostics Core Laboratory of the NCI Branch.  (NOTE:  D. Arthur no longer at 
NIH/NCI, her involvement ended and these studies no longer being done as of 
Amendment M.) 
iv. Myelomatous plasma cells will be studied at the single cell level by multiparametric 
flow cytometry for markers of autophagy, pre- and post-therapy, including but not 
limited to the technique described by S.T. Rosen et al. J. Biol. Chem. 284:26816-
26830, 2009 under the direction of Jane Trepel.   
v. Flow cytometry for proteasomes under the direction of Irina Maric, MD. 
vi. Cell Sorting, GEP profiling, whole exome sequencing, microRNA analysis and 
microenvironment interactions - Marrow aspirate will be sent to the lab of Dr. 
Katherine Calvo (Building 10 Room 2C418A) in the Department of Laboratory 
Medicine and sorted into CD 138 + and CD 138 – fractions.  Dr. Calvo and Dr. 
Wang will also perform the below assays for unsorted bone marrow aspirate for VDJ 
sequencing and assessment of MRD negativity.  
• GEP profiling targeted exome sequencing, and VDJ sequencing for MRD 
assessment: Bone marrow aspirates will be collected and sent to the Calvo 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 Memorial Sloan Kettering (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 


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36 
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. in a coded, linked  manner. 
• CD 138- fractions will be analyzed for microenvironment interactions such as 
cytokine profiling, miRNAs, etc. in the Calvo 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 5.2.1 for storage of bone marrow biobank. As of Amendment N, 
aspirate samples will be stored in DLM under Dr. Calvo. 
• Aspirate samples may also undergo identification of downstream signaling 
targets, proteasome activity, and ubiquitination pathways on cell lysate or 
marrow aspirate. 
vii. Additional but optional 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 included 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) and batched at the NIH until 
time for shipment, at which time, the samples will be sent to:  
ATTN: Elliot Rosen  
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 


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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 and 2 years, and during follow up phase. 
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 aberations. 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 approach used in solid malignancies. Blood collection will 
involve two 10 mL EDTA tubes. 
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.  
5.1.2 Research Blood/Serum and Urine  
Blood: 
a. 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, Day 2, Day 8 and Day 15 of Cycle 1, Day 1 of 
every cycle during cycles 2-8, Day 1 of every third cycle during cycles 9 and beyond 
during extended dosing phases (I and II), during Cycles 1-8 if CR is achieved or at the 
end of cycle 8, during cycles 9-20 if CR is achieved or at the end of cycle 20, during 
cycles 21-32 if CR is achieved or at treatment termination, and at any time point if the 
patient has progression of disease.   
Samples may be collected within 2 days prior to each of the above time points during 
the induction phase; and within 7 days prior to each of the above time points during the 
extension phase I and II phase. This does not include the blood draws for 


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38 
pharmacokinetic analysis as outlined below.  Samples may also be collected every 3-6 
months during the post-maintenance follow-up period. 
b. The standard number of peripheral blood research tubes drawn for collection and 
storage at each of the above timepoints may include but are not limited to the 
following:  one 8 mL serum separator tube (SST), one 10 mL sodium heparin tube 
(GGT), 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 Calvo Lab.   
Urine: 
a. 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 2, Day 8 and Day 15 of Cycle 1, Day 1 of 
every cycle during cycles 2-8, Day 1 of every third cycle during cycles 9 and beyond 
during extended dosing phases (I and II), during Cycles 1-8 if CR is achieved or at the 
end of cycle 8, during cycles 9-20 if CR is achieved or at the end of cycle 20, during 
cycles 21-32 if CR is achieved or at treatment termination, and at any time point if the 
patient has progression of disease.  
Samples may be collected within 2 days prior to each of the above time points during 
the induction phase; and within 7 days prior to each of the above time points during the 
extension phase I and II phase. The amount of urine collected will be dictated by the 
number of experiments to be performed.  
All Samples: 
a. Collection and storage of peripheral blood and urine outlined in Appendix C.  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. Please e-mail Julie Barnes at 
Julie.barnes@nih.gov and Paula Carter pcartera@mail.nih.gov at least 24 hours before 
transporting samples (the Friday before is preferred). 
For sample pickup, page 102-11964. 
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 Julie Barnes by e-mail or at 240-
760-6044. 
b. 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: 
i. 
Peripheral blood flow cytometry assessing for circulating plasma cells under 
the direction of Maryalice Stetler-Stevenson, MD.   
ii. 
Subunit profiling and activity of circulating proteasomes by enzyme-like 


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39 
immunosorbent assay  
iii. 
Apoptosis assays pre and post-carfilzomib to identify necrotic or late stage 
apoptotic cells  
iv. 
Immunolocalization studies   
v. 
Markers of bone turnover and disease activity 
vi. 
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.  
vii. 
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 under the direction of Irina Maric, MD 
5.1.3 Pharmacokinetic Samples 
a. PK Sampling Schedule:  Samples will be collected at the following time points on 
C1D1: pre-dose, end of infusion, 5, 15, and 30 minutes and 1, 1.5, 2, 4, 6, and 24 hr 
post administration for carfilzomib. The plasma levels of lenalidomide will be collected 
on Cycles 2-8 D1 during induction phase and every 3 cycles during extended dosing 
with lenalidomide to determine steady-state lenalidomide levels. 
b. Sample Requirements and Handling:  A venous blood sample will be collected in a 6-
ml sodium heparin (green top) tube (BD Sodium Heparin 367878 or 367879) at each 
time point. Samples should immediately be placed on wet ice and refrigerated. The date 
and exact time of each blood draw should be recorded on the sample tube and the PK 
sheet.  Questions regarding the collection of these samples can be directed to Dr. Mark 
Roschewski. A 6.0 ml aliquot of whole blood will be spun to obtain the plasma, which 
will be kept frozen at -70C until analysis. For sample pickup, page 102-11964. 
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 Julie Barnes by e-mail or at 240-
760-6044.  
c. Sample Analysis:  The determination of lenalidomide and carfilzomib concentrations in 
all plasma samples, as well as the pharmacokinetic data analysis, will be performed by 
the Blood Processing Core (BPC) (For questions regarding sample processing, contact 
Julie Barnes by e-mail or at 240-760-6044). Samples will be analyzed using a validated 
LC-MS/MS method developed at the end of the trial.  
d. Pharmacokinetic Analysis:  Non-compartmental and compartmental pharmacokinetic 
and pharmacodynamic modeling of carfilzomib in plasma will be performed using 
WinNonlin 5.0 (Pharsight, Inc., Mountain View, CA).  PK parameters derived from 
plasma concentration-time data may include CMAX, TMAX, AUC, CL, Vd, and t1/2. 
5.1.4 Imaging 
5.1.4.1 FDG-PET/CT 
5.1.4.1.1 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 


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40 
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. Patients who remain 
on study will have PET scans performed on an approximate annual basis during the post-
maintenance follow-up phase. At PI discretion, patient may be asked to have an additional PET-
CT at progression.  
5.1.4.1.2 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. 
5.1.4.1.3 Research Radiation Exposure  
The radiation dose from the procedure will be a maximum of 2.1 rem per year; this is within the 
RSC guidelines of 5.0 rem per year for adults. 
5.1.4.2 DW-MRI 
5.1.4.2.1 Schedule  
We plan to obtain DW-MRI scans on patients on an annual basis through completion of follow up for 
comparison with PET/CT findings. 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. 
5.1.4.2.2 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 this 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. 


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5.1.4.2.3 Results 
Patients will be informed of 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. 
5.2 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. 
Should a CRIS screen not be available, the CRIS downtime procedures will be followed. 
Samples will not be sent outside NIH without appropriate approvals and/or agreements, if 
required. 
5.2.1 Procedures for Collecting, Processing, and Storage of Bone Marrow biopsies 
• See Appendix B. 
• 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.   
• Materials for research studies will be documented on form NIH 2803-1. 
• 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 Calvo Lab/DLM). 
• For the purposes of storage, all research samples except stored serum and urine will be 
assigned a unique number and cataloged.  Viably frozen cells will be stored in a 
temperature controlled, alarm secured nitrogen tank in the NIH Clinical Center 
Department of Hematopathology.  Frozen bone marrow biopsies and processed biologic 
material (such as RNA and protein) will be stored at -80°C in a temperature-controlled, 
alarm-secured freezer.  Prior to Amendment N, all research samples were stored in the 
laboratory of the Lymphoid Malignancies branch. As of Amendment N, 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 Dickran Kazandjian, M.D. at 240-383-6311 or Katherine Calvo, MD, PhD 
at 301-594-9578. 
• 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. 
5.2.2 Procedures for stored serum, peripheral blood, and urine specimens in the Blood 
Processing Core: 
See Appendix C for processing of samples. 
Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the 
Friday before is preferred). 
For sample pickup, page 102-11964. 


