Lenalidomide Maintenance Therapy in Multiple Myeloma: A Phase II Clinical and Biomarker Study
Phase: PHASE2
Conditions: Multiple Myeloma
Sponsor: National Cancer Institute (NCI)

Amendment
Protocol Number:
12C0192-E
Principal Investigator: Mark Roschewski 
NCI 
LYMB 
301.451.9021 
roschewskimj@nhlbi.nih.gov
(NIH Employee Name, Institute/Branch, Telephone and e-mail)
Reference Number:
366568
Protocol Title:
Lenalidomide Maintenance Therapy in Multiple Myeloma: A Phase II Clinical and Biomarker Study
SIGNATURES
Principal Investigator (*): 
Mark Roschewski - applied signature on 02/08/2017 6:52 AM EST 
Mark Roschewski - applied signature on 03/14/2017 5:03 PM EDT
Accountable Investigator:
PI is the Accountable Investigator
Branch Chief/CC Department Head (**):
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Referral Contact signatures:
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Other IC Clinical Director signatures:
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APPROVALS
IRB Chair:
Michael Hamilton - applied signature on 03/15/2017 8:52 PM EDT
Clinical Director:
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** I have reviewed this research project and considered the NIH Policy for Inclusion of Women and Minorities in Clinical Research. Taking into 
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IRB Meeting Date:
Expedited
DEC Clearance Date:
01/18/2017
Protocol Version Date:01/06/2017
N. Almodovar
N. Almodovar
3/27/17
AM E 

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Abbreviated Title: Revlimid maintenance for MM 
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Abbreviated Title: Revlimid Maintenance for MM  
NCI Protocol# 12-C-0192 E 
Version Date: 01/06/2017 
 
Lenalidomide Maintenance Therapy in Multiple Myeloma: A Phase II Clinical and 
Biomarker Study 
 
NCI Principal Investigator: Mark Roschewski, M.D.A-F 
Lymphoid Malignancies Branch (LYMB), CCR, NCI 
National Institutes of Health 
10 Center Drive, Building 10, Room 4N115 
Bethesda, MD 20892 
Phone:  240-760-6183 
Email:  roschewskimj@mail.nih.gov   
 
 
NIH Associate Investigators:  
Ravi Madan, M.D., GMB, CCR, NCI B,E-F 
James Gulley, M.D., Ph.D., GMB, CCR, NCI B,E-F 
William D. Figg, Pharm.D., GMB, CCR, NCI B,E-F 
Seth Steinberg, Ph.D., BDMS, OCD, CCR, NCI B,E-F  
Maryalice Stetler-Stevenson, M.D., Lab of Path, NCI B,E-F 
Katherine Calvo, M.D., Ph.D., Heme Service, CC B,E-F 
 
Non NIH Associate Investigator:  Dickran Kazandjian, M.D., FDA, Volunteer A-F 
 
Referral Contact:  
 
Mark Roschewski, M.D. 
 
Study Coordinator:  
 
Jen Hsu Albert, R.N., OCN A,B 
Phone:  240-760-6108 
Email:  hsuj@mail.nih.gov  
 
 
 

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Investigator Roles: 
A. Obtaining information by intervening or interacting with living individuals for research 
purposes 
B. Obtaining identifiable private information about living individuals 
C. Obtaining the voluntary informed consent of individuals to be subjects 
D. Making decisions about subject eligibility 
E. Studying, interpreting, or analyzing identifiable private information or data/specimens for 
research purposes 
F. Studying, interpreting, or analyzing de-identified data or specimens for research purposes 
G. Some/all research activities performed outside NIH 
 
Commercial Agents:  
Lenalidomide 
 
Identifying Words: Revlimid, immunomodulatory drugs, T cell activity, gene expression 
 
 
 
 

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Précis  
Background: 
 
Multiple myeloma (MM) remains largely an incurable disease with an estimated median 
survival of 6-7 years in standard risk myeloma and 2-3 years in high risk disease despite 
treatment with autologous stem cell transplantation (ASCT). 
 
Maintenance therapy to achieve sustained suppression of residual disease following 
chemotherapy or ASCT has long been viewed as a desirable approach for extending 
survival in MM.  
 
Giving the immunomodulatory drug lenalidomide after induction or re-induction 
treatment may stimulate the immune system in various ways to stop or slow the return of 
cancer. 
 
It is not yet known how immune stimulatory effects of extended dosing with 
lenalidomide in the maintenance setting correlate with clinical benefits. 
Objective: 
 
Assess T cell (CD4, CD8), NKT and NK cell numbers in peripheral blood during the 
course of lenalidomide maintenance therapy in treated MM patients. 
Eligibility: 
 
Patients with multiple myeloma who have achieved stable disease or better reponse, 
assessed at ≥ 4 weeks after completing induction or re-induction treatment 
 
Age ≥ 18 years  
 
ECOG PS of 0-2 
 
Adequate hematological parameters defined by: absolute neutrophil count  ≥ 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 x ULN  
 
Adequate renal function with creatinine clearance (CrCl) of greater than or equal to 40 
mL/min. CrCl will be calculated using the Cockcroft-Gault method.  If the calculated 
CrCl based on Cockcroft-Gault method is <40 mL/min, patient will have a 24 hr urine 
collection to measure CrCl. The measured CrCl must also be ≥ 40 ml/min 
Design:  
 
Single arm, single stage, phase II trial of lenalidomide maintenance for treated MM 
patients who have stable or responsive disease. 
 
After screening, eligibility determination, and enrollment; subjects will receive 
lenalidomide 10 mg by mouth daily on days 1-21 of repeated 28-day cycles. When 
necessary, lenalidomide will be held and restarted in accordance with accepted clinical 
dose modification guidelines. 
 
Subjects may continue lenalidomide until disease progression, unacceptable toxicity or 
completion of two years of lenalidomide therapy and the 30 day safety follow-up visit. 
 
Blood will be obtained to assess changes in T cell (CD4, CD8), NKT and NK cell 
numbers by flow-cytometric analysis at pre-specified time points during lenalidomide 
maintenance.   
 
Blood samples and/or bone marrow samples where possible, will be used for additional 
research studies, which may include functional analyses of immune-cell subsets, analyses 
for cytokines, chemokines, antibodies, tumor cell antigen targets, and/or other markers.  

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TABLE OF CONTENTS  
Précis ............................................................................................................................................... 3 
Table of Contents ............................................................................................................................ 4 
1 
INTRODUCTION .................................................................................................................. 6 
1.1 
Study Objectives .............................................................................................................. 6 
1.2 
Background and Rationale ............................................................................................... 6 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 11 
2.1 
Eligibility Criteria .......................................................................................................... 11 
2.2 
Screening Evaluation ...................................................................................................... 13 
2.3 
Registration Procedures.................................................................................................. 14 
2.4 
Baseline Evaluation ........................................................................................................ 15 
3 
STUDY IMPLEMENTATION ............................................................................................ 15 
3.1 
Study Design .................................................................................................................. 15 
3.2 
Drug Administration ...................................................................................................... 15 
3.3 
Dose Modifications ........................................................................................................ 16 
3.4 
Study Calendar ............................................................................................................... 20 
3.5 
Criteria for Removal from Protocol Therapy and Off Study Criteria ............................ 22 
4 
CONCOMITANT MEDICATIONS/MEASURES .............................................................. 23 
4.1 
Tumor lysis syndrome .................................................................................................... 23 
4.2 
Bone Disease/Extramedullary Disease ........................................................................... 23 
4.3 
Use of steroids ................................................................................................................ 23 
4.4 
Hypercalcemia ................................................................................................................ 23 
4.5 
Transfusions/Growth factors .......................................................................................... 23 
4.6 
Anti-coagulation ............................................................................................................. 23 
4.7 
Anti-emetics ................................................................................................................... 23 
4.8 
PCP prophylaxis ............................................................................................................. 24 
5 
BIOSPECIMEN COLLECTION .......................................................................................... 24 
5.1 
Biomarker Studies for Research ..................................................................................... 24 
5.2 
Biomarker Studies: Methods .......................................................................................... 26 
5.3 
Sample Storage, Tracking and Disposition .................................................................... 28 
6 
DATA COLLECTION AND EVALUATION ..................................................................... 29 
6.1 
Data Collection ............................................................................................................... 29 

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6.2 
Response Criteria ........................................................................................................... 30 
6.3 
Toxicity Criteria ............................................................................................................. 32 
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
 
33 
7.1 
Definitions ...................................................................................................................... 33 
7.2 
NCI-IRB Reporting ........................................................................................................ 36 
7.3 
Data and Safety Monitoring Plan ................................................................................... 37 
8 
STATISTICAL CONSIDERATIONS.................................................................................. 38 
8.1 
Study Design/Primary Endpoints ................................................................................... 38 
8.2 
Sample Size/Accrual Rate .............................................................................................. 38 
8.3 
Statistical Analysis of Secondary Endpoints .................................................................. 38 
9 
COLLABORATIVE AGREEMENTS ................................................................................. 39 
9.1 
Cooperative Research and Development Agreement (CRADA) ................................... 39 
9.2 
Material Transfer Agreement (MTA) ............................................................................ 39 
10 HUMAN SUBJECTS PROTECTIONS ............................................................................... 39 
10.1 
Rationale For Subject Selection ................................................................................. 39 
10.2 
Participation of Children ............................................................................................ 39 
10.3 
Evaluation of Benefits and Risks/Discomforts ........................................................... 39 
10.4 
Risks/Benefits Analysis .............................................................................................. 40 
10.5 
Consent and Assent Process and Documentation ....................................................... 40 
11 PHARMACEUTICAL INFORMATION ............................................................................. 40 
11.1 
Lenalidomide .............................................................................................................. 40 
12 REFERENCES ..................................................................................................................... 44 
13 APPENDIX A-Performance Status Criteria ......................................................................... 48 
14 Appendix B: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth 
Control Methods ........................................................................................................................... 49 
15 APPENDIX C: Peripheral Blood and Urine Collection And Storage .................................. 53 
16 APPENDIX D: Isolation and cryopreservation of peripheral blood mononuclear cells 
(PBMC) ......................................................................................................................................... 56 
17 APPENDIX E: COCKCROFT-GAULT EQUATION ......................................................... 57 
18 Appendix F: Bone Marrow Aspirate Collection, Sorting and Storage ................................. 58 
 

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1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective: 
 
Assess T cell (CD4, CD8), NKT and NK cell numbers in peripheral blood of MM 
patients during the course of lenalidomide maintenance therapy. 
1.1.2 Secondary Objectives: 
 
Determine progression free survival 
 
Determine duration of response 
 
Assess NK cell function and activity  
 
Assess changes in B cell subsets, myeloid derived suppressor cells and T regulatory 
cells by phenotypic analysis during the course of therapy 
 
Assess expression of CRBN, and how it relates to NK cell number and activity 
1.2 
BACKGROUND AND RATIONALE 
Multiple myeloma overview 
Multiple myeloma (MM) accounts for 1% of all cancers and approximately 10% of all 
hematologic malignancies [1]. It is defined as a clonal proliferation of malignant plasma cells in 
the bone marrow, with the presence of a monoclonal protein in serum or urine and with features 
of end-organ damage including hypercalcemia, renal insufficiency, anemia, and bone lytic 
lesions [2]. Almost all patients evolve from an asymptomatic premalignant state termed 
monoclonal gammopathy of undetermined significance (MGUS) [3]. MM is incurable with an 
estimated median survival of 6-7 years in standard risk myeloma and 2-3 years in high risk 
disease despite treatment with autologous stem cell transplantation (ASCT) [4]. 
Maintenance therapy in MM  
Maintenance therapy to achieve sustained suppression of residual disease following 
chemotherapy induction or ASCT has long been viewed as a desirable approach for extending 
survival in MM. Even the most intensive therapy followed by ASCT is usually unable to extend 
progression-free survival (PFS) to beyond 36 months, with the majority of patients eventually 
experiencing relapse.  Efforts to establish long-term maintenance regimens using alkylating 
agents, interferons, and corticosteroids have been hindered by unacceptable toxicity and have 
largely failed to improve survival [5]. One study in which patients were randomized to receive 
either prednisone 50mg or 10mg per day showed an overall survival (OS) benefit in the 50mg 
arm of 37 v. 26 months, P=0.05 [6]. However, these results have not been confirmed in a 
subsequent controlled clinical trial, and patients treated with corticosteroid maintenance are less 
responsive to these agents at relapse [7]. Increased survival in MM has been achieved with the 
introduction of novel therapeutic agents including the immunomodulatory drug lenalidomide 
(Revlimid; Celgene) [8]. 
Investigational drug lenalidomide 

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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 
 
 
Lenalidomide possesses diverse tumoricidal and immunomodulatory properties and a favorable 
toxicity profile. Lenalidomide overcomes many of the issues associated with long-term 
thalidomide therapy, especially neuropathy. Lenalidomide in combination with dexamethasone 
received FDA approval after two parallel studies demonstrated response rates of 61% for 
lenalidomide plus dexamethasone versus 22% for dexamethasone alone in patients with 
relapsed/refractory multiple myeloma [9].  The drug has also been studied in newly diagnosed 
patients in combination with low-dose dexamethasone, as well as with bortezomib and 
dexamethasone. 
Lenalidomide role as maintenance therapy 
A pilot phase 2 study showing the feasibility and efficacy of lenalidomide consolidation and 
maintenance therapy laid the basis for further clinical testing of lenalidomide. Recently, three 
large phase III trials comparing lenalidomide maintenance to placebo found significant 
progression-free survival (PFS) benefit for both ASCT-eligible [10, 11] and ineligible [12] 
patients. Additionally, one study [11] reported a significant difference in 3 year OS between the 
lenalidomide and placebo arms, 88% v. 80%, p=0.03. In all three studies [10-12], the 
progression-free survival benefit of lenalidomide was independent of the response to induction 
therapy at randomization, age, disease stage, β2-microglobulin level, use or nonuse of 
lenalidomide or thalidomide induction therapy, and presence or absence of cytogenetic 
abnormalities (though cytogenetic data were available only in the study by Attal et al. [10] and 
only in a few patients). 
These findings are summarized in table 1. 
 
