Clinical trial NCT01731886
Conditions: Multiple Myeloma
Keywords: Stem cell transplant plasma cell myeloma multiple myeloma
Sponsor: Columbia University
Start date: 2012-09-01; Completion date: 2017-04-11
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study is being done to compare the combination of lenalidomide and dexamethasone followed by autologous peripheral blood stem cell transplant (PBSCT) and lenalidomide and dexamethasone without PBSCT in patients with untreated multiple myeloma. This comparison will include how the subjects respond to each study treatment combination, and what side effects are caused by each combination.

Detailed description:
Multiple myeloma is a malignant plasma cell proliferative disorder responsible for 11, 000 deaths each year in the United States. Approximately one third of myeloma patients develop hypercalcemia and about two thirds present with anemia. As the second most common hematologic malignancy, myeloma remains incurable. In the last forty years, options for therapy have included melphalan-prednisone, anthracyclines, and vinca alkaloids; however, relapse with those regimens continues to be inevitable with a median survival of 3 years.

Arms: arm 1: Subjects will receive the current standard of care treatment. Lenalidomide and dexamethasone for four 28-day cycles followed by steam cell collection and autologous peripheral blood stem cell transplant. After 90 days, start the maintenance phase (lenalidomide days 1-21 every 28 days for two years or until your disease progresses). arm 2: Subjects will receive the new treatment that will be compared with the standard of care. Lenalidomide and dexamethasone for eight 28-day cycles. After four cycles your stem cells will be collected (stem cell collection). After an additional four cycles of lenalidomide (a total of 8 cycles), start the maintenance phase (lenalidomide days 1-21 every 28 days for two years or until your disease progresses).
Interventions: intervention 1: Autologous peripheral blood stem cell transplant intervention 2: Lenalidomide intervention 3: Dexamethasone intervention 4: Stem cell collection intervention 5: Melphalan intervention 6: G-CSF intervention 7: Cyclophosphamide intervention 8: Mesna
Intervention descriptions: intervention 1: Subjects deemed suitable by the principal investigator will undergo autologous peripheral blood stem cell transplantation on day 0. intervention 2: Administered orally at a dose 25 mg daily on days 1-21 of each 28-day cycle. intervention 3: Administered orally at a dose of 40 mg daily on days 1, 8, 15, 22 of each cycle. intervention 4: Peripheral stem cell collection will be performed at marrow recovery, usually when white blood cell (WBC) is \>2500 x 109 cells/liter; platelet count is \>20 x 103/mm3. intervention 5: Subjects undergoing autologous peripheral blood stem cell transplant will receive melphalan 200 mg/m2 intravenously on days -2 and -1 or only on day -2. intervention 6: Subjects will receive G-CSF subcutaneously daily beginning on day 5 and until blood counts recover. intervention 7: Subjects may receive up to the maximum recommended high-dose of cyclophosphamide at 4 gm/m2 intravenously. intervention 8: Mesna will be provided with the cyclophosphamide.

Protocol documents:
Prot_SAP_000.pdf: 
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Investigator Protocol 19 June 2015  
 
IRB PROTOCOL NUMBER 
CUMC AAAJ2355 
 
TITLE 
A Randomized Clinical Trial of Lenalidomide (CC-5013) 
and Dexamethasone With and Without Autologous 
Peripheral Blood Stem Cell Transplant in Patients With 
Newly Diagnosed Multiple Myeloma 
 
ORIGINAL DATE  
 
25 January 2013 
 
CURRENT AMENDMENT 
16 December 2013 
 
VERSION DATE 
 
 
19 June 2015 
 
PRINCIPAL INVESTIGATOR 
Suzanne Lentzsch, M.D. 
 
 
SITE  
 
 
 
Columbia University Medical Center 
 
 
 
 
 
Herbert Irving Comprehensive Cancer Center 
 
 
 
 
 
Herbert Irving Pavilion 
 
 
 
 
 
161 Fort Washington Avenue 
 
 
 
 
 
New York, NY 10032 
 
ClinicalTrials.gov Registration 
NCT01731886 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Investigator Protocol 19 June 2015  
 
 
 
 
PROTOCOL SIGNATURE PAGE 
 
IRB PROTOCOL NUMBER 
CUMC AAAJ2355 
 
TITLE 
A Randomized Clinical Trial of Lenalidomide (CC-5013) 
and Dexamethasone With and Without Autologous 
Peripheral Blood Stem Cell Transplant in Patients With 
Newly Diagnosed Multiple Myeloma 
 
I have read this protocol and agree that it contains all necessary details for carrying out this 
study.  I will conduct the study as outlined herein and will complete the study within the time 
designated, in accordance with all stipulations of the protocol and in accordance with Good 
Clinical Practices, local regulatory requirements, and the Declaration of Helsinki.  
 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study.  I will discuss this material with them to ensure that 
they are fully informed regarding the study agent(s) and the conduct of the study.  
 
 
 
 
 
 
 
 
Printed Name of Investigator  
Signature of Investigator 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Investigator Protocol 19 June 2015  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect 
stem 
cells 
 
Lenalidomide 
25 (oral) daily on days 1-21 
x 4 cycles 
Each cycle consists of 28 
days 
Dexamethasone 
40 mg/ day (oral) 
Days 1,8,15,22 
Aspirin  
At least 81 mg/day (oral) on 
days 1-28 of each cycle 
during treatment with 
Lenalidomide and 
dexamethasone unless the 
patient is treated with 
alternate prophylaxis with 
either low molecular weight 
heparin or coumadin as 
recommended in section 
5.2.1 
 
Lenalidomide 
25 (oral) daily on days 1-21 x 
4 cycles 
Each cycle consists of 28 
days 
Dexamethasone 
40 mg/ day (oral) 
Days 1,8,15,22 for up to 8 
cycles 
Aspirin  
At least 81 mg/day (oral) on 
days 1-28 of each cycle 
during treatment with 
Lenalidomide and 
dexamethasone unless the 
patient is treated with 
alternate prophylaxis with 
either low molecular weight 
heparin or coumadin as 
recommended in section 
5.2.1 
 
 
R
A
N
D
O
M 
I 
Z 
E 
 
Collect 
stem 
cells 
Autologous 
Peripheral 
Blood Stem 
Cell 
Transplant 
 
E
V 
A 
L
U
A 
T
E 
Maintenance 
lenalidomide 
alone 
15 mg d1-21 
every 4 weeks 
until PD 
Start day 90-
110 after 
transplant 
Maintenance 
lenalidomide 
alone 
15 mg d1-21 
every 4 weeks 
until PD 
Start 
immediately 
after 8 cycles 
4 
cycles 
ARM A: Standard Arm 
ARM B: Treatment Arm 
4 
cycles 
4 
cycles 
 
E
V 
A 
L
U
A 
T
E 


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Investigator Protocol 19 June 2015  
 
 
 