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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 NCIBloodcore@mail.nih.gov. 
• All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered 
and stored in the LABrador (aka LabSamples) utilized by the BPC. This is a secure 
program, with access to LABrador limited to defined BPC personnel, who are issued 
individual user accounts. Installation of LABrador is limited to computers specified by 
Dr. Figg. These computers all have a password restricted login screen. All BPC lab 
personnel with access to patient information complete the NIH online Protection of 
Human Subjects course.  
• LABrador creates a unique barcode ID for every sample and sample box, which cannot 
be traced back to patients without LABrador 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 LABrador. 
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 LABrador. 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.  
5.2.3 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 Hematology 
Section (HS) of the NCI Laboratory of Pathology (LP) or the Hematology Section (HS) 


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of the DLM, CC.  
• Samples are coded by the LP HS, DLM HS or Calvo Lab.  Tissue sections, or peripheral 
blood samples will be obtained and stored in the Calvo lab without any personal 
identifiers and will be labeled with the anonymous LP HS or DLM HS 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 Dr. 
Katherine Calvo.  
• The Calvo laboratory may 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 Calvo 
laboratory. 
5.3 
SAMPLES FOR GENETIC/GENOMIC ANALYSIS 
5.3.1 Description of the scope of genetic/genomic analysis 
Genomic testing will be done as described in Section 5.1.1.  
5.3.2 Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized 
Confidentiality for genetic samples will be maintained as described in Section 5.2.  In addition, a 
Certificate of Confidentiality has been obtained for this study. 
5.3.3 Management of Results 
Subjects will be contacted if 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 
incidental 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 blood 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. 
5.3.4 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.    
6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system (C3D) and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 


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with the data management efforts. All data obtained during the conduct of the protocol will be 
kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant. 
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed from Study Day 1 through 30 days after the last dose of study drug 
or until return to baseline or stabilization of event, whichever is later, or until the subject comes 
off-study. 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 considered an AE 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 the 
requirements in section 7.2.  
6.1.1 Long-term follow-up  
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. All relevant data will also be entered on a computer database 
from which formal analyses are done. The primary source documentation will include patient 
eligibility 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, data will be entered into the study database and filed 
in the medical record. Additional blood or tissue samples/results drawn on patients enrolled in 


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this protocol between scheduled visits may be forwarded and entered into the database as 
indicated. 
6.2 
DATA SHARING PLANS 
6.2.1 Human Data Sharing Plan 
What data will be shared? 
I will share human data generated in this research for future research as follows: 
_X_ Coded, linked  data in an NIH-funded or approved public repository.  _X_ Coded, linked 
data in BTRIS (automatic for activities in the Clinical Center) 
_X_ Identified or coded, linked or identified data with approved outside collaborators under 
appropriate agreements. How and where will the data be shared?  
Data will be shared through: 
_X_ An NIH-funded or approved public repository.  Insert name or names: 
ClinicalTrials.gov, dbGAP 
_X_ BTRIS (automatic for activities in the Clinical Center) 
_X_ Approved outside collaborators under appropriate individual agreements. 
_X_ Publication and/or public presentations. 
When will the data be shared? 
_X_ At the time of publication or shortly thereafter. 
6.2.2 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 
6.3.1 Timing 
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 and 18 and every third cycle during Cycles 21-32:  
Cycles 21, 24, 27, 30 and end of 32. 
6.3.2 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 


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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 
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”(30). 
6.3.3 Response Criteria from International Myeloma Working Group Criteria(31) and addition 
of nCR category(6, 21): 
6.3.3.1 Evaluation of Response Criteria 
• 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(6, 21) 
• Very Good Partial Response (VGPR)  
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 


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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:  
▪ 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.  
▪ Urine M-component and/or (the absolute increase must be ≥200mg/24h  
▪ 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.  
▪ Bone marrow plasma cell percentage: the absolute % must be ≥10%  
▪ Definite development of new bone lesions or soft tissue plasmacytomas or definite 
increase in size of existing bone lesions or soft tissue plasmacytomas  
▪ Development of hypercalcemia that can be attributed solely to the plasma cell 
proliferative disorder  
• Relapse from CR 
Any one or more of the following: 
▪ Reappearance of serum or urine M-protein by immunofixation or electrophoresis. 
(Appearance of monoclonal or oligoclonal bands that are different from original 
isotype may not be defined as “relapse from CR”. 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”.(32, 33)) 
▪ Development of ≥ 5% plasma cells in the bone marrow 
▪ Appearance of any other sign of progression (i.e., new plasmacytoma, lytic bone 
lesion, hypercalcemia 
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.    
6.3.5 Progression-Free Survival 
PFS is defined as time of start of treatment to time of progression or death, whichever occurs 
first. 
6.3.6 Overall Survival 
Overall survival is defined as the time of start of treatment to death from any cause. 
6.3.7 Overall response rates after 8 cycles 
Overall response rates (ORR) is PR+VGPR+CR after 8 cycles of therapy. 
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 


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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).  
6.4.1 Attribution of the AE 
• Definite: The AE is clearly related to the study treatment. 
• Probable: The AE is likely related to the study treatment. 
• Possible: The AE is may be related to the study treatment. 
• Unlikely: The AE is doubtfully related to the study treatment. 
• Unrelated: The AE is clearly NOT related to the study treatment. 
7 
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN 
7.1 
DEFINITIONS 
Please refer to definitions provided in Policy 801: Reporting Research Events found here. 
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 here. 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 here.  
7.3 
NCI CLINICAL DIRECTOR REPORTING 
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical 
Director.  A separate submission is not necessary as reports in iRIS will be available to the 
Clinical Director. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to 
progressive disease.   
To report these deaths, please send an email describing the circumstances of the death to Dr. 
Dahut at 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 once a week when patients are being actively treated on the 
trial to discuss each patient in detail. 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 in a timely manner. Events meeting requirements for expedited reporting 
as described in section 7.2 will be submitted within the appropriate timelines. .  
The principal investigator will review adverse event and response data on each patient to ensure 


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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 PROTOCOL/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 convenience) is not considered a serious adverse event.  
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 


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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. 
• 
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. 


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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/pages/viewpage.action?pageId=157942842 
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 due to disease progression is part of the study objectives, and captured as an endpoint in 
this study, it 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 CCRsafety@mail.nih.gov.  
The CCR Office of Regulatory Affairs will send all reports to the manufacturer as described 
below. 
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 
faxed/emailed together to Amgen Global Safety. 
FAX: 888-814-8653 (toll-free, US only) 
Toll-free Number: 888-814-8653  
Email: svc-ags-in-us@amgen.com 
8.5.2 SAE Reporting to Celgene  
All adverse experience reports must include the patient number, age, sex, weight, severity of 
reaction (e.g. mild, moderate, severe), relationship to drug (e.g. probably related, unknown 
relationship, definitely not related), date and time of administration of test medications and all 
concomitant medications, and medical treatment provided.   The investigator is responsible for 
evaluating all adverse events to determine whether criteria for “serious” and as defined above are 
present.  The investigator is responsible for reporting adverse events to Celgene as described 
below. 
Serious adverse events (SAE) are defined above.  The investigator must inform Celgene in 
writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE as soon as possible 
or at least within 24 hours of being aware of the event.  The date of awareness should be noted 
on the report.  The written report must be completed and supplied to Celgene by facsimile within 
24 hours/1 business day at the latest on the following working day.  The initial report must be as 


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complete as possible, including an assessment of the causal relationship between the event and 
the investigational product(s), if available.  Information not available at the time of the initial 
report (e.g., an end date for the adverse event or laboratory values received after the report) must 
be documented on a follow-up report.  A final report to document resolution of the SAE is 
required.  The Celgene tracking number (RV-MM-PI-0663) and the institutional protocol 
number should be included on SAE reports (or on the fax cover letter) sent to Celgene.  A copy 
of the fax transmission confirmation of the SAE report to Celgene should be attached to the SAE 
and retained with the patient records. 
Celgene Corporation 
Drug Safety 
86 Morris Avenue 
Summit, N.J. 07901 
Toll Free:  (800)-640-7854 
Phone:  
(908) 673-9667 
Fax: 
(908) 673-9115 
8.5.3 E-mail:  
drugsafety@celgene.com Reporting Pregnancy to Amgen 
If a subject or spouse or partner of a subject becomes pregnant while enrolled in this clinical trial 
or up to three months following administration of carfilzomib, Amgen Drug Safety must be 
notified within 24 hours of the Investigator, designee, or site personnel learning of the pregnancy 
(See Amgen Drug Safety and Pharmacovigilance Contact information above).  If the subject is 
pregnant, carfilzomib must be withheld.   
Subjects, spouses, or partners will be followed through the outcome of the pregnancy.  The 
Investigator will be required to report the results to Amgen Drug Safety. 
If the outcome of the pregnancy meets a criterion for immediate classification as an SAE—
spontaneous abortion (any congenital anomaly detected in an aborted fetus is to be documented), 
stillbirth, neonatal death, or congenital anomaly—the Investigator should repeat the procedures 
for expedited reporting of SAEs as outlined above. 
8.5.4 Reporting Pregnancy to Celgene  
Pregnancy of a female subject or the female partner of a male subject occurring while the subject 
is on lenalidomide or within 4 weeks after the subject’s last dose of lenalidomide are considered 
expedited reportable events.  If the subject is on lenalidomide, it is to be discontinued 
immediately and the subject is to be instructed to return any unused portion of lenalidomide to 
the Investigator.  The pregnancy must be reported to Celgene Drug Safety within 24 hours of the 
Investigator’s knowledge of the pregnancy by phone and facsimile using the SAE Form. 
The Investigator will follow the pregnant female until completion of the pregnancy, and must 
notify Celgene Drug Safety of the outcome as specified below.  The Investigator will provide 
this information as a follow-up to the initial SAE. 
If the outcome of the pregnancy meets the criteria for immediate classification as a SAE (i.e., 
spontaneous abortion [any congenital anomaly detected in an aborted fetus is to be documented], 
stillbirth, neonatal death, or congenital anomaly), the Investigator should follow the procedures 
for Expedited Reporting of SAEs to Celgene (i.e., report the event to Celgene Drug Safety by 
facsimile within 24 hours of the Investigator’s knowledge of the event). 
Any suspected fetal exposure to lenalidomide must be reported to Celgene within 24 hours of 


