Clinical trial NCT01380106
Conditions: Multiple Myeloma
Keywords: Multiple myeloma Relapsed Revlimid
Sponsor: Boston VA Research Institute, Inc.
Start date: 2010-08-01; Completion date: 2017-09-11
Enrollment: 33 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a research study to evaluate two different Lenalidomide doses (15 mg vs. 25 mg) in combination with low dose dexamethasone in patients with relapsed multiple myeloma.

The investigators propose to use the need for dose reduction as a criterion to judge tolerability from various causes. In the veteran population which predominantly is in the older age category with number of co-morbidities, a lower dose regimen may be safer and advantageous.

This study expects to enroll approximately 80 subjects from participating VA sites across the nation.

The investigators will evaluate the safety of the two dose regimens by comparing frequency of dose reductions. The investigators will also measure how long the responses last with each dose.

Lenalidomide is approved by the Food and Drug Administration (FDA) for the treatment of specific types of myelodysplastic syndrome (MDS) and in combination with dexamethasone for patients with multiple myeloma (MM) who have received at least 1 prior therapy. MDS and MM are cancers of the blood. It is currently being tested in a variety of cancer conditions. In this case it is considered experimental.

At the time of enrollment, one-half of the subjects will be chosen at random to receive the 15 mg Lenalidomide dose and the other half will take the 25 mg dose regimen of Lenalidomide. Depending on lenalidomide treatment assignment, subjects will receive either 15 mg p.o. q.d. or 25 mg p.o. q.d. for days 1-21 of a 28 day cycle. In addition, dexamethasone (40 mg) will be added once a week (Days 1, 8, 15 and 22) to the Lenalidomide regimen, with a dose reduction on the same schedule if the patient cannot tolerate the higher dose of dexamethasone. ASA (81 or 325mg) will be given daily for anticoagulation prophylaxis. Patients intolerant to ASA may use low molecular weight heparin. Lovenox is recommended. Coumadin will be allowed provided the patient is fully anticoagulate with INR 2.0 to 2.5.

Detailed description:
Primary Objective:

• Evaluate the frequency of dose reductions in two different lenalidomide dose regimens.

Secondary Objectives:

* Evaluate the efficacy of two different lenalidomide dose regimens in patients with multiple myeloma using the EBMT and IMWG criteria.
* Evaluate the duration of response of 15 mg Lenalidomide and 25 mg of Lenalidomide when used in combination with Low Dose Dexamethasone.
* Evaluate the safety of 15 mg and 25 mg of Lenalidomide regiments when in combination with dexamethasone.
* Explore blood and cellular levels of angiogenic factors, cytokines, and adhesion molecules.

Arms: arm 1: Subjects will receive oral lenalidomide 25mg once daily for days 1-21 out of a 28 cycle arm 2: Subjects will receive oral lenalidomide 15mg once daily for days 1-21 out of a 28 cycle
Interventions: intervention 1: Lenalidomide 15mg intervention 2: Lenalidomide 25mg
Intervention descriptions: intervention 1: Subjects will receive oral lenalidomide 15 mg once daily for 1-21 of a 28 day cycle. intervention 2: Subjects will receive oral lenalidomide 25mg once daily for days 1-21 out of a 28 cycle

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
Version date 02.14.2013 
Protocol Title:  A Controlled, Parallel-Group, 
Randomized, Open-Label Study to Evaluate Two 
Lenalidomide Dose Regimens When Used in 
Combination With Low Dose Dexamethasone for the 
Treatment of Subjects with Relapsed Multiple Myeloma 
 
STUDY DRUG   
Lenalidomide (Revlimid®) 
PROTOCOL NUMBER:  
RV-PI-MM-0345 
DRAFT VERSION: 
DATE FINAL: 
 
 
 9-17-2009  
AMENDMENT:   
9-13-2010 
2nd AMENDMENT: 
     3rd AMENDMENT: 
4th AMENDMENT: 
 
 
8-2-2011 
5-24-2012 
2-14-2013 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the 
extent necessary to obtain informed consent, may not be disclosed to another party 
unless law or regulations require such disclosure.  Persons to whom the information is 
disclosed must be informed that the information is confidential and may not be further 
disclosed by them. 
 
 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
Version date 02.14.2013 
 
 
 
 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
 
 
Principal Investigator: 
 
 
 
 
 
 
Signature of Investigator 
 
Date 
 
Printed Name of Investigator 
 
 
 
By my signature, I agree to personally supervise the conduct of this study 
and to ensure its conduct in compliance with the protocol, informed 
consent, IRB/EC procedures, instructions from Celgene representatives, 
the Declaration of Helsinki, FDA Regulations, ICH Good Clinical Practices 
guidelines, and the applicable parts of the United States Code of Federal 
Regulations or local regulations governing the conduct of clinical studies. 
 
 
 
 
 
 
 
 
 
 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
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STUDY PERSONNEL 
 
Supporter: 
 
Celgene Corporation 
86 Morris Ave, 
Summit,  NJ   07901 
1-800-742-3107 
 
 
 
Study Location: 
 
VA Boston Healthcare System 
Principal Investigator: 
 
Nikhil Munshi, M.D. 
Study Coordinator: 
 
 
Jasmine Lee 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
Version date 02.14.2013 
 
STUDY CHAIRS: 
Nikhil Munshi, M.D. 
Boston VAHCS 
150 South Huntington Ave. (151MAV) 
Boston, MA  02130 
nikhil_munshi@dfci.harvard.edu 
 
David Roodman, MD 
Indianapolis VAMC 
Garson.Roodman@va.gov 
 
Alan Lichtenstein, MD 
Los Angeles VA Medical Center 
Alan.Lichtenstein@med.va.gov 
 
Paulette Mehta, MD 
Little Rock VA Medical Center 
Paulette.Mehta@va.gov 
 
 
ADDITIONAL SITES AND OTHER INVESTIGATORS: 
 
Suman Kambhampati, MD 
Kansas City Veterans Affairs Medical Center 
suman.kambhampati@va.gov 
 
Alan Lichtenstein, MD 
Los Angeles VA Medical Center 
Alan.Lichtenstein@med.va.gov 
 
Andrew Liman, MDPittsburgh VA Medical Center 
Andrew.Liman@va.gov 
Sarvari Yellapragada, MD 
Michael E. DeBakey VA Medical Center 
Sarvari.Yellapragada@va.gov 
 
Nirmala Bhoopalam, MD  
Edward Hines, Jr. VA Hospital  
Nirmala.Bhoopalam@va.gov  
 
Paulette Mehta, MD 
Little Rock VA Medical Center 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
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Paulette.Mehta@va.gov 
 
Christiane Dorothea Thienelt, MD 
VA Eastern Colorado Health Care System 
Christiane.Thienelt@va.gov 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
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Table of Contents 
Protocol Synopsis………………………………………………………………….1 
Schedule of Study Assessments…………………………………………………2 
Background and Rationale………………………………………………………..3 
Study Objectives and End Points………………………………………………...4 
Investigational Plan………………………………………………………………..5 
Serious Adverse Events…………………………………………………………..6 
Response Criteria………………………………………………………………….7 
Protocol Amendments and Deviations…………………………………………..8 
Data Management…………………………………………………………………9 
Biostatistical Analysis……………………………………………………………..10 
Regulatory Considerations……………………………………………………….11 
References…………………………………………………………………………12 
Appendices……………………………………………………………………….. 
Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth 
Control Methods…………………………………………………………………...A 
ECOG Performance Status………………………………………………………B 
Response Evaluation Criteria……………………………………………………C 
NCI CTC Version 3.0……………………………………………………………...D 
 
 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
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1  Protocol Synopsis 
PROTOCOL TITLE: A CONTROLLED, PARALLEL-GROUP, RANDOMIZED, OPEN-LABEL 
STUDY TO EVALUATE TWO LENALIDOMIDE DOSE REGIMENS WHEN USED IN 
COMBINATION WITH LOW DOSE DEXAMETHASONE FOR THE TREATMENT OF SUBJECTS 
WITH RELAPSED MULTIPLE MYELOMA 
 
PROTOCOL NUMBER:  
RV 
DATE PROTOCOL FINAL: 
9-17-2009 
STUDY DRUG:  
Revlimid®, lenalidomide 
INDICATION: 
15 mg and 25 mg of lenalidomide in 
conjunction with low dose dexamethasone 
STUDY PHASE: 
II 
BACKGROUND AND RATIONALE:  Several studies have shown that combination 
chemotherapy with addition of other alkylating agents such as cyclophosphamide or nitrosureas 
and anthracyclines does not improve the prognosis of subjects with multiple myeloma beyond 
results obtained with standard MP (Oken, 1994; Oken, et al. 1997). Notably, the median survival 
of subjects who achieve stable disease (lack of disease progression) is similar to that in subjects 
who respond to therapy and is superior to survival in subjects whose disease progresses (49 
months versus 48 months versus 15 months) (Durie and Salmon, 1975). A recent trial conducted 
by Eastern Cooperative Oncology Group (ECOG) compared MP therapy to the combination 
treatment regimen of vincristine, carmustine, melphalan, cyclophosphamide, and prednisone 
(VBMCP) (Oken, et al. 1997). Although VBMCP resulted in a 72% objective response compared 
to 52% for MP, the median survivals of both Cohorts were not different. Interferon (IFN), either as 
part of induction treatment or as maintenance therapy, is only of marginal benefit (Ludwig, et al. 
1995). Although subjects with progressive disease despite initial therapy or those who become 
resistant to initial therapy have a 50 to 75% response to salvage regimens such as vincristine, 
doxorubicin, and dexamethasone (VAD) (Barlogie, et al. 1984; Monconduit, et al. 1986), these 
responses are usually of short (months) duration. Myeloma, therefore, remains universally fatal, 
and the median survival of affected subjects is 3 to 4 years.  
The primary rationale is to utilize Revlimid at dose that will be well tolerated and effective. We 
propose to use the need for dose reduction as a criterion to judge tolerability from various causes. 
In the veteran population which predominantly is in the older age category with number of co-
morbidities, a lower dose regimen may be safer and advantageous. In a recent multi-institutional 
study, the 009 and 010 studies, patients were randomized to receive Revlimid with 
dexamethasone versus dexamethasone alone. A logistic regression was performed using dose 
reduction (i.e., whether or not having any lenalidomide dose reduction as the dependent 
variable). Treatment-emergent neutropenia and thrombocytopenia were the causes of the 
majority of dose reductions. Predictors analyzed included: age, prior transplant (yes vs. no), high 
vs. low risk (disease stage variable), previous thalidomide exposure (yes vs. no), previous lines of 
therapy (<=2 vs. 3+), prior medical history of neutropenia or thrombocytopenia. Among the 353 
patients in the Revlimid/Dexamethasone groups, 131 (37.1%) had at least one dose reduction of 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
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Revlimid. Age, whether used as a continuous variable or dichotomized one (<=65 vs. 66+), was 
the single significant predictor for dose reduction; 46% of the patients aged 66 or older required at 
least one dose reduction, as compared to 31% of the patients aged 65 or younger. Of 
interest, when the elderly population was specifically examined, the outcomes were similar for 
response rate, time to progression and overall survival than the younger group, suggesting that 
dose reduction had no significant effect on efficacy. 
STUDY OBJECTIVES: 
Primary:   
• 
The primary objective of the study is to evaluate the frequency of dose reductions in two 
different lenalidomide dose regimens. 
Secondary:   
Secondary objectives are to: 
• 
Evaluate the efficacy of two different lenalidomide dose regimens in patients with multiple 
myeloma using the EBMT and IMWG criteria.   
• 
Evaluate the duration of response of 15 mg Lenalidomide and 25 mg of Lenalidomide 
when used in combination with Low Dose Dexamethasone. 
• 
Evaluate the safety of 15 mg and 25 mg of Lenalidomide regiments when in combination 
with dexamethasone. 
• 
Explore blood and cellular levels of angiogenic factors, cytokines, and adhesion 
molecules. 
STUDY DESIGN: 
This is a multi-center, controlled, open-label, randomized (1:1) parallel group study intended to 
select a tolerable dose regimen with acceptable efficacy of lenalidomide, when used in 
combination with dexamethasone.  
 