TABLE OF CONTENTS 
 
1 
BACKGROUND AND RATIONALE 
6 
1.1 
Disease Under Study 
6 
1.2 
Role of Autotransplant with Non-Thalidomide Chemotherapy 
6 
1.3 
Role of Maintenance 
6 
1.4 
Lenalidomide 
7 
1.5 
Low Dose Dexamethasone 
8 
1.6 
Melphalan 
8 
1.7 
Vein Thrombosis and Anticoagulation 
9 
1.8 
Study Rationale 
9 
2 
OBJECTIVES 
10 
2.1 
Primary Objective 
10 
2.2 
Secondary Objectives 
10 
3 
SUBJECT SELECTION 
11 
3.1 
Inclusion Criteria 
11 
3.2 
Exclusion Criteria 
13 
3.3 
Inclusion of Women 
14 
4 
SUBJECT REGISTRATION 
14 
4.1 
Registration Guidelines 
14 
4.2 
Assignment of Study Numbers 
14 
4.3 
Revlimid REMS Designed for Clinical Studies Program 
15 
5 
TREATMENT PLAN 
15 
5.1 
Study Agents 
17 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
18 
5.3 
Dosing Delays and Dose Modifications 
21 
5.4 
Duration of Treatment 
25 
5.5 
Duration of Follow Up 
25 
6 
STUDY CALENDAR 
26 
7 
MEASUREMENT OF EFFECT 
28 
7.1 
Definitions 
28 
7.2 
Guidelines for Evaluation of Measurable Disease 
29 
7.3 
Response Criteria 
30 
7.4 
Confirmatory Measurement and Duration of Response 
31 
7.5 
Response Review 
32 
8 
CORRELATIVE STUDIES 
32 
9 
REGULATORY OBLIGATIONS 
32 
9.1 
Adverse Event Reporting 
32 
9.2 
Data and Safety Monitoring Plan 
36 
9.3 
Record Retention 
37 
9.4 
Protocol Amendment and Deviation 
37 
9.5 
Study Monitoring and Auditing 
37 


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9.6 
Informed Consent 
37 
9.7 
Subject Confidentiality 
38 
10 
STATISTICAL CONSIDERATIONS 
38 
10.1 
Study Objectives and Endpoints 
38 
10.2 
Statistical Analysis 
39 
10.3 
Interim Analysis 
40 
11 
PREMATURE DISCONTINUATION OF STUDY 
40 
12 
REFERENCES 
41 
 
Appendix A Subject Medication Diary 
44 
 
Appendix B Performance Status Criteria 
45 
 
Appendix C Impaired Renal Function Dosing Schedule 
46 
 
Appendix D Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods 
47 
 
Appendix E Staging of Myeloma: Durie-Salmon System and International 
Staging System 
50 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1 
BACKGROUND AND RATIONALE 
 
1.1 
Disease Under Study 
Multiple myeloma is a malignant plasma cell proliferative disorder responsible for 11, 000 
deaths each year in the United States.1  Approximately one third of myeloma patients 
develop hypercalcemia and about two thirds present with anemia.  As the second most 
common hematologic malignancy, myeloma remains incurable.  In the last forty years, 
options for therapy have included melphalan-prednisone, anthracyclines, and vinca 
alkaloids; however, relapse with those regimens continues to be inevitable with a median 
survival of 3 years. 
 
1.2 
Role of Autotransplant with Non-Thalidomide Chemotherapy 
In 1996, Attal et al. through the Intergroupe Francais du Myelome confirmed in a 
randomized trial that high dose chemotherapy combined with autologous bone marrow 
transplantation as opposed to conventional-dose chemotherapy improved the response rate, 
event-free survival, and overall survival in previously untreated myeloma patients less than 
65 years old.2   Complete response was seen in 22% of those receiving high dose therapy 
who, in addition, underwent autologous bone marrow transplantation.  Median overall 
survival exceeded 5 years after high dose chemotherapy with autologous peripheral blood 
stem cell transplantation (PBSCT). However, there was no significant difference in overall 
survival (OS) whether autologous PBSCT was performed as first-line therapy or as rescue 
treatment after receiving monthly courses of vincristine, melphalan, cyclophosphamide, and 
prednisone.3  These data suggest that transplant given for the first relapse or as primary 
therapy results in the same OS.  The Medical Research Council Myeloma VII Trial found an 
increase in median survival of one year and in progression-free survival among subjects 
randomized to receive high dose therapy followed by autologous PBSCT as compared to 
those receiving conventional chemotherapy.4  However, Blade et al via PETHEMA showed 
that subjects randomized to HDT followed by autologous PBSCT as opposed to 
conventional chemotherapy had no impact on progression free survival and overall survival 
but was associated with a significantly increased complete response of 30%.5  Taken 
together as a result of several randomized trials, autologous stem cell transplant currently is 
recommended for newly diagnosed multiple myeloma patients.   
 
1.3 
Role of Maintenance 
Over the last years, many studies provided evidence that continuation of Lenalidomide 
treatment beyond 8 cycles increases response rates and prolongs PFS.  During the 2009 ASH 
Annual Meeting Palumbo et al reported significant increase of the PFS for subjects receiving 
Lenalidomide maintenance after melphalan, prednisone and lenalidomide (MPR-R) in 
comparison to subjects without maintenance (MPR).6 In addition at the November 2009 
CALGB group meeting, the CALGB Data and Safety Monitoring Board reviewed follow-up 
interim analysis of the CALGB 100104, “A Phase II Double Blind Study of Maintenance 
Therapy with CC-4047 (NSC #703813) or Placebo Following Autologous Stem Cell 
Transplantation for Multiple Myeloma.”  The results of the analysis indicated a statistically 


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significant improvement in the time to progression for subjects receiving lenalidomide 
compared to the placebo group.  Based on these findings the study was un-blinded to 
subjects and their physicians. The CALGB recommended that subjects receiving 
lenalidomide maintenance therapy should continue until disease progression.  Subjects who 
were receiving placebo maintenance were to stop placebo treatment and switch to 
lenalidomide maintenance therapy.  It was further recommended to discuss the initiation of 
maintenance therapy beyond day 110 post transplant with the subject in cases where the 
subject was still in remission.   
 
Based on these data, we think that an amendment of our current protocol which does not 
include maintenance is necessary in order to continue testing our hypothesis and at the same 
time providing the best available care. 
 