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being made aware of the event.  The pregnant female should be referred to an 
obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and 
counseling. 
All neonatal deaths that occur within 30 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 30 days that the Investigator suspects is 
related to the in utero exposure to lenalidomide should also be reported. 
In the case of a live “normal” birth, Celgene Drug Safety should be advised as soon as the 
information is available 
8.6 
REPORTING PREGNANCY TO CCR   
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 
SAEs.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) 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 and for 28 
days after the last dose of study therapy. 
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 28 days after the last dose 
should, if possible, be followed up and documented. 
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 NON-ADHERENCE REPORTING 
Protocol non-adherence is defined as any noncompliance with the clinical trial protocol, GCP, or 
protocol-specific procedural requirements on the part of the participant, the Investigator, or the 


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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 non-adherence identified by 
the Staff or the site Monitor on the OSRO Site Protocol Non-Adherence Log.  The protocol-
specific, cumulative non-adherence log should be maintained in the site essential documents file 
and submitted to OSRO via OSROMonitoring@mail.NIH.gov on the first business day of each 
month over the duration of the study. In addition, any non-adherence to the protocol should be 
documented in the participant’s source records and reported to the local IRB per their guidelines. 
OSRO required protocol non-adherence 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  
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary study endpoints; adherence to the protocol, regulations, and 
SOPs; and human subjects protection. This is done through independent verification of study 
data with source documentation focusing on: 
• Informed consent process 
• Eligibility confirmation 
• Drug administration and accountability 
• Adverse events monitoring 
• Response assessment. 
The monitoring program also extends to multi-site research when the CCR is the coordinating 
center. 
This trial will be monitored by personnel employed by an CCR contractor. Monitors are 
qualified by training and experience to monitor the progress of clinical trials. Personnel 
monitoring this study will not be affiliated in any way with the trial conduct. 
10 STATISTICAL CONSIDERATIONS   
10.1 STUDY DESIGN/PRIMARY ENDPOINTS 
This is a single arm phase II study designed to evaluate efficacy of combinational therapy of 
carfilzomib, dexamethasone, and lenalidomide in newly diagnosed untreated MM patients.  The 
primary objectives of this study are to determine if the combination of carfilzomib, lenalidomide 
and dexamethasone has acceptable toxicity in patients with newly diagnosed MM.  
10.2 SAMPLE SIZE DETERMINATION 
The sample size on which the trial will be based will be that necessary to demonstrate if the rate 
of grade 3 or worse neurologic toxicity is lower than 10%, or if it could be consistent with a rate 
which is greater than 10%, in which case it would be considered excessive. 
We will plan to enroll a total of 45 evaluable patients in a single cohort and score each patient for 
the development of grade 3 or worse neurologic toxicity in the first two completed cycles of 
treatment. If we enroll 45 patients and if 5 or more have grade 3 or worse neurologic toxicity, 


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then the probability that the true rate of grade 3+ neurologic toxicity is 5% is 7.3% while the 
probability that the true rate of grade 3+ neurologic toxicity is 15% is 82.5%. Thus, the 
appearance of 5 or more patients with grade 3+ neurologic toxicity in 45 patients will provide 
evidence that the true rate of toxicity is consistent with 15%, and will be considered excessive. 
10.3 STATISTICAL ANALYSES 
10.3.1 Analysis of the Primary Endpoints 
The 90% and 95% confidence intervals will be constructed around the observed fraction of 
patients with grade 3+ neurologic toxicity, and will be reported along with the observed 
incidence. If 5/45 are noted to have grade 3+ neurologic toxicity, the exact two-sided 90% CI 
bound extends from 4.5% to 22.0%, thus confirming that this rate of toxicity is likely to exceed 
5%, and is consistent with as high as 22%. 
As an early stopping rule for toxicity for the first 20 patients: if 4 patients are found to have 
grade 3+ neurologic toxicity in the first two completed cycles of treatment, no further patients 
will be enrolled. As soon as this can be determined, since the lower 80% one-sided confidence 
bound around 4/20 is 11.7%, which, being greater than 10%, would be considered demonstration 
of excessive toxicity. In fact, the lower 80% bounds range from 67% for observing 4 patients 
with grade 3+ neurologic toxicity in the first 4 patients to 12% for observing 4 patients with 
grade 3+ neurologic toxicity in 20 patients. 
The rates of VGPR+CR and CR alone will also be estimated and reported. These rates are 
expected to be fairly high. Two-sided 95% confidence interval bounds will be formed around 
each of these measures. 
In order to allow for a small number of inevaluable patients, the accrual ceiling will be set at 50.  
It is anticipated that 2-3 patients per month may enroll on this trial; thus, 2 years is anticipated as 
the accrual period for this study. 
10.3.2 Analysis of the Secondary Endpoints 
Secondary endpoints are to estimate overall response rates (ORR) according to International 
Myeloma Working Group criteria after 8 cycles(31), progression free survival (PFS), duration of 
response and overall survival.  Progression free survival, duration of response and overall 
survival will be estimated using the Kaplan-Meier method and reported along with 95% 
confidence intervals at appropriate time points. 
A number of correlative studies will be performed in order to assess carfilzomib in vitro 
biological activity and investigate minimal residual disease in MM.  Minimal residual disease 
will be further explored using multi-parametric flow cytometry and PET-CT imaging. 
11 COLLABORATIVE AGREEMENTS  
11.1 AGREEMENT TYPE 
11.1.1 Cooperative Research and Development Agreement (CRADA) 
The following CRADAs are associated with this protocol:  Amgen, Inc. (formerly directly with 
Onyx Pharmaceuticals), Inc. (#02695) for Carfilzomib; Celgene Corporation (#02696) for 
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11.1.2 Material Transfer Agreements (MTA)  
11.1.2.1 Memorial Sloan Kettering Cancer Center (MSKCC) 
An MTA was executed before any of the samples described in Section 5 were shipped to Ola 
Landgren, MD, PhD at Memorial Sloan Kettering Cancer Center (MSKCC #37998).  Dr. 
Landgren will use samples for analyses of the causation, diagnostics and prognostics, and natural 
history of multiple myeloma and its precursor conditions. Additionally, the samples may be used 
for analyses of related hematologic malignancies and their precursors states (including chronic 
lymphocytic leukemia and monoclonal B-cell lymphocytosis (MBL); Waldenstrom's 
macroglobulinemia and IgM MGUS), as well as myeloproliferative neoplasms.  
Dr. Landgren is a former NIH staff member and PI/AI on this study whose ongoing role was 
originally intended to be covered by an NIH FWA Coverage Agreement to continue work on this 
study. In reviewing the samples sent to Dr. Landgren, it has been determined that samples 
received by him were coded in such a manner that it would not be possible for him to identify the 
subjects from which the samples were obtained.  Dr. Landgren also does not have any access to 
the code key to identify the subjects.  Therefore, with Amendment P, Dr. Landgren’s 
involvement on study has been updated to a Non-NIH Collaborator as he does not have access to 
patient identifiers. 
11.1.2.2 Food and Drug Administration (FDA) 
An MTA will be executed to allow the samples described in Section 5 to be shipped to the Office 
of Biotechnology at the FDA as part of the collaborative effort. The MTA will be a global CCR 
MTA (#43656) to include multiple protocols; however, Dr. Kazandjian will be the responsible PI 
regarding the multiple myeloma protocols both at the NIH and FDA site. 
12 HUMAN SUBJECTS PROTECTIONS  
12.1 RATIONALE FOR SUBJECT SELECTION 
MM is an almost always incurable plasma cell neoplasm that comprises approximately 10% 
of all hematologic malignancies.  MGUS, SMM, and MM increase in incidence with age.  
According to SEER statistics, from 2003-2007, the median age at death for myeloma is 75 years 
of age.(1) 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.(1) Despite this, 
MM affects all genders and races. 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 