N
N
H
O
O
O
NH2

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Table1: Lenalidomide maintenance studies after ASCT and conventional chemotherapy 
Study  
Induction 
No.  
Maintenance 
PFS/TTP 
(median) 
OS  
Discontinue 
due to AE 
 
IFM 2005-02 
[10]  
VAD/other 
Single or double ASCT 
 Len. consolidation x 
2 cycles 
 
a. 307 
 
 
b. 307  
a. Len. 10 mg /d with dose 
adaptations (5-15 mg/d)  
 
b. Placebo 
 
 
a. 41 mo 
 
 
b. 21 mo 
p <0.001 
HR 0.50  
a. 73%  
(4 y OS) 
 
b. 75% 
p = 0.70 
HR 1.06 
a. 27% 
 
 
b.15% 
CALGB 
100104 
[11] 
Any  
ASCT 
a. 231 
 
 
b. 229  
a. Len. 10-15 mg/d  
 
 
b. Placebo  
a. 46 mo 
(TTP) 
 
b. 27mo 
p <0.001  
a.88%) 
 (3 y OS) 
 
b. 80% 
p= 0.03 
a. 12% 
 
 
b. 2% 
MM 015 
[12]  
a. Mel. + Pred. + Len. 
 
b. Mel. + Pred. + Len. 
 
c. Mel. + Pred. 
a. 152 
 
b. 153 
 
c. 154  
a. Len. 10 mg/d, days 1-21 
  
b. Placebo 
 
c. Placebo  
a. 31 mo 
 
b. 14 mo 
 
c. 13 mo 
p <0.001  
a. 70%  
(3 y OS ) 
b. 62% 
  
c. 66% 
p =0.254 
a. 20% 
 
b. 16% 
 
c. 2.9% 
PFS- progression free survival; TTP- time to progression; OS- overall survival; SPM- second primary malignancies; VAD- 
vincristine, adrimaycin, dexamethasone; ASCT- autologous stem cell transplant; Mel.-melphalan; Pred.-prednisone; Len.- 
lenalidomide; AE - adverse events 
 
Lenalidomide maintenance therapy was well tolerated with expected and manageable side effects 
including mild hematotoxicity and infections. There was no increase in neurotoxicity or 
thromboembolic complications. Most patients were able to continue maintenance treatment 
without the need to discontinue therapy because of adverse events. Of note, there was a 7 to 8% 
rate of second primary cancers in the lenalidomide groups as compared with 3 to 4% in the 
placebo groups. This increase in second cancers led to discontinuation of lenalidomide in the 
trial reported by Attal et al [10]. Post hoc analysis with second cancers scored as events showed a 
median event-free survival of 40 to 43 months versus 23 to 27 months in both transplantation 
trials [10, 11] and 29 months versus 13 months in the trial that compared MPR-R with placebo 
[12], providing support for a magnitude of benefit associated with lenalidomide that seems to 
outweigh the risk of second cancers.  The development of second primary cancers may also be 
due in part to other factors, some of which include prior use of various MM drugs with known 
leukemogenic potential, MM-related disease factors, host-related factors, as well as 
environmental and behavioral factors [13]. Further studies are needed to evaluate the true risk of 
this complication, to identify risk factors for its development, and hopefully, to develop 
strategies for the prevention of second primary cancers. Before more information is available, 
physicians and patients must weigh the benefits of lenalidomide maintenance therapy against the 
low but relevant risk of second cancers.  
Lenalidomide mechanism of action 
The mechanism of action of lenalidomide remains to be fully characterized. Although the exact 
mechanisms of lenalidomide’s action are unknown, a number of mechanisms are postulated to be 
responsible for lenalidomide’s ability to provide disease control. The anti-MM effect of 
lenalidomide is thought to be mediated by the combined effects of activation of immune effector 
cells (both T and NK cells), tumor down regulation of critical pro-survival cytokines (including 

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IL-6, TNF-α, PDGF and VEGF), direct inhibition of plasma cell proliferation, and suppression of 
angiogenesis [14, 15, 16].  
Lenalidomide effect on NK, NKT, and T cells 
Data suggest that part of the therapeutic efficacy of lenalidomide may be via the promotion of 
NK cell–mediated responses against MM cells. A number of studies and our unpublished 
preclinical work from (table 2) has demonstrated that as the disease progresses to advanced states 
from MGUS to MM, there is an associated decline in the NK cell number, and associated anti-
MM activity[17, 18, 19].  
Table 2: Data from natural history study 10-c-0096 comparing NK cell numbers in subjects with 
monoclonal gammopathy of uncertain significance and smoldering multiple myeloma  
Disease 
N 
Variable 
Mean (k/µL) 
p-value 
MGUS 
33 
WBCs 
6.41 
0.03 
SMM 
37 
5.32 
MGUS 
33 
NK cells 
0.89 
0.07 
SMM 
37 
0.69 
Mayo Clinic SMM 
Risk Score 1 
17 
NK cells 
0.85 
0.004 
Mayo Clinic SMM 
Risk Score 2 
18 
0.53 
MGUS- monoclonal gammopathy of undetermined significance; SMM- smoldering multiple myeloma 
Lenalidomide can augment NK cell number, cytotoxicity and NK cell–driven antibody-
dependent cell-mediated cytotoxicity (ADCC) in several ways [14]. In vitro studies have shown 
that peripheral blood mononuclear cells (PBMCs) are required for lenalidomide-induced NK cell 
function, and this is achieved indirectly through activation of nuclear factor of activated T cell 2 
(NFAT2) in T cells [20, 21]. In this way, lenalidomide activates T cells to produce IL-2, which 
in turn stimulates NK cell activation and function against MM [20]. Lenalidomide causes 
enhancement of antigen-specific CD8+ T-cell cytolysis, upregulation of Fc-gamma receptor 
signaling leading to increased NK cell activity, and activation of NKT cells [14]. Lenalidomide 
has been shown to increase CD16 expression on NK cells and facilitate ADCC against MM [22].  
Lenalidomide can also down-modulate suppressor of cytokine signaling (SOCS) 1 expression in 
NK cells, resulting in a higher sensitivity to activating stimuli in the microenvironment [23]. 
Finally, lenalidomide also appears to favorably modulate the balance of NK cell activating and 
inhibitory ligand expression on MM targets. This action of lenalidomide may be of particular 
interest as initiation of a cytotoxic response by an NK cell is mediated through balance of signals 
obtained through inhibitory receptors such as killer immunoglobulin-like receptors (KIRs) and 
CD94–NKG2A [24], and activating receptors including NKG2D, DNAM-1, and Nkp46 [24]. 
Lenalidomide up regulates expression of ULBP-1 on MM cells and decreases expression of PD-
L1, which both result in improved NK cell surveillance, recognition and lysis of MM tumor 
targets [26, 27]. Changes in NK cell receptor ligand expression on MM cells and, hence, their 
resistance to NK cell–mediated killing may underlie the development of more proliferative and 
refractory plasma cell clones as MM progresses [28, 29] and treatment with lenalidomide in 
maintenance setting may  provide a means to promote NK cell–mediated control over MM .  

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Furthermore, prior smaller investigations in relapsed multiple myeloma have reported 
lenalidomide to increase the numbers of T cells (CD4, CD8), NKT and NK cells patients [30, 
31]. Similar findings have been reported in studies based on myeloma cell lines [32, 33]. In a 
recent study lenalidomide was found to be particularly active in patients with higher cereblon 
(CRBN) expression, suggesting CRBN plays a role in lenalidomide-mediated immune activation 
[34]; however, the relationship between these observations and a clinical benefit is unclear.  
Lenalidomide in combination with dexamethasone has been FDA-approved to treat relapsed and 
refractory MM.  Interestingly, however, in the setting of a clinical trial of lenalidomide and 
dexamethasone, correlative studies demonstrated that while NK cell number was increased from 
a mean of 2.20 ± 0.05 × 10^5/mL (baseline) to a mean of 3.90 ± 0.03 × 10^5/mL (cycle 6; P = 
.05), cytotoxicity was irreversibly reduced from 48.9% ± 6.8% to 27.6% ± 5.1% (P = .0028), 
attributed mainly to blunting of lenalidomide’s immunostimulatory effects on patient NK cells 
by concurrent dexamethasone administration [35]. Hence, single-agent lenalidomide seems to be 
the logical choice for maintenance treatment when tumor load has already been reduced 
significantly and control of the residual tumor cells by active immune surveillance is the 
clinically relevant priority. Given the presumed broad immune stimulatory effects of 
lenalidomide, it may be of clinical and scientific importance to investigate changes in immune 
cells in the setting of extended dosing (i.e. maintenance therapy) with this agent. Currently, there 
is no information available on this topic. 
Lenalidomide effect on B cell subsets, MDSC and T regulatory cells 
Regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) have been shown to 
inhibit the activation and function of T cells that participate in antigen-specific immune 
responses. Tregs are potent immunosuppressive cells of the immune system that promote 
progression of cancer through their ability to limit antitumor immunity and promote 
angiogenesis. Higher proportions of Tregs have been reported in the PBMCs of patients with 
several types of tumors [36, 37, 38] including MM [39, 40]. Lenalidomide has been shown to 
inhibit the proliferation of FOXP3+ CTLA-4+CD4+CD25high Tregs in vitro [41]. In humans, 
MDSCs are defined as CD14-CD11b+ or cells that express the myeloid marker CD33 and lack 
markers for mature myeloid and lymphoid cells in combination with low expression of HLA-DR 
[42]. Recently, new populations of CD14+HLA-DR−/low MDSCs have been identified in 
patients with hepatocellular carcinoma [43] and MM [44]. MDSCs accumulate as a consequence 
of factors associated with inflammation, such as increased secretion of vascular endothelial 
growth factor (VEGF), GM-CSF, IL-1β, IL-6 and PGE2, factors that are also elevated in patients 
with MM [45] These changes in Treg and MDSC populations have not been characterized in the 
setting of lenalidomide maintenance in patients with MM. Cytokines and growth factors directly 
regulate proliferation, differentiation and death of normal B-lymphocytes, and abnormal cytokine 
networks clearly exist within the MM  microenvironment. A recent in vitro study showed that 
lenalidomide significantly suppresses immunoglobulin synthesis by B cells [45], but we have 
limited knowledge of lenalidomide’s effect on B cell populations in patients receiving 
maintenance therapy.  
To conduct a comprehensive evaluation of a range of immune cells in relation to lenalidomide 
maintenance therapy, we will include analyses of B-, T-, NK and NKT cells and important 
signaling cytokines. 