1.4 
Lenalidomide 
CC-5013 (lenalidomide) is an immunomodulatory derivative of thalidomide that is 
potentially safer, with significantly more potent immunomodulatory effects, and has shown 
synergy in preclinical studies with dexamethasone.7  In pre-clinical models, Lenalidomide is 
50 to 2,000 times more potent compared to thalidomide in T-cell proliferation and 50 to 100 
times more potent than thalidomide in increasing IL-2 and IFN-gamma production.7   
Lenalidomide showed high anti-myeloma activity in human xenograft mice models.8  Based 
on these laboratory results, two phase I clinical trials with Lenalidomide were initiated in 
2001.These studies showed that the maximum tolerated dose of Lenalidomide was 25mg 
daily. In a University of Arkansas study, 8 of 15 subjects with relapsed refractory myeloma 
(53%) responded to therapy.9  In the Dana-Farber study, 17 of 24 subjects (71%) responded 
to therapy.  Specifically, 7 of 24 subjects (29%) had at least a 50% reduction in paraprotein.7  
These results were impressive because subjects selected had failed to respond to at least two 
prior regimens of treatment.  Specifically, 11 of the 24 subjects (46%) had failed prior 
thalidomide.  Another trial compared two doses of Lenalidomide: 30mg once a day versus 
15mg twice daily. Lenalidomide was administered for 3 weeks (days 1-21) followed by one-
week rest. Of 101 subjects treated, at least a 25% reduction in paraprotein levels was 
observed in 39% of subjects, including complete responses in 5 subjects with advanced, 
refractory disease.10  The mechanism of action of Lenalidomide is unclear, but preclinical 
studies show that it decreases binding of myeloma cells to stroma, and inhibits IL-6, VEGF, 
and TNF-alpha production. 7,11,12,13,14  It also appears to block angiogenesis, and stimulate 
natural killer cell mediated immune responses to myeloma cells.14 In murine myeloma 
models, Lenalidomide inhibited tumor growth and angiogenesis, prolonging host survival. 
 
Lenalidomide is administered orally. It is dispensed as 5, 10 or 25 mg hard gelatin capsules.  
The dosing used in ongoing trials is 25 mg given orally daily on days 1-21 and repeated 
every 28 days (days 22-28 are rest days). Doses are modified based on toxicity. Unlike 
thalidomide, Lenalidomide causes no significant sedation, constipation or neuropathy. In 
animal models it has shown no teratogenicity. The main side effects are Grade 3 to 4 
thrombocytopenia (20%) and neutropenia (30%).10 The activity appears to be further 
enhanced with the addition of dexamethasone.  Dimopolous and colleagues presented 
preliminary data regarding 351 subjects with relapsed and refractory subjects treated with 
Lenalidomide and dexamethasone compared with dexamethasone as a single agent and 


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showed a complete response rate of 15.0% for the combination versus 3.4% for 
dexamethasone alone. Similarly, Weber et al showed a complete response rate of 12.9% in 
relapsed and refractory subjects receiving lenalidomide and dexamethasone as opposed to 
0.6% complete response rate in those receiving dexamethasone alone.  In the Dimopoulos 
study, the incidence of DVT was comparable to that of thalidomide.15,16  In a phase 2 trial of 
34 newly diagnosed myeloma subjects, Rajkumar and colleagues further demonstrated that 
lenalidomide plus dexamethasone achieved an overall objective response in 31 of 34 
subjects (91%) with 2 subjects (6%) achieving complete response.1   
 
During 2010 ASH Annual meeting, Palumbo et al reported an increase in secondary 
malignancies with lenalidomide maintenance therapy, when used in combination with 
melphalan. Currently the data are under further evaluation. 16 
1.5 
Low Dose Dexamethasone 
Dexamethasone in combination with thalidomide is known to produce several toxicities.  
When comparing thalidomide plus dexamethasone with dexamethasone alone, Rajkumar and 
colleagues demonstrated greater toxicity with the combination.17   Dexamethasone in both 
arms was given at a dose of 40 mg orally on days 1 to 4, 9 to 12, and 17 to 20.  Cycles were 
repeated every 4 weeks.  The incidence rates of grade 3 or higher deep vein thrombosis, rash, 
bradycardia, peripheral neuropathy, and any grade 4 to 5 toxicities in the first four months 
were significant increased with thalidomide plus dexamethasone (45%) as opposed to 
dexamethasone alone (21%).  The incidence of DVT was higher in the combination arm 
(17%) than in the single arm (3%).   Grade 3 neutropenia was seen in 9% of subjects 
receiving combination and 6% of subjects receiving dexamethasone alone.  
 
In an ongoing phase III randomized trial (ECOG4A03,) Rajkumar and colleagues are 
comparing low-dose dexamethasone (40 mg orally on days 1, 8, 15, and 22) and 
lenalidomide with high-dose dexamethasone (40 mg orally 4 days on, and 4 days off) and 
lenalidomide.  Preliminary results as presented at ASCO 200718 demonstrated a statistically 
significant increased one-year survival probability with low-dose dexamethasone and 
lenalidomide (0.96; 95%CI 0.82,0.92) as compared to with high-dose dexamethasone and 
lenalidomide (0.87; 95%CI 0.94,0.99).  In addition, the high-dose 
dexamethasone/lenalidomide combination was associated with a statistically significant 
increased incidence of neutropenia, DVT/PE, infections and pneumonia compared those 
seen with the low-dose dexamethasone/lenalidomide regimen.  
 
1.6 
Melphalan 
Melphalan 200 mg/m2 intravenously will be used as the conditioning regimen prior to 
autologous peripheral blood stem cell transplant.  In a prospective and randomized trial, the 
Intergroupe Francophone du Myelome compared 200 mg/m2 melphalan (HDM200) and 8 
Gy total body irradiation plus 140 mg/m2 melphalan (HDM140 + TBI) as a conditioning 
regimen in newly diagnosed myeloma subjects who had received 4 cycles of VAD.19  
HDM200 was significantly associated with lower rates of grade 3-4 mucositis, duration of 
neutropenia and thrombocytopenia, number of red blood cell and platelet transfusions, 
numbers of days on antibiotics, and duration of hospitalization.  Event-free survival and 
survival after relapse rates were equivalent in both groups.  Overall survival was increased at 


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Investigator Protocol 19 June 2015  
 
45 months in those receiving HDM200 although this was of borderline significance 
(p=0.05).  Thus, HDM200 is a less toxic but as effective conditioning regimen compared to 
HDM140 + TBI. 
 
1.7 
Vein Thrombosis and Anticoagulation 
Lenalidomide has now been used in a number of phase I, II, and III trials.  One of the most 
common side effects associated with lenalidomide is venous thromboembolism. Rajkumar 
and colleagues reported a 3% incidence in deep vein thrombosis/pulmonary embolism in 
subjects receiving lenalidomide/dexamethasone for newly diagnosed myeloma.1   Ongoing 
analyses have implicated that erythropoietin as well as high dose dexamethasone might 
contribute to the development of TEE.  Knight and colleagues in a multivariate analysis of 
two placebo-controlled studies demonstrated that there was an independent correlation 
between the presence of thrombosis and treatment with higher dose dexamethasone and 
thrombosis erythropoietin.20  Rajkumar et al also reported thromboembolic events from their 
ongoing randomized ECOG trial comparing lenalidomide plus high-dose dexamethasone 
and lenalidomide plus low-dose dexamethasone.21,22  Venous thromboembolic events were 
reported in 18% of subjects receiving lenalidomide/high-dose dexamethasone and 3.7% of 
subjects receiving lenalidomide/low-dose dexamethasone.  The trial has since changed to 
include ASA 81-325 mg daily as prophylaxis unless the subject is already being treated with 
low molecular weight heparin or warfarin.  Second, LMWH or warfarin is recommended for 
subjects randomized to the high-dose dexamethasone arm.  Third, use of concomitant 
erythropoietin use is being limited in that study regardless of arm.  For this reason, we 
recommend using ASA 325 mg daily as routine thromboprophylaxis.  Subjects with risk 
factors such as strong family history or prior history of a thromboembolic event should 
receive prophylaxis with warfarin or low molecular weight heparin. (Please see Section 5.2.) 
 