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12.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol.  However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (Section 12.4), all subjects ≥ age 18 will be offered the opportunity to fill 
in their wishes for research and care, and assign a substitute decision maker on the “NIH 
Advance Directive for Health Care and Medical Research Participation” form so that another 
person can make decisions about their medical care in the event that they become incapacitated 
or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team (ACAT) for evaluation as needed for the following: an 
independent assessment of whether an individual has the capacity to provide consent; assistance 
in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the 
capacity to appoint a surrogate.  For those subjects that become incapacitated and do not have 
pre-determined substitute decision maker, the procedures described in MAS Policy 87-4 4 and 
NIH HRPP SOP 14E for appointing a surrogate decision maker for adult subjects who are (a) 
decisionally impaired, and (b) who do not have a legal guardian or durable power of attorney, 
will be followed. 
12.4 RISKS/BENEFITS ANALYSIS 
Currently, MM is an incurable malignancy with frequent complications of skeletal fractures, 
anemia, renal failure and hypercalcemia.  Combination use of novel agents, such as proteasome 
inhibitors, have significantly prolonged survival in this disease population.  However, toxicity 
from bortezomib has impacted patients with frequent episodes of debilitating neuropathy.  
Carfilzomib, a new-generation proteasome inhibitor, has been tested in phase 1 trials in 
combination with lenalidomide and dexamethasone.   
Such combinations seem to be well-tolerated with minimal toxicity and significant benefit.  The 
most recent phase 1 trial in newly diagnosed MM patients has shown 100% PR or better in 19 
patients with a median of 4 months administered.  More importantly, this treatment protocol 
takes a unique approach to investigating minimal residual disease in MM by applying novel 
techniques such as multiparametric flow cytometry and FDG PET CT as it relates to traditional 
IMWG response criteria.  
The procedures required to obtain 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, DW-
MRI and annual bone marrow biopsies, clinical experience has shown that the medical risk is 
limited.     
Adults who become unable to consent are allowed to remain on study because the protocol offers 
a prospect of direct benefit. The ongoing risks and benefits of participation for adults who 
become unable to consent are no different than those described for less vulnerable patients. 
12.5 CONSENT PROCESS AND DOCUMENTATION 
Informed consent will be obtained from all patients on this trial. There will be no minors enrolled 
< 18 years of age; therefore, assent is unnecessary. The informed consent contains all elements 
required for consent. In addition, the Principal Investigator or an associate investigator or 


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member of the research team will discuss the protocol in detail with the patient and will be 
available to answer all patient questions to allow the patient to give informed consent. 
12.5.1 Telephone Re-consent 
Telephone consent applies to instances of re-consent only. Telephone re-consent will be obtained 
and documented per OHSRP/IRBO and CCR policies and procedures. 
13 PHARMACEUTICAL INFORMATION   
13.1 CARFILZOMIB (IND # 112587) 
13.1.1 Source 
Carfilzomib was provided to investigator by Onyx Pharmaceuticals, Inc. under a CRADA.  Onyx 
provided carfilzomib during the active recruitment and treatment of this study.  However, 
ongoing communication and sharing of information, including updated risks for carfilzomib, is 
through an agreement with Amgen. 
13.1.2 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. 
Amendment P, new information from Amgen, Inc: As of July 2019, carfilzomib has been 
examined in approximately 11,000 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 
13.1.3 Formulation and Preparation  
Carfilzomib for Injection will be provided as a lyophilized powder which, when reconstituted, 
contains 2 mg/mL isotonic solution of carfilzomib Free Base in 10 mM sodium citrate buffer 
(pH 3.5) containing 10% (w/v) sulfobutylether--cyclodextrin (SBE--CD, Captisol®).  
Lyophilized Carfilzomib for Injection is stored in a refrigerator at 2°C–8°C. Water for injection 
is the only acceptable solution for reconstitution.  After addition of the appropriate amount of 
water for injection and vigorous mixing, the solution is administered as an IV infusion.  Vials are 
for single use. A volume of carfilzomib appropriate for a patient's dose will be added to 5% 
Dextrose Injection (D5W) in a sufficient amount to yield a volume to administer 100 mL (qs. 
100 mL) in a polyvinyl chloride or polyolefin container. 
For clinical use, Carfilzomib products will contain excess drug-containing fluid to compensate 
for product container and administration set priming volumes. 
Before dispensing Carfilzomib products from the Pharmacy, an administration set suitable for a 
portable pump (e.g., Gemstar set 13758-28) will be attached, the administration set tubing will be 
primed with drug-containing fluid, air will be purged from the tubing (but not the product 
container), and the administration set will be capped with a Luer locking cap. 
Lyophilized Drug Product:   Lyophilized Carfilzomib for Injection is an investigational 
therapeutic agent provided in a single-dose vial as a sterile, lyophilized powder in the following 
dosages: 
• 25 mg Single-Use Glass Vial / 8 pk Carton 
Each single-dose vial contains 25 mg of carfilzomib in a 20 mL labeled glass vial with an 
elastomeric stopper and Red flip-off lid. The product is supplied to the site in labeled 


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carton(s) containing eight (8) single-use vials/carton and is shipped and stored between 
2°C - 8°C (36°F - 46°F).  Remove the Red flip-off lid on the vial and aseptically add 12 
mL of Water for Injection, USP to the lyophilized drug.  Gently invert the vial multiple 
times and let stand to yield a clear solution containing 2 mg/mL carfilzomib.  After 
reconstitution as instructed, a maximum total of 12.5 mL deliverable volume containing 
25 mg of carfilzomib can be withdrawn from the vial. 
• 45 mg Single-Use Glass Vial / 6 pk Carton 
Each single-dose vial provides 45 mg of carfilzomib in a 30 mL labeled glass vial with an 
elastomeric stopper and Yellow flip-off lid. The product is supplied to the site in labeled 
carton(s) containing six (6) single-use vials/carton and is shipped and stored between 2°C 
- 8°C (36°F - 46°F).  Remove the Yellow flip-off lid on the vial and aseptically add 22 
mL of Water for Injection, USP to the lyophilized drug.  Gently invert the vial multiple 
times and let stand to yield a clear solution containing 2 mg/mL carfilzomib.  After 
reconstitution as instructed, a maximum total of 22.5 mL deliverable volume containing 
45 mg of carfilzomib can be withdrawn from the vial. 
• 60 mg Single-Use Glass Vial / 4 pk Carton 
Each single-dose vial provides 60 mg of carfilzomib in a 50 mL labeled glass vial with an 
elastomeric stopper and Blue flip-off lid. The product is supplied in labeled carton(s) 
containing four (4) single-use vials/carton and is shipped and stored between 2°C - 8°C 
(36°F - 46°F).  Remove the Blue flip-off lid on the vial and aseptically add 29 mL of 
Water for Injection, USP to the lyophilized drug.  Gently invert the vial multiple times 
and let stand to yield a clear solution containing 2 mg/mL carfilzomib.  After 
reconstitution as instructed, a maximum total of 30 mL deliverable volume containing 60 
mg of carfilzomib can be withdrawn from the vial.   
Inspection:  The reconstituted drug solution in the vial should be a clear liquid. Inspect all vials 
for the presence of any suspended particles, particulate matter, discoloration or hazy solution 
prior to administration.  
If the solution is not clear or particles exist in inspected vials, record the observation in the 
appropriate Drug Accountability Log and notify Amgen immediately.  
• DO NOT USE THE DRUG. 
• Place the vial(s) into a plastic bag labeled as "Quarantined" with the date. 
• Store labeled quarantined drug in a temperature-monitored refrigerator and ensure they 
are physically segregated from the drug that is available for use. 
• Amgen will instruct the clinical site on how to proceed with quarantined vial(s). 
Calculation of Dose:  Each dose will consist of Carfilzomib for Injection administered on 
a mg/m2 basis, and should be based on the patient's actual calculated body surface area 
(BSA).  
The BSA should be calculated based upon the institution's practice and method of calculation 
should remain consistent throughout a subject's participation in the trial. 
Subjects with a BSA > 2.2 m2 will receive a dose based upon a 2.2 m2 BSA. 
Dose adjustments do not need to be made for weight gains/losses of ≤ 20%. 
13.1.4 Stability and Storage 
Lyophilized Drug Product:  Lyophilized Carfilzomib for Injection must be kept in the labeled 


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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 
Reconstituted Drug Product:  Once a drug vial is reconstituted and inspected, the clear solution 
can be stored in a refrigerator (recommended) controlled from 2°C - 8°C (36°F - 46°F) or at 
room temperature from 15°C - 30°C (59°F - 86°F) until use. Once reconstituted, Carfilzomib for 
Injection must be used on the day of reconstitution or else it must be destroyed. Prior to 
administration, all reconstituted drug should be equilibrated to room temperature. DO NOT 
FREEZE LYOPHILIZED OR RECONSTITUTED DRUG. 
Diluted Drug Product:  After dilution with D5W for clinical use, Carfilzomib should be stored 
under refrigeration. 
13.1.5 Administration Procedures 
Carfilzomib will be administered by intravenous infusion over 30-minutes through a peripheral 
or central venous access device via portable (ambulatory) pump. Care should be taken in placing 
and maintaining the product container at a level physically higher than the pump to avoid 
advancing air into the administration set tubing.  
If the patient has a dedicated line for carfilzomib administration, the line must be flushed with a 
minimum of 20 mL of normal saline prior to and after drug administration. 
13.1.6 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.  
13.2 LENALIDOMIDE   
13.2.1 Source 
REVLIMID® (lenalidomide) is provided to investigator by Celgene Inc. under Cooperative 
Research and Development Agreement (CRADA). 
13.2.2 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 