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Proposed Study Investigation with Biomarker Studies 
The primary objective of this study is a longitudinal assessment of T cell (CD4, CD8), NKT and 
NK cell populations during the course of lenalidomide maintenance therapy in patients with 
MM. Peripheral blood samples from all enrolled patients will be collected and batched for 
biomarker analysis at baseline, after cycles 1, 3, and 6, and then after every 6 cycles while 
receiving lenalidomide therapy, until completion of the study. The assays will be run on the 
batched samples for first ten patients at baseline, after cycles 1, 3, and 6 to determine the 
appropriate time points of assays for the subsequent patients. Samples will also be collected from 
all patients at the time of disease progression. Blood samples and bone marrow samples will be 
used for additional research studies, which may include functional analyses of immune-cell 
subsets, analyses for cytokines, chemokines, antibodies, tumor cell antigen targets, and/or other 
markers. Effective with Amendment D, bone marrow aspirate and biopsy will be obtained for 
research studies at the discretion of the PI. Patients' tumor cells, where possible, will be 
characterized by gene expression profiling to enhance our understanding of lenalidomide 
efficacy and safety in a genetically diverse tumor population.  
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
2.1.1.1 Patients with multiple myeloma treated with induction therapy or re-induction 
therapy, who at the time of study enrollment have documented evidence of stable 
disease response or better according to International Myeloma Workshop Consensus 
Panel as provided in Section 6.2. The response assessment must occur at least 4 
weeks after completion of their last treatment.   
2.1.1.2 Age ≥18 years.  Because no dosing or adverse event data are currently available on 
the use of lenalidomide in patients <18 years of age, children are excluded from this 
study, but may be eligible for future pediatric trials. 
2.1.1.3 ECOG performance status ≤ 2 (see Appendix A). 
2.1.1.4 Patient must have adequate hematologic, renal, hepatic, and cardiac function as 
defined by:  
 
Absolute neutrophil count ≥ 1.0K /μL independent of growth factor support 
 
Platelets ≥ 75K/μL  
 
Hemoglobin ≥ 8 g/dL (transfusions are permissible) 
 
Calculated creatinine (CrCl) clearance of greater than or equal to 40 mL/min. 
using the Cockcroft-Gault method (see Appendix E).  If the calculated CrCl 
based on Cockcroft-Gault method is <40 mL/min, patient will have a 24 hr 
urine collection to measure CrCl. The measured CrCl must also be ≥ 40 ml/min. 
 
Total bilirubin ≤ 1.5 mg/dL, AST (SGOT) and ALT (SGPT) ≤ 3 x ULN 
2.1.1.5 Females of childbearing potential (FCBP) must agree to use two effective 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 study drug; 2) while participating in the study; and 3) for at least 

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28 days after discontinuation from the study. The two methods of effective 
contraception must include one highly effective method (i.e. intrauterine device 
(IUD), hormonal [birth control pills, injections, or implants], tubal ligation, partner's 
vasectomy) and one additional effective (barrier) method (i.e. latex condom, 
diaphragm, cervical cap). FCBP must be referred to a qualified provider of 
contraceptive methods if needed. 
2.1.1.6 A FCBP is defined as a sexually mature woman 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). 
2.1.1.7 A FCBP must have two negative serum or urine pregnancy tests prior to starting 
study drug. The first pregnancy test must be performed within 10-14 days prior to the 
start of study drug and the second pregnancy test must be performed within 24 hours 
prior to prescribing the study drug. The prescriptions of study drug must be filled 
within 7 days. 
2.1.1.8 Male patients must agree to use a latex condom during sexual contact with FCBP 
while participating in the study and for at least 28 days following discontinuation 
from the study even if he has undergone a successful vasectomy. 
2.1.1.9 Patient must be able to take aspirin (81 or 325 mg) daily as prophylactic 
anticoagulation. Patients intolerant to ASA may use warfarin or low molecular 
weight heparin. 
2.1.1.10 Patient must understand and voluntarily sign an informed consent form, with the 
understanding that the patient may withdraw consent at any time without prejudice to 
future medical care. 
2.1.2 Exclusion Criteria 
2.1.2.1 Patients with progressive or refractory MM, as defined by International Myeloma 
Workshop Consensus Panel criteria provided in section 6.2 
2.1.2.2 Refractory to lenalidomide in the most recent line of therapy, as defined by the 
International Myeloma Consensus Panel criteria [47]- as failure to achieve minimal 
response or development of progressive disease while on lenalidomide or within 30 
days of lenalidomide therapy 
2.1.2.3 Patients who are receiving any other investigational agents with the intent to treat 
myeloma. Permitted concurrent therapies include: 
 
Bisphosphonates 
 
Radiotherapy to single stable disease site 
2.1.2.4 Plasma cell leukemia 
2.1.2.5 Pregnant or lactating females.  Because there is a potential risk for adverse events to 
nursing infants secondary to treatment of the mother with lenalidomide, lactating 
females must agree not to breast feed while taking lenalidomide.  
2.1.2.6 Uncontrolled hypertension or diabetes 
2.1.2.7 Active hepatitis B or C infection  

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2.1.2.8 Diagnosed or treated for another malignancy within 3 years prior to study 
enrollment, with the exception of complete resection of non-melanoma skin cancer, 
or an in situ malignancy.  
2.1.2.9 Previous diagnosis of another malignancy with any evidence of residual disease.  
2.1.2.10 Patients seropositive for the human immunodeficiency virus (HIV), and/or those who 
are taking anti-retroviral treatment for HIV/AIDS 
2.1.2.11 Prior organ transplant requiring immunosuppressive therapy 
2.1.2.12 Prior allogeneic stem cell transplant 
2.1.2.13 Patients requiring continuous, systemic immunosuppressive therapy 
2.1.2.14 Patients with myocardial infarction within 6 months prior to enrollment, New York 
Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe 
uncontrolled cardiac arrhythmias, or electrocardiographic evidence of acute ischemia 
2.1.2.15 Patients with conditions that would prevent absorption of the study drug 
2.1.2.16 Uncontrolled intercurrent illness including but not limited to uncontrolled infection 
or psychiatric illness/social situations that would compromise compliance with study 
requirements 
2.1.2.17 Significant neuropathy ≥Grade 3 at baseline 
2.1.2.18 Contraindication to concomitant anticoagulation prophylaxis 
2.1.2.19 Major surgery within 1 month prior to enrollment 
2.1.2.20 Patients who were previously exposed and who developed severe adverse events, 
hypersensitivity or desquamating rash to either thalidomide or lenalidomide 
2.1.3 Recruitment Strategies 
1) Patients with newly diagnosed MM who have completed induction treatment with 
CRd on trial 11-C-0221.   
2) Patients with relapsed multiple myeloma after completing treatment on expanded 
access CRd trial 12-C-0043 or other appropriate NCI trials.  
3) Other participant sources will be from outside physician referrals. 
4) Our ongoing multiple myeloma treatment study and outside physician referral 
network has a high representation of minorities. 
2.2 
SCREENING EVALUATION 
2.2.1 Clinical evaluation must be completed within 4 weeks prior to study enrollment: 
A complete history and physical examination with documentation of type of response 
(sCR, CR, VGPR, PR, MR or SD according to criteria described in section 6.2) to 
induction or re-induction treatment, the time interval from last treatment to 
documentation of response, and assessment of performance status using the ECOG 
scale must be performed prior to study entry. Patients will be evaluated for baseline 
neuropathy.  

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2.2.2 The following studies and laboratory tests will be completed within 4 weeks prior to 
study entry: 
2.2.2.1 CBC with differential  
2.2.2.2 Reticulocyte count 
2.2.2.3 Acute care panel, calculated creatinine clearance using Cockgroft-Gault formula 
(within 2 weeks prior to study entry) 
2.2.2.4 Mineral panel, Hepatic panel, Uric acid, LDH, and Beta-2 Microglobulin 
2.2.2.5 PT, PTT 
2.2.2.6 Serum protein electrophoresis (SPEP) and immunofixation to assess for presence and 
quantity of monoclonal protein (M-protein) 
2.2.2.7 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 response to 
prior (re)induction treatment, or if calculated creatinine clearance is <40 ml/min.  
2.2.2.8 Serum free light chain studies 
2.2.2.9 Quantitative immunoglobulins 
2.2.2.10 Viral serologies:  
 
Hepatitis B surface antigen 
 
Anti Hepatitis C (HCV) antibody. If positive, will follow with HCV RNA PCR 
 
HIV ELISA screening test. If positive, will follow with confirmatory Western 
Blot test 
2.2.2.11 Review of bone marrow core biopsy or aspirate 
2.2.2.12 Serum or urine pregnancy test in women of child-bearing potential (complete within 
10-14 days and again within 24 hours prior to prescribing lenalidomide for cycle 1) 
2.2.2.13 12-lead EKG 
2.2.2.14 Skeletal survey of the axial and appendicular skeleton.  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 confirmatory 
interpretation by the Department of Radiology. 
2.3 
REGISTRATION PROCEDURES 
2.3.1 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 faxed to 301-480-0757.  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 the research team. A 
recorder is available during non-working hours.  

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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 
biomarker studies. 
2.4.2 Peripheral Blood/Urine (see section 5) 
2.4.2.1 For storage and establishing a biobank (AppendixC in section 15) 
2.4.2.2 Flow cytometry and other assays (see section 5): 
 
Phenotypic analysis of NK, NKT, and T cells 
 
Phenotypic analysis of B cell subsets 
 
Proliferation assays for human T cells (CD4 and CD8) 
 
Functional NK cell analysis 
 
Regulatory T cell and myeloid derived suppressor cell (MDSC) phenotype 
 
Chemokine and cytokine assay 
 
Selected tumor cell antigen targets 
2.4.3 Bone Marrow (see section 5). Bone marrow aspirate and biopsy will be used for 
histopathological evaluation, to determine the immunophenotyping of aberrant clonal 
plasma cells by multiparametric flowcytometry, CD 138+ and CD 138- fractions cell 
sorting with subsequent correlatives on both fractions, and the expression of CRBN by 
gene expression profiling and quantitative PCR.  
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
 
Patients with newly diagnosed or relapsed MM with stable disease or better clinical 
response after induction or re-induction treatment will be enrolled on this phase II 
study and treated with a maintenance dose of lenalidomide 10 mg daily on days 1 to 
21 of repeated 28-day cycles. 
 
Patients who complete at least 3 cycles will be evaluable for primary endpoints. 
Patients who do not complete three cycles of therapy will not be included in the 
analysis of primary or non-primary endpoints; and will be replaced by new patients.  
 
Using flow cytometry on peripheral blood, the four primary outcomes of T cell (CD4, 
CD8), NKT and NK cell numbers will be measured at pre-specified treatment time 
points to determine the difference in the counts of these parameters for each patient.  
3.2 
DRUG ADMINISTRATION 
 
Lenalidomide10 mg once daily, given by mouth on days 1-21, of repeated 28-day 
cycles, to continue until disease progression, unacceptable toxicity or completion of 
two years of lenalidomide therapy and the 30 day safety follow-up visit.  
 
Lenalidomide will be prescribed monthly by 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 beginning with Cycle 4.  

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 
Females of childbearing potential (FCBP) patients will be required to have pregnancy 
testing as outlined in AppendixAppendix B: Risks of Fetal Exposure, Pregnancy 
Testing Guidelines and Acceptable Birth Control Methods: Risks of Fetal Exposure, 
Pregnancy Testing Guidelines and Acceptable Birth Control Methods; 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. 
 
Lenalidomide capsules should be swallowed whole, and should not be broken, chewed 
or opened. 
 
If vomiting occurs within 15 minutes and the whole capsule is present in the emesis 
then the dose can be repeated.    
 
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 for females of 
childbearing potential and 14 days for all other risk categories.  Only enough 
lenalidomide for one cycle of therapy will be supplied to the patient each cycle. 
 
Patients should be instructed never to give lenalidomide to another person and to 
return any unused capsules to their research coordinator at the end of treatment.  
 
Patients should not donate blood during therapy and for at least 28 days following 
discontinuation of lenalidomide. 
 