1.8 
Study Rationale 
Due to the fact that lenalidomide alone can achieve similar response rates as transplant, more 
and more subjects treated with lenalidomide refuse transplant after achieving CR.   Currently 
it is unclear whether transplant will result in a longer duration of remission, even if 
transplant and lenalidomide alone achieve similar initial RR.  Therefore, it is most important 
to define the role of transplant in newly diagnosed patients.   
 
By analyzing complete response and furthermore survival achieved by lenalidomide, this 
randomized clinical trial is designed to determine if there is ultimately a need for autologous 
peripheral blood stem cell transplant in subjects receiving lenalidomide and low-dose 
dexamethasone with newly diagnosed myeloma.  Using a lower dose of dexamethasone and 
using lenalidomide instead of thalidomide are two ways in which this trial builds on the 
potency and minimizes the toxicity of the currently used thalidomide/dexamethasone 
induction regimen.   
 
As a primary goal, the trial will compare complete response rates and duration of complete 
response of subjects receiving at least 8 cycles of therapy with lenalidomide plus low-dose 
dexamethasone and followed by lenalidomide maintenance until disease progression (ARM 
B) versus subjects receiving 4 cycles of therapy with lenalidomide plus low-dose 


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dexamethasone followed by autologous peripheral blood stem cell transplant conditioned 
with 200 mg/m2 melphalan and followed by lenaliidomide maintenance until disease 
progression (ARM A). Cyclosphosphamide followed by granulocyte colony stimulating 
factor (G-CSF) with or without AMD3100 will be used to mobilize peripheral blood stem 
cells in both arms. This will optimize further reduction of malignant cells in the autograft 
with a concomitant anti-myeloma effect.  By comparing the two CRRs and the durations of 
complete response, the study will determine whether the CR achieved by a non-transplant 
regimen such as lenalidomide and dexamethasone is equal to the CR achieved by autologous 
transplant.  In ARM A, subjects will undergo autologous peripheral blood stem cell 
transplant if CR or PR is achieved after completing the 4 cycles of 
lenalidomide/dexamethasone therapy.  Regarding ARM B, subjects will undergo stem cell 
collection as described above.  Stem cell collection after cyclophosphamide mobilization 
will make both arms more comparable for effect of transplant or response.   
 
As a second goal, the trial will determine if there is a benefit in progression-free survival in 
those subjects receiving autologous peripheral blood stem cell transplant after undergoing 4 
cycles of lenalidomide/dexamethasone versus in those receiving 8 cycles of lenalidomide 
and dexamethasone without transplant followed by maintenance.  Also, the trial will 
compare overall survival in subjects receiving autologous peripheral blood stem cell 
transplant after undergoing induction therapy with lenalidomide and dexamethasone versus 
in those receiving only lenalidomide and dexamethasone.  The estimation of sample size for 
this trial is based on the 6% complete response rate with lenalidomide and dexamethasone in 
subjects with newly diagnosed myeloma1 and the 30% complete response rate with 
autologous stem cell transplantation in subjects with multiple myeloma.5.  
 
2 
OBJECTIVES 
 
2.1 
Primary Objective 
▪ To determine and compare the complete response rates of 8 cycles lenalidomide and low-
dose dexamethasone versus  that 4 cycles lenalidomide and low-dose dexamethasone 
followed by autologous peripheral blood stem cell transplant in subjects with newly 
diagnosed multiple myeloma.  
 
2.2 
Secondary Objectives 
▪ To compare the duration of complete response induced by lenalidomide and 
dexamethasone versus that of lenalidomide and dexamethasone followed by autologous 
peripheral blood stem cell transplant, followed by lenalidomide maintenance in both arms.  
▪ To compare the overall response rate induced by lenalidomide and dexamethasone versus 
that induced by lenalidomide and dexamethasone followed by autologous peripheral blood 
stem cell transplant, followed by lenalidomide maintenance in both arms. 
▪ To determine if there is a benefit in progression-free survival in subjects receiving 
autologous peripheral blood stem cell transplant after undergoing 4 cycles of lenalidomide 
and dexamethasone vs in those receiving 8 cycles of lenalidomide and dexamethasone, 
followed by lenalidomide maintenance in both arms. 
▪ To compare overall survival and time to progression in subjects receiving autologous 


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peripheral blood stem cell transplant after undergoing induction therapy with lenalidomide 
and dexamethasone versus in those receiving only lenalidomide and dexamethasone, 
followed by lenalidomide maintenance in both arms. 
▪ To analyze the time to transplant in both arms   
▪ To compare the toxicity of lenalidomide and dexamethasone followed by autologous 
peripheral blood stem cell transplant versus lenalidomide and dexamethasone alone, 
followed by lenalidomide maintenance in both arms. 
 