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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 and serious dermatologic reactions including Stevens-Johnson 
syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be 
fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should 
not 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 
13.2.3 Formulation and Preparation 
Lenalidomide will be supplied as capsules for oral administration. Celgene Inc. will provide 
lenalidomide 5, 10, 15 and 25 mg capsules for the Induction Phase of the protocol and for the 
extended dosing phase(s).  
13.2.4  Stability and Storage 
Lenalidomide should be stored at room temperature away from direct sunlight and protected from 
excessive heat and cold. 
13.2.5 Administration Procedures 
Celgene Corporation 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.    
13.2.6 Incompatibilities 
Results from human in vitro metabolism studies and nonclinical studies show that REVLIMID is 


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neither metabolized by nor inhibits or induces the cytochrome P450 pathway suggesting that 
lenalidomide is not likely to cause or be subject to P450- based metabolic drug interactions in 
man. 
Digoxin:  When digoxin was co-administered with lenalidomide, the digoxin AUC was not 
significantly different; however, the digoxin Cmax was increased by 14%. Periodic monitoring 
of digoxin plasma levels, in accordance with clinical judgment and based on 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  
13.3 DEXAMETHASONE 
13.3.1 Source 
Dexamethasone will be provided from commercial sources by the NIH Clinical Center Pharmacy 
Department.  
13.3.2 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%) 
13.3.3 Formulation and Preparation 
• 
Oral Tablet (Scored): 4 mg 
• 
Injection, solution, as sodium phosphate:  4 mg/mL (1 mL, 5 mL, 30 mL) 
13.3.4 Administration Procedures 
• 
Oral: Administer with meals to decrease GI upset.  
• 
I.V.: Administer intravenously over 10 minutes.  


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13.3.5 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 (probable) 
 
 
 
 


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Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D, Vesole DH, Jagannath S, et al. A 
phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone 
as a frontline treatment for multiple myeloma. Blood. 2012;120(9):1801-9. 
22. 
Paiva B, Vidriales MB, Cervero J, Mateo G, Perez JJ, Montalban MA, et al. 
Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple 
myeloma patients who undergo autologous stem cell transplantation. Blood. 2008;112(10):4017-
23. 
23. 
Martinez-Sanchez P, Montejano L, Sarasquete ME, Garcia-Sanz R, Fernandez-Redondo 
E, Ayala R, et al. Evaluation of minimal residual disease in multiple myeloma patients by 
fluorescent-polymerase chain reaction: the prognostic impact of achieving molecular response. 
Br J Haematol. 2008;142(5):766-74. 
24. 
Mena E, Choyke P, Tan E, Landgren O, and Kurdziel K. Molecular imaging in myeloma 
precursor disease. Semin Hematol. 2011;48(1):22-31. 
25. 
McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, et al. 
Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 
2012;366(19):1770-81. 
26. 
Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, et al. Continuous 
lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 
2012;366(19):1759-69. 
27. 
Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T, et al. Lenalidomide 
maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 
2012;366(19):1782-91. 
28. 
Thomas A, Mailankody S, Korde N, Kristinsson SY, Turesson I, and Landgren O. 
Second malignancies after multiple myeloma: from 1960s to 2010s. Blood. 2012;119(12):2731-
7. 


Abbreviated Title:  CRd in Newly Diagnosed MM 
Version Date:  03/27/2020 
 
66 
29. 
Dimopoulos MA, Richardson PG, Brandenburg N, Yu Z, Weber DM, Niesvizky R, et al. 
A review of second primary malignancy in patients with relapsed or refractory multiple myeloma 
treated with lenalidomide. Blood. 2012;119(12):2764-7. 
30. 
Lane C, Brown M, Dunsmuir W, Kelly J, and Mangos G. Can spot urine 
protein/creatinine ratio replace 24 h urine protein in usual clinical nephrology? Nephrology 
(Carlton). 2006;11(3):245-9. 
31. 
Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. 
Consensus recommendations for the uniform reporting of clinical trials: report of the 
International Myeloma Workshop Consensus Panel 1. Blood. 2011;117(18):4691-5. 
32. 
Guimaraes C, Bergantim R, Ramalho R, Couto N, Guimaraes JT, and Trigo F. Prognostic 
value of unrelated atypical serum immunofixation patterns during multiple myeloma therapy. J 
Hematol Oncol. 2012;5:33. 
33. 
Mark T, Jayabalan D, Coleman M, Pearse RN, Wang YL, Lent R, et al. Atypical serum 
immunofixation patterns frequently emerge in immunomodulatory therapy and are associated 
with a high degree of response in multiple myeloma. Br J Haematol. 2008;143(5):654-60. 
 
 


Abbreviated Title:  CRd in Newly Diagnosed MM 
Version Date:  03/27/2020 
 
67 
15 APPENDICES 
15.1 APPENDIX A:  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 Celgene Customer 
Care Center at 1-888-423-5436.  Male patients will be asked to take the survey monthly.  
Female patients will be asked to take survey periodically (monthly if females of 
childbearing potential and every 6 months if females of not childbearing potential).   
• Female patients should not donate blood during therapy and for at least 28 days following 
discontinuation of lenalidomide. 
• Male patients should not donate blood, semen or sperm during therapy or for at least 28 
days following discontinuation of lenalidomide.   
• Only enough lenalidomide for one cycle of therapy may be prescribed with each cycle of 
therapy. Monthly phone counseling is required per the REMS® program in order to 
prescribe a one-month supply of lenalidomide.  
• All patients will be required to sign the REVLIMID, Patient-Physician Agreement Form. 
• Males must practice complete abstinence or use a condom during sexual contact with 
pregnant females or females of childbearing potential throughout the entire duration of 
lenalidomide treatment, during dose interruptions and for at least 28 days following 
lenalidomide discontinuation, even if he has undergone a successful vasectomy.  See 
below for further details 
• Females of childbearing potential must agree to use two reliable forms of contraception 
simultaneously or to practice complete abstinence from heterosexual intercourse during 
the following time periods related to this study: 1) for at least 28 days before starting 
lenalidomide; 2) throughout the entire duration of lenalidomide treatment; 3) during dose 
interruptions; and 4) for at least 28 days after lenalidomide discontinuation.  See below 
for further details. 
Females not of childbearing potential must sign the REVLIMID, Patient-Physician Agreement 
Form that says you are presently not pregnant and do not have the ability to have children.   
Risks Associated with Pregnancy 
The use of lenalidomide in pregnant females and nursing mothers has not been studied nor has 
the effect of the lenalidomide on human eggs and sperm.  Lenalidomide is structurally related to 
thalidomide.  Thalidomide is a known human teratogenic active substance that causes severe life-
threatening birth defects.  An embryofetal development study in animals indicates that 
lenalidomide produced malformations in the offspring of female monkeys who received the drug 
during pregnancy.  The teratogenic effect of lenalidomide in humans cannot be ruled out.  
Therefore, a risk minimization plan to prevent pregnancy must be observed. 
All study participants must be registered into the mandatory REMS® program, and be willing and 
able to comply with the requirements of REMS®. 


Abbreviated Title:  CRd in Newly Diagnosed MM 
Version Date:  03/27/2020 
 
68 
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:   
• Highly effective methods: 
▪ Intrauterine device (IUD) 
▪ Hormonal (birth control pills, injections, implants) 
▪ Tubal ligation 
▪ Partner’s vasectomy 
• Additional effective methods: 
▪ Male condom 
▪ Diaphragm 
▪ Cervical Cap 
Because of the increased risk of venous thromboembolism in patients with multiple myeloma 
taking lenalidomide and dexamethasone, combined oral contraceptive pills are not recommended. 
If a patient is currently using combined oral contraception the patient should switch to one of the 
effective method listed above. The risk of venous thromboembolism continues for 4−6 weeks after 
discontinuing combined oral contraception. The efficacy of contraceptive steroids may be reduced 
during co-treatment with dexamethasone. 
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of 
infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be 


Abbreviated Title:  CRd in Newly Diagnosed MM 
Version Date:  03/27/2020 
 
69 
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 


Abbreviated Title:  CRd in Newly Diagnosed MM 
Version Date:  03/27/2020 
 
70 
treatment, during dose interruptions and for at least 28 days following lenalidomide 
discontinuation, even if he has undergone a successful vasectomy.   
• If pregnancy or a positive pregnancy test does occur in the partner of a male study patient 
during study participation, the investigator must be notified immediately. 
 
 
 


Abbreviated Title:  CRd in Newly Diagnosed MM 
Version Date:  03/27/2020 
 
71 
15.2 APPENDIX B:  BONE MARROW ASPIRATE COLLECTION, SORTING AND STORAGE 
NOTE:  Refer to Section 5.1 for correlative study bone marrow timepoints and study calendar 
Section 3.4 
Collection of Bone Marrow:   
• 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, slowly aspirate 5-8 mL of bone marrow for flow cytometry and cell sorting.   
• 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. 
• For aspirate specified for flow cytometry under the direction of Maryalice Stetler- 
Stevenson, 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 B1B58 (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 Maryalice Stetler-Stevenson’s lab.   
• For aspirate specified for flow cytometry under the direction of Jane Trepel, immediately 
discharge 1 mL of aspirated marrow syringe into heparin syringe tube.   
• For aspirate designated for CD138 sorting, VDJ sequencing, exome sequencing, and 
microenvironment studies, send remaining aspirate sample Calvo Laboratory in the 
Department of Laboratory Medicine Clinical Center (Attn: Dr. Weixin Wang, Building 
10 Room 2C418A).  Place aspirate sample in EDTA syringe immediately on ice.  
Transfer within 30 minutes of sampling to the lab for processing.  CD138+ plasma cells 
will be viably frozen and batched to be sent to Adaptive Technologies for VDJ 


Abbreviated Title:  CRd in Newly Diagnosed MM 
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72 
sequencing and to MSKCC for exome sequencing.  CD138- fractions will be studied by 
Dr.’s Wang and Calvo.  At subsequent time points, CD138+ sorting will not be done if 
the patient is in remission. 
• For aspirate specified for cytogenetics/FISH, aspirate will be sent to Diane Arthur.  
(NOTE:  D. Arthur no longer at NIH/NCI, her involvement ended and these studies no 
longer being done as of Amendment M.)  
 