Subjects will receive either oral lenalidomide 25 mg once daily for days 1-21 out of a 28 cycle or 
lenalidomide 15 mg once daily for 1-21 of a 28 day cycle. Subjects will be assessed before the 
start of treatment, and every 4 weeks while on therapy. Subjects will also receive 40 mg of 
dexamethasone once a week, (days 1,8,15, 22), and ASA (81 or 325 mg) will be given daily for 
anticoagulation prophylaxis. Lenalidomide will be reduced if patients develop grade 3 or greater 
toxicities.  If patient has progressive disease after 2nd cycle, then the patient will be taken off the 
study. If at least a minimal response (MR) has not resulted after cycle 4 then the patient will be 
taken off the study. (see Section 5.7). Subjects who continue to show evidence of myeloma 
response will remain on the study and will be evaluated every 4 weeks for response and/or 
progression.  
STUDY ENDPOINTS 
Primary: 
• 
Type, frequency, severity and timing of adverse events and their relationship to 
combination therapy with lenalidomide plus dexamethasone 
Secondary: 
• 
Duration of M-Protein response during combination therapy with lenalidomide plus 
dexamethasone 
• 
Confirmed M-Protein response 
• 
Expression of angiogenic factors, cytokines, adhesion molecules, and myeloma 
biomarker expression 
STUDY DURATION: Subjects who respond to 
lenalidomide 
plus 
dexamethasone 
may 
continue on therapy until there is evidence of 
TOTAL SAMPLE SIZE: Approximately 80 
subjects will be enrolled. 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
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progression 
or 
unacceptable 
toxicity. 
All 
subjects 
will 
be 
followed 
for 
survival 
indefinitely. 
DOSING 
REGIMEN(S): 
Depending 
on 
lenalidomide treatment assignment, subjects 
will receive either 15 mg p.o. q.d. or 25 mg p.o. 
q.d. for days 1-21 of a 28 day cycle.. In 
addition, dexamethasone (40 mg) will be added 
once a week (Days 1, 8, 15 and 22) to the 
Lenalidomide regimen, with a dose reduction 
on the same schedule if the patient cannot 
tolerate the higher dose of dexamethasone.  
ASA (81 or 325mg) will be given daily for 
anticoagulation prophylaxis. 
STUDY DRUG SUPPLIES: 
Celgene Corporation will supply lenalidomide 
as 5 mg and 25 mg capsules.   
 
 
 


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  Protocol  
 
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2 Schedule of Study Assessments *  
 
 
Procedure 
Screening 
 14 days from 
Baseline (First day 
study drug 
administration) 
Cycle 1 
12Cycles  
2, 4, 6, 8+ 
12Cycles  
3, 5, 7, 9+ 
 
Discontinuation 
From Study 
Drug 
Day  
1 
Day  
8 
Day  
15 
    Day   
22 
Day   
1 
Day 
1 
Record prior medications, treatments 
X 
 
 
 
 
 
 
 
Record prior anti-cancer therapies 
X 
 
 
 
 
 
 
 
Physical examination, vital signs 
X 
X 
 
 
 
X 
X 
X 
Weight 
X 
 
 
 
 
 
 
 
ECOG performance status 
X 
 
 
 
 
 
 
 
Chest x-ray 1 
X1 
 
 
 
 
 
 
X1 
ECG 
X 
 
 
 
 
 
 
 
Register patient for RevAssist®11 
X 
 
 
 
 
 
 
 
Pregnancy testing 2,3 
X3  
X 
X 
X 
X 
X3 
X3 
X3 
Education and counseling checklist 4 
X4  
X4  
 
 
 
X4  
X4  
 
Skeletal Survey 
X 
 
 
 
 
 
 
X 
Hematology 
• CBC, differential, platelets 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Serum chemistry  
• Electrolytes, BUN, glucose, creatinine 
• Liver profile: SGOT, SGPT, alkaline 
phosphatase, total bilirubin , total 
protein, albumin 
• Calcium 
• CrCl ≥ 40 ml/min 
• Amylase  2.5x upper limit of normal 
 
X 
X 
 
 
 
X 
X 
X 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
X 
Multiple Myeloma Disease Assessment: 
• 2-microglobulin, C-reactive protein5 
• Serum protein electrophoresis with 
quantitated M-protein and Freelite 
 
 X5 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Serum Secretors: 
• Quantitative immunoglobulins 
• Serum immunofixation 
 
X 
X 
 
 
 
 
 
X 
X 
 
X 
X 
 
X 
X 
Urine Secretors: 
• 24hr Urine total protein and urine 
protein electrophoresis and urine 
freelite  
• Immunofixation from 24hr urine 
 
X5 
 
 
X5 
 
 
 
 
 
X6 
 
 
X6 
 
X6 
 
 
X6 
 
X5 
 
 
X5 


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  Protocol  
 
Version date 02.14.2013 
 
Procedure 
Screening 
 14 days from 
Baseline (First day 
study drug 
administration) 
Cycle 1 
12 Cycles 
2, 4, 6, 8+ 
12 Cycles 
3, 5, 7, 9+ 
Discontinuation 
From Study 
Drug 
Day  
1 
Day  
8 
Day  
15 
Day   
22 
Day   
1 
Day 
1 
Non-secretors: 
• FreeliteTM 
• Bidemensional measurement of soft 
tissue plasmacytomas if present7 
 
X 
X 
 
 
 
 
 
X 
X7 
 
X 
X7 
 
X 
X7 
Bone marrow aspirate and biopsy 
• Cytogenetics8 
• Morphology 
 
 X8 
X 
 
 
 
 
 
 
  
 
X9 
HIV Test 
X 
 
 
 
 
 
 
 
Hep A,B,C titers (HAV, HBV, HCV) 
X 
 
 
 
 
 
 
 
Dispense Cycle 1 study drug 
 
X 
 
 
 
 
 
 
Response assessment10 
 
 
 
 
 
X10 
X10 
X 
Record adverse events 
 
X 
X 
X 
X 
X 
X 
X 
Record concomitant meds/procedures 
 
X 
 
 
 
X 
X 
X 
Dispense study drug for next cycle 
 
 
 
 
X 
X 
X 
 
Perform drug accountability 
 
 
 
 
X 
X 
 
X 
 
* An unscheduled visit can occur at any time during the study.  Source must be maintained for these unscheduled visits. The date for the visit and any data 
generated must be recorded on the appropriate CRF.  Source documents for these unscheduled visits must also be maintained. 
 
1 Not needed if Chest CT scan has been obtained. 
2 Pregnancy tests 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). 
3 Pregnancy tests must occur 10 – 14 days and again within 24 hours prior to initiation of lenalidomide.  FCBP with regular or no menstruation must have a pregnancy test 
weekly for the first 4 weeks 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 weekly for the first 4 weeks 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). All counseling will be done through RevAssist® 
4 Patients are required to complete counseling every 28 days during treatment with lenalidomide, follow the pregnancy testing and birth control requirements of the program 
that are appropriate for the patient and take telephone surveys regarding compliance with the program.    
5 Mandatory at the beginning and end of study 
6 Repeat every cycle only if protein present in urine at screening and/or 24hr IFE is positive. 
7 Repeat to verify response for response assessment and q 2 months and/or as clinically indicated for follow-up 
8 Cytogenetics only at screening; do not repeat if information available from an earlier bone marrow biopsy. (BMB). 
9 Repeat as clinically indicated or to confirm CR. 
10 If patient has progressive disease after 2nd cycle, then the patient will be taken off the study. If at least a minimal response (MR) has not resulted after cycle 4, then the 
patient will be taken off the study. Subjects who continue to show evidence of myeloma response will remain on the study and will be evaluated every 4 weeks for 
response/progression.  


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  Protocol  
 
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11 All patients enrolled in the study must register through RevAssist® and must comply with all requirements of the RevAssist® program.  Prescriptions must be filled within 
7 days for females of childbearing potential and 14 days for all other risk categories.  Drug will be shipped on a per patient basis by the contract pharmacy to the clinic site.  
Only enough lenalidomide for one cycle of therapy will be supplied to the patient each cycle.  
12 All subjects who respond to lenalidomide plus dexamethasone may continue on therapy until there is evidence of progression or unacceptable toxicity. All 
subjects will be followed for survival indefinitely.