3 
SUBJECT SELECTION 
 
3.1 
Inclusion Criteria 
▪ Subjects must have histologically or cytologically confirmed Multiple Myeloma, Salmon-
Durie Stage II or III or International Staging System II or III that has not been previously 
treated.  (See Appendix E) 
▪ Bone marrow plasmacytosis with > or = 10% plasma cells, or sheets of plasma cells or a 
biopsy-proven plasmacytoma which must be obtained up to 6 weeks prior to registration.   
▪ Measurable levels of monoclonal protein (M protein): 1 g/dL IgG or .5 g/dL IgA on serum 
protein electrophoresis or > 200 mg of monoclonal light chain on a 24 hour urine protein 
electrophoresis which must be obtained within 4 weeks prior to registration.  If both serum 
and urine monoclonal components are present, both must be followed in order to evaluate 
response.     
Serum free light chains (FLC) should be measured with each SPEP and is recommended to 
monitor for subjects with light chain disease.  Non-secretory MM subjects will be included if 
they have measurable parameters to follow, e.g. extramedullary plasmocytoma or 
measurable bone marrow infiltration, or FLC level ≥ 10 mg/dL (≥ 100 mg/L) provided 
serum FLC ratio is abnormal.29 
Both SPEP and UPEP must be performed within 28 days prior to registration.    
For subjects presenting with aggressive disease or requiring immediate intervention, up to 
two weeks or two pulses of high dose dexamethasone (40 mg x 4 days = 1 pulse) is allowed, 
prior to the start of study treatment.  If dexamethasone is given at reduced dose, the total 
allowed dose is 320 mg prior to enrollment.  Prior systemic glucocorticosteroid use for the 
treatment of non-malignant disorders is permitted; concurrent use after subject is on study 
treatment of non-malignant disorders is permitted; concurrent use for non-malignant 
disorders after a subject is on study treatment is permitted, but should be restricted to the 
equivalent of prednisone 10mg per day. Prior or concurrent topical or localized 
glucocorticosteroid therapy to treat non-malignant comorbid disorders is permitted.    
Subjects should not have received any radiation for the preceding 4 weeks before entry onto 
the study.  Exception: local radiation therapy for symptomatic bone lesions (eg, uncontrolled 
pain or high risk of pathologic fracture), superior or inferior vena cava syndrome, spinal cord 
compression or extramedullary soft tissue lesions, as clinically indicated to relieve severe 
symptoms.  Subjects with prior solitary plasmacytoma treated with radiation therapy with 
curative intent are eligible if the disease has now progressed to active multiple myeloma 
meeting all the eligibility criteria for this protocol. 
▪ Age >18 years. 
▪ Life expectancy of greater than 12 months. 


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▪ ECOG performance status <2 (Karnofsky >60%) (See Appendix B).  
▪ Subjects must have adequate organ and marrow function as defined below, obtained within 
4 weeks prior to registration: 
Hgb 
≥ 9 g/dL (which may be supported by transfusion or growth factors)  
Absolute Neutrophil 
Count 
>1,500/ ml (use of growth factors to meet screening requirements is 
not permitted) 
Platelets 
>50,000/mm3 (administration of platelet transfusions during 
screening to meet eligibility criteria is not allowed.  However, 
platelet transfusions may be administered as clinically indicated to 
subjects in both treatment arms who have begun lenalidomide 
therapy) 
Total Bilirubin 
<1.5 mg/dL 
AST(SGOT) / 
ALT(SGPT)  
<2.5 X institutional upper limit of normal 
Creatinine 
 
<2.0 mg/dL (subjects with creatinine > 2 should receive 
lenalidomide according to the dosing schedule (Appendix C). 
Creatinine 
Clearance 
 
>50 ml/min (estimated).   
Subjects with creatinine clearance < 50 ml/min should receive 
lenalidomide according to the dosing schedule (Appendix C). 
 
▪ All study participants must be registered into the mandatory Revlimid REMS® program, 
and be willing and able to comply with the requirements of the REMS® program. 
▪Females of reproductive potential must adhere to the scheduled pregnancy testing as 
required in the Revlimid REMS® program. 
Ability to understand and the willingness to sign a written informed consent document.  
Subject must be informed of the investigational nature of this study. 
▪ Subjects with a history of prior malignancy are eligible provided there is no active 
malignancy and a low expectation of recurrence within 6 months.  
▪ Subjects must be willing and able to take prophylaxis with either aspirin at 81 mg/day or 
alternative prophylaxis with either low molecular weight heparin or warfarin as 
recommended. 
▪ Subjects who are eligible for transplant with an age up to and including 75 years.   
▪ Subjects in ARM A who are refusing transplant can go onto ARM B and will be evaluated 
separately.   
▪ All study participants must be registered into the mandatory Revlimid REMS® program, 
and be willing and able to comply with the requirements of Revlimid REMS®. 
▪ Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy 
test with a sensitivity of at least 50 mIU/mL within 10 – 14 days prior to and again within 24 
hours of prescribing lenalidomide (prescriptions must be filled within 7 days) and must 
either commit to continued abstinence from heterosexual intercourse or begin TWO 
acceptable methods of birth control, one highly effective method and one additional effective 
method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide.  
FCBP must also agree to ongoing pregnancy testing.  Males must agree to use a latex 
condom during sexual contact with a FCBP even if they have had a successful vasectomy.  
(See Appendix D: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable 


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Birth Control Methods) 
 
 
3.2 
Exclusion Criteria 
▪ Subjects who have had chemotherapy or radiotherapy for multiple myeloma prior to 
entering the study.  Subjects should not have received any radiation for the preceding 4 
weeks before entry onto the study.  Exception: local radiation therapy for symptomatic bone 
lesions (e.g., uncontrolled pain or high risk of pathologic fracture), superior or inferior vena 
cava syndrome, spinal cord compression or extramedullary soft tissue lesions, as clinically 
indicated to relieve severe symptoms.  Subjects with prior solitary plasmacytoma treated 
with radiation therapy with curative intent are eligible if the disease has now progressed to 
active multiple myeloma meeting all the eligibility criteria for this protocol. 
▪ Subjects receiving any other investigational agents or therapy within 28 days of baseline. 
▪ Subjects with known brain metastases will be excluded from this clinical trial because of 
their poor prognosis and because they often develop progressive neurologic dysfunction that 
would confound the evaluation of neurologic and other adverse events. 
▪ Subjects who are pregnant or breast feeding.  Due to the potential teratogenic properties of 
lenalidomide, the use of this drug in subjects that are pregnant is absolutely contraindicated.  
Further, all women of childbearing potential and sexually active males must agree to avoid 
conception while participating in this study.  Specifically, women of childbearing potential 
must either agree to refrain from sexual intercourse or employ a dual method of 
contraception, one of which is highly effective (IUD, birth control pills, tubal ligation or 
partners vasectomy), and another additional method (condom, diaphragm, or cervical cap) 
for 4 weeks prior to receiving lenalidomide, and for four weeks after discontinuing this 
therapy.  Sexually active males cannot participate unless they agree to use a condom (even if 
they have undergone a prior vasectomy) while having intercourse with a woman of child 
bearing potential while taking lenalidomide and for four weeks after stopping treatment.  
Women of child bearing potential (those who have not had a hysterectomy or the absence of 
menstrual periods for at least 24 consecutive months) must have a negative pregnancy test 
10-14 days prior to the initiation of therapy and a repeat negative pregnancy test 24 hours 
prior to the initiation of lenalidomide. 
▪ Inability to comply with study and/or follow-up procedures. 
▪ Subjects with a history of previous deep vein thrombosis or pulmonary embolism must be 
on anticoagulation therapy with low molecular weight heparin or warfarin at therapeutic 
dosages (e.g. INR 2-3).   
▪ If a subject is on full-dose anticoagulants, the following criteria should be met for 
enrollment: 
Must not have active bleeding or pathological conditions that carry high risk of bleeding 
(e.g. tumor involving major vessels, known varices). 
Must not have thrombocytopenia requiring transfusion. 
Must have a platelet count >50,000. 
Must have stable INR between 2-3. 
▪ Subjects with smoldering myeloma or monoclonal gammopathy of undetermined 
significance are not eligible. 
▪ Subjects must not have active, uncontrolled infection. 