Abbreviated Title:  CRd in Newly Diagnosed MM 
Version Date:  03/27/2020 
 
73 
15.3 APPENDIX C:   RESEARCH PERIPHERAL BLOOD AND URINE COLLECTION AND STORAGE 
NOTE:  Refer to Sections 3.4 Study Calendar and 5.1 for research blood and urine collection 
time points for samples to the Blood Processing Core (BPC).   
Venipuncture:   
a. Up to 100 mL of peripheral blood will be collected into serum separator tubes (SST), 
sodium heparin tubes (GGT), 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.  
b. Serum  
• Collect 7-10 mL blood in a serum separator tube (SST). 
• Allow the blood to clot by standing at room temperature for 30 minutes. 
• Separate serum from cells by centrifuging at 4 degrees C for 5 minutes at 
1200xg.   
• Pipette 2 aliquots of 1.5mLs each into two 2mL cryovials. 
• Freeze immediately at -20 or lower 
• Maintain in -80 freezer for storage until shipment 
c. Plasma 
• Collect 7 mL blood in a sodium heparin tube (green top). 
• Place immediately on wet ice and refrigerate until time of processing. 
• Separate plasma from cells by centrifuging at 4 degrees C for 5 minutes at 
1200xg. 
• Pipette 2 aliquots of 1.5mLs each into two 2mL cryovials. 
• Freeze and store in -80C freezer. 
d. Complete blood count 
• 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: 
a. 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.   
b. Transfer to a screw-cap conical tube 
c. Freeze immediately at -20 or lower 
d. Maintain in -80 freezer for storage until shipment 
Labeling of Samples:   
a. 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 #  
• sample type 
• date/time of draw (DD/MMM/YY 24:00) 
• timepoint (ex. C1D1 pre, C1D1 24hr post) 


Abbreviated Title:  CRd in Newly Diagnosed MM 
Version Date:  03/27/2020 
 
74 
• any collection issues (short draw, delayed processing, etc.) 
• protocol title/number 
• institute name 
• contact information 
b. 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: 04/20/2020
Page 1 of 28
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR: 
Dickran Kazandjian, M.D.
STUDY TITLE:
Carfilzomib, Lenalidomide, and Dexamethasone in Newly 
Diagnosed Multiple Myeloma Patients; Clinical and 
Correlative Phase II Study
STUDY SITE:
National Cancer Institute
Cohort: 
Affected subject 
Consent Version:
04/20/2020 
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator: 
Dickran Kazandjian, M.D.
Phone:  301-480-0532 
Email:  kazandjiandg@mail.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.
If the individual being asked to participate in this research study is not able to give consent to be 
in this study, you are being asked to give permission for this person as their decision-maker. The 
term “you” refers to you as the decision-maker and/or the individual being asked to participate in 
this research, throughout the remainder of this document. 
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 myeloma.
Carfilzomib (KyprolisTM) 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 
IRB NUMBER: 11C0221
IRB APPROVAL DATE: 05/05/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/20/2020
Page 2 of 28
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
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 
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 newly diagnosed and untreated 
multiple myeloma.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
A minimum of 20 patients and a maximum of 50 patients.
DESCRIPTION OF RESEARCH STUDY 
What will happen if you take part in this research study? 
As a newly diagnosed untreated person with multiple myeloma, you will receive a total of 8 
cycles of combination therapy of carfilzomib, lenalidomide, and dexamethasone. Each cycle is 
28 days. After at least four cycles of therapy, if you are eligible for stem cell transplant, you will 
have stem cells collected and stored for an autologous (with your own cells) stem cell 
transplantation if and when your multiple myeloma returns. After stem cell collection, you will 
continue to receive 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).
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:
IRB NUMBER: 11C0221
IRB APPROVAL DATE: 05/05/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/20/2020
Page 3 of 28
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

History and physical examination

Blood work

Urine laboratory tests

24 hour-urine sample may be required (you will be notified if this applies to you).

A bone survey (series of x-rays of all of your bones)

A bone marrow procedure to obtain aspirate and core biopsy is required for the diagnosis 
of MM and can provide important additional information. We will request that you 
undergo such a biopsy.

Urine or blood Pregnancy test
You will be asked if you would like to provide extra research samples of blood, urine and bone 
marrow aspirate. These studies are optional and will be used to learn more about myeloma. 
Whenever possible, if you have given permission, these samples will be collected at the same time 
as when routine cancer care testing is done. You do not have to give these research samples in 
order to participate in this trial. You will not have to pay for the costs of collecting and analysis of 
these research samples. You will be asked at the end of this consent form to indicate your choice 
about giving research samples of blood, urine and bone marrow aspirate.
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

Blood work

Urine collection

Bone marrow biopsy and aspirate to assess the status of your myeloma

Register into the REMS® program of Celgene Corporation (see below for more 
information about REMS®)

Urine or blood pregnancy tests in women of child bearing potential

PET/CT Scans
If you agree to donate extra blood, urine and bone marrow aspirate samples, you will be asked to 
give the following amounts at the time points listed in the Study Chart and the samples will be 
used for research purposes only.

Research blood samples (about 3 tablespoons)

Research urine samples (about 2 ounces)

Research bone marrow aspirate (about 2 teaspoons)

Research FDG-PET for imaging of whole body

Research DW-MRI (diffusion weighted whole body magnetic resonance imaging 
scans) 
IRB NUMBER: 11C0221
IRB APPROVAL DATE: 05/05/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/20/2020
Page 4 of 28
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
The research blood, bone marrow aspirate, and urine samples are not mandatory.
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) over 30-minutes on 
Days 1, 2, 8, 9, 15, and 16 of the 28 day cycle.

IV fluids will be administered with the carfilzomib treatment.

On days 1 and 2 of cycle 1, carfilzomib will be given alone without lenalidomide or 
dexamethasone.

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 (part1) for cycles 9-20. During cycles 9-20, you 
will be given lenalidomide oral tablets days 1-21 of a 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 or restart “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 treatment works, or why they may cause side effects. These samples 
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 
IRB NUMBER: 11C0221
IRB APPROVAL DATE: 05/05/2020


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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.   We will ask you to have an additional 
tube of blood drawn to verify the findings we have seen in our lab. If the results are verified, you 
will be re-contacted and offered a referral to a genetic healthcare provider to discuss the results. 
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.
IRB NUMBER: 11C0221
IRB APPROVAL DATE: 05/05/2020


PATIENT IDENTIFICATION
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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.  We may get imaging with FDG-PET about once per year to 
monitor your disease.  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.
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)
24 hour urine collection (including urine research sample if you choose to 
donate)
Bone marrow biopsy and aspirate to assess the status of your myeloma
Register for the REMS® Program
Urine or blood pregnancy test in women of child bearing potential 
(performed 10-14 days prior to receiving prescription of lenalidomide)
Bone series (X-rays of all of your bones)
Research FDG-PET (if you choose to participate)
Cycle 1
Day 1
Receive infusion of intravenous fluid and Day 1 carfilzomib
Day 2
Optional research bone marrow on Day 2
Receive infusion of intravenous fluid and Day 2 carfilzomib
Routine blood work and optional research blood work if you choose to 
donate
Routine and optional urine if you choose to donate
Begin oral lenalidomide and continue from day 2-21
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
IRB NUMBER: 11C0221
IRB APPROVAL DATE: 05/05/2020


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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
Day 22 and 23
Receive oral/IV dexamethasone
Routine blood work
Day 28
Finish cycle 1
Cycles 2-8
Day 1 and 2
Receive infusion of optional intravenous fluid and Day 1 and 2 
carfilzomib
Receive oral/IV dexamethasone
Begin oral lenalidomide and continue from day 1-21
Day 1: Routine blood work and optional research blood if you 
choose to donate
Day 1: Routine and optional research urine if you choose to donate
Urine or blood pregnancy test in women of child bearing potential
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
Day 22 and 23
Receive oral/IV dexamethasone
Day 28
Finish day of each cycle
After 4 cycles
Transplant eligible subjects will undergo evaluation at transplant 
center for stem cell collection
Any point that 
complete remission 
is achieved (no 
monoclonal protein 
in blood) 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 will be performed on whole body imaging if 
you choose to participate
Cycles 9 –and beyond– Extended dosing of lenalidomide
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
Start lenalidomide and continue days 1-21
IRB NUMBER: 11C0221
IRB APPROVAL DATE: 05/05/2020