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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3 Background and Rationale 
3.1 Introduction 
Lenalidomide, a thalidomide analog, belongs to a proprietary class of Celgene 
compounds called immunomodulatory drugs (IMiDs®).  IMiDs® have both 
immunomodulatory and anti-angiogenic properties which could confer antitumor 
and antimetastatic effects.  
Although the exact antitumor mechanism of action of lenalidomide is unknown, a 
number of mechanisms are postulated to be responsible for lenalidomide’s 
activity against multiple myeloma. Lenalidomide has direct activity against 
multiple myeloma and induces apoptosis or G1growth arrest in multiple myeloma 
cell lines and in multiple myeloma cells of patients resistant to melphalan, 
doxorubicin and dexamethasone (5). Lenalidomide, a thalidomide analog, has 
been demonstrated to possess anti-angiogenic activity through inhibition of 
bFGF, VEGF and TNF-alpha induced endothelial cell migration, due at least in 
part to inhibition of Akt phosphorylation response to bFGF.(1).  In addition, 
lenalidomide has a variety of immunomodulatory effects.  Lenalidomide 
stimulates T cell proliferation, and the production of IL-2, IL-10 and IFN-gamma, 
inhibits IL-1 beta and IL-6 and modulates IL-12 production.(2)  Upregulation of T 
cell derived IL-2 production is achieved at least in part through increased AP-1 
activity. (3)The increased level of these circulating cytokines augment natural killer 
cell number and function, and enhance natural killer cell activity to yield an 
increase in multiple myeloma cell lysis (4).  
3.2 Clinical experience in multiple myeloma with lenalidomide 
In 2 phase I studies in multiple myeloma, a total of 41 patients have been treated 
with lenalidomide.  In one study at the University of Arkansas, 15 patients who 
relapsed or were refractory to high dose melphalan therapy with stem cell 
transplant were treated for 4 weeks in an open-label safety study and were 
permitted to continue therapy in an extension phase of the trial.  Patient cohorts 
were treated at the following daily doses: 5mg, 10mg, 25mg, and 50mg (9).  In a 
similar study at the Dana Farber Cancer Institute, 27 patients with rapidly 
advancing refractory multiple myeloma were enrolled (10).   
Anti-myeloma activity was observed in each of these 2 phase I studies.  
Decreases in neutrophil and platelet counts were the dose-limiting toxicities 
associated with lenalidomide.  The maximum tolerated dose (MTD) was not 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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reached within 28 days.  Due to dose modifications associated with 
myelosuppression observed beyond Day 28 at the 25mg and 50mg daily dose 
levels, the dose schedule most widely used in future studies has been 
lenalidomide 25 mg on Days 1-21, repeated every 28 days.   
Pharmacokinetic analyses were performed on 15 multiple myeloma patients 
treated in the phase I studies.  Absorption was found to be rapid on both Day 1 
and Day 28 with time to maximum blood levels ranging from 0.7 to 2.0 hours at 
all dose levels (5mg, 10mg, 25mg, and 50mg).  Plasma lenalidomide declined in 
a monophasic manner with elimination half-life ranging from 2.8 to 6.1 hours on 
both Day 1 and 28 at all 4 doses.  No plasma accumulation was observed with 
multiple daily dosing.  Peak and overall plasma concentrations were dose 
proportional over the dosing range of 5mg to 50mg (11). 
A multicenter, randomized, phase II trial compared 2 syncopated dose schedules 
of lenalidomide (15 mg B.D. vs. 30 mg O.D.) used alone or in combination with 
dexamethasone in the treatment of relapsed or refractory multiple myeloma.  All 
patients were treated on Days 1-21 of a 28-day cycle.  Patients treated with 
15mg BID experienced more myelosuppression and dose reductions compared 
with patients treated with 30mg daily.  Anti-myeloma activity was observed with 
each dose and schedule of single agent lenalidomide.  The addition of 
dexamethasone to lenalidomide yielded responses in some patients who had not 
responded to lenalidomide alone (12). 
Celgene Corporation sponsored 2 multicenter, randomized, double-blinded, 
placebo-controlled phase III trials [1 U.S. (MM-009) and 1 international (MM-
010)] in patients with relapsed or refractory multiple myeloma (14).  More than 350 
patients were enrolled into each of these studies.  All patients had to be 
considered sensitive to dexamethasone and were treated with dexamethasone 
40mg daily on Days 1-4, 9-12 and 17-20.  In addition to receiving 
dexamethasone, patients were randomized to lenalidomide 25mg or placebo 
each given daily on Days 1-21.  Cycles were repeated every 28 days.   After 4 
cycles, there was a predetermined reduction of the dexamethasone dose to 
40mg daily on Days 1-4 repeated every 28 days.  In both studies, a pre-specified 
interim analysis conducted by an Independent Data Monitoring Committee 
demonstrated that subjects receiving the combination of lenalidomide (Len) plus 
dexamethasone (Dex) had significantly longer times to progression and higher 
response rates (D 27% vs. 2D 61%, p<0.001) than those treated with single-
agent dexamethasone.  These studies led to the FDA approval of lenalidomide in 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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patients that have received at least one prior therapy. Based on an excellent 
efficacy in relapsed patients, a recent phase II trial utilizing lenalidomide plus 
dexamethasone for newly diagnosed multiple myeloma patients was recently 
reported by the Mayo Clinic. Lenalidomide was given orally 25 mg daily on days 
1-21 of a 28-day cycle. Dexamethasone was given orally 40 mg daily on days 1-
4, 9-12, 17-20 of each cycle. Objective response was defined as a decrease in 
serum monoclonal protein by 50% or greater and a decrease in urine M protein 
by at least 90% or to a level less than 200 mg/24 hours, confirmed by two 
consecutive determinations at least 4 weeks apart. Thirty-one of 34 (91%) 
patients achieved an objective response, including 2 (6%) achieving complete 
response (CR), and 11 (32%) meeting criteria for both very good partial response 
and near complete response, resulting in an overall objective response rate of 
91%. Of the 3 remaining patients not achieving an objective response, two had 
minor response (MR) and one stable disease. Forty-seven percent of patients 
experienced grade 3 or higher non-hematologic toxicity, most commonly fatigue 
(15%), muscle weakness (6%), anxiety (6%), pneumonitis (6%) and rash (6%). 
Revlimid®/dexamethasone is a highly active regimen with manageable side-
effects in the treatment of newly diagnosed myeloma.(18) 
3.3 Rationale 
The primary rationale is to utilize Revlimid at dose that will be well tolerated and 
effective. We propose to use the need for dose reduction as a criterion to judge 
tolerability from various causes. In the veteran population which predominantly is 
in the older age category with number of co-morbidities, a lower dose regimen 
may be safer and advantageous. In a recent multi-institutional study, the 009 and 
010 studies, patients were randomized to receive Revlimid with dexamethasone 
versus dexamethasone alone. A logistic regression was performed using dose 
reduction (i.e., whether or not having any lenalidomide dose reduction as the 
dependent variable). Treatment-emergent neutropenia and thrombocytopenia 
were the causes of the majority of dose reductions. Predictors analyzed included: 
age, prior transplant (yes vs. no), high vs. low risk (disease stage variable), 
previous thalidomide exposure (yes vs. no), previous lines of therapy (<=2 vs. 
3+), prior medical history of neutropenia or thrombocytopenia. Among the 353 
patients in the Revlimid/Dexamethasone groups, 131 (37.1%) had at least one 
dose reduction of Revlimid. Age, whether used as a continuous variable or 
dichotomized one (<=65 vs. 66+), was the single significant predictor for dose 
reduction; 46% of the patients aged 66 or older required at least one dose 
reduction, as compared to 31% of the patients aged 65 or younger. Of 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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interest, when the elderly population was specifically examined, the outcomes 
were similar for response rate, time to progression and overall survival than the 
younger group, suggesting that dose reduction had no significant effect on 
efficacy. 
3.3.1 INDICATIONS AND USAGE: 
Revlimid® is approved in combination with dexamethasone for the treatment of 
patients with multiple myeloma that have received at least one prior therapy.  
Revlimid® (lenalidomide) is also indicated for the treatment of patients with 
transfusion-dependent 
anemia 
due 
to 
Low- 
or 
Intermediate-1-risk 
myelodysplastic syndromes associated with a deletion 5q cytogenetic 
abnormality with or without additional cytogenetic abnormalities.  
3.4 Adverse Events 
Most frequently reported adverse events reported during clinical studies with 
lenalidomide in oncologic and non-oncologic indications, regardless of presumed 
relationship to study medication include: anemia, neutropenia, thrombocytopenia 
and pancytopenia, abdominal pain, nausea, vomiting and diarrhea, dehydration, 
rash, itching, infections, sepsis, pneumonia, UTI, Upper respiratory infection,  
atrial fibrillation, congestive heart failure, myocardial infarction, chest pain, 
weakness, hypotension, hypercalcemia, hyperglycemia, back pain, bone pain, 
generalized pain, dizziness, mental status changes, syncope, renal failure, 
dyspnea, pleural effusion, pulmonary embolism, deep vein thrombosis, CVA, 
convulsions,  spinal cord compression, disease progression, death not specified 
and fractures.  Tumor flare reaction (TFR) has been reported frequently in CLL 
patients treated with lenalidomide.  Tumor lysis syndrome (TLS) has been 
reported in CLL patients treated with lenalidomide.  Precautions must be taken to 
prevent TLS including proper selection of patients with regard to renal function, 
correction of electrolyte abnormalities, and TLS prophylaxis and monitoring.  
Lenalidomide has been shown to increase the level of digoxin in the blood in 
some patients. 
 
Second new cancers 
According to researchers, patients with cancer have a higher risk of developing a 
second new cancer when compared to people without cancer. In clinical studies 
of newly diagnosed multiple myeloma, a higher number of second cancers were 
reported in patients treated with induction therapy (treatment as first step to 
reducing number of cancer cells) and/or bone marrow transplant then 
lenalidomide for a long period of time compared to patients treated with induction 
therapy and/or bone marrow transplant then placebo (a capsule containing no 
lenalidomide). Patients should make their doctors aware of their medical history 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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and any concerns they may have regarding their own increased risk of other 
cancers.  
 
Complete and updated adverse events are available in the Investigational Drug 
Brochure and the IND Safety Letters. 
4 Study Objectives and Endpoints 
4.1 Objectives 
4.1.1 Primary objectives 
• Evaluate the frequency of dose reductions in two different lenalidomide 
dose regimens. 
4.1.2 Secondary study objectives 
• Evaluate efficacy of two different lenalidomide dose regimens in patients 
with multiple myeloma using the EBMT and IMWG criteria. 
• Evaluate the duration of response of 15 mg lenalidomide and 25 mg 
lenalidomide when used in combination with low-dose dexamethasone 
• Evaluate the safety of 15 mg and 25 mg lenalidomide regiments when in 
combination with dexamethasone 
• Explore the blood and cellular levels of angiogenic factors, cytokines, and 
adhesion molecules 
4.2 Endpoints 
4.2.1 Primary Endpoint 
• Type, frequency, severity and timing of adverse events and their 
relationship 
to 
combination 
therapy 
with 
lenalidomide 
plus 
dexamethasone. 
4.2.2 Secondary Endpoints 
• Duration of M-Protein response during combination therapy with 
Lenalidomide plus dexamethasone 
• Confirmed M-Protein response  
• Expression of angiogenic factors, cytokines, adhesion molecules, and 
myeloma biomarker expression 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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5 Investigational Plan 
5.1 Overall design 
This is a multi-center, controlled, open-label, randomized (1:1) parallel group 
study intended to select the dose regimen with the most promising efficacy of 
Lenalidomide, when used in combination with dexamethasone.  
Subjects will receive either oral Lenalidomide 25 mg once daily for days 1-21 out 
of a 28 cycle or Lenalidomide 15 mg once daily for 1-21 of a 28 day cycle.  
Subjects will also receive 40 mg of dexamethasone once a week (Days 1, 8, 15 
and 22) with a dose reduction on the same schedule if the patient cannot 
tolerate the higher dose of dexamethasone (refer to Section 5.5.3).  ASA (81 or 
325 mg will be given orally for anticoagulation prophylaxis. If patient has 
progressive disease after 2nd cycle, then the patient will be taken off the study. If 
at least a minimal response (MR) has not resulted after cycle 4, then the patient 
will be taken off the study. Subjects who continue to show evidence of myeloma 
response will remain on the study and will be evaluated every 4 weeks for 
response/progression.  
5.1.1 Investigational Drug  
5.1.1.1 Lenalidomide Description 
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:  
5.1.1.1.1.1.1 
Chemical Structure of Lenalidomide 
 
N
N
H
O
O
O
NH2
 
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione 
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular 
weight is 259.3.  
Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic 
solvent/water mixtures, and buffered aqueous solvents. Lenalidomide is more 
soluble in organic solvents and low pH solutions. Solubility was significantly lower 
in less acidic buffers, ranging from about 0.4 to 0.5 mg/ml. Lenalidomide has an 
asymmetric carbon atom and can exist as the optically active forms S(-) and 
R(+), and is produced as a racemic mixture with a net optical rotation of zero. 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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REVLIMID® (lenalidomide) is available in 5 mg and 25 mg capsules for oral 
administration.  
 
5.1.1.2 CLINICAL PHARMACOLOGY 
Mechanism of Action:  
The mechanism of action of lenalidomide remains to be fully characterized. 
Lenalidomide possesses immunomodulatory and antiangiogenic properties.  
Lenalidomide inhibited the secretion of pro-inflammatory cytokines and increased 
the secretion of anti-inflammatory cytokines from peripheral blood mononuclear 
cells.  Lenalidomide inhibited cell proliferation with varying effectiveness (IC50s) 
in some but not all cell lines.  Of cell lines tested, lenalidomide was effective in 
inhibiting growth of Namalwa cells (a human B cell lymphoma cell line with a 
deletion of one chromosome 5) but was much less effective in inhibiting growth of 
KG-1 cells (human myeloblastic cell line, also with a deletion of one chromosome 
5) and other cell lines without chromosome 5 deletions.  Lenalidomide inhibited 
the expression of cyclooxygenase-2 (COX-2) but not COX-1 in vitro.   
5.1.1.3 Pharmacokinetics and Drug Metabolism: 
Absorption: 
Lenalidomide, in healthy volunteers, is rapidly absorbed following oral 
administration with maximum plasma concentrations occurring between 0.625 
and 1.5 hours post-dose. Co-administration with food does not alter the extent of 
absorption (AUC) but does reduce the maximal plasma concentration (Cmax) by 
36%. The pharmacokinetic disposition of lenalidomide is linear. Cmax and AUC 
increase proportionately with increases in dose. Multiple dosing at the 
recommended dose-regimen does not result in drug accumulation. 
Pharmacokinetic sampling in myelodysplastic syndrome (MDS) patients was not 
performed. In multiple myeloma patients maximum plasma concentrations 
occurred between 0.5 and 4.0 hours post-dose both on Days 1 and 28.  AUC and 
Cmax values increase proportionally with dose following single and multiple 
doses. Exposure (AUC) in multiple myeloma patients is 57% higher than in 
healthy male volunteers.  
 