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▪ Subjects must not have active, uncontrolled seizure disorder. Subjects must have had no 
seizures in the last 6 months. 
▪ Concurrent use of other anti-cancer agents or treatments. 
▪ Known positive for HIV or infectious hepatitis, type B or C. 
▪ Known hypersensitivity to thalidomide. 
▪ 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. 
 
3.3 
Inclusion of Women 
Both men and women and members of all races and ethnic groups are eligible for this study. 
 
Breastfeeding women are excluded as this regimen may be harmful to a developing fetus or 
nursing child.  Pregnant women are excluded from this study because lenalidomide is related 
to an agent, thalidomide, with teratogenic or abortifacient effects.  Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to treatment of 
the mother with lenalidomide or, breastfeeding should be discontinued if the mother is 
treated with lenalidomide.  These potential risks may also apply to other agents used in this 
study. Women of child bearing potential (those who have not had a hysterectomy or the 
absence of menstrual periods for at least 24 consecutive months) must have a negative 
pregnancy test 10-14 days prior to the initiation of therapy and a repeat negative pregnancy 
test 24 hours prior to the initiation of lenalidomide.  During therapy with lenalidomide, 
pregnancy tests will be obtained weekly for the first four weeks, and then every 4 weeks if 
the subject has regular menstruation, or every 2 weeks if their periods are irregular.   
 
4 
SUBJECT REGISTRATION 
 
4.1 
Registration Guidelines 
Eligible subjects will be block randomized to ARM A or ARM B by the CUMC Research 
Pharmacy.  Treatment cannot begin prior to registration.  However, if good medical practice 
dictates the subject needs to receive some form of therapy prior to registration, up to two 
weeks or two pulses of dexamethasone (without Melphalan or bortezomib) may be given. 
 
4.2 
Assignment of Study Numbers 
Each subject enrolled in the study will be registered in Velos eResearch at the Herbert Irving 
Comprehensive Cancer Center (HICCC) at study entry.  Velos eResearch is a web based 
comprehensive clinical research information system to manage clinical trials. eResearch 
employs standardized data elements that define protocols, subject characteristics, visits and 
procedures.  Velos eResearch is available for use by researchers at outside institutions, if 
those institutions are enrolling subjects on a trial for which Columbia University Medical 
Center (CUMC) is the coordinating site.  If the outside institutions are unable to access 
Velos eResearch remotely, the outside institutions should submit their information, source 
documents and Case Report Forms to the CUMC researchers via telephone and shipment.  
The CUMC researchers will enter the subject information on behalf of the outside 
institutions.   Each subject enrolled will be assigned a sequential study identifier by Velos 


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Investigator Protocol 19 June 2015  
 
eResearch. 
 
 
4.3 
RevLimid REMS® Designed for Clinical Studies Program 
Lenalidomide (Revlimid®) is approved for marketing under a special restricted Distribution 
program called Revlimid REMS®.  Subjects enrolled in this study will also be enrolled in 
the Revlimid REMS® Designed for Clinical Studies Program. 
 
5 
TREATMENT PLAN 
 
Treatment will be administered on an outsubject basis.  Each treatment cycle will be 28 days.  
No investigational or commercial agents or therapies other than those described below may 
be administered with the intent to treat the subject's malignancy.  
 
Subjects are randomized to ARM A or ARM B as follows: 
 
ARM A 
 
Lenalidomide Administered orally at a dose 25 mg daily on days 1-21 of each cycle. 
Dexamethasone Administered orally at a dose of 40 mg daily on days 1, 8, 15, 22 of each 
cycle. 
Stem Cell Mobilization Subjects may receive up to the maximum recommended high-dose 
of cyclophosphamide at 4 gm/m2 intravenously with mesna at a total of 2.4 gm/m2 
intravenously or orally divided over 3 doses.  Subjects then will receive mobilization using 
daily filgrastim (G-CSF) at 10 mcg/kg subcutaneously starting 24 hours after 
cyclophosphamide is completed and until stem cell collection.  The use of AMD3100 
(Plerixafor) is permitted.  Peripheral stem cell collection will be performed at marrow 
recovery, usually when WBC is >2500 x 109 cells/liter; platelet count is >20 x 103/mm3.   
Autologous peripheral blood stem cell transplant Subjects deemed suitable by the principal 
investigator will receive melphalan 200 mg/m2 intravenously on days -2 and -1 or only on 
day -2, and will undergo autologous peripheral blood stem cell transplantation on day 0.  
Subjects will receive G-CSF subcutaneously daily beginning on day 5 and until blood counts 
recover. 
 
Maintenance will be started on day 90-110 after transplant.  Subjects will receive 
lenalidomide 15 mg/day on day 1-21 every 28 days until disease progression.  Dose can be 
reduced to 10 mg per treating physician discretion in case subject doses not tolerate 15 
mg/day. If subject does not tolerate 10 mg/day lenalidomide, discontinue maintenance. 
Maintenance with 5 mg/day is not recommended except due to impaired renal function. 
Subjects may receive up to total 2 years maintenance therapy. 
  
ARM B 
Lenalidomide Administered orally at a dose 25 mg daily on days 1-21 of each cycle for 8 
cycles.  After cycle four, subjects will have peripheral stem cell collection.  The final four 
cycles of lenalidomide and dexamethasone will be started within 4 weeks after stem cell 
collection. 


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Dexamethasone Administered orally at a dose of 40 mg daily on days 1, 8, 15, 22 of each 
cycle. 
Stem Cell Mobilization Subjects may receive up to the maximum recommended high-dose 
of cyclophosphamide at 4 gm/m2 intravenously with mesna at a total of 2.4 gm/m2 
intravenously or orally divided over 3 doses.  Subjects then will receive mobilization using 
daily filgrastim (G-CSF) at 10 mcg/kg subcutaneously starting 24 hours after 
cyclophosphamide is completed and until stem cell collection.  The use of AMD3100 
(Plerixafor) is permitted.  Peripheral stem cell collection will be performed at marrow 
recovery, usually when WBC is >2500 x 109 cells/liter; platelet count is >20 x 103/mm3 
 
After 8 cycles with lenalidomide/ dexamethasone, maintenance will be started  15 mg/day on 
days 1-21 every 28 days until disease progression.  Dose can be reduced to 10 mg per 
treating physician discretion in case subject doses not tolerate 15 mg/day. If subject does not 
tolerate 10 mg/day lenalidomide, discontinue maintenance. Maintenance with 5 mg/day is 
not recommended except due to impaired renal function. Subjects may receive up to total 2 
years maintenance therapy. 
  
For subjects on maintenance therapy of lenalidomide at a dose 10mg/day at the time protocol 
v11-30-10 is approved, lenalidomide dose will be increased to 15 mg/day on next cycle. 
 