Patients will be required to take oral Aspirin 81 mg or 325 mg or alternative 
anticoagulation therapy every day for the duration of their participation in the study. 
3.3 
DOSE MODIFICATIONS 
Before each cycle, patients will be evaluated for possible toxicities that may have occurred after 
the previous dose(s). Toxicities will be assessed according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) (http://ctep.cancer.gov/reporting/ctc.html). Each adverse 
event (AE) attributed to lenalidomide will be carefully recorded, so that the dose modifications 
can be made accordingly. If multiple toxicities are noted, the dose adjustments and/or delays will 
be made according to guidelines that address the most severe toxicity.  
3.3.1 Dose reduction steps: 

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Dose   
Lenalidomide  
Baseline dose 
10 mg  
One level dose reduction 
5 mg  
Two level dose reductions 
5 mg every other day 
 
3.3.2 Dose adjustments for Thrombocytopenia: 
*In case of thrombocytopenia, the decision to modify the dose of lenalidomide, administer platelet 
transfusions, and resume anti-coagulation may be based on the clinical judgement of the PI.  
3.3.3 Dose adjustments for Neutropenia:  
Neutropenia  
Recommended Course  
First  episode- 
(Neutropenia is the only hematologic toxicity) 
ANC < 0.5 x 109/L  (grade 4) 
ANC < 1.0 x 109/L (grade 3) with fever/sepsis 
Hold lenalidomide. Consider growth factors.  
Monitor CBC weekly.  
ANC returns to ≥ 0.5 x 109/L, and fever/sepsis have resolved.  
Resume lenalidomide at same dose level, and consider 
stopping growth factors.  
First  episode- 
(Hematologic toxicities other than neutropenia are 
observed) 
ANC < 0.5 x 109/L (grade 4) 
ANC < 1.0 x 109/L (grade 3) with fever/ sepsis 
Hold lenalidomide. Consider growth factors. 
Monitor CBC weekly.  
ANC returns to ≥ 0.5 x 109/L, other toxicities and fever/sepsis 
have resolved.  
Resume lenalidomide at next lower dose level, and consider 
stopping growth factors.  
Thrombocytopenia  
Recommended Course  
First Episode-  
Platelet count  < 25 x 109/L  
Hold lenalidomide. Hold prophylactic anti-coagulation. 
Monitor CBC weekly.  
Platelet count returns to ≥ 25 x 109/L.  
Resume lenalidomide at 10 mg. Resume prophylactic anti-
coagulation, if no bleeding. 
Subsequent Episodes-  
Platelet count < 25  x 109/L  
Hold lenalidomide. Hold prophylactic anti-coagulation. 
Monitor CBC weekly.  
Platelet count returns to ≥ 25 x 109/L. 
Resume lenalidomide at next lower dose level. Resume 
prophylactic anti-coagulation, if no bleeding.   
Do not decrease dose below 5 mg every other day. 

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Subsequent Episodes-  
ANC < 0.5 x 109/L (grade 4) 
ANC < 1.0 x 109/L (grade 3) with fever/sepsis  
 
Hold lenalidomide. Add growth factors.  
Monitor CBC weekly.   
ANC returns to ≥ 0.5 x 109/L, and fever/sepsis have resolved.  
Resume lenalidomide at next lower dose level and consider 
stopping growth factors.  
Do not decrease dose below 5 mg every other day.  
*Fever defined as single temperature of 38.3oC or sustained temperature of 38oC for > 1 hour.  In case of 
neutropenia, the decision to start/continue growth factors (such as filgrastim, pegfilgrastim), and/or 
reduce the dose of lenalidomide may be based on the clinical judgment of the PI. 
3.3.4 Dose adjustments for Non hematologic toxicity  
Lenalidomide Common Non-
hematologic Toxicities 
Dose Modifications 
Non Blistering Rash 
If Grade 3, hold lenalidomide, and restart at next lower dose level once 
rash improves to ≤ Grade 2. 
Blistering, exfoliative or bullous rash 
(any grade), or suspected Stevens 
Johnson Syndrome (SJS) or Toxic 
Epidermal Necrolysis (TEN) 
Discontinue lenalidomide and remove patient from therapy. 
Venous or arterial  
thrombosis/embolism 
Hold lenalidomide and start therapeutic anticoagulation.  Restart 
lenalidomide at investigator’s discretion at current or reduced dose 
level. Patient should continue anticoagulation therapy during the course 
of lenalidomide treatment. Additional work up to determine the cause of 
thromboembolic events may be done as clinically indicated at the 
discretion of investigator.  
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 – no dose modifications 
 
CrCl ≤30 mL/min (not requiring dialysis) – Dose reduce 
Lenalidomide to 10 mg every 48 hours  
 
CrCl ≤30 mL/min (requiring dialysis) – Decrease Lenalidomide to 
5 mg daily and on dialysis days, dose lenalidomide after 
dialysis.  
Other non-hematologic grade 3/4 
toxicities judged to be related to 
lenalidomide. Readily reversible 
electrolyte and metabolic abnormalities 
or infections controlled by appropriate 
therapy are exempt. 
Hold treatment and restart at next lower dose level when toxicity has 
resolved to ≤Grade 2 
3.3.5 Monitoring (see study calendar for more specific details) Please Note: Day 1 may be 
delayed for up to one week for Cycle 2 and beyond.  
3.3.5.1 Routine labs (CBC with diff, retic count, acute care panel, mineral panel, hepatic 
panel, LDH, uric acid) will be performed on Day 1 (within 3 days prior) and Day 15 

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(within 3 days prior) of first cycle, on Day 1 (within 3 days prior) of  cycles 2, 4 and 
7 and on Day 1 (within 3 days prior) of every third  cycle starting at cycle 10 at 
scheduled clinic visits, at the time of documented CR, and at disease progression  
(see study calendar).  
3.3.5.2 Random urine sample for protein electrophoresis (UPEP) and immunofixation to 
assess for monoclonal protein in the urine (Bence-Jones proteinuria) will be 
performed at baseline, on Day 1 (within 3 days prior) of cycles 2, 4 and 7 and on 
Day 1 (within 3 days prior) of every third cycle starting at cycle 10 at scheduled 
clinic visits, at the time of documented CR, and at disease progression (see study 
calendar).  
3.3.5.3 Myeloma tests including serum protein electrophoresis, serum immunofixation, 
serum free light chains, quantitative immunoglobulins, beta-2 microglobulin will be 
performed at baseline, on Day 1 (within 3 days prior) of cycles 2, 4 and 7 and on 
Day 1 (within 3 days prior) of every third cycle starting at cycle 10 at scheduled 
clinic visits, at the time of documented CR, and at disease progression (see study 
calendar).   
3.3.5.4 Patients will have clinic visits with H&P or standard progress notes assessing for 
toxicity/side effects on Day 1(within 3 days prior), and 15 (within 3 days prior) of 
cycle 1 and Day 1 (within 3 days prior) of cycles 2, 4 and 7 and on Day 1 (within 3 
days prior) of every third cycle starting at cycle 10 at scheduled clinic visits (see 
study calendar). 
3.3.5.5 Skeletal survey to assess disease status will be performed at baseline. The skeletal 
survey at the time of documented CR or disease progression is optional.    
3.3.5.6 Evaluation of bone marrow for disease status will be performed at baseline, and then 
at the time of documented CR or disease progression.  Additional bone marrow 
samples to evaluate disease status, treatment effect, or biomarker studies will be 
obtained at the discretion of PI, if patients are willing. 
3.3.5.7 Additional laboratory studies and clinic visits may be performed as clinically 
indicated. 
3.3.5.8 Patients removed from protocol therapy for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event. Further follow-up can 
be assessed either by phone consultation or clinic appointment at the discretion of the 
PI. 
 

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3.4 
STUDY CALENDAR 
Study 
Pre-
treatment 
(Screening/ 
Baseline) 
Maintenance Treatment 
until progression, unacceptable toxicity or completion of two years of 
lenalidomide therapy and the 30 day safety follow-up visit  
Progressive 
disease 
Follow up- off protocol therapyl, m 
Cycle 1 
Cycles 2, 4 
and 7 
Cycle 10 and 
beyond-every 3 
cycles 
CR 
achieved 
 
Any cycle 
Determine at  PI's discretion 
Dayk 1 
Dayk 15 
Day m 
 1 
Day m 
1 
Any day 
 
Medical Record 
Review 
x 
 
 
 
 
 
 
 
x 
H&P/clinic visit 
x 
x 
x 
x 
x 
x 
x 
x 
 
ECOG 
x 
x 
x 
x 
x 
x 
x 
x 
 
Informed 
Consent 
x 
 
 
 
 
 
 
 
 
Routine Labsa 
x 
x 
x 
x 
x 
x 
x 
x 
 
Viral Studiesb 
x 
 
 
 
 
 
 
 
 
Register for 
REMS 
x 
 
 
 
 
 
 
 
 
Pregnancy Testc 
xc 
xd 
xe 
xe 
xe 
xe 
 
 
 
Myeloma testsf 
x 
 
 
x 
x 
x 
x 
x 
 
Urine for UPEP 
and IFE g 
x 
 
 
x 
x 
x 
x 
x 
 
Bone 
marrow/aspirateh 
x 
 
 
 
 
x 
x 
x 
 
Blood for -
biomarkers 
 
x 
 
x 
x 
x 
x 
x 
 
12 lead EKG 
x 
 
 
 
 
 
 
 
 
Skeletal survey 
x 
 
 
 
 
 
xj  
xj 
 
Adverse 
Events/Toxicity 
 
x 
 
 
 
 
 
 
 
Storage 
blood/urine 
 
x 
 
x 
x 
x 
x 
x 
 
 

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a. 
Routine tests include CBC, reticulocyte count, acute care panel, mineral panel and hepatic panel, uric acid, LDH and calculated CrCl. PT and PTT will only be performed at 
baseline. 
b. Viral studies include: HIV, 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) 
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, , serum free light chains, quantitative immunoglobulins, and beta-2 microglobulin will be 
performed at baseline, on Day 1 (within 3 days prior) of Cycle 2, Cycle 4, and Cycle 7, and thereafter every 3 cycles, at the time of documented CR, and at  disease 
progression.     
g. Random urine sample for protein electrophoresis (UPEP) and immunofixation to assess for monoclonal protein in the urine (Bence-Jones proteinuria) will be performed at 
baseline, on Day 1 (within 3 days prior) of Cycle 2, Cycle 4, and Cycle 7, and thereafter every 3 cycles, at the time of documented CR, and at disease progression. 
h. Bone marrow aspirate and biopsy can be performed +/- 21 days of intended cycle day. Bone marrow aspirate and biopsy will be sent to Hematology Service of the 
Department of Laboratory Medicine and Flow cytometry for immunophenotyping of plasma cells. CD 138 sorting/GEP/quantitative PCR/ storage will be done in Molecular 
pathology or Lymphoid Malignancies Branch lab... For questions regarding these samples, please contact Mark Roschewski at 301-451-9021. Effective with Amendment D, 
bone marrow aspirate and biopsy will be obtained for research studies at the discretion of the PI.  
i. 
Blood for biomarker analysis will be collected on D1 (within 3 days prior) of Cycle 1, Cycle 2, Cycle 4, Cycle 7 and every 6 cycles thereafter. 
j. 
Skeletal survey to assess disease status will be performed at baseline. The skeletal survey at the time of documented CR or disease progression is optional. 
k. Variations of +/- 3 days of scheduled visits are permitted. 
l. 
Patients removed from protocol therapy for unacceptable toxicities will be followed until resolution or stabilization of the adverse event. Further follow-up for patients taken 
off protocol therapy can be assessed either by phone consultation or clinic appointment at the discretion of the PI.  
m. Day 1 may be delayed for up to one week for Cycle 2 and beyond. 
 

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3.5 
 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
3.5.1 Criteria for removal from protocol therapy 
3.5.1.1 Patients with medically concerning grade 3 or 4 adverse events related to study drug 
may be taken off therapy at the discretion of the principal investigator.    
3.5.1.2 Toxicity has not resolved after 8 weeks of withholding treatment  
3.5.1.3 Grade 4 non-blistering rash, or blistering rash of any grade  
3.5.1.4 Grade 4 neuropathy 
3.5.1.5 Grade 4 hypersensitivity reaction 
3.5.1.6 Progression of disease 
3.5.1.7 Patient chooses to go off therapy 
3.5.1.8 The principal investigator may remove patient from protocol therapy if deemed 
necessary due to medical conditions, compliance, etc. 
3.5.1.9 Diagnosis of new malignancy  
3.5.1.10 Patient becomes pregnant. 
3.5.2 Criteria for removal from study 
3.5.2.1 Patient requests to be withdrawn from study 
3.5.2.2 Death 
3.5.2.3 Physician’s determination that withdrawal is in the patient’s best interest 
3.5.2.4 Effective with amendment D, version date February 12, 2015, patients, will be 
removed from the study when they have completed two years of lenalidomide 
therapy and the 30 day safety follow-up visit. Patients who have on-going 
toxicity(ies) will be followed as described in Section 7.1.1.  
3.5.2.5 Study closure  
3.5.3 Off Study Procedure 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off-
study. An off-study form from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed and 
faxed to 301-480-0757. 