Pharmacokinetic Parameters: 
Distribution: 
In vitro (14C)-lenalidomide binding to plasma proteins is approximately 30%. 
Metabolism and Excretion: 
The metabolic profile of lenalidomide in humans has not been studied. In healthy 
volunteers, approximately two-thirds of lenalidomide is eliminated unchanged 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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through urinary excretion. The process exceeds the glomerular filtration rate and 
therefore is partially or entirely active.  Half-life of elimination is approximately 3 
hours.  
5.1.1.4 Supplier(s) 
Celgene Corporation will supply Revlimid® (lenalidomide) to study participants at 
no charge through the RevAssist® program.   
5.1.1.5 Dosage form 
Lenalidomide will be supplied as 5 mg and 25 mg capsules for oral 
administration.   
5.1.1.6 Packaging 
Lenalidomide will be shipped to the pharmacy at the study site in individual 
bottles.   Bottles will contain a sufficient number of capsules to last for one cycle 
of dosing. Study drug must be dispensed in the original packaging with the label 
clearly visible.   Only enough lenalidomide for 1 cycle of therapy may be 
provided to the patient each cycle. 
5.1.1.7 Labeling 
Lenalidomide investigational supplies are dispensed to the patients in individual 
bottles of capsules.  Each bottle will identify the contents as study medication.  In 
addition, the label will bear Celgene’s name, quantity contained and the standard 
caution statement as follows:  Caution: New drug - Limited by Federal law to 
investigational use.  The study drug label must be clearly visible.  For appropriate 
drug accountability, it is recommended that the institution mark each bottle with 
the institutional protocol number or Celgene tracking number (RV-PI-MM-0345) 
upon receipt.  Additional labels must not cover the Celgene label. 
5.1.1.8 Receipt of study drug 
The Investigator or designee is responsible for taking an inventory of each 
shipment of study drug received, and comparing it with the accompanying study 
drug accountability form.  The Investigator will verify the accuracy of the 
information on the form, sign and date it, retain a copy in the study file, and return 
a copy to Celgene or its representative.   
5.1.1.9 Storage 
At the study site, all investigational study drugs will be stored in a locked, safe 
area to prevent unauthorized access. 
The study drug should be stored at room temperature away from direct sunlight 
and protected from excessive heat and cold. 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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5.1.1.10 Unused study drug supplies 
Celgene will instruct the Investigator on the return or destruction of unused study 
drug.  If any study drug is lost or damaged, its disposition should be documented 
in the source documents.  Study drug supplies will be retained at the clinical site 
pending instructions for disposition by Celgene.  Patients will be instructed to 
return empty bottles or unused capsules.  
5.1.1.11  Drug dispensing requirements 
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 RevAssist® program of 
Celgene Corporation.  Per standard RevAssist® 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 RevAssist® program.  Prescriptions must be filled 
within 7 days for females of childbearing potential and 14 days for all other risk 
categories.  Drug will be shipped on a per patient basis by the contract pharmacy 
to the clinic sites.  Only enough lenalidomide for one cycle of therapy will be 
supplied to the patient each cycle. 
Pregnancy Testing    
 
Refer to Appendix A: Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods).  All counseling will be done through 
RevAssist®. 
 
5.2 Screening and Eligibility 
The Investigator is responsible for keeping a record of all subjects who sign an 
Informed Consent Form for entry into the study.  All subjects will be screened for 
eligibility.  Screening procedures are outlined in Section 2, Schedule of Study 
Assessments and unless otherwise specified, must take place within 14 days 
prior to initiation of therapy.  
Approximately 80 of subjects with active multiple myeloma will be screened for 
enrollment and must meet the eligibility criteria below. 
5.2.1 Inclusion Criteria 
Subjects must meet the following inclusion/exclusion criteria to be eligible for the 
study. 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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Inclusion criteria  
5.2.1.1 Subject was previously diagnosed with multiple myeloma based on 
standard diagnostic criteria as follows. 
Diagnostic Criteria for Multiple Myeloma, Myeloma Variants, and 
Monoclonal Gammopathy of Unknown Significance  
 
Monoclonal gammopathy of undetermined significance (MGUS) 
• 
M-protein in serum <30 g/l 
• 
Bone marrow clonal plasma cells <10% 
• 
No evidence of other B-cell proliferative disorders 
• 
No myeloma related organ or tissue impairment (no end organ damage, including 
bone lesions) 
 
Asymptomatic myeloma (smoldering myeloma). 
• 
M-protein in serum ≥ 30 g/l and/or 
• 
Bone marrow clonal plasma cells ≥10% 
• 
No myeloma related organ or tissue impairment (no end organ damage, including 
bone lesions) or symptoms 
 
Symptomatic multiple myeloma. 
• 
M-protein in serum and/or urine 
• 
Bone marrow (clonal) plasma cells* or plasmacytoma 
• 
Myeloma related organ or tissue impairment (end organ damage, including bone 
lesions) 
• 
*If flow cytometry is performed, most plasma cells (> 90%) will 
show a ‘neoplastic’ phenotype. 
 
Non-secretory myeloma. 
• 
No M-protein in serum and/or urine with immunofixation 
• 
Bone marrow clonal plasmacytosis ≥ 10% or plasmacytoma 
• 
Myeloma-related organ or tissue impairment (end organ damage, including bone 
lesions) 
 
Solitary plasmacytoma of bone. 
• 
No M-protein in serum and/or urine* 
• 
Single area of bone destruction due to clonal plasma cells 
• 
Bone marrow not consistent with multiple myeloma 
• 
Normal skeletal survey (and MRI of spine and pelvis if done) 
• 
No related organ or tissue impairment (no end organ damage 
• 
other than solitary bone lesion)* 
• 
*A small M-component may sometimes be present. 
_________________________________________________________________ 
Myeloma-related organ or tissue impairment (end organ damage) (ROTI)  
• 
*Calcium levels increased: serum calcium > 0.25 mmol/l above the upper limit of 
normal or > 2.75 mmol/l 
• 
*Renal insufficiency: creatinine >173 mmol/l 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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• 
*Anemia: haemoglobin 2 g/dl below the lower limit of normal or haemoglobin <10 
g/dl 
• 
*Bone lesions: lytic lesions or osteoporosis with compression fractures (MRI or 
CT may clarify) 
Other: symptomatic hyperviscosity, amyloidosis, recurrent bacterial infections (> 
2 episodes in 12 months) 
5.2.1.1 Patients must have relapsed or refractory disease (refractory is defined as 
progression during treatment or within 60 days after the completion of 
treatment) requiring 2nd or 3rd line therapy (see Appendix C) 
5.2.1.2 Patients may have received lenalidomide and/or dexamethasone 
5.2.1.3 Patients with measurable disease defined as: 
• 
Serum monoclonal protein > 0.5 g/dL and/or 0.2 g/24hr urine light chain 
excretion 
• 
Patients with lower M-protein values or non-secretory myeloma will be 
eligible if measurable disease can be established, such as serum 
FreeliteTM chain ratio > 5x normal limit, measurable soft tissue 
plasmacytoma > 2 cm by either physical exam and/or applicable 
radiographs (i.e. MRI, CT-scan) and/or bone marrow involvement > 30% 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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5.2.1.4 Age 18 years at the time of signing the informed consent form. 
5.2.1.5 All necessary baseline studies for determining eligibility must be obtained within 
14 days prior to enrollment.  Serum pregnancy tests (sensitivity of at least 50 
mIU/mL), for females of childbearing potential (WCBP) must be completed.  
The first test must be performed within 10-14 days, and the second test within 
24 hours prior to initiation of lenalidomide. 
5.2.1.6 Pre-study ECOG performance status 0-2.  Patients with lower performance  
status based solely on bone pain will be eligible. 
5.2.1.7 Patients must have adequate liver functions: AST and ALT  3x upper limit of 
normal, alkaline phosphatase  3.0x upper limit of normal, except if attributed to 
tumor, and bilirubin  2 x upper limit of normal. 
5.2.1.8 Patients must have amylase  2.5x upper limit of normal 
5.2.1.9 All study participants must be registered into the mandatory RevAssist® 
program, and be willing and able to comply with the requirements of 
RevAssist®. 
5.2.1.10 Subject must be able to adhere to the study visit schedule and other protocol 
requirements 
5.2.1.11 Subject must understand and voluntarily sign an informed consent document. 
5.2.1.12 Females of childbearing potential (FCBP)† must have a negative serum or urine 
pregnancy test with a sensitivity of at least 50 mIU/mL 10 – 14 days prior to and 
again within 24 hours of starting Lenalidomide for Cycle 1 (prescriptions must 
be filled within 7 days as required by RevAssist) and must either commit to 
continued abstinence from heterosexual intercourse or begin TWO acceptable 
methods of birth control, one highly effective method and one additional 
effective method AT THE SAME TIME, at least 28 days before she starts taking 
lenalidomide.  FCBP must also agree to ongoing pregnancy testing.  Men must 
agree to use a latex condom during sexual contact with a FCBP even if they 
have had a successful vasectomy.  All patients must be counseled at a 
minimum of every 28 days about pregnancy precautions and risks of fetal 
exposure through the RevAssist® program.  See Appendix A: Risks of Fetal 
Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control 
Methods. All counseling will be done through RevAssist®. 
5.2.1.13 Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation. 
Patients intolerant to ASA may use low molecular weight heparin. Lovenox is 
recommended.  Coumadin will be allowed provided the patient is fully 
anticoagulate with INR 2.0 to 2.5. 
 
† A female of childbearing potential is 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). 
 
 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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5.2.1.14 Patients may receive a bisphosphonate. 
 
5.2.2 Exclusion criteria   
5.2.2.1 Any serious medical condition, laboratory abnormality, or psychiatric illness that 
would prevent the subject from signing the informed consent form. 
5.2.2.2 Pregnant or breast feeding females. (Lactating females must agree not to 
breast feed while taking lenalidomide).  
5.2.2.3 Any condition, including the presence of laboratory abnormalities, which places 
the subject at unacceptable risk if he/she were to participate in the study or 
confounds the ability to interpret data from the study. 
5.2.2.4 Renal insufficiency of creatinine clearance < 40 mL/min 
5.2.2.5 Known hypersensitivity to thalidomide or lenalidomide. 
5.2.2.6 The development of erythema nodosum if characterized by a desquamating 
rash while taking thalidomide or similar drugs. 
5.2.2.7 Concurrent use of other anti-cancer agents or treatments. 
5.2.2.8 Known seropositive for an active viral infection with human immunodeficiency 
virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV).  Patients who are 
seropositive because of hepatitis B virus vaccine are eligible. 
5.2.2.9 Subjects with hemoglobin < 8.0 g/dL.  The use of transfusion with pRBC to 
correct anemia and meet eligibility criteria will not be allowed. 
5.2.2.10 Patient has an absolute neutrophil count < 1.0 x 109/L within 14 days before 
enrollment 
5.2.2.11 Peripheral neuropathy of grade 3 or greater.  Patients with painful grade 2 
neuropathy are also excluded. 
5.2.2.12 Patient has platelet count < 75 x 109/L within 14 days before enrollment. 
5.2.2.13 Plasma cell leukemia at time of study entry. 
 
5.3 Visit schedule and assessments 
Screening Assessments and all on study scheduled visits and assessments are 
outlined in Section 2 Table of Study Assessments.  