In ARM A, lenalidomide/dexamethasone therapy will be given through 4 cycles followed by 
melphalan-based autologous peripheral blood stem cell transplant.  In ARM B, 
lenalidomide/dexamethasone therapy will be given through 8 cycles.  If complete response 
(CR) or partial response (PR) is achieved after 8 cycles, subjects will continue with 
lenalidomide alone (maintenance) until disease progression or severe toxicity occurs despite 
dose reduction.   
 
Subjects who progress in either arm may be offered to end protocol treatment and proceed to 
alternate therapy.  Subjects who progress in ARM B will be off treatment and have the 
option ultimately to undergo autologous peripheral blood stem cell transplant.  Subjects 
refusing transplantation in ARM A have the option to go onto ARM B and will be evaluated 
separately.  
 
Subjects will come off treatment for unacceptable toxicity, withdrawal of consent, non-
compliance, and completion of protocol therapy.   
 
Subjects who progress in either arm will end protocol treatment and proceed to alternate 
therapy.   
 
The start of the next cycle can be delayed by 2 weeks at the discretion of the treating 
physician. 
 
 
 
 
 


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5.1 
Study Agents 
Lenalidomide (CC-5013) will be administered orally at a dose of 25 mg PO daily on days 1-
21 of cycle.  Administration will be during cycles 1-4 in Arm A and cycle 1-8 in Arm B.  
Maintenance will be lenalidomide 15 mg/day for a maximum of 2 years or until disease 
progression.   
 
Supply 
 
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 Celgene Corporation’s Revlimid REMS® program.  
Per standard Revlimid REMS® program 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 Revlimid 
REMS® program.   
 
Only enough lenalidomide for one cycle of therapy will be supplied to the patient each cycle. 
 
Packaging 
Lenalidomide will be shipped directly to subjects.   Bottles will contain a sufficient number 
of capsules for one cycle of dosing.  
 
Storage 
Lenalidomide should be stored at room temperature away from direct sunlight and protected 
from excessive heat and cold. 
Route and Method of Administration 
Oral.  Clinical studies have shown that Lenalidomide administration coincident with food 
intake appears to delay absorption to some degree, although the extent of absorption is not 
altered.  Therefore, Lenalidomide can be taken with or without food. 
 
If a dose of Lenalidomide is missed, it should be taken as soon as possible on the same day.  If 
it is missed for the entire day, it should not be made up. 
 
Patients who take more than the prescribed dose of Lenalidomide should be instructed to seek 
emergency medical care if needed and contact study staff immediately. 
 
Females of childbearing potential should not handle or administer Lenalidomide unless they 
are wearing gloves. 
 
Dexamethasone will be administered 40 mg PO on days 1, 8, 15, 22. 
Supply 
Decadron, Hexadrol, Dexameth, Dexone, DXM, others 


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Investigator Protocol 19 June 2015  
 
Commercially available in 0.25, 0.5, 0.75, 1, 1.5 , 2, 4, and 6 mg tablets 
Route of Administration 
Oral. 40 mg PO will be administered on days 1, 8, 15, 22. 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
Thrombosis  
All patients will receive enteric coated aspirin, at least 81 mg, QD while on study 
(thrombosis prophylaxis, see Section 5.4.1 below). Aspirin can be held per treating 
physician’s discretion if clinically indicated, such as for procedures. If patient is unable to 
tolerate aspirin, patient should receive other types of anti-coagulation such as warfarin or 
low molecular weight heparin.  There is an increased risk of deep vein thrombosis (DVT) 
with thalidomide/dexamethasone therapy for myeloma, which is higher than the baseline risk 
of DVT in newly diagnosed myeloma (approximately 3% with dexamethasone alone and 4-
10%  with VAD).  Data on prophylaxis is limited, but it appears that fixed dose (1 mg 
warfarin) may not be effective. Low molecular weight heparin at prophylactic doses 
(enoxaparin 40 mg once a day subcutaneously or equivalent) appears effective in decreasing 
the risk of DVT associated with Thal/Dex therapy.  Given the potential risk of DVT in 
myeloma in general, the increased risk seen previously with Thal/Dex, and recently reported 
increased risk with lenalidomide, enteric coated aspirin 81-325 mg once daily is 
recommended for all patients.  Enoxaparin 40 mg subcutaneously once daily and full dose 
warfarin with a therapeutic INR 2-3 are acceptable alternatives and should be given to 
patients with a higher risk of venous thromboembolism.  Patients with high risk are shown in 
the below table.    
 
Risk Factors for VTE During  
Lenalidomide Plus Dexamethasone Treatment23  
Central Venous Line 
Ongoing infection/inflammation 
Concomitant Chemotherapy 
Older age 
Doxorubicin use 
Previous VTE 
Erythropoietin use 
Pre-existing coagulation disorders 
High-dose dexamethasone use 
Thrombophilia 
High tumor mass 
 
Immobilization 
 
 
For information on the risk of venous thromboembolism with combined oral contraception 
see Appendix D: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable 
Birth Control Methods. 
 
Gastrointestinal  
All patients will receive prophylaxis with either an H-2 blocker or proton pump inhibitor 
(PPI) while on Dexamethasone. Suggested medications included ranitidine 150 mg PO BID 
or omeprazole 20 mg PO daily or equivalent.  Antiemetic therapy may be necessary if 
vomiting occurs.  Diarrhea and constipation are frequent toxicities with lenalidomide.  
Diarrhea may be treated with loperamide (Imodium).  Constipation may be treated with 


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Investigator Protocol 19 June 2015  
 
lactulose or any other laxatives according to the choice of the physician.   
 
Fever and Infection  
Routine prophylaxis with one double-strength tablet of trimethoprim/sulfamethoxazole 
orally three times per week is recommended for all patients on lenalidomide/dexamethasone.  
If trimethoprim/sulfamethoxazole is not tolerated, then dapsone 100 mg orally daily, 
atovaquone 1500 mg orally daily with food, pentamidine 4 mg/kg IV monthly, or nebulized 
pentamidine 300 mg inhaled monthly are acceptable alternatives.  In case of a history of 
zoster or fungal infection, prophylaxis with acyclovir 200 mg orally tid or fluconazole 100 
mg orally daily should also be considered.  For autologous peripheral stem cell transplant, 
ciprofloxacin 500 mg orally bid, acyclovir 400 mg orally tid, and fluconazole 200 mg orally 
daily are recommended for prophylaxis starting no later than day -2 of transplant.   
 