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4 
CONCOMITANT MEDICATIONS/MEASURES 
4.1 
TUMOR LYSIS SYNDROME 
4.1.1 Allopurinol is optional and will be prescribed at the Investigator’s discretion.  
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 Subjects may receive radiation if clinically indicated for treatment of uncontrolled pain, 
cord compression, vertebral instability/impending fracture, etc, in the face of non 
progressive disease 
4.2.2 Kyphoplasty/Vertebroplasty:  Subjects may receive kyphoplasty/vertebroplasty for 
symptomatic vertebral compression fractures in the face of non progressive disease. 
4.2.3 Bisphophonate therapy:  Approved bisphophonate therapy (zoledronic acid or 
pamidronate) is allowed.  Patients will be monitored for renal function and 
osteonecrosis of the jaw.  Patients may require prior evaluation from dental specialist 
before instituting bisphosphonates.   
4.3 
USE OF STEROIDS 
4.3.1 Use of corticosteroids during maintenance therapy with the intent to treat myeloma is 
not permitted. However, corticosteroids may be used as medically indicated for non-
myeloma related acute indications e.g. to control symptoms of asthma flare. 
Corticosteroids should be discontinued as soon as possible. 
4.4 
HYPERCALCEMIA 
4.4.1 Patients may receive treatment for hypercalcemia including hydration, bisphophonates, 
furosemide, steroids, calcitonin, etc.  
4.5 
TRANSFUSIONS/GROWTH FACTORS 
4.5.1 Subjects may receive RBC or platelet transfusions if clinically indicated.   
4.5.2 Subjects may receive supportive care with erythropoietin or darbopoetin.   
4.5.3 Prophylactic use of growth factors (i.e. filgrastim, pegfilgrastim) is not permitted. 
However, therapeutic use of filgrastim or sargramostim in patients with serious 
neutropenic conditions, such as sepsis, febrile neutropenia may be considered at the 
investigator’s discretion. Colony-stimulating factors may be used if grade 4 neutropenia 
occurs but should not be given prophylactically.   
4.6 
ANTI-COAGULATION 
4.6.1 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. 
4.7 
ANTI-EMETICS  

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4.7.1 Anti-emetics should not be given prophylactically. If a patient demonstrates the need 
for anti-emetics, their use will be at the treating physician's discretion. 
4.8 
PCP PROPHYLAXIS  
4.8.1 The use of medication (e.g. Bactrim) for PCP prophylaxis is at the investigator's 
discretion. 
5 
BIOSPECIMEN COLLECTION 
5.1 
BIOMARKER STUDIES FOR RESEARCH 
1) Blood/Urine 
Sampling Time Points for biomarker studies/ biospecimen banking  
 
Baseline 
C 2 D1  
 (within 3 
days 
prior)  
C 4 D1  
 (within 3 
days 
prior)  
C 7 D1  
 (within 3 
days 
prior) 
Every 3 
cycles 
starting 
at cycle 7 
D1 
(within 3 
days 
prior)  
Every 6 
cycles 
starting 
at cycle 7 
D1 
(within 3 
days 
prior) 
Disease 
progression 
At CR 
Blood for 
biomarker analysis 
x 
x 
x 
x 
 
x 
x 
x 
Bone marrow*  
x 
 
 
 
 
 
x 
x 
Blood/Urine 
Biopspecimen 
storage bank 
 
x 
x 
x 
x 
x 
 
x 
x 
a. Blood samples for biomarker studieswill be collected from all patients at 
baseline, after cycles 1, 3, and 6, and then after every 6 cycles while receiving 
lenalidomide therapy, until completion of the study. The samples will be 
batched for later analysis. 
b. The assays will be run on the batched samples for first ten patients at baseline, 
and after cycles 1, 3, and 6 to determine the appropriate time points of assays 
for the subsequent patients.  
c. Blood and urine specimens will be collected from all patients who agree to 
participate in optional studies and stored for establishing biospecimen storage 
bank. These specimens will be collected at baseline, after cycles 1, 3, and 6 
and after every three cycles while receiving lenalidomide. Specimens will also 
be collected and stored at the time of documented CR and disease progression. 
IRB approval will be obtained before using any samples to conduct studies 
that are not described within this protocol.   

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d. Collection and storage of peripheral blood and urine for biospecimen storage 
bank is outlined in appendix C. 
e. Processing of peripheral blood for biomarker studies is outlined in appendix 
D.  
f. 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.  
g.  The standard number of peripheral blood tubes drawn for storage at each of 
the above time points may include but are not limited to the following:  one 7-
8 mL serum tube, one 7-8 mL plasma heparinized tube, and one 7-8 mL 
EDTA tube. 
h. The standard number of peripheral blood tubes drawn for biomarker analysis 
at each of the above time points may include but are not limited to the 
following: two 7-8 mL plasma heparinized tubes. 
i. 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 timepoints.   
j. 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 page Dr. 
Figg’s lab at 102-11964 for immediate pick-up. 
2) Bone Marrow 
Effective with Amendment D, bone marrow aspirate and biopsy will be obtained for 
research studies at the discretion of the PI. 
a. Bone marrow specimens (aspirate and biopsy) will be collected for at 
baseline, and then at the time of documented CR or disease progression. Bone 
marrow samples will be used to determine the molecular characteristics of the 
tumor cells and the expression of CRBN by gene expression profiling and 
quantitative PCR.  
b. Additional bone marrow samples for other biomarker studies will be obtained 
at the discretion of PI, if patients are willing. 
c. Collection of bone marrow, sorting of bone marrow and storage of bone 
marrow samples is outlined in appendix F.  
d. Biomarker 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 Service for morphological evaluation by Irina Maric, MD and 

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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.   
ii. 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. Cell Sorting, molecular characterization - Marrow aspirate will be sent to 
the Lymphoid Malignancies Branch lab and sorted into CD 138 + and CD 
138 – fractions.  For questions regarding these samples, please contact 
Mark Roschewski at 301-451-9021.   
 GEP profiling: CD138+ plasma cells will be purified from 
bone marrow aspirates harvested at each indicated time point.  
GEP will be performed in the Lymphoid Malignancies Branch 
lab using the Affymetrix U133 Plus 2.0 microarray platform.  
Gene expression profiles will be analyzed to identify potential 
markers of response to lenalidomide such as CRBN and 
markers for progression.  Changes in selected genes will be 
confirmed by quantitative PCR if suggested to be related to 
response or progression. 
 Both CD 138+ and CD 138- fractions will be collected, 
batched, and entered into a biobank.  See section 5.3.1 and 
Appendix F in section 18 for storage of bone marrow biobank. 
5.2 
BIOMARKER STUDIES: METHODS 
While it has been shown that lenalidomide-induced NK cell activation is IL-2 dependent, the 
specific subset of cells responsible for mediating this effect has not been clearly elucidated. To 
conduct a comprehensive evaluation of a range of immune cells in relation to lenalidomide 
maintenance therapy, we will include analyses of B-, T-, NK and NKT cells and important 
signaling cytokines. 
 
Phenotypic analysis of PBMCs: Patients' PBMCs will be FACS-sorted into NK cells 
(CD3−CD16+CD56+), CD4 (CD3+CD4+), and CD8 (CD3+CD8+) T-cell subsets. The 
percentage of T cells (CD4, CD8), NKT and NK cells will be determined by 
phenotypic analysis of peripheral blood mononuclear cells (PBMCs) stained for CD56, 
CD3, CD4, CD8, and CD16. To obtain total numbers per milliliter of peripheral blood, 
the percentage of CD4 T or NK cells will be multiplied by the total lymphocyte count. 
 
Phenotypic analysis of B cell subsets: B cell subsets will be analyzed by phenotypic 
analysis of PBMCs stained for CD19, CD38 CD45, CD27 and CD138. 

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 
Proliferation assay for human T cells (CD4 and CD8): 100 μl of PBMC (1 x 
10^6cells/ml) will be added to each well of a in a 96-well round-bottom plate. The 
plate is coated with 100 μl anti-CD3 (OKT3; eBioscience) at a concentration of 10 
μg/ml. Incubate plate in a humidified 37o C, 5% CO2 incubator. All cells are cultured 
in medium RPMI 1640 (Mediatech, Inc., Herndon, VA) supplemented with 10% heat 
inactivated human AB serum (Gemini Bio-Products, Woodland, CA); 100 units/ml 
penicillin and 100μg/ml streptomycin (Mediatech, Inc.); 2 mM L-glutamine 
(Mediatech, Inc.). Cells are incubated for 3 days. Proliferation will be assessed by 
[3H]thymidine (1 μCi [0.037 MBq] per well) (Perkin-Elmer, Boston, MA) 
incorporation pulsed on day 4 and quantified 18 hours later using a liquid scintillation 
counter (Wallac, Gaithersburg, MD). All experiments will be performed in triplicate.  
 
Functional NK analysis: A 4-h 111In-release assay will be used to measure NK 
activity in patients. Cell line K562 will be used as target. Target cells will be labeled 
with 50 μCi of 111In-oxyquinoline in a volume of 0.25 ml of RPMI-1640 for 15 min 
at 37o C according to a modification of the procedure described by Wiltrout et al [48]. 
Target cells (1 x 104) in 50 μl will be added to each well of assay plates containing 96-
U-bottom wells. Effector cells (sorted NK cells) to target cell (E/T) ratios of 50:1, 
25:1, 12.5:1 and 6.25:1 will be assayed. The plates will be incubated for 4-h at 37o C 
in a humidified atmosphere containing 5% CO2. Supernatants will be harvested for 
gamma counting using Skatron Harvesting Frames. Experiments will be carried out in 
triplicate. Specific lysis will be calculated using the formula: 
 
Lysis (%) =  
Observed release (cpm)-spontaneous release (cpm) 
 
 
___________________________________________   X 100 
 
 
Total release (cpm)-spontaneous release (cpm)  
 
 
Regulatory T cell (Treg) and MDSC phenotype: The number and phenotype of Tregs 
in PBMCs from patients in this study will be determined by 9-color flow cytometry 
analysis. Cells will be resuspended in staining buffer (phosphate-buffered saline 
containing 3% fetal bovine serum) and stained for CD4, CD25, CD127, FoxP3, 
CTLA-4, CD45RA, PDL-1, DR and CD8. The ratios of Treg to effector cells will also 
be analyzed. MDSCs will be analyzed by staining for CD34, CD33, CD11b, CD15, 
CD13 CD14 and DR. 
 
Chemokine and Cytokine Assay: The presence of IL-4, IL-10, IL-8, IL-13, TNF-
alpha, IFN-gamma, IL-12p70, GM-CSF, IL-5, and IL-6 in serum obtained from 
patients pre- and post-treatment will be determined using a multi-plex assay (Meso 
Scale Discovery, Gaitherburg, MD). Assays will also be performed for cytokines such 
as TGF-beta, IL-17, VEGF and IL-23. 
 
Other Assays: Using flow cytometry and immunohistochemistry, we will determine 
selected tumor cell antigen targets including, but not limited to MUC1, Brachyury, 
PD1 ligands, MAGE-A, and NYESO. Patient serum and bone marrow samples will be 
evaluated for previously studied prognostic markers including M-spike, percent bone 
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immunophenotype by flow cytometry, albumin, and ß2-microglobulin. Patients' tumor 
cells will be characterized by gene expression profiling to enhance our understanding 
of lenalidomide efficacy and safety in a genetically diverse tumor population. 
 
Future Assays: The information obtained from this study regarding immune effector 
cells in MM will provide the framework for the development of immune-based 
therapeutic options like novel vaccines or monoclonal antibodies, and the development 
of therapies designed specifically to increase NK cell cytotoxicity against MM. It will 
also allow for analysis of myeloma cell-immune cell interactions.  
5.3 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
5.3.1 Procedures for Collecting, Processing, and Storage of Bone Marrow biopsies 
 See Appendix F 
 Orders for bone marrow biopsies should be placed in the Clinical Research 
Information System (Clinical Research Center, NIH, Bethesda, MD). Samples will 
be ordered and tracked through the CRIS Screens.  Should a CRIS screen not be 
available, the NIH form 2803-1 will be completed and will accompany the 
specimen and be filed in the medical record.  Samples will not be sent outside NIH 
without IRB notification and an executed MTA. 
 Bone marrow biopsies will be submitted in native condition to the NCI Laboratory 
of Pathology 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. 
 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 NCI 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.  All research samples except stored serum will be stored in 
the Lymphoid Malignancies Branch lab. For questions regarding these samples, 
please contact Mark Roschewski at 301-451-9021. 
 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. 
5.3.2 Procedures for stored serum, peripheral blood, and urine specimens: 
 See Appendix C for processing and storage procedures for Dr. Figg’s lab. 