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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5.4 Drug Administration 
5.4.1 Treatment assignments 
Subjects who qualify for the study will be randomized to either Lenalidomide 15 
mg p.o. q.d. days 1-21 of a 28 day cycle or Lenalidomide 25 mg p.o. q.d. for days 
1-21 of a 28 day cycle. In addition, dexamethasone (40mg) will be added once a 
week (Days 1, 8, 15, 22) to the lenalidomide regimen  
5.4.2 Dosing regimen 
The planned dose of lenalidomide for investigation is either 15 or 25 mg/day, 
orally on days 1 - 21 followed by 7 days rest (28 day cycle).  Dosing will be in the 
morning at approximately the same time each day.  Only enough lenalidomide 
for one cycle of therapy will be supplied to the patient each cycle. 
Lenalidomide capsules should be swallowed whole, and should not be broken, 
chewed or opened.    
If a dose of lenalidomide is missed, it should be taken as soon as possible on the 
same day.  If it is missed for the entire day, it should not be made up. 
Patients who take more than the prescribed dose of lenalidomide should be 
instructed to contact study staff immediately.  Patients should be instructed on 
secondary contacts, such as a poison control center, should study staff be 
unavailable. 
All subjects will receive dexamethasone 40 mg once a week (Days 1, 8, 15 and 
22) with a dose reduction on the same schedule if the patient cannot tolerate the 
higher dose of dexamethasone (refer to Section 5.5.3).  
ASA (81 or 325mg) will be given for anticoagulation prophylaxis. If unable to take 
ASA then other anticoagulation therapy should be given. 
Subjects experiencing adverse events may need study treatment modifications 
(See section 5.5). 
5.4.3 Special Handling Instructions 
Females of childbearing potential should not handle or administer lenalidomide 
unless they are wearing gloves. 
5.4.4 Record of administration 
Accurate records will be kept of all study drug administration (including 
dispensing and dosing) will be made in the source documents.   


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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5.5 Dose Continuation, Modification and Interruption    
Subjects will be evaluated for AEs at each visit with the NCI CTCAE v3.0 
(Appendix D: NCI CTCAE v3.0) used as a guide for the grading of severity.  
5.5.1 Dose Reduction Steps 
 
Table 1: LENALIDOMIDE Dose Reduction Steps 
 
 
Starting Dose 
25 mg daily for 21 days every 28 
days 
 
15 mg daily for 21 days every 28 
days 
Dose Level – 1 
15 mg daily for 21 days every 28 
days 
10 mg daily for 21 days every 28 
days 
Dose Level – 2 
10 mg daily for 21 days every 28 
days 
5 mg daily for 21 days every 28 
days 
Dose Level – 3 
Discontinue treatment 
Discontinue treatment 
 
5.5.2 Instructions for initiation of a New Cycle  
A new course of treatment may begin on the scheduled Day 1 of a new cycle if: 
• The ANC is ≥ 1000/mm³ 
• The platelet count is ≥ 50000/mm3 
• Any 
drug-related 
rash, 
allergic 
reaction/hypersensitivity 
or 
sinus 
bradycardia/ other cardiac arrhythmia adverse event that may have 
occurred has resolved to ≤ grade 1 severity; 
• Any other drug-related adverse events that may have occurred have 
resolved to ≤ grade 2 severity.  
If these conditions are not met on Day 1 of a new cycle, the subject will be 
evaluated weekly and a new cycle of treatment will not be initiated until the 
toxicity has resolved as described above.  If lenalidomide dosing was halted 
during the previous cycle and was restarted with a one-level dose reduction 
without requiring an interruption for the remainder of the cycle, then that reduced 
dose level will be initiated on Day 1 of the new cycle. If lenalidomide dosing was 
omitted for the remainder of the previous cycle or if the new cycle is delayed due 
to toxicity newly encountered on the scheduled Day 1, then the new cycle will be 
started with a one-level dose reduction of lenalidomide. Treatment may be 
delayed upto 21 days from the original schedule but patients must follow the 
schedule for subsequent cycles. 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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5.5.3 Instructions for dose modifications or interruption during a cycle. 
Table 2: Dose Modifications 
NCI CTC Toxicity Grade 
Onset Day 2-14 of Cycle 
Onset ≥ Day 15 of Cycle 
Grade 3 neutropenia 
associated with fever 
(temperature ≥ 38.5º C) 
or Grade 4 neutropenia 
• 
Hold (interrupt) lenalidomide dose. 
• 
Follow CBC weekly. 
• 
If neutropenia has resolved to ≤ 
grade 2 prior to Day 21, restart 
lenalidomide at next lower dose 
level and continue the cycle 
through Day 21.  If neutropenia is 
the only toxicity for which a dose 
reduction is required, G-CSF may 
be used and the lenalidomide dose 
maintained 
• 
Omit lenalidomide for 
remainder of cycle 
• 
See Instructions for 
Initiation of a New 
Cycle and reduce the 
dose of lenalidomide 
by 1 dose level.  
Omitted doses are not 
made up.  If 
neutropenia is the 
only toxicity for which 
a dose reduction is 
required, G-CSF may 
be used and the 
lenalidomide dose 
maintained for the 
next cycle at the 
investigators 
discretion. 
Thrombocytopenia 
≥Grade 3 (platelet count 
< 50,000/mm³) 
• 
Hold (interrupt) lenalidomide dose. 
• 
Follow CBC weekly. 
• 
If thrombocytopenia resolves to ≤ 
grade 2 prior to Day 21, restart 
lenalidomide at next lower dose 
level and continue the cycle 
through Day 21 of the current 
cycle. 
• 
Hold prophylactic anti-coagulation, 
if applicable. 
• 
Restart prophylactic anti-
coagulation when platelet count is 
≥ 50,000/mm³. 
• 
Omit lenalidomide for 
remainder of cycle 
• 
See Instructions for 
Initiation of a New 
Cycle and reduce the 
dose of lenalidomide 
by 1 dose level at the 
start of the next cycle. 
Omitted doses are not 
made up.   
• 
Hold prophylactic anti-
coagulation, if 
applicable. 
• 
Restart prophylactic 
anti-coagulation when 
platelet count is ≥ 
50,000/mm³. 
Non-blistering rash 
Grade 3 
 
 
 
 
 
             Grade 4 
• 
If Grade 3, hold (interrupt) 
lenalidomide dose.  Follow weekly. 
• 
If the toxicity resolves to ≤ grade 1 
prior to Day 21 of the current cycle, 
restart lenalidomide at next lower 
dose level and continue the cycle 
through Day 21 of the current 
cycle. 
 
 
 
• 
Discontinue lenalidomide.  Remove 
patient from study. 
• 
Omit lenalidomide for 
remainder of cycle.  
• 
See Instructions for 
Initiation of a New 
Cycle and reduce the 
dose of lenalidomide 
by 1 dose level at the 
start of the next cycle. 
Omitted doses are not 
made up.    
 
• 
Discontinue 
lenalidomide.  
Remove patient from 
study. 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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Table 2: Dose Modifications 
NCI CTC Toxicity Grade 
Onset Day 2-14 of Cycle 
Onset ≥ Day 15 of Cycle 
Desquamating 
(blistering) rash- any 
Grade  
• 
Discontinue lenalidomide.  Remove 
patient from study. 
• 
Discontinue 
lenalidomide.  
Remove patient from 
study. 
Neuropathy 
 
Grade 3 
 
 
 
 
 
 
 
Grade 4 
 
• 
If Grade 3, hold (interrupt) 
lenalidomide dose.  Follow at least 
weekly. 
• 
If the toxicity resolves to ≤ grade 1 
prior to Day 21 of the current cycle, 
restart lenalidomide at next lower 
dose level and continue through 
the scheduled Day 21 of the 
current cycle.   
 
 
• 
If Grade 4, discontinue 
lenalidomide.  Remove patient from 
study. 
• 
Otherwise, omit for 
remainder of cycle 
and reduce the dose 
of lenalidomide by 1 
dose level at the start 
of the next cycle.  
Omitted doses are not 
made up. 
 
 
 
• 
If Grade 4, 
discontinue 
lenalidomide.  
Remove patient from 
study. 
Erythema multiforme ≥  
Grade 3 
• 
Discontinue lenalidomide.  Remove 
patient from study. 
• 
Discontinue 
lenalidomide.  
Remove patient from 
study. 
Sinus bradycardia/ 
other cardiac 
arrhythmia 
 
Grade 2 
 
 
 
 
            ≥ Grade 3 
 
• 
Hold (interrupt) lenalidomide dose.  
Follow at least weekly. 
• 
If the toxicity resolves to ≤ grade 1 
prior to Day 21, restart 
lenalidomide at next lower dose 
level and continue the cycle 
through Day 21. 
 
 
 
 
• 
Discontinue lenalidomide.  Remove 
patient from study. 
• 
Omit lenalidomide for 
the remainder of the 
cycle.  
• 
See Instructions for 
Initiation of a New 
Cycle and reduce the 
dose of lenalidomide 
by 1 dose level. 
 
 
 
• 
Discontinue 
lenalidomide.  
Remove patient from 
study. 


 
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Table 2: Dose Modifications 
NCI CTC Toxicity Grade 
Onset Day 2-14 of Cycle 
Onset ≥ Day 15 of Cycle 
Allergic reaction or 
hypersensitivity 
 
Grade 2-3 
 
 
 
 
 
Grade 4 
 
• 
Hold (interrupt) lenalidomide dose.  
Follow at least weekly. 
• 
If the toxicity resolves to ≤ grade 1 
prior to Day 21, restart 
lenalidomide at next lower dose 
level and continue the cycle 
through Day 21. 
 
 
 
 
• 
Discontinue lenalidomide.  Remove 
patient from study. 
• 
Omit lenalidomide for 
the remainder of the 
cycle. 
• 
See Instructions for 
Initiation of a New 
Cycle and reduce the 
dose of lenalidomide 
by 1 dose level. 
 
 
 
• 
Discontinue 
lenalidomide.  
Remove patient from 
study. 
Venous 
thrombosis/embolism 
≥ Grade 3 
• 
Hold (interrupt) lenalidomide and 
start anticoagulation; restart 
lenalidomide at investigator’s 
discretion (maintain dose level). 
See Anticoagulation Consideration 
(Section 5.6.1.2) 
• 
Omit lenalidomide for 
remainder of cycle. 
See Anticoagulation 
Consideration 
(Section 5.6.1.2) 
other non-hematologic 
toxicity ≥ Grade 3 
• 
Hold (interrupt) lenalidomide dose.  
Follow at least weekly. 
• 
If the toxicity resolves to ≤ grade 2 
prior to Day 21 restart lenalidomide 
and continue through the 
scheduled Day 21 of the current 
cycle. 
• 
Omit lenalidomide for 
remainder of cycle. 
Omitted doses are not 
made up.   
• 
See Instructions for 
Initiation of a New 
Cycle and reduce the 
dose of lenalidomide 
by 1 dose level when 
restarting 
Lenalidomide at the 
start of next cycle.  
Hyperthyroidism or 
hypothyroidism 
• 
Omit lenalidomide for remainder of 
cycle, evaluate etiology, and initiate 
appropriate therapy.  
• 
See Instructions for Initiation of a 
New Cycle and reduce the dose of 
lenalidomide by 1 dose level. 
• 
Omit lenalidomide for 
remainder of cycle, 
evaluate etiology, and 
initiate appropriate 
therapy.  
• 
See Instructions for 
Initiation of a New 
Cycle and reduce the 
dose of lenalidomide 
by 1 dose level. 
 
Dexamethasone (40 mg) will be administered at a dose of 40mg once a week 
(Days 1, 8, 15 and 22) to the Lenalidomide regimen, with a dose reduction to 
20mg on the same schedule if the patient cannot tolerate the higher dose of 
dexamethasone. 
 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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Grade 3 or 4 toxicity attributable to dexamethasone (e.g., proximal myopathy, 
glucose intolerance uncontrolled by insulin) may warrant dose modification of 
dexamethasone to 20 mg on the same schedule.  If patient continues to have 
dexamethasone related toxicity then dexamethasone will be discontinued and 
lenalidomide will be continued as single agent as long as the response criteria 
are satisfied. 
5.5.4 Treatment compliance 
At all times, when dispensing study drug, research center personnel will review 
the dosing instructions, printed on the packaging, with subjects. Subjects will be 
asked to maintain a diary to record the drug administration. Subjects will be 
asked to bring any unused study drug to the research center at their next visit.  
Research personnel will count and record the number of used and unused study 
drug capsules at each visit and reconcile with the patient diary.   
5.6 Concomitant therapy   
5.6.1 Recommended concomitant therapy   
Subjects should receive full supportive care, including transfusions of blood and 
blood products, antibiotics, and antiemetics when appropriate.  
 