PATIENT IDENTIFICATION
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Day 21
Stop lenalidomide
Day 28
Finish day of each cycle
Any point that 
complete remission is 
achieved (no 
monoclonal protein in 
blood) or at the end of 
cycle 20/cycle 32 if 
participating in 
extended dosing part 
2, and beyond 32 
cycles
Optional research blood, urine and bone marrow biopsy and aspirate if 
you choose to donate
Optional FDG-PET 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
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; (except FDG-PET and DW-
MRI which will be performed annually, if you are able and willing). 
All of the above will then be repeated if you experience progression of 
your disease.
BIRTH CONTROL
Lenalidomide is related to thalidomide. Thalidomide is known to cause severe life-threatening 
human birth defects. Findings from a monkey study 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. Females must not 
become pregnant while taking lenalidomide. You have been informed that the risk of birth defects 
is unknown. If you are female, you agree not to become pregnant while taking lenalidomide. 
Lenalidomide is present at very low levels in human semen of healthy men for three days after 
stopping the drug according to a study. For some men, such as men with kidney problems, 
lenalidomide may be present in semen for more than three days. Because of the risk of birth 
defects, all patients taking lenalidomide must read the following statements that apply to them 
according to gender and menopausal status.
For these reasons, 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 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.
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.
IRB NUMBER: 11C0221
IRB APPROVAL DATE: 05/05/2020


PATIENT IDENTIFICATION
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
* 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 
after discontinuation from the study.  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
Additional Effective Methods

Latex condom 

Diaphragm 

Cervical Cap
You must not breastfeed a baby while you are participating in this study and for at least 28 days 
after you have been discontinued from the study.
Females of childbearing potential with regular or no menstrual cycles must agree to have 
pregnancy tests weekly for the first 28 days of study participation and then every 28 days while on 
study, at study discontinuation, and at day 28 following discontinuation from the study. If 
menstrual cycles are irregular, the pregnancy testing must occur weekly for the first 28 days and 
then every 14 days while on study, at study discontinuation, and at days 14 and 28 following 
discontinuation 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 is 
unknown at this time. For these reasons, male patients receiving lenalidomide 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 and for at least 28 days after stopping therapy, 
even if you have had a successful vasectomy. You must NEVER donate blood, sperm, or semen 
while you are participating in this study and for at least 28 days after you have stopped therapy.
All Patients:
IRB NUMBER: 11C0221
IRB APPROVAL DATE: 05/05/2020


PATIENT IDENTIFICATION
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
You must NEVER share lenalidomide (or other study drugs) with someone else. You must 
NEVER donate blood while you are participating in this study 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.
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. 
IRB NUMBER: 11C0221
IRB APPROVAL DATE: 05/05/2020


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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH 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 July 2019, approximately 11,000 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

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):

Fatigue (tiredness)

Nausea

Anemia (decreased red blood cell count which may lead to feeling tired)

Shortness of breath (at rest or with exertion) which in rare cases may be life-threatening or 
resulting in death 

Thrombocytopenia (decreased platelet count which may lead to bleeding or bruising)

Diarrhea

Mild decreases in renal function which are generally reversible 

Vomiting 

Fever 

Headache

Constipation

Neutropenia (decreased white blood cell counts which may lead to a decreased ability to 
fight infection
IRB NUMBER: 11C0221
IRB APPROVAL DATE: 05/05/2020


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
Swelling of hands, feet or ankles

Cough, including cough with phlegm

Back pain and/or joint pain

Pain in limbs, hands or feet

General weakness, or lack of energy or strength

Runny nose or nasal congestion

Respiratory tract infection

Pneumonia (lung infection)

Loss or decrease in appetite which may lead to weight loss

Muscle spasms, pain, or weakness

Numbness, tingling, or decreased sensation in hands and/or feet 

Dizziness

Infusion reactions (see ‘Conditions you need to look out for’)

Insomnia (difficulty sleeping)

Changes to blood tests (decreased blood levels of potassium, increased blood levels of 
sugar and/or creatinine)

Hypertension (high blood pressure) 

Bronchitis

Sore throat, swelling and inflammation of the nose and throat 
Common (may affect up to 1 in 10 people who receive carfilzomib):

Stomach Pain 

Heart attack (may have a life-threatening or fatal outcome)

Heart failure and heart problems including arrhythmias

Low white blood cell count, which may be associated with fever

Pulmonary hypertension

Fluid in the lungs 

Blood clot in the lungs 

Change in voice or hoarseness

Rash and/or itching, redness of the skin

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. 

Chills or feeling too hot, increased sweating

Anxiety 

Blurred or double vision

Cataract 
IRB NUMBER: 11C0221
IRB APPROVAL DATE: 05/05/2020


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
Generalized pain 

Pain in the bones and muscles 

Toothache

Aching muscles 

Abdominal pain, discomfort, or swelling 

Indigestion (upset stomach) 

Urinary tract infection 

Nosebleeds 

Dehydration

Wheezing

Serious infection in the blood (sepsis)

Viral infection

Kidney problems, including decreased ability to make urine, increased creatinine in the 
blood, and kidney failure which can lead to dialysis

Liver problems including an increase in your liver enzyme in the blood

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)

Blood clots in the veins

Tinnitus

Hypotension (low blood pressure)

Pain in throat 

Feeling unwell

Infection and/or irritation of your stomach and bowels

Chest pain

Muscle weakness

Flushing
Uncommon and rare (may affect less than 1 in 100 people who receive carfilzomib):

Lung Problems (see ‘Conditions you need to look out for’); bleeding in the lungs

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

Decreased or worsening heart function including chest pain, sudden loss of heart function, 
heart muscle disease which may cause shortness of breath and tiredness, reduced blood 
flow to the heart, and abnormal amount of fluid between the heart and the lining around 
the heart.
IRB NUMBER: 11C0221
IRB APPROVAL DATE: 05/05/2020


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
Thrombotic microangiopathy (TMA):  damage to the smallest blood vessels inside many 
organs, most commonly the kidneys and brain

Allergic reaction including total body rash, hives, and difficulty breathing

Severe infections of the blood causing low blood pressure and low blood flood to the 
different organs.

Tumor lysis syndrome (TLS) (see ‘Conditions you need to look out for’)

Multi-organ failure 

Bleeding in the brain

Allergy to carfilzomib

Stroke

Extremely high blood pressure (see ‘Conditions you need to look out for’)

Bleeding in the stomach or bowels

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’)
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 

Perforation (hole or tear) in the stomach, small or large intestine.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)

Progressive Multifocal Leukoencephalopathy (PML): a fatal disease characterized by 
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:
IRB NUMBER: 11C0221
IRB APPROVAL DATE: 05/05/2020


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
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. 
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, 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.
IRB NUMBER: 11C0221
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
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). 

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). 

Worsening of fatigue and yellow discoloration of the skin or eyes. These symptoms may 
suggest hepatitis B. Hepatitis B Reactivation is a potential side effect of Carfilzomib. 
Hepatitis B Reactivation refers to the sudden increase in hepatitis B virus in an individual 
who has inactive or resolved HBV. In patients with a history of HBV infection, taking 
rituximab could cause this sudden increase in HBV. If you experience HBV reactivation, 
we will treat your HBV and monitor you closely while on study.
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 6,600 patients who have participated 
in previous and ongoing clinical studies involving lenalidomide. These events were considered 
by the study doctors to be related to lenalidomide. Side effects may be mild to very severe. 
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 or a decrease in white blood cells that can make you more prone to infections 

Thrombocytopenia or a decrease in platelets which can cause you to bruise or bleed easily

Constipation or difficulty moving your bowels 

Diarrhea or loose/frequent bowel movements 

Nausea 

Loss of appetite

Back pain 

Joint pain 
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IRB APPROVAL DATE: 05/05/2020


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
Muscle cramps 

Swelling of the arms and legs 

Problems falling asleep or staying asleep 

Fever 

Cough 

Shortness of breath or difficulty catching your breath

Upper respiratory infection 

Rash

Itching and dry skin

Lack or loss of strength

Dizziness

Headache

Lymphopenia (decreased white blood cells that fight infection)
Less Likely (occurring in ≥ 1% of patients):

Neutropenia associated with a fever

Atrial fibrillation or irregular heartbeat 

Progression of the disease being studied 

Pneumonia or an infection of the lungs

Sepsis or an infection of the blood

Dehydration

Kidney failure

Pulmonary embolism: blood clot in or around the lungs

Deep vein thrombosis: blood clot in a large blood vessel
Rare (occurring in < 1% of patients):

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). 

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.   