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5.3.3 Procedures for Collecting, Processing, and Storage of Blood samples for biomarker 
studies 
 See Appendix D for processing and storage procedures for Dr. Figg's lab 
 Batched blood samples for research purposes will be further analyzed for biomarker 
studies in Dr. Schlom's lab as per the methods detailed in section 5.1 
5.3.4 Protocol Completion & Sample Destruction 
 The principal investigator will report destroyed samples to the IRB if samples 
become unsalvageable because of environmental factors (ex. a broken freezer or 
lack of dry ice in a shipping container) or if a patient withdraws consent.  Samples 
will also be reported as lost if they are lost in transit between facilities or misplaced 
by a researcher.  Freezer problems, lost samples, or other problems associated with 
samples will also be reported to the IRB, the NCI Clinical Director, and the office 
of the Center for Cancer Research of the NCI. 
6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
 
Data will be prospectively collected and entered into the NCI C3D clinical trials 
database. All adverse events that are Grade 3 or higher related to lenalidomide and/or 
research procedures will be collected into the NCI C3D database.  All data will be 
kept secure. Personal identifiers will not be used when collecting and storing data. An 
enrollment log will be maintained in the regulatory binder/file which is the only 
location of personal identifiers with unique subject identification number. 
 
When patients complete protocol treatment but remain on-study, the following data 
will be collected: 
o adverse events related to lenalidomide 
o survival status which will be collected by phone or clinic visit 
o additional cancer therapy received  
 
Record Keeping: 
Complete records must be maintained on each patient; these records will consist of 
the hospital chart as well as any other information obtained from outside laboratories, 
radiology reports, or physician’s records. These records will serve as the primary 
source material that forms the basis for the research record. 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. 
 
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 who 

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will enter the data into the study database. Additional blood or tissue samples drawn 
on patients enrolled in this protocol between scheduled visits may be forwarded and 
entered into the database as well. 
6.2 
RESPONSE CRITERIA 
6.2.1 Response assessments will be performed on Day 1 (+/- 3 days) of cycles 2, 4 and 7; and 
on Day 1 (+/-3 days) of every third cycle starting at cycle 10 at scheduled clinic visits, 
at the time of documented CR, and at disease progression Disease Parameters 
 
Patients who have a measurable serum or urine M-protein. A "measurable" serum 
M-protein is ≥ 1 g/dL and a "measurable" urine M-spike is ≥ 200 mg/24 hours. If 
patient does not have a "measurable" serum or urine M-protein, but has either a 
serum kappa or lambda FREE light chain of 10 mg/dL along with an abnormal 
kappa to lambda free light chain ratio, patient is considered to have "measurable" 
disease. 
 
The serum free light chain (FLC) assay is of particular use in monitoring response 
to therapy in patients who have oligo-secretory disease. When using this assay, it is 
important to note that the FLC levels vary considerably with changes in renal 
function and do not solely represent monoclonal elevations. Thus both the level of 
the involved and the uninvolved FLC isotype (i.e., the involved/uninvolved ratio or 
involved-uninvolved difference) should be considered in assessing response. The 
serum FLC assay should be used in assessing response only if the baseline serum 
and/or urine M proteins are not “measurable” by traditional criteria (serum M 
protein ≥ 1gm/dL and/or urine M protein ≥ 200 mg/24), and the baseline level of 
the involved FLC is 10mg/dL and clonal (abnormal ratio). Patients included on the 
study on the basis of FLC alone (i.e., no measurable serum/urine) should be the 
only ones who are evaluated using FLC response criteria. The others should follow 
usual criteria and ignore FLC results. 
 
In order to be classified as a hematologic response, confirmation of serum 
monoclonal protein, serum immunoglobulin free light chain (when primary 
determinant of response) and urine monoclonal protein (when primary determinant 
of response) results must be made by verification on two consecutive 
determinations. 
 
Caution must be exercised to avoid rating progression or relapse on the basis of 
variation of radiological technique alone. Compression fracture does not exclude 
continued 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. 
6.2.2 Response Criteria from International Myeloma Workshop Consensus Panel Criteria47: 
6.2.2.1  Evaluation of Response Criteria 
o Stringent Complete Response (sCR)  
Complete Response as defined below plus:  

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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).  
o Complete Response (CR)  
Negative immunofixation on the serum and urine and disappearance of any soft 
tissue plasmacytomas and ≤5% plasma cells in bone marrow.  Patients in whom 
the only measurable disease is by serum FLC levels: CR in such patients 
indicates a normal FLC ratio of 0.26 to 1.65 in addition to CR criteria listed 
above. 
o 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 
unmeasureable, a ≥90% decrease in the difference between involved and 
uninvolved FLC levels is required in place of the M-protein criteria. 
o 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 
unmeasureable, a ≥50% decrease in the difference between involved and 
uninvolved FLC levels is required in place of the M-protein criteria.  
o Minimal Response (MR)  
 ≥ 25% but ≤ 49% reduction of serum M protein and reduction in 24-hour urine 
M-protein by 50%-89% In addition to the above criteria, if present at baseline, 
25%-49% reduction in the size of soft tissue plasmacytomas is also required . If 
the serum and urine M-protein are unmeasureable, a 25- 49% decrease in the 
difference between involved and uninvolved FLC levels is required in place of 
the M-protein criteria. No increase in size or number of lytic bone lesions is 
required (development of compression fracture does not exclude response)  
o Stable Disease (SD)  
Not meeting criteria for CR, VGPR, PR, MR or progressive disease.  All 
categories also require no known evidence of progressive or new bone lesions if 
radiographic studies were performed. Radiographic studies are not required to 
satisfy these response requirements.  
o Progressive disease (PD) 
Requires any one or more of the following:  
 Increase of ≥25% from baseline or lowest reponse value in Serum M 
component, Urine M component, FLC or bone marrow plasma cell 
percentage. Lowest response value does not need not to be a confirmed 
value. 
 Serum M-component 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 absolute increase must be ≥200mg/24h  
 Only in patients without measurable serum and urine M-protein levels: 
the absolute increase in difference between involved and uninvolved 
FLC levels must be >10mg/dl.  

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 Only in patients without measurable serum and urine M protein levels 
and without measurable disease by FLC levels, bone marrow plasma cell 
absolute percentage 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 (corrected serum calcium > 11.5 mg/dL) 
that can be attributed solely to the plasma cell proliferative disorder  
o Refractory Myeloma 
Refractory myeloma is defined as disease that is nonresponsive while on 
primary or salvage therapy, or progresses within 30 days of last therapy. 
Nonresponsive disease is defined as either failure to achieve minimal response 
or development of progressive disease (PD) while on therapy. 
o Relapse from CR 
Any one or more of the following: 
 CR patients will need to progress to the same level as VGPR and PR 
patients to be considered PD. A positive immunofixation alone is 
therefore not sufficient.  
 Development of ≥ 5% plasma cells in the bone marrow 
 Appearance of any other sign of progression (ie, new plasmacytoma, 
lytic bone lesion, hypercalcemia 
 
6.2.3 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.    
6.2.4 Progression-Free Survival 
PFS is defined as time of start of treatment to time of progression or death, whichever occurs 
first. 
6.2.5 Overall Survival 
Overall survival is defined as the time of start of treatment to death from any cause. 
6.2.6 Overall response rates  
Overall response rates (ORR) is PR+VGPR+CR after n cycles of therapy. 
6.3 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40).  
 
Attribution of the AE: 

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- Definite: The AE is clearly related to the study treatment. 
- Probable: The AE is likely related to the study treatment. 
- Possible: The AE 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 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 
7.1 
DEFINITIONS 
7.1.1 Adverse Event 
An adverse event is defined as any reaction, side effect, or untoward event that occurs during the 
course of the clinical trial associated with the use of a drug in humans, whether or not the event 
is considered related to the treatment or clinically significant. For this study, AEs will include 
events reported by the patient, as well as clinically significant abnormal findings on physical 
examination or laboratory evaluation. A new illness, symptom, sign or clinically significant 
laboratory abnormality or worsening of a pre-existing condition or abnormality is considered an 
AE.  All AEs that are Grade 3 or higher must be recorded on the AE case report form. 
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed until return to baseline or stabilization of event. Serious adverse 
events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of at least possibly related to the agent/intervention 
should be recorded and reported as per section 7.2.   
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. 
7.1.2 Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
7.1.3 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 

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if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. 
"Unexpected”, also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
7.1.4 Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
7.1.5 Serious Adverse Event 
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 drug experience 
 
Inpatient hospitalization or prolongation of existing hospitalization 
 
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. 
Per Celgene: Examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse.  
A new diagnosis of cancer during the course of a treatment should be considered as 
medically important.  
 
Pregnancy 
7.1.6 Disability 
 A substantial disruption of a person’s ability to conduct normal life functions. 
7.1.7 Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that had it occurred in a more severe form, might have caused death. 
7.1.8 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB approved research protocol.  

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7.1.9 Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) 
policies, IRB requirements, or regulatory requirements for the protection of human research 
subjects. 
7.1.10 Unanticipated Problem 
Any incident, experience, or outcome that: 
  Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
 Is related or possibly related to participation in the research; AND 
 Suggests that research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
7.1.11 Pregnancies 
7.1.11.1 Reporting Pregnancy to Celgene  
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on lenalidomide, or within  28 
days of the subject’s last dose of lenalidomide, are considered immediately reportable events. 
Lenalidomide is to be discontinued immediately. The pregnancy, suspected pregnancy, or 
positive pregnancy test must be reported to Celgene Drug Safety immediately by facsimile or 
email using the Pregnancy Initial Report Form. The female subject should be referred to an 
obstetrician-gynecologist, preferably one experienced in reproductive toxicity for further 
evaluation and counseling. 
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form.  If the outcome of the 
pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the Investigator should 
report the abnormal outcome as an AE. If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety immediately by facsimile, or other 
appropriate method, within 24 hours of the Investigator’s knowledge of the event using the SAE 
Report Form. 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the investigational product (IP) should also be reported to 
Celgene Drug Safety immediately by facsimile, or other appropriate method, within 24 hours of 
the Investigator’s knowledge of the event using the SAE Report Form.  
Male Subjects 

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If a female partner of a male subject taking investigational product becomes pregnant, the male 
subject taking lenalidomide should notify the Investigator, and the pregnant female partner 
should be advised to call her healthcare provider immediately. 
 
Celgene Drug Safety Contact Information: 
Celgene Corporation      
Global Drug Safety and Risk Management    
Connell Corporate Park      
300 Connell Dr.  Suite 6000     
Berkeley Heights, NJ  07922        
Fax: (908) 673-9115 
E-mail: drugsafety@celgene.com 
7.2 
NCI-IRB REPORTING 
7.2.1 NCI-IRB Expedited Reporting of Unanticipated Problems and Deaths 
The Protocol PI will report to the NCI-IRB: 
 All deaths, except deaths due to progressive disease  
 All Protocol Deviations 
 All Unanticipated Problems 
 All serious non-compliance 
Reports must be received by the NCI-IRB within 7 working days of PI awareness via iRIS. 
7.2.2 NCI-IRB Requirements for PI Reporting at Continuing Review 
The protocol PI will report to the NCI-IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the 
deviation occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
 
All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research;  
 
All Grade 5 events regardless of attribution;  
 
All Serious Events regardless of attribution.  
NOTE: Grade 1 and Grade 2 events are not required to be reported.  
7.2.3 NCI-IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be 
reported to the NCI IRB. 

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7.2.4 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 
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-NCI-0718) 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 
E-mail:  
drugsafety@celgene.com 
7.3 
DATA AND SAFETY MONITORING PLAN 
The following plans will be used for this study. 
7.3.1 Principal Investigator/Research Team  
The clinical research team will meet on a regular basis 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. Adverse events will be reported as required above. 
Any safety concerns, new information that might affect either the ethical and or scientific 
conduct of the trial, or protocol deviations will be immediately reported to the IRB using iRIS 
and if applicable to the Sponsor.  