5.6.1.2 Anticoagulation Consideration   
Lenalidomide increases the risk of thrombotic events in patients who are at high 
risk or with a history a thrombosis, in particular when combined with other drugs 
known to cause thrombosis. When lenalidomide is combined with other agents 
such as steroids (e.g. dexamethasone, prednisone), anthracyclines (Doxil, 
Adriamycin) and erythropoietin the risk of thrombosis is increased.  
Daily aspirin (81 or 325 mg) or some other form of prophylaxis as deemed 
appropriate is required. Low molecular weight heparin may be utilized in patients 
that are intolerant to ASA. Coumadin should be used with caution and close 
monitoring of INR. 
5.6.2 Prohibited concomitant therapy 
Concomitant use of sargramostim (GM-CSF), other anti-cancer therapies, 
including radiation, thalidomide, or other investigational agents is not permitted 
while subjects are receiving study drug during the treatment phase of the study. 


 
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5.7 Discontinuation of Study Treatment  
Treatment will continue until the occurrence of any of the following events.   
• Disease progression as defined in Appendix C 
• Adverse event(s) that, in the judgment of the Investigator, may cause 
severe or permanent harm or which rule out continuation of the treatment 
regimen. 
• Discontinuation of lenalidomide for any reason. 
• Major violation of the study protocol. 
• Withdrawal of consent 
• Lost to follow up 
• Death 
• Pregnancy 
• Patient requests to be removed from study 
5.8 
Follow-Up   
Subjects who discontinue treatment for any reason will not be followed.  At 
treatment discontinuation, 
subjects 
will 
undergo a 
safety 
assessment 
approximately 28 days post the last dose of study drug.  In addition, off study 
evaluations per the Schedule of Assessments, Section 2 will be done. All 
subjects who respond to treatment will be followed for survival indefinitely. 
6 Adverse events 
6.1 Serious Adverse Event (SAE) Definition  
A serious adverse event is one that at any dose (including overdose): 
 
Results in death 
 
Is life-threatening1 
 
Requires inpatient hospitalization or prolongation of existing 
hospitalization 
 
Results in persistent or significant disability or incapacity2 
 
Is a congenital anomaly or birth defect 
 
Is an important medical event3 


 
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 1“Life-threatening” means that the subject was at immediate risk of death at the time of 
the serious adverse event; it does not refer to a serious adverse event that hypothetically 
might have caused death if it were more severe. 
2“Persistent or significant disability or incapacity” means that there is a substantial 
disruption of a person’s ability to carry out normal life functions. 
3Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in situations where none of the outcomes listed above occurred.  
Important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above should also usually be considered 
serious.  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.  
6.2 Adverse Drug Reaction Reporting 
Toxicity will be scored using CTCAE Version 3.0 for toxicity and adverse event 
reporting.  A copy of the CTCAE Version 3.0 can be downloaded from the CTEP 
homepage (HTTP://CTEP.INFO.NIH.GOV).  All appropriate treatment areas should 
have access to a copy of the CTCAE Version 3.0.  All adverse clinical 
experiences, whether observed by the investigator or reported by the patient, 
must be recorded, with details about the duration and intensity of each episode, 
the action taken with respect to the test drug, and the patient’s outcome.  The 
investigator must evaluate each adverse experience for its relationship to the test 
drug and for its seriousness. 
 
The investigator must appraise all abnormal laboratory results for their clinical 
significance.  If any abnormal laboratory result is considered clinically significant, 
the investigator must provide details about the action taken with respect to the 
test drug and about the patient’s outcome. 
 
SPMs are considered events of interest and should be included as part of the 
assessment of adverse events throughout the course of the study.  Investigators 
are to report any second primary malignancies as serious adverse events 
regardless of causal relationship to lenalidomide, occurring at any time for the 
duration of the study   For all subjects who develop second primary 
malignancies, sites will be required to submit all diagnostic reports (eg pathology, 
cytogenetics, flow cytometry results) from the indication diagnostic confirmation 
samples submitted at screening and all reports for the tumor samples  from the 
SPM diagnosis.  For SPMs diagnosed at another institution (outside the 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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investigational site), sites are to make every effort to obtain these reports for the 
SPM confirmation. 
 
6.2.1 Pregnancies 
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 after the subject’s last dose of 
lenalidomide are considered immediately reportable events.  If the subject is on 
lenalidomide, it is to be discontinued immediately and the subject is to be 
instructed to return any unused portion of lenalidomide to the Investigator.  The 
pregnancy must be reported to Celgene Drug Safety immediately of the 
Investigator’s knowledge of the pregnancy by phone and facsimile using the 
Pregnancy Initial Report Form. 
 
The Investigator will follow the 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 lenalidomide should 
also be reported to Celgene Drug Safety immediately by facsimile, or other 
appropriate method, within 24 hours of the Investigator’s knowledge of the event 
using the SAE Report Form.  
 
Male Subjects 
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 their healthcare provider 
immediately. 
 
6.2.2 Celgene Drug Safety Contact Information: 
 
Celgene Corporation 
Connell Corporate Park      


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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300 Connell Dr.  Suite 6000     
Berkeley Heights, NJ  07922        
 
Fax:  
(908) 673-9115 
E-mail:  
drugsafety@celgene.com 
 
 
6.3 Investigator Reporting Responsibilities 
The conduct of the study will comply with all FDA safety reporting requirements.   
 
IND Annual Reports 
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, 
that an annual report is provided to the FDA within 60-days of the IND 
anniversary date.  21 CRF 312.33 provides the data elements that are to be 
submitted in the report.  The Annual Report should be filed in the study's 
Regulatory Binder (or some such phrase), and a copy provided to Celgene 
Corporation as a supporter of this study as follows. 
 
 
Celgene Corporation 
 
Attn: Medical Affairs Operations 
 
Connell Corporate Park  
 
400 Connell Drive Suite 700 
 
Berkeley Heights, NJ  07922 
 
All adverse experience reports must include the patient number, age, sex, 
weight, severity of reaction (mild, moderate, severe), relationship to study drug 
(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. 
6.3.1 Expedited reporting by investigator to Celgene 
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 within 24 hours of being aware of the event.  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), Information not available at the time of 
the initial report (e.g., an end date for the adverse event or laboratory values 


 
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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-PI-MM-0345), and the institutional protocol number, and the patient 
ID 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. 
 
Any SAEs incurred at subsites must be reported immediately to the VA BOSTON  
office and to Celgene within 24 hours/1 business day at the latest on the 
following working day of awareness of the event.   
6.3.2 Report of Adverse Events to the Institutional Review Board 
The principal Investigator is required to notify his/her Institutional Review Board 
(IRB) of a serious adverse event according to institutional policy.   
6.3.3 Investigator Reporting to the FDA 
Serious adverse events (SAEs) that are unlisted/unexpected, and at least 
possibly associated to the drug, and that have not previously been reported in 
the Investigators brochure, or reference safety information document should be 
reported promptly to the Food and Drug Administration (FDA) by telephone or by 
fax.  Fatal or life threatening SAEs that meet the criteria for reporting to the FDA 
must be reported to the FDA within 7 calendar days after awareness of the event.  
All other SAEs that meet the criteria for reporting to the FDA must be reported to 
the FDA within 15 calendar days after awareness of the event.  A clear 
description of the suspected reaction should be provided along with an 
assessment as to whether the event is drug or disease related.    
 
Participating study sites should NOT report SAEs to the FDA.  Participating sites 
should report SAEs to Celgene and the VA Boston site, and the VA Boston site 
will be responsible for reporting to FDA. 
 
6.4 Adverse event updates/IND safety reports 
Celgene shall notify the Investigator via an IND Safety Report of the following 
information: 
 
• Any AE associated with the use of study drug in this study or in other 
studies that is both serious and unexpected. 
• Any finding from tests in laboratory animals that suggests a significant risk 
for human subjects including reports of mutagenicity, teratogenicity, or 
carcinogenicity. 
 
The Investigator shall notify his/her IRB/EC promptly of these new serious and 
unexpected AE(s) or significant risks to subjects. 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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The Investigator must keep copies of all AE information, including 
correspondence with Celgene and the IRB/EC, on file (see Section 11.4 for 
records retention information). 
7 Response Criteria 
Efficacy assessments are scheduled to occur on day 1 of each even cycle (cycle 
2, 4, 6, etc.). 
All partial and complete responses must be confirmed with another efficacy 
assessment in no less than 4 weeks apart.  
Response and progression will be evaluated in this study using the EBMT and 
IMWG criteria   
Instructions for interpreting response criteria and best overall response may be 
found in Appendix C: Response Evaluation Criteria.  
8 Protocol Amendments/Deviations 
8.1 Protocol amendments 
Any amendment to this protocol must be agreed to by the Principal Investigator 
and reviewed by Celgene.  Amendments should only be submitted to IRB/EC 
after consideration of Celgene review.  Written verification of IRB/EC approval 
will be obtained before any amendment is implemented.   
8.2 Protocol deviations 
When an emergency occurs that requires a deviation from the protocol for a 
subject, a deviation will be made only for that subject.  A decision will be made as 
soon as possible to determine whether or not the subject (for whom the deviation 
from protocol was effected) is to continue in the study.  The subject’s medical 
records will completely describe the deviation from the protocol and state the 
reasons for such deviation.  In addition, the Investigator will notify the IRB/EC in 
writing of such deviation from protocol. 
Non-emergency minor deviations from the protocol will be permitted with 
approval of the Principal Investigator.  


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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9 Study Monitoring and Auditing 
9.1 
Investigator responsibilities 
Investigator responsibilities are set out in the ICH guideline for Good Clinical 
Practice (GCP) and in the US Code of Federal Regulations. 
Investigators must enter study data onto CRFs or other data collection system.  
The Investigator will permit study-related monitoring visits and audits by Celgene 
or its representatives, IRB/EC review, and regulatory inspection(s) (e.g., FDA, 
EMEA, TPP), providing direct access to the facilities where the study took place, 
to source documents, to CRFs, and to all other study documents. 
The Investigator, or a designated member of the Investigator’s staff, must be 
available at some time during monitoring visits to review data and resolve any 
queries and to allow direct access to the subject’s records (e.g., medical records, 
office charts, hospital charts, and study related charts) for source data 
verification.  The data collection must be completed prior to each visit and be 
made available to the Celgene representative so that the accuracy and 
completeness may be checked. 
10   Biostatistical Analysis 
10.1 Overview 
This is a multi-center, controlled, open-label, randomized, parallel group study 
intended to select a tolerable dose regimen with acceptable efficacy of 
lenalidomide, when used in combination with dexamethasone.  Patients will be 
randomized 
with 
1:1 
ratio 
to receive 
lenalidomide 
25 
mg + dexamethasone or lenalidomide 15mg + dexamethasone.  The 
primary 
objective of the study is to evaluate the frequency of dose reductions in two 
different lenalidomide dose regimens. The study will help in selecting a safe 
lenalidomide dose for the elderly population. 
 
10.2 Datasets to be analyzed 
All analyses will be based on mITT population defined as below. 
Modified Intent-to-treat (mITT) population: The mITT population will be defined as 
all subjects randomized into the trial who received at least one dose of 
lenalidomide. Treatment classification will be based on the randomized 
treatment. 


 
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Patients who did not receive any treatment of lenalidomide will not be included in 
the statistical analysis. Patients who have received at least one dose of 
lenalidomide will be considered evaluable for statistical analysis.  
10.3 Statistical Methodology 
Each treatment arm will be further stratified into those patients who received a 
reduction in dosage level and those who did not. As a first step, potential 
differences among the four groups on demographic variables will be tested. 
Those variables that are categorical will be analyzed by Chi Sq.; those variables 
that are quantitative will be analyzed by two-way between-groups Analyses of 
Variance. Any variable where a significant difference is established will be 
controlled by entry into future analyses as covariates. 
 