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.
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
Occasional events such as atrial fibrillation (irregular heartbeat), myocardial infarction 
(heart attack), and congestive heart failure (condition where the heart becomes weak and 
cannot pump enough blood to the rest of the body)
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 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. Your doctor will monitor for the development of 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 
IRB NUMBER: 11C0221
IRB APPROVAL DATE: 05/05/2020


PATIENT IDENTIFICATION
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
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 Study Risks  
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: You may feel a pulling sensation and brief discomfort as 
the marrow is withdrawn and a pressure sensation when the needle is being inserted. The amount 
of 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, and infection. Both of these are 
very rare. Bleeding can be stopped by applying local pressure and an infection can be treated with 
antibiotics.
PET/CT: There is discomfort related to the PET/CT scans involved with this study. You must fast 
4 to 6 hours prior to the PET/CT scan. You will be asked to drink water during this time and void 
prior to the injection. The PET/CT examination discomforts include the placement of an 
intravenous line (IV). The risks of an IV include bleeding, infection, or inflammation of the skin 
and vein with pain and swelling. The scan will begin approximately 1 hour after injection.  During 
the scan, it will be necessity to remain still on your back for 30 minutes. 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: This research study involves exposure to radiation from up to 2 PET/CT 
scans in one year (maximum 10 mCi per injection). This radiation exposure is not required for 
your medical care and is for research purposes only. The maximum amount of radiation you will 
receive is 2.1 rem in one year which is below the guideline of 5 rem (or 0.5 rem in children) per 
year allowed for research subjects by the NIH Radiation Safety Committee. The average person in 
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the United States receives a radiation exposure of 0.3 rem per year from natural sources, such as 
the sun, outer space, and the earth's air and soil. If you would like more information about radiation, 
please ask the investigator for a copy of the pamphlet, An Introduction to Radiation for NIH 
Research Subjects.
While there is no direct evidence that the amount of exposure received from participating in this 
study is harmful, there is indirect evidence it may not be completely safe. There may be a very 
slight increase in the risk of cancer.
Please tell your doctor if you have had any radiation exposure in the past year, either from other 
research studies or from medical tests or care, so we can make sure that you will not receive too 
much radiation. Radiation exposure includes x-rays taken in radiology departments, cardiac 
catheterization, and fluoroscopy as well as nuclear medicine scans in which radioactive materials 
were injected into your body.
If you are pregnant you will not be permitted to participate in this research study. If you are breast 
feeding and the protocol involves injection of radioactive material, you will not be permitted to 
participate. It is best to avoid radiation exposure to unborn or nursing infants since they are more 
sensitive to radiation than adults. 
DW-MRI scan procedure: Magnetic resonance imaging (MRI) uses a strong magnetic field and 
radio waves to take pictures of the body. The cells that make up your body contain a great deal of 
water. DW-MRI differ from other MRIs in that they generate images through measuring how this 
water moves in your body. Receiving a DWI-MRI on this study is optional. 
We will obtain pictures of your whole body for this study. The MRI scanner is a metal cylinder 
surrounded by a strong magnetic field.  During the MRI, you will lie on a table that can slide in 
and out of the cylinder.  We will place soft padding or a coil around your body. You will be in the 
scanner about 45-60 minutes. You may be asked to lie still for up to 60 minutes at a time. While 
in the scanner you will hear loud knocking noises, and you will be fitted with earplugs or earmuffs 
to muffle the sound. You will be able to communicate with the MRI staff at all times during your 
scan, and you may ask to be moved out of the machine at any time.
People are at risk for injury from the MRI magnet if they have some kinds of metal in their body.  
It may be unsafe for you to have an MRI scan if you have pacemakers or other implanted electrical 
devices, brain stimulators, some types of dental implants, aneurysm clips (metal clips on the wall 
of a large artery), metal prostheses (including metal pins and rods, heart valves, and cochlear 
implants), permanent eyeliner, tattoos, an implanted delivery pump, or shrapnel fragments. 
Welders and metal workers may have small metal fragments in the eye. You will be screened for 
these conditions before having any MRI scan.  If you have a question about metal in your body, 
you should inform the staff. You will be asked to complete an MRI screening form before each 
MRI scan you have. 
In addition, all magnetic objects (like watches, coins, jewelry, and credit cards) must be removed 
before entering the MRI scan room.
People with fear of confined spaces may become anxious during an MRI. Those with back 
problems may have back pain or discomfort from lying in the scanner.  The noise from the scanner 
is loud enough to damage hearing, especially in people who already have hearing loss. Everyone 
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having a research MRI scan will be fitted with hearing protection. If the hearing protection comes 
loose during the scan, you should let us know right away.
There are no known long-term risks of MRI scans.
The DW-MRI scan does not require the use of the contrast agent, Gadolinium. Therefore, you will 
not be receiving Gadolinium while on this study. 
PSYCHOLOGICAL OR SOCIAL RISKS ASSOCIATED WITH LOSS OF PRIVACY 
Other General Issues Related to the Protocol: 
The following general points are indirectly related to your participation in the research study.
1.
Unanticipated medical information: During the course of this investigation, it is possible 
(although not likely) that we will obtain unanticipated information about your health or genetic 
background.  
2.
Release of medical records.  In the course of applying for certain types of insurance (e.g., 
medical insurance, life insurance, or disability insurance), people are often asked to sign forms 
that authorize insurance companies to obtain their medical records.  If you sign such a release 
form at some point in the future, it is possible that the insurance company would present this 
signed release form to the Clinical Center of the National Institutes of Health.  In that event, 
the National Institutes of Health would comply with your request to provide the insurance 
company with your medical record.  It is possible that information contained in your medical 
record might affect (either favorably or unfavorably) the willingness of the insurance company 
to sell you insurance.  Your employability may also be affected.
3.
Release of genetic information:  

Your privacy is very important to us and we will use many safety measures to protect your 
privacy. However, in spite of all of the safety measures that we will use, we cannot 
guarantee that your identity will never become known. Although your genetic information 
is unique to you, you do share some genetic information with your children, parents, 
brothers, sisters, and other blood relatives. Consequently, it may be possible that genetic 
information from them could be used to help identify you. Similarly, it may be possible 
that genetic information from you could be used to help identify them. 

While the controlled-access databases developed for this project will not contain 
information that is traditionally used to identify you, such as your name, address, telephone 
number, or social security number, people may develop ways in the future that would allow 
someone to link your genetic or medical information in our databases back to you. For 
example, someone could compare information in our databases with information from you 
(or a blood relative) in another database and be able to identify you (or your blood relative). 
It also is possible that there could be violations to the security of the computer systems 
used to store the codes linking your genetic and medical information to you.

Since some genetic variations can help to predict the future health problems of you and 
your relatives, this information might be of interest to health providers, life insurance 
companies, and others. Patterns of genetic variation also can be used by law enforcement 
agencies to identify a person or his/her blood relatives. Therefore, your genetic information 
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potentially could be used in ways that could cause you or your family distress, such as by 
revealing that you (or a blood relative) carry a genetic disease.

There also may be other privacy risks that we have not foreseen.
There are state and federal laws that protect against genetic discrimination. There is also a new 
federal law called the Genetic Information Nondiscrimination Act (GINA). In general, this law 
makes it illegal for health insurance companies, group health plans, and most employers to 
discriminate against you based on your genetic information. However, it does not protect you 
against discrimination by companies that sell life insurance, disability insurance, or long-term care 
insurance. GINA also does not apply to members of the United States military, to veterans 
obtaining health care through the Veteran’s Administration or the Indian Health Service. Lastly, 
GINA does not forbid insurance medical underwriting based on your current health status.
Family relationships: In the course of this study, it is possible that we may learn information about 
relationships within the family.  For example, if we collected samples from family members and 
compared the results within families, it is possible that we might learn that a family member is not 
the biological child of the parents with whom he/she lives (for example, because of adoption).  We 
will not ordinarily provide this type of information to any member of the family or the referring 
physician. 
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
•
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:
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•
if he/she believes that it is in your best interest
•
if your disease 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 and/or 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
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review 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.
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study. This is allowed under federal rules and is not a 
conflict of interest.
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.  This means it is possible that the results of this study could 
lead to payments to NIH scientists and to the NIH.  By law, government scientists are required to 
receive such payments for their inventions.  You will not receive any money from the development 
of Carfilzomib and/or Lenalidomide.
OPTIONAL 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. The needle is removed. The risks of the bone marrow 
procedure include pain, bleeding, infection of the skin or tissues, and allergy to the local anesthetic. 
You may have some soreness at the site for a day or so after the procedure. 
The biopsy to be performed is exclusively for research purposes and will not benefit you. It might 
help other people in the future. Even if you decide to have the biopsy you can change your mind 
at any time. Please think about your choice. 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.
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You will be asked to sign a separate consent for each of the bone marrow procedures.
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 
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.
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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: 04/20/2020
Page 25 of 28
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH 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 compensation for participation in this study. 
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. The amount and form 
of these payments are determined by the NCI Travel and Lodging Reimbursement Policy.   You 
will be given a summary of the policy which provides more 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

Qualified representatives from Amgen Inc., the pharmaceutical company who produces 
Carfilzomib. 

Qualified representatives from Celgene Corporation, the pharmaceutical company who 
produces Lenalidomide.
IRB NUMBER: 11C0221
IRB APPROVAL DATE: 05/05/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/20/2020
Page 26 of 28
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
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 
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 
IRB NUMBER: 11C0221
IRB APPROVAL DATE: 05/05/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/20/2020
Page 27 of 28
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
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.
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, Dickran 
Kazandjian, M.D, Building 10 Room 4N115, Telephone: 240-383-6311. 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.
IRB NUMBER: 11C0221
IRB APPROVAL DATE: 05/05/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/20/2020
Page 28 of 28
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
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
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness to the oral short-form consent process only: This section is only required if you are doing the oral 
short-consent process and this English consent form has been approved by the IRB for use as the basis of 
translation.
Witness:
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: 11C0221
IRB APPROVAL DATE: 05/05/2020