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The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
8 
STATISTICAL CONSIDERATIONS 
8.1 
 STUDY DESIGN/PRIMARY ENDPOINTS 
This is a single arm, single stage, phase II trial to evaluate maintenance therapy with the 
immunomodulatory agent lenalidomide in treated MM patients who have stable or responsive 
disease. After screening, eligibility determination, and enrollment; subjects will receive 
lenalidomide 10 mg by mouth daily on days 1-21 of a 28-day cycle. Subjects may continue 
lenalidomide until disease progression, diagnosis of new malignancy, unacceptable toxicity, 
investigator discretion, or voluntary withdrawal. When necessary, lenalidomide will be held and 
restarted in accordance with accepted clinical dose modification strategies. 
The primary objective of this study is a longitudinal assessment of T cell (CD4, CD8), NKT and 
NK cell populations during the course of lenalidomide maintenance therapy in patients with 
MM. Using flow cytometry on peripheral blood obtained at baselines and after 3 cycles of 
therapy, we will determine the primary measures at both time points. Comparisons at other time 
points will be considered exploratory..  
With 28 patients enrolled, we will have 80% power to detect an effect equal to 0.67 SD of the 
difference in counts (0.67 SD effect size) of T cells (CD4, CD8), NKT and NK cells with a two-
tailed paired t-test and a significance level of 0.013 for each test. Thus, using a strict Bonferroni 
adjustment, we would have an overall significance level of 0.05 for the four tests. In practice, a 
less overly conservative Hochberg adjustment may be used instead of a Bonferroni adjustment. 
In addition, if the difference in the numbers of any type of cells is not normally distributed 
(p<0.05 by a Shapiro- Wilks test), then a Wilcoxon signed rank test will be performed instead.  
Results will be presented in a descriptive format. 
8.2 
SAMPLE SIZE/ACCRUAL RATE 
It is anticipated that 2-3 patients per month may enroll on this trial; thus, approximately 14 
months may be required to enroll the 28 patients. 
8.3 
STATISTICAL ANALYSIS OF SECONDARY ENDPOINTS 
Secondary endpoints include duration of response and progression-free survival. Duration 
of response is defined as time from response to disease progression or death. Progression-
free survival is defined as the time from study entry until progression or death. Duration 
of response and progression-free survival will be estimated using the Kaplan-Meier 
method. Where possible, blood samples and bone marrow samples will be used for 
additional research studies, which may include functional analyses of immune-cell 
subsets, analyses for cytokines, chemokines, antibodies, tumor cell antigen targets, and/or 
other markers. Due to the sample size, the results from those efforts will be exploratory, 
and the main goal is to generate data for future studies. 

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9 
COLLABORATIVE AGREEMENTS  
9.1 
COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) 
There is an approved collaborative agreement, CRADA, with Celgene Corporation for 
lenalidomide. 
9.2 
Material Transfer Agreement (MTA) 
An MTA will be executed before the samples described in Section 5 are shipped to Ola 
Landgren, MD, PhD at Memorial Sloan Kettering Cancer Center.  
The samples and accompanying personally identifiable information, or code to personally 
identifiable information, will be used 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. 
The samples will also be used for clinical, molecular and imaging based characterization of the 
above disorders. 
10 HUMAN SUBJECTS PROTECTIONS  
10.1 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. Incidence rates of myeloma are 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. 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.     
10.2 PARTICIPATION OF CHILDREN 
Pediatric patients with MM 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. 
10.3 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
Currently, MM is an incurable malignancy with frequent complications of skeletal fractures, 
anemia, renal failure and hypercalcemia.  Maintaining or improving upon the clinical responses 
achieved following induction therapy is viewed as an important strategy to prolong survival in 
MM. Lenalidomide is an attractive drug with immunomodulatory activity for maintenance 

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therapy with the advantage of oral administration. Two trials of lenalidomide maintenance after 
ASCT and one trial after conventional chemotherapy induction therapy showed a significant risk 
reduction for PFS, with one of the transplant trials also showing a prolongation of OS. 
Lenalidomide maintenance therapy was well tolerated with almost negligible hematotoxicity, no 
neurotoxicity, and no increase in thromboembolic complications or infections. The observation 
of an increased occurrence of second primary malignancies (SPM), however, is notable. There 
was a 7 to 8% rate of second primary cancers in the lenalidomide groups as compared with 3 to 
4% in the placebo groups. Post hoc analysis supported for a magnitude of benefit associated with 
lenalidomide that seems to outweigh the risk of second cancers.  The development of second 
primary cancers is not just attributed to lenalidomide and may also be due in part to other factors, 
some of which include prior use of various MM drugs with known leukemogenic potential, MM-
related disease factors, host-related factors, as well as environmental and behavioral factors.  
10.4 RISKS/BENEFITS ANALYSIS 
On a clinical note, for most patients, multiple myeloma still remains an incurable malignancy 
and, on average, the general risk of dying is substantially higher than the risk of developing a 
second cancer. Lenalidomide maintenance has significantly improved progression free survival 
in three clinical trials.  
Further studies are needed to evaluate the true risk of developing second primary cancers, to 
identify risk factors for their development, and hopefully, to develop strategies for the prevention 
of second primary cancers. Before more information is available, physicians and patients must 
weigh the benefits of lenalidomide maintenance therapy against the low but relevant risk of 
second cancers.  
The procedures required to obtain samples/data for experimental purposes (venipuncture, urine 
collection, PET/CT scan and bone marrow biopsy) are of limited risk to the patient.  Although 
patients will suffer some additional pain or discomfort from bone marrow biopsies, clinical 
experience has shown that the medical risk is limited.     
10.5 CONSENT AND ASSENT PROCESS AND DOCUMENTATION 
Informed consent will be obtained from all patients on this trial by one of the investigators. 
There will be no minors enrolled < 18 years of age; therefore, assent is unnecessary. The 
informed consent procedure contains all elements required for consent. In addition, the Principal 
Investigator or an associate investigator or 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. 
11 PHARMACEUTICAL INFORMATION   
11.1 LENALIDOMIDE   
11.1.1 Source  
REVLIMID® (lenalidomide) is provided to investigator by Celgene Inc. under Cooperative 
Research and Development Agreement (CRADA). 

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NOTE:  
Before lenalidomide is dispensed, patients must 1) have a negative pregnancy test (if 
applicable) and 2) be counseled by a trained counselor. Pharmacists may be trained 
counselors (see Lenalidomide Counselor Program Site Counselor Identification Form in 
the protocol). The counseling requirements for investigational-use lenalidomide are 
separate from the REMS program. Only a 28-day supply may be dispensed to a patient at 
one time.  

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Mode of Action: Lenalidomide, a thalidomide analog, is an immunomodulatory agent with a 
spectrum of activity that is still under investigation. Some of its effects include inhibition of 
inflammation, inhibition of angiogenesis, inhibition of hematopoetic tumor cell proliferation, 
modulation of stem cell differentiation and upregulation of T cell and NK cell responses.  
11.1.2 Toxicity 
Fetal Risk  
Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb 
abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that 
causes severe life-threatening human birth defects.  If lenalidomide is used during pregnancy, it 
may cause birth defects or death to a developing baby. In women of childbearing potential, 
obtain 2 negative pregnancy tests before starting REVLIMID® treatment. Women of 
childbearing potential must use 2 forms of contraception or continuously abstain from 
heterosexual sex during and for 4 weeks after REVLIMID treatment 
Hematologic Toxicity 
REVLIMID can cause significant neutropenia and thrombocytopenia.  
In the pooled MM studies Grade 3 and 4 hematologic toxicities were more frequent in patients 
treated with the combination of REVLIMID and dexamethasone than in patients treated with 
dexamethasone alone 
Deep Vein Thrombosis and Pulmonary Embolism 
Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary 
embolism) have occurred in patients with MM treated with lenalidomide combination therapy.  
A significantly increased risk of DVT and PE was observed in patients with MM who were 
treated with REVLIMID and dexamethasone therapy in a clinical trial.  
Allergic Reactions 
Angioedema 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, 
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11.1.3 Formulation and preparation  
Lenalidomide will be supplied as capsules for oral administration. Celgene Inc. will provide 
lenalidomide 5, 10, mg capsules while patients are being treated on this protocol.  
11.1.4  Stability and Storage  
Lenalidomide should be stored at room temperature away from direct sunlight and protected 
from excessive heat and cold. 
11.1.5 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.    
11.1.6 Incompatibilities  
Results from human in vitro metabolism studies and nonclinical studies show that REVLIMID is 
neither metabolized by nor inhibits or induces the cytochrome P450 pathway suggesting that 
lenalidomide is not likely to cause or be subject to P450- based metabolic drug interactions in 
man. 
Digoxin 
When digoxin was co-administered with lenalidomide, the digoxin AUC was not significantly 
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.  
 
 
 

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the antitumor activity of lenalidomide and pomalidomide. Blood 2011; 118:4771-
79. 
35. Hsu AK, Quach H, Tai T, . The immuno-stimulatory effect of lenalidomide on 
NK cell function is profoundly inhibited by concurrent dexamethasone therapy. 
Blood 2011;117:1605–1613.  
36. Ke X, Wang J, Li L, et al. Roles of CD4+CD25(high) FOXP3+ Tregs in 
lymphomas and tumors are complex. Front Biosci 2008;13:3986-4001. 
37. Shen Z, Zhou S, Wang Y, Li RL, et al. Higher intratumoral infiltrated Foxp3+ 
Treg numbers and Foxp3+/CD8+ ratio are associated with adverse prognosis in 
resectable gastric cancer. J Cancer Res Clin Oncol. 2010;136(10):1585-95. 
38. Kordasti SY, Ingram W, Hayden J, et al. CD4+CD25high Foxp3+ regulatory T 
cells in myelodysplastic syndrome (MDS). Blood. 2007;110:847-850. 
39. Giannopoulos K, Kaminska W, Hus I, Dmoszynska A. The frequency of T 
regulatory cells modulates the survival of multiple myeloma patients: detailed 
characterisation of immune status in multiple myeloma.Br J Cancer. 
2012;106:546-552 
40. Feyler S, von Lilienfeld-Toal M, Jarmin S, Marles L, Rawstron A, Ashcroft AJ, 
Owen RG, Selby PJ, Cook G. CD4(+)CD25(+)FoxP3(+) regulatory T cells are 
increased whilst CD3(+)CD4(-)CD8(-)alphabetaTCR(+) Double Negative T cells 
are decreased in the peripheral blood of patients with multiple myeloma which 
correlates with disease burden. Br J Haematol. 2009;144:686-695 
41. Galustian C, Meyer B, Labarthe MC, Dredge K, Klaschka D, Henry J, Todryk S, 
Chen R, Muller G, Stirling D, Schafer P, Bartlett JB, Dalgleish AG. The anti-
cancer agents lenalidomide and pomalidomide inhibit the proliferation and 
function of T regulatory cells. Cancer Immunol Immunother. 2009;58:1033-1045 
42. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the 
immune system. Nat Rev Immunol 2009;9:162–174. 
43. Hoechst B, Ormandy LA, Ballmaier M et al. A new population of myeloid-
derived suppressor cells in hepatocellular carcinoma patients induces 
CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology 2008;135:234–243. 
44. Brimnes MK, Vangsted AJ, Knudsen LM, Gimsing P, Gang AO, Johnsen HE, 
Svane IM. Increased level of both CD4+FOXP3+ regulatory T cells and 
CD14+HLA-DR-/low myeloid-derived suppressor cells and decreased level of 
dendritic cells in patients with multiple myeloma. Scand J Immunol. 2010;72:540-
547 
45. Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells: linking 
inflammation and cancer. J Immunol 2009;182:4499–4506. 
46. Shannon E, Sandoval F, Greig N, Stagg P. Lenalidomide alone or lenalidomide 
plus dexamethasone significantly inhibit IgG and IgM in vitro... A possible 

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explanation for their mechanism of action in treating multiple myeloma. Int 
Immunopharmacol. 2012;12:441-446.  
47. Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et 
al; International Myeloma Workshop Consensus Panel 1. Consensus 
recommendations for the uniform reporting of clinical trials: report of the 
International Myeloma Workshop Consensus Panel 1. Blood 2011;117:4691-
4695. 
48. Wiltrout RH, Gorelik E, Brunda MJ et al. Assessment of in vivo natural antitumor 
resistance and lymphocyte. Migration in mice: comparison of 125I- 
iododeoxyuridine with 111indium-oxine and 51chromium as cell labels. Cancer 
Immunol Immunother1983;14(3):172-179. 
 