The primary outcome variable is the proportion of patients in each treatment arm 
that received any dosage reduction, independent of when in the course of 
treatment this reduction occurred or how many subsequent reductions were 
introduced. These data will be analyzed by logistic regression with treatment arm 
as the main predictor and any variables found significant in the first step entered 
as covariates. A secondary analysis will consider the rate at which any dose 
reductions were introduced. For example, it is possible that the proportion of 
patients that receive a dose reduction may be equivalent in the two treatment 
arms, but that those patients in one arm may have received their reductions 
earlier. This will be examined by a Cox Proportional Hazard test, and, if 
necessary, with the same covariates identified above. 
 
Power analysis shows that with a total N = 80 (40/group) power = .80 to detect 
an effect size difference in proportions of 32% (p=.05, 2-tail) (Borenstein M, 
Rothstein H and Cohen J.  Power and Precision (2004). Englewood, NJ, Biostat). 
 
This sample size provides adequate power to observe similar difference in dose 
reduction between the two groups for a range of dose reductions (10% - 40%) 
in 15mg dose group. 
 
Secondary endpoints: Although this study is not powered to compare response 
as well as duration of response to the 2 dose regimen, we will collect and 
analyze both using power analysis.  Objective response rate is defined as the 
proportion of randomized subjects who have evidence of either partial response 
or complete response as determined using the EBMT and IMWG criteria. One-
sided 95% confidence limits on the lower limit of the percentage of responders 
will be established to determine if this lower bound exceeds 45%. Duration of 
response is computed among the subgroup of subjects whose best response is 
PR or better. It is defined as is the time from when measurement criteria are first 
met for objective response until the date of progression or death. A subject with 
an objective response who does not have a progression event will be censored 
at the same time as he or she was censored under the primary definition of PFS. 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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The data on growth factors and other markers will be collected. For each protein, 
the proportion of patients who are up or down-regulated will be reported along 
with the 90% CI. The Fisher’s exact test (two sided significance level of 5%) will 
be used to compare the proportions of patients with CR+PR for those who are 
upregulated vs. those who are down-regulated. 
 10.4 Safety evaluation 
Data from all subjects who receive any study drug will be included in the safety 
analyses. Subjects who entered the study and did not take any of the study 
drug(s) and had this confirmed, will not be evaluated for safety. 
The severity of the toxicities will be graded according to the NCI CTCAE v3.0 
whenever possible.  
10.5 Sample size and power considerations 
Assume the dose reduction rate for 25 mg arm is 50%, a sample size of 80 
subjects (40 per arm) will provide a power of 81.6% to detect a difference of 30% 
(the rate of dose reduction assumed to be 20%) at significance level of 0.05.  
11 
Regulatory Considerations 
11.1 Institutional Review Board/Ethics Committee approval 
The protocol for this study has been designed in accordance with the general 
ethical principles outlined in the Declaration of Helsinki and FDA Regulations.  
The review of this protocol by the IRB/EC and the performance of all aspects of 
the study, including the methods used for obtaining informed consent, must also 
be in accordance with principles enunciated in the declaration, as well as ICH 
Guidelines, Title 21 of the Code of Federal Regulations (CFR), Part 50 Protection 
of Human Subjects and Part 56 Institutional Review Boards. 
The Investigator will be responsible for preparing documents for submission to 
the relevant IRB/EC and obtaining written approval for this study.  The approval 
will be obtained prior to the initiation of the study. 
The approval for both the protocol and informed consent must specify the date of 
approval, protocol number and version, or amendment number. 
Any amendments to the protocol after receipt of IRB/EC approval must be 
submitted by the Investigator to the IRB/EC for approval.  The Investigator is also 
responsible for notifying the IRB/EC of any serious deviations from the protocol, 
or anything else that may involve added risk to subjects. 


 
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Any advertisements used to recruit subjects for the study must be reviewed and 
approved by the IRB/EC prior to use. 
11.2 Informed consent 
The Investigator must obtain informed consent of a subject or his/her designee 
prior to any study related procedures as per GCPs as set forth in the CFR and 
ICH guidelines. 
Documentation that informed consent occurred prior to the subject’s entry into 
the study and the informed consent process should be recorded in the subject’s 
source documents.  The original consent form signed and dated by the subject 
and by the person consenting the subject prior to the subject’s entry into the 
study, must be maintained in the Investigator’s study files. 
11.3 Subject confidentiality 
Celgene affirms the subject’s right to protection against invasion of privacy.  In 
compliance with United States federal regulations, Celgene requires the 
Investigator to permit Celgene’s representatives and, when necessary, 
representatives of the FDA or other regulatory authorities to review and/or copy 
any medical records relevant to the study in accordance with local laws. 
Agents or designee of Celgene Corporation may visit and or meet the Principal 
Investigator and examine the facilities at any study location upon reasonable 
advance notice and with reasonable frequency, during normal business hours to 
observe the progress of the study and, review all documents, records, data 
(including study data) information, and materials relating to this study. The 
Principal Investigator will assist Celgene in scheduling such visits. 
Should direct access to medical records require a waiver or authorization 
separate from the subject’s statement of informed consent, it is the responsibility 
of the Investigator to obtain such permission in writing from the appropriate 
individual. 
11.4 Study records requirements 
The Investigator must ensure that the records and documents pertaining to the 
conduct of the study and the distribution of the study drug, that is copies of CRFs 
and source documents (original documents, data, and records [e.g., hospital 
records; clinical and office charts; laboratory notes; memoranda; subject’s diaries 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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or evaluation checklists; pharmacy dispensing records; recorded data from 
automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiches; photographic negatives, microfilm, or 
magnetic media; x-rays; subject files; and records kept at the pharmacy, at the 
laboratories, and at medico-technical departments involved in the clinical study; 
documents regarding subject treatment and study drug accountability; original 
signed informed consents, etc.]) be retained by the Investigator for as long as 
needed to comply with national and international regulations (generally 2 years 
after discontinuing clinical development or after the last marketing approval).  
The Investigator agrees to adhere to the document/records retention procedures 
by signing the protocol. 
The data collected from all sites will be transferred to an excel spread sheet by 
the coordinator and will be stored in a password protected VA computer housed 
in a locked office at the Boston VA. All information concerning the trial, including 
any PHI, will be securely protected in this password protected database or in a 
locked filing cabinet on VA campus. 
11.6 Premature discontinuation of study 
11.6.1 Single center 
The responsible local clinical Investigator as well as Celgene have the right to 
discontinue this study at any time for reasonable medical or administrative 
reasons in any single center.  Possible reasons for termination of the study could 
be but are not limited to: 
• Unsatisfactory enrollment with respect to quantity or quality. 
• Inaccurate or incomplete data collection. 
• Falsification of records. 
• Failure to adhere to the study protocol. 
11.6.2    Study as a whole 
Celgene reserves the right to terminate this clinical study at any time for 
reasonable medical or administrative reasons. 
Any possible premature discontinuation would be documented adequately with 
reasons being stated, and information would have to be issued according to local 
requirements (e.g., IRB/EC, regulatory authorities, etc.). 


 
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12 
References 
 
(1) Dredge K, Horsfall R, Robinson S, Zhang L-H, Lu L, et al.  Orally 
administered lenalidomide (lenalidomide) is anti-angiogenic in vivo and 
inhibits endothelial cell migration and Akt phosphorylation in vitro.  
Microvascular Research 69 (2005) 56-63. 
(2) Corral LF, Haslett PAJ, Muller FW, Chen R, Wong LM, Ocampo CJ, 
Patterson RT, Stirling DI, Kaplan G.  Differential cytokine modulation and 
T cell activation by two distinct classes of thalidomide analogues that are 
potent inhibitors of TNF-alpha.  J Immunol. 1993;163:380-386. 
(3) Schafer PH, Gandhi AK, Loveland MA, Chen RS, Man H-W, et al.  
Enhancement of cytokine production and AP-1 transcriptional activity in T 
cells 
by 
thalidomide-related 
immunomodulatory 
drugs. 
 
J 
of 
Pharmacology and Exp Therapeutics, 305:1222-1232, 2003. 
(4) Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai YT, Lin B, 
Podar K, Gupta D, Chauhan D, Treon SP, Richarson PG, Schlossman 
RL, Morgan GJ, Muller GW, Stirling DI, Anderson KC.  Thalidomide and 
immunomodulatory derivatives augment natural killer cell cytotoxicity in 
multiple myeloma.  Blood. 2001;98:210-216. 
(5) Hideshima T, Chauhan D, Shima Y, Raje N, Davies F, Tai YT, Treon SP, 
Lin B, Schlossman RL, Richarson P, Muller G, Stirling DI, Anderson KC.  
Thalidomide and its analogs overcome drug resistance of human multiple 
myeloma cells to conventional therapy.  Blood. 2000;96:2943-2950. 
(6) Bartlett JB, Michael A, Clarke IA, Dredge K, Nicholson S, et al.  Phase I 
study to determine the safety, tolerability and immunostimulatory activity 
of thalidomide analog lenalidomide in patients with metastatic malignant 
melanoma and other advanced cancers.  British J of Cancer (2004) 90, 
955-961 
(7) Fine HA, Kim L, Royce C, Duic JP, Cohen LJ, Mitchell S.  A phase I trial 
of lenalidomide, a potent thalidomide analog, in patients with recurrent 
high-grade gliomas and other refractory CNS malignancies.  Proc ASCO 
2003, Abstract #418. 
(8) Liu Y, Tohnya TM, Figg WD, Gulley JL, Arlen PM, et al.  Phase I study of 
lenalidomide (Revimid), a thalidomide derivative, in patients with 
refractory metastatic cancer.  Proc ASCO 2003, Abstract #927. 
(9) Zangari M, Tricot G, Zeldis J, Eddlemon P, Saghafifar F, Barlogie B.  
Results of phase I study of lenalidomide for the treatment of multiple 
myeloma (MM) patients who relapse after high dose chemotherapy 
(HDCT). Blood 2001; 98:775a (Abstract #3226). 
(10) Richardson PG, Schlossman RL, Weller E, Hideshima T, Mitsiades C, et 
al.  Immunomodulatory drug (lenalidomide) overcomes drug resistance 
and is well tolerated in patients with relapsed multiple myeloma.  Blood 
2002; 100:3063-3067. 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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(11) Wu A, Scheffler MR.  Multiple-dose pharmacokinetics and safety of 
lenalidomide in 15 multiple myeloma patients.  Proc ASCO 2004, Abstract 
#2056. 
(12) Richardson PG, Jagannath S, Schlossman R, Zeldenrust S, Rajkumar 
SV, et al.  A multi-center, randomized, phase 2 study to evaluate the 
efficacy and safety of two CDC-5013 dose regimens when used alone or 
in combination with dexamethasone (Dex) for the treatment of relapsed or 
refractory multiple myeloma (MM). Blood 2003, Abstract #825. 
(13) Hussein MA, Karam MA, Brand C, Pearce G, Reed J, et al.  Doxil (D), 
vincristine (V), reduced frequency dexamethasone (d) and Revlimid (R) 
(DVd-R) a phase I/II trial in advanced relapsed/refractory multiple 
myeloma (Rmm) patients.  Blood 2004, Abstract #208. 
(14) Data on file.  Celgene Corporation 
(15) List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, et al.  Efficacy of 
lenalidomide in myelodysplastic syndromes.  N Engl J Med 2005; 
352:549-57. 
(16) List AF, Dewald G, Bennett J, Giagounadis A, Raza A, et al.  Hematologic 
and cytogenetic (CTG) response to lenalidomide (lenalidomide) in 
patients with transfusion-independent (TD) myelodysplastic syndrome 
(MDS) and chromosome 5q31.1 deletion: Results of the multicenter MDS-
003 study.  Proc ASCO 2005, abstract #5. 
(17) Therasse P, Arbuck S, Eisenhauer E, Wanders J, Kaplan R, et al. 2000.  
New Guidelines to Evaluate the Response to Treatment in Solid Tumors.  
Journal of the National Cancer Institute.  2000; 92: 205-216. 
(18) Rajkumar SV, Hayman SR, Lacy MQ et al. Combination therapy with 
lenalidomide plus dexamethasone (REV/DEX) for newly diagnosed 
myeloma. Blood 2005; 2005-2007. 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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Appendices 
 