 

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13 APPENDIX A-PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, 
able to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and 
about more than 50% of waking 
hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated.  Death 
not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
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14 APPENDIX B: RISKS OF FETAL EXPOSURE, PREGNANCY TESTING 
GUIDELINES AND ACCEPTABLE BIRTH CONTROL METHODS 
Risks Associated with Pregnancy 
The use of lenalidomide in pregnant females and nursing mothers has not been studied nor has 
the effect of the lenalidomide on human eggs and sperm.  Lenalidomide is structurally related to 
thalidomide.  Thalidomide is a known human teratogenic active substance that causes severe life-
threatening birth defects.  An embryofetal development study in animals indicates that 
lenalidomide produced malformations in the offspring of female monkeys who received the drug 
during pregnancy.  The teratogenic effect of lenalidomide in humans cannot be ruled out.  
Therefore, a risk minimization plan to prevent pregnancy must be observed. 
All study participants must be registered into the mandatory REMS® program, and be willing 
and able to comply with the requirements of REMS®. 
Criteria for females of childbearing potential (FCBP) 
This protocol defines a female of childbearing potential as a sexually mature female who: 1) has 
not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally 
postmenopausal 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 or pregnant female, 
and that he understands the need for the use of a condom even if he has had a vasectomy, 
if engaged in sexual activity with a female of childbearing potential.   
Contraception 
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two reliable 
forms of contraception simultaneously or to practice complete abstinence from heterosexual 
intercourse during the following time periods related to this study: 1) for at least 28 days before 
starting lenalidomide; 2) throughout the entire duration of lenalidomide treatment; 3) during dose 
interruptions; and 4) for at least 28 days after lenalidomide discontinuation.  
The two methods of reliable contraception must include one highly effective method and one 
additional effective (barrier) method. FCBP must be referred to a qualified provider of 
contraceptive methods if needed. The following are examples of highly effective and additional 
effective methods of contraception:   
o Highly effective methods: 
 Intrauterine device (IUD) 
 Hormonal (birth control pills, injections, implants) 

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 Tubal ligation 
 Partner’s vasectomy 
o Additional effective methods: 
 Male condom 
 Diaphragm 
 Cervical Cap 
Because of the increased risk of venous thromboembolism in patients with multiple myeloma 
taking lenalidomide and dexamethasone, combined oral contraceptive pills are not 
recommended. If a patient is currently using combined oral contraception the patient should 
switch to one of the effective methods listed above. The risk of venous thromboembolism 
continues for 4−6 weeks after discontinuing combined oral contraception. The efficacy of 
contraceptive steroids may be reduced during co-treatment with dexamethasone. 
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk 
of infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics 
should be considered particularly in patients with neutropenia.  
Pregnancy testing 
Medically supervised pregnancy tests with a minimum sensitivity of 50 mIU/mL must be 
performed for females of childbearing potential, including females of childbearing potential who 
commit to complete abstinence, as outlined below. 
Before starting lenalidomide 
Female Patients: 
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 
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including dose interruptions, at lenalidomide discontinuation, and at Day 14 and Day 28 
following lenalidomide discontinuation.   
 At each visit, the Investigator must confirm with the FCBP that she is continuing to use 
two reliable methods of birth control at each visit during the time that birth control is 
required.   
 If pregnancy or a positive pregnancy test does occur in a study patient, lenalidomide must 
be immediately discontinued. 
 Pregnancy testing and counseling must be performed if a patient misses her period or if 
her pregnancy test or her menstrual bleeding is abnormal.  Lenalidomide treatment must 
be temporarily discontinued during this evaluation. 
 Females must agree to abstain from breastfeeding during study participation and for at 
least 28 days after lenalidomide discontinuation. 
Male Patients: 
 Must practice complete abstinence or use a condom during sexual contact with pregnant 
females or females of childbearing potential throughout the entire duration of 
lenalidomide treatment, during dose interruptions and for at least 28 days following 
lenalidomide discontinuation, even if he has undergone a successful vasectomy.   
 If pregnancy or a positive pregnancy test does occur in the partner of a male study patient 
during study participation, the investigator must be notified immediately. 
 Male patients should not donate semen or sperm during therapy or for at least 28 days 
following discontinuation of lenalidomide. 
Additional precautions 
 Patients should be instructed never to give lenalidomide to another person. 
 Patients should not donate blood during therapy and 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.  
 Any unused lenalidomide must be returned as instructed through REMS program. 
Requirements for REMS 
 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).   
 All patients will be required to sign the REVLIMID, Patient-Physician Agreement Form. 

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Females not of childbearing potential must sign the the REVLIMID, Patient-Physician 
Agreement Form that says you are presently not pregnant and do not have the ability to have 
children.   
 
 

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15 APPENDIX C: Peripheral Blood and Urine Collection And Storage  
Venipuncture  
 Up to 100 mL of peripheral blood will be collected into heparinized tubes or EDTA 
tubes.  The amount of blood collected will be dictated by the number of experiments to 
be performed, and by the patient’s peripheral blood count.   
 Serum   
o Collect 7-8 mL blood in a serum separator tube (SST or red top).  
o Allow the blood to clot by standing at room temperature for 30 minutes. o 
Separate serum from cells by centrifuging at 4 degrees C for 5 minutes at 1200xg.    
o Pipette 3 aliquots of 1mL each into three 2mL cryovials.  
o Freeze immediately at -20C or lower.o Maintain in -80C freezer for storage until 
shipment. 
 Plasma  
o Collect 7-8 mL blood in a sodium heparin tube (green top).  
o Place immediately on wet ice and refrigerate until time of processing. o Separate 
plasma from cells by centrifuging at 4 degrees C for 5 minutes at 1200xg.  
o Pipette 3 aliquots of 1mL each into three 2mL cryovials. o Freeze and store in -
80C freezer.  
 Complete blood count 
o A venous blood sample for a CBC will be collected in a 10ml EDTA lavender top 
(BD EDTA 366643) tube.  Keep at room temperature until processing begins.   
 Mononuclear Cells 
o A venous blood sample for harvesting mononuclear cells will be collected in a 
10ml EDTA lavender top (BD EDTA 366643) tube.  Keep at room temperature 
until processing begins.     
Urine Sample Collection  
 Approximately 45 mL of urine will be collected into a standard urine collection cup for 
further analysis.  The amount of urine collected will be dictated by the number of 
experiments to be performed.    
 Transfer two even aliquots to two screw-cap 50 mL conical tubes.  
 Freeze immediately at -20C or lower.  
 Maintain in -20C freezer for storage until shipment. 
Labeling of Samples  
 All specimens are to be labeled per the local site’s standard procedures. The following 
information, if not provided on the specimen label, must be linked to the specimen label 
and provided on the inventory sheet:   
- 
patient study ID #   
- 
sample type  
- 
date/time of draw (DD/MMM/YY 24:00)  
- 
timepoint (ex. C1D1 pre, C1D1 24hr post)  
- 
any collection issues (short draw, delayed processing, etc.)  

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- 
protocol title/number  
- 
institute name  
- 
contact information  
 Do not include the patient name, medical record number, or initials.   
Sample Data Collection:   
 All samples sent to the Clinical Pharmacology Program (CPP) will be barcoded, with 
data entered and stored in the Patient Sample Data Management System (PSDMS) 
utilized by the CPP. This is a secure program, with access to the PSDM System limited to 
defined CPP personnel, who are issued individual user accounts. Installation of PSDMS 
is limited to computers specified by Dr. Figg. These computers all have a password 
restricted login screen. All CPP personnel with access to patient information annually 
complete the NIH online Protection of Human Subjects course.   
 PSDMS creates a unique barcode ID for every sample and sample box, which cannot be 
traced back to patients without PSDMS 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.).   
Sample Storage:  
 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 CPP and 
offsite at NCI Frederick Central Repository Services (Fisher Bioservices) 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 the PSDM 
System. 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 CPP. 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), and 
reported as such to the IRB. Any samples lost (in transit or by a researcher) or destroyed 
due to unknown sample integrity (i.e. broken freezer allows for extensive sample 
thawing, etc.) will be reported as such to the IRB.  
Sample barcodes are linked to patient demographics and limited clinical information. This 
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PSDMS. 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 
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16 APPENDIX D: ISOLATION AND CRYOPRESERVATION OF PERIPHERAL 
BLOOD MONONUCLEAR CELLS (PBMC) 
 
A.  Isolation of mononuclear cells by Lymphocyte Separation Medium (LSM) (Ficoll-Hypaque 
solution)  
1.    Place fresh heparinized blood (not longer than 1 hour after drawing) (approx. 15 ml) 
into a 50-ml conical centrifuge tube. Using a sterile pipet, add an equal volume of room-
temperature PBS. Mix well.  
2.    Slowly layer the Lymphocyte Separation Medium (LSM) underneath the blood/PBS  
mixture by placing the tip of the pipet containing LSM at the bottom of the sample tube.  
Use 3 ml of LSM per 10 ml blood/PBS mixture. 
3.    Centrifuge 30 min. at 2000 rpm (900 xg), 18°C to20°C, with no brake.  
4.    Using a sterile pipet, remove the upper layer that contains the plasma and most of the  
platelets. Using another pipet, transfer the mononuclear cell layer to another tube.  
Wash cells by adding excess Hanks balanced salt solution (HBSS) with 3X the volume  
of the removed supernatant. Resuspend cells in HBSS, and repeat the wash once to  
remove most of the platelets.  
5.    Resuspend mononuclear cells in RPMI-1640 medium containing 10% FCS. Count cells and 
determine viability by Trypan Blue exclusion. 
 
B.  Cryopreservation of PBMC  
1.   Prepare and label cryovials with patient #, cell concentration and date. (It is best to  
have all vials labeled prior to pelleting of the cells).  
2.    Aspirate supernatant. 
3.    Resuspend cells in a volume of formulate freezing medium to give desired concentration  
(approx 5-10 x 106 cells/vial). Please use Sarstedt Cryovial=0.5 and 2 ml screw cap  
Micro Tube (1-800-257-5101; catalogue # 72.694.006).  
Preparation of Freezing media: 
(a)   Measure out 45ml of heat inactivated human AB serum into a 50 ml centrifuge tube. 
(b)  Add 5 ml DMSO to the tube.  
(c)  Cap and invert tube for several times to mix.  
(d)  If not all freezing media is to be used within 2 hours, aliquot extra portion   into 15 ml 
centrifuge tubes and transfer to -20°C freezer for storage. Freezing media will expire one year 
after preparation. 
 4.   Immediately dispense cells into the labeled cryovials ensuring that the cell concentration  
in each vial is labeled correctly.  
5.   Place full cryovials in a programmed freezer cooled to 4°C and begin the freezing at  -
1°C/min. 
6.    After freezing has been completed, transfer all vials to liquid nitrogen storage.  
 
 

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17 APPENDIX E: COCKCROFT-GAULT EQUATION  
(140-age [years])*(Weight [kg])*(0.85 if female) / 72 * serum creatinine [mg/dL] 
 
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41. 
 
 
 
 

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18 APPENDIX F: BONE MARROW ASPIRATE COLLECTION, SORTING AND 
STORAGE 
Collection of Bone Marrow 
 Refer to section 5.1 for biomarker study bone marrow timepoints and study calendar 
section 3.4 
 Orders for bone marrow biopsies should be placed in the Clinical Research Information 
System (Clinical Research Center, NIH, Bethesda, MD). 
 Notify the CCR Hematology lab that flow immunophenotyping is being performed 
(301-496-4473).  The hematology BM collection tech will bring a 10 mL tube sodium 
heparin Vacutainer tube to the specimen collection site and prepare an extra smear for the 
Flow Cytometry Laboratory. 
 Get sterile heparin suitable for injection from the nurse’s station.  Rinse syringe and 
needle with sterile heparin, leaving no less than 0.5 mL in syringe. 
 Bone marrow samples will be collected as bone marrow core biopsies and aspirates for 
analyses. Aspirate first 2 cc of marrow for morphology first and give specimen to CCR 
Hematology lab technician to be given to CCR Pathology department (1 mL will go to 
Hematopathology and 1 mL 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.  
 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).     
 For aspirate designated for sorting, GEP profiling, microenvironment studies, send 
remaining aspirate sample to the Lymphoid Malignancies Branch lab.  For questions 
regarding these samples, please contact Mark Roschewski at 301-451-9021. Place aspirate 
sample in EDTA syringe immediately on ice.  Transfer within 30 minutes of sampling to the 
lab for processing.