Appendix A: 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. 
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 (amenorrhea following cancer therapy 
does not rule out childbearing potential) for at least 24 consecutive months (i.e., 
has had menses at any time in the preceding 24 consecutive months). 
Counseling 
For a female of childbearing potential, lenalidomide is contraindicated unless all 
of the following are met (i.e., all females of childbearing potential must be 
counseled concerning the following risks and requirements prior to the start of 
lenalidomide study therapy):  
• She understands the potential teratogenic risk to the unborn child 
• She understands the need for effective contraception, without interruption, 
28 days before starting lenalidomide, throughout the entire duration of 
lenalidomide treatment, including dose interruptions, and for 28 days after 
the end of lenalidomide treatment 
• She should be capable of complying with effective contraceptive 
measures 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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• She is informed and understands the potential consequences of 
pregnancy and the need to notify her study doctor immediately if there is a 
risk of pregnancy 
• She understands the need to commence the study treatment as soon as 
lenalidomide is dispensed following a negative pregnancy test 
• She understands the need and accepts to undergo pregnancy testing 
based on the frequency outlined in this protocol. 
• She acknowledges that she understands the hazards and necessary 
precautions associated with the use of lenalidomide 
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, and acknowledge the aforementioned 
requirements 
• Females NOT of childbearing potential acknowledge that she understands 
the hazards and necessary precautions associated with the use of 
lenalidomide 
• Male patients taking lenalidomide acknowledge that he understands that 
traces of lenalidomide have been found in semen, that he understands the 
potential teratogenic risk if engaged in sexual activity with a female of 
childbearing potential, and that he understands the need for the use of a 
condom even if he has had a vasectomy, if engaged in sexual activity with 
a female of childbearing potential.   
Contraception 
Females of childbearing potential (FCBP)† 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) while participating in the 
study; and 3) for at least 28 days after discontinuation from the study.  
 
 
† A female of childbearing potential is 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). 
 
 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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The two methods of reliable contraception must include one highly effective 
method and one additional effective (barrier) method FCBP must be referred to a 
qualified provider of contraceptive methods if needed. The following are 
examples of highly effective and additional effective methods of contraception:   
o Highly effective methods: 
▪ Intrauterine device (IUD) 
▪ Hormonal (birth control pills, injections, implants) 
▪ Tubal ligation 
▪ Partner’s vasectomy 
o Additional effective methods: 
▪ Male condom 
▪ Diaphragm 
▪ Cervical Cap 
  
Because of the increased risk of venous thromboembolism in patients with 
multiple myeloma taking lenalidomide and dexamethasone, combined oral 
contraceptive pills are not recommended.  If a patient is currently using combined 
oral contraception the patient should switch to one of the effective method listed 
above. The risk of venous thromboembolism continues for 4−6 weeks after 
discontinuing combined oral contraception. The efficacy of contraceptive steroids 
may be reduced during co-treatment with dexamethasone. 
Implants and levonorgestrel-releasing intrauterine systems are associated with 
an increased risk of infection at the time of insertion and irregular vaginal 
bleeding. Prophylactic antibiotics should be considered particularly in patients 
with neutropenia.  
Pregnancy testing 
Medically supervised pregnancy tests with a minimum sensitivity of 50 mIU/mL 
must be performed for females of childbearing potential, including females of 
childbearing potential who commit to complete abstinence, as outlined below. 
 
Before starting lenalidomide:   
Female Subjects:   


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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FCBP must have two negative pregnancy tests (sensitivity of at least 50 
mIU/mL) prior to starting lenalidomide .  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 the 
start of study drug.  The patient may not receive study drug until the 
Investigator has verified that the results of these pregnancy tests are 
negative. 
Male Subjects:   
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 discontinuation from 
the study: 
Female Subjects:   
 
• FCBP with regular or no menstrual cycles must agree to have pregnancy 
tests weekly for the first 28 days of lenalidomide treatment, including dose 
interruptions, and then every 28 days throughout the remaining duration of 
lenalidomide treatment, including dose interruptions, at lenalidomide 
discontinuation, and at Day 28 following lenalidomide discontinuation.  If 
menstrual cycles are irregular, the pregnancy testing must occur weekly 
for the first 28 days of lenalidomide treatment, including dose 
interruptions, and then every 14 days throughout the remaining duration of 
lenalidomide treatment, including dose interruptions, at lenalidomide 
discontinuation, and at Day 14 and Day 28 following lenalidomide 
discontinuation.   
• At each visit, the Investigator must confirm with the FCBP that she is 
continuing to use two reliable methods of birth control at each visit during 
the time that birth control is required.   
• Counseling about pregnancy precautions and the potential risks of fetal 
exposure must be conducted at a minimum of every 28 days throughout 
the entire duration of lenalidomide treatment, including dose interruptions.  


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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• 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 Subjects: 
• 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.   
• Counseling about the requirement for condom use during sexual contact 
with females of childbearing potential and the potential risks of fetal 
exposure must be conducted at a minimum of every 28 days throughout 
the entire duration of lenalidomide treatment, including dose interruptions.   
• 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. 
Additional precautions 
• Patients should be instructed never to give lenalidomide to another person 
and to return any unused capsules to the Investigator at the end of 
treatment. 
• Female patients should not donate blood during therapy and for at least 
28 days following discontinuation of lenalidomide. 
• Male patients should not donate blood, semen or sperm during therapy or 
for at least 28 days following discontinuation of lenalidomide. 
• Only enough lenalidomide for one cycle of therapy may be dispensed with 
each cycle of therapy.  
 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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 Appendix B – ECOG Performance Status Scale 
 
 
 
SCORE 
DESCRIPTION 
0 
Fully 
active, 
able 
to 
carry 
on 
all 
pre-disease 
performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory 
and able to carry out work of a light or sedentary nature, 
e.g., light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to 
carry out any work activities.  Up and about more than 
50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
Dead. 
 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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Appendix C – Response Evaluation Criteria  
Disease Response Criteria 
Response 
Criteria for Response 
Complete Response (CR) 
Requires all of the following: 
• 
Disappearance of the original monoclonal protein from 
the blood and urine on at least two determinations for a 
minimum of six weeks by immunofixation studies 
• 
< 5% plasma cells in the bone marrow on at least one 
determination 
• 
No increase in the size or number of lytic bone lesions 
(development of a compression fracture does not 
exclude response) 
• 
Disappearance of soft tissue plasmacytomas for at least 
six weeks. 
Near CR 
• 
Requires all of above except immunofixation remains 
positive 
• 
Or normal FLC ratio 
Partial Response (PR) 
Requires all of the following: 
• 
> 50% reduction in the level of serum monoclonal 
protein for at least two determinations six weeks apart 
• 
If present, reduction in 24-hour urinary light chain 
excretion by either > 90% or to < 200 mg for at least two 
determinations six weeks apart 
• 
> 50% reduction in the size of soft tissue 
plasmacytomas (by clinical or radiographic examination) 
for at least six weeks 
• 
No increase in size or number of lytic bone lesions 
(development of compression fracture does not exclude 
response) 
• 
If the serum and urine M-protein are unmeasurable a ≥ 
50% decrease in the difference between involved and 
uninvolved FLC levels is required in place of the M-
protein criteria 
Minimal Response (MR) 
Requires all of the following: 
• 
> 25% to< 49% reduction in the level of serum 
monoclonal protein for at least two determinations six 
weeks apart 
• 
If present, a 50 to 89% reduction in 24 hour light chain 
excretion, which still exceeds 200 mg/24hr, for at least 
two determinations six weeks apart. 
• 
For patients with non-secretory myeloma only, a 25 to 
49% reduction in plasma cells in the bone marrow for a 
minimum of six weeks 
• 
no increase in size or number of lytic bone lesions 
(development of compression fracture does not exclude 
response) 
Stable Disease 
Not meeting the criteria for CR, PR or PD 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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Response 
Criteria for Response 
Progressive Disease 
Requires one or more of the following: 
• 
> 25% increase in the level of serum monoclonal 
paraprotein, which must also be an absolute increase of 
at least 5G/dL and confirmed on a repeat investigation 
• 
> 25% increase in 24-hour urinary light chain excretion, 
which must also be an absolute increase of at least 200 
mg/24hours and confirmed on a repeat investigation 
• 
> 25% increase in plasma cells in a bone marrow 
aspirate or on trephine biopsy, which must also be an 
absolute increase of at least 10% 
• 
Only in patients without measureable serum and urine 
M-protein levels: the difference between involved and 
uninvolved FLC levels (absolute increase must be 
<10mg/L) 
• 
Definite increase in the size of existing lytic bone lesions 
or soft tissue plasmacytomas or definite development of 
new bone lesions or soft tissue plasmacytomas 
• 
Development of hypercalcemia (corrected serum 
calcium > 11.5 mg/dL or 2.8 mmol/L not attributable to 
any other cause) 
 
Relapse from CR 
Requires at least one of the following: 
• 
Reappearance of serum or urinary paraprotein on 
immunofixation or routine electrophoresis confirmed by 
at least one follow-up and excluding oligoclonal immune 
reconstitution 
• 
> 5% plasma cells in the bone marrow aspirate or 
biopsy 
• 
Development of new lytic bone lesions or soft tissue 
plasmacytomas or definite increase in the size of 
residual bone lesions (not including compression 
fracture). 
• 
Development of hypercalcemia (corrected serum 
calcium > 11.5 mg/dL or 2.8 mmol/L not attributable to 
any other cause).  
 
*Note clarification to IMWG criteria for coding CR and VGPR in patients in whom the only 
measurable disease is by serum FLC levels: CR in such patients a normal FLC ratio of 0.26-
1.65 in addition to CR criteria listed above. VGPR in such patients is defined as a >90% decrease 
in the difference between involved and uninvolved free light chain FLC levels.  
Based on the criteria for evaluating disease response and progression in patients with multiple 
myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma 
Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol. 
102: 1998; 1115-1123. and International Myeloma Working Group. Criteria for the classification of 
monoclonal gammopathies, multiple myeloma and related disorders: a report of the International 
Myeloma Working Group. 
Br J Haematol 2003; 121: 749–757. 
 
 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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10.1 
Time to Treatment Failure 
Time to treatment failure will be defined as the period of time, on study, from 
the first day of drug treatment to the time when progressive disease, 
treatment related toxicity resulting in discontinuation of treatment, or death 
(from any cause) is clearly documented. 
 
 
10.2 
Time to Disease Progression 
Time to disease progression will be defined as the period of time, on study 
including follow-up, from the first day of drug treatment to the time when a 
disease progression or relapse is clearly documented 
10.3 
 
Duration of Response 
Duration of response will be defined as the period of time, on study and 
including follow-up, from the first day of attainment of a response to treatment 
(CR or PR) to the time when a disease progression or relapse is clearly 
documented 
 


 
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Lenalidomide (Revlimid®)                                                                                  Protocol :  
 
 
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Appendix D - NCI CTC Version 3.0 
 
TOXICITY WILL BE SCORED USING NCI  CTC VERSION 3.0 FOR TOXICITY 
AND ADVERSE EVENT REPORTING.  A COPY OF THE NCI CTC VERSION 
3.0 CAN BE DOWNLOADED FROM THE CTEP HOMEPAGE: 
(HTTP://CTEP.INFO.NIH.GOV).  ALL APPROPRIATE TREATMENT AREAS 
HAVE ACCESS TO A COPY OF THE CTC VERSION