Myelosuppression 
Growth factors, specifically filgrastim (granulocyte-colony stimulating factor; G-CSF) or 
pegfilgrastim only, can be used to treat neutropenia that occurs as a result of lenalidomide 
therapy and also starting day +5 from autologous peripheral stem cell transplant. The usual 
dose of filgrastim is 5 micrograms/kg/day given for neutropenia and 10 μg/kg for stem cell 
mobilization subcutaneously until the ANC is greater than 1,000 x 2 subsequent readings. G-
CSF can be rounded to the nearest vial size. The usual dose of pegfilgrastim is a single dose 
of 6 mg administered subcutaneously.  No additional doses of pegfilgrastim are permitted in 
the next 28-day period.  The major adverse event with filgrastim and pegfilgrastim is bone 
pain. Other side effects are rare and include nausea, fatigue, diarrhea, vomiting, constipation, 
fever, anorexia, headache, taste perversion, dyspepsia, myalgia, insomnia, abdominal pain, 
arthralgia, generalized weakness, peripheral edema, and dizziness.  Reversible elevations in 
LDH, alkaline phosphatase, and uric acid, not requiring therapy have also been observed. 
 
Bone Disease 
All patients with bone involvement should receive pamidronate (90 mg intravenously over 
2-4 hours) or zoledronate (4 mg intravenously over 15 minutes) every 4 weeks as part of 
standard supportive care for myeloma, unless in the discretion of the treating physician such 
therapy produces toxicity or is felt to be medically unsafe.  Dose modification may be 
necessary if hypocalcemia or renal insufficiency.  Patients receiving bisphosphonates may 
receive an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of 
vitamin D daily.  Serum creatinine should be monitored prior to bisphosphonate infusion 
since the drugs can cause nephrotoxicity. 
 
Local radiation therapy for symptomatic bone or extramedullary lesions (eg, uncontrolled 
pain, high risk of pathologic fracture), superior or inferior vena cava syndrome, spinal cord 
compression is permitted.   
 
Hyperglycemia  
Hyperglycemia, sometimes severe, including diabetic coma or ketoacidosis can occur with 
dexamethasone therapy. Therefore blood sugars should be monitored in diabetic patients, 
borderline patients, and in patients at risk for hyperglycemia or diabetes. 
 


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Anemia  
Patients with chronic anemia that is transfusion dependent should be considered for 
erythropoietin replacement. Patients with hemoglobin <8 mg/dl and/or symptomatic should 
receive transfusion.   The risk of DVT may be significant increased when erythropoietin is 
administered concurrent with lenalidomide therapy.  Thus, we recommend that the use of 
erythropoietin be minimized as much as possible. 
 
Thrombocytopenia 
Administration of platelet transfusions during screening to meet eligibility criteria is not 
allowed.  However, platelet transfusions may be administered as clinically indicated to 
subjects in both treatment arms who have begun lenalidomide therapy. 
 
Secondary malignancies 
Recent data show increase in secondary malignancies with lenalidomide maintenance 
therapy. The data are under evaluation. 16-2 We will closely follow up for secondary 
malignancies during the patients’ lifetime. 
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 of the subject’s last dose of lenalidomide, are considered immediately reportable 
events. Lenalidomide  is to be discontinued immediately. The pregnancy, suspected 
pregnancy, or positive pregnancy test must be reported to Celgene Drug Safety immediately 
by facsimile or email using the Pregnancy Initial Report Form. The female subject should be 
referred to an obstetrician-gynecologist, preferably one experienced in reproductive toxicity 
for further evaluation and counseling. 
 
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal 
or abnormal outcome) using the Pregnancy Follow-up Report Form.  If the outcome of the 
pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the Investigator should 
report the abnormal outcome as an AE. If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety immediately by facsimile, or 
other appropriate method, within 24 hours of the Investigator’s knowledge of the event using 
the SAE Report Form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects 
is related to the in utero exposure to the IP should also be reported to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, within 24 hours of the Investigator’s 
knowledge of the event using the SAE Report Form.  
 
Male Subjects 
 
If a female partner of a male subject taking investigational product becomes pregnant, the 


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Investigator Protocol 19 June 2015  
 
male subject taking lenalidomide  should notify the Investigator, and the pregnant female 
partner should be advised to call their healthcare provider immediately. 
 
 
5.3 
Dosing Delays and Dose Modifications 
 
LENALIDOMIDE 
Dosage of lenalidomide must be adjusted according to renal function throughout protocol 
treatment.  Patients with creatinine clearance ≤50mL/min (estimated) should receive 
lenalidomide according to the dosing schedule in Appendix C. 
 
The start of the next cycle may be delayed by 2 weeks at the discretion of the treating 
physician. 
 
All other treatment modifications are based on adverse events, which are possibly, probably, 
or definitely related to drug.  Al adverse events should be graded according to the Common 
Terminology Criteria for Adverse Events (CTCAE, v.4.0). 
 
Lenalidomide Treatment Adjustments 
If Grade 3 or 4 neutropenia is the only adverse event present for which treatment adjustment 
is necessary, then the first dose reduction step is Dose Level -1.  For all other adverse events 
requiring treatment adjustment, the first treatment adjustment step is Dose Level -2.   
 
For subjects experiencing a ≥ grade 3 adverse events (AE), lenalidomide will be held until 
resolution of the AE as described in the below table: Lenalidomide Dose Modifications 
based on Adverse Events.  For all labs related to AE ≥ grade 3, recheck must occur in ≤ 7 
days.  For Grade 3 or 4 AEs which occur prior to Day 15 of a cycle and resolve to ≤ grade 1 
in severity prior to Day 15 of the cycle, administration of lenalidomide during the current 
cycle is to be continued until Day 21 with a one-level dose reduction according to the table 
below (Lenalidomide Treatment Adjustment Steps).  The next cycle will then continue with 
this reduced dose level.  For grade 3 or 4 AEs which occur on or after Day 15 of a cycle, the 
subject’s study drug is to be held for the remainder of the cycle and will be reduced by one 
dose level beginning with the next cycle.  Once a subject’s dose has been reduced, no dose-
re-escalation is permitted.  Exception: Patients with renal impairment (Appendix C). 
 
If a dose reduction of lenalidomide is indicated both as a result of decreased renal function 
and ≥ grade 3 AE, please consult with the principal investigator.   
 
When lenalidomide needs to be held at time of re-treatment for adverse events, 
dexamethasone should also be held unless the subject requires continued dexamethasone 
treatment per investigator’s discretion.  As noted in the table, lenalidomide can be introduced 
after resolution of certain toxicities, midway through the cycle, provided the toxicity 
revolves prior to day 15.  If both need to be held at the time  
of re-treatment for adverse events, then the date when treatment is resumed with either drug 
is considered day 1 of the new treatment cycle.  Patients requiring a treatment delay of both 
agents beyond 6 weeks will end protocol treatment. 


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During maintenance phase, in case of toxicity, hold dose of lenalidomide for any grade 3 AE 
possible related to lenalidomide. Restart lenalidomide when AE resolves to grade 1 or 
baseline.  
 
If the grade 3 event occurred at 15mg, reduce dose  to 10mg. If the grade 3 event occurred at 
10mg, restart dose at 10mg.  However, a recurrence in any subsequent cycle of the same 
grade 3 event requires the patient be taken off maintenance permanently. Dose reduction is 
not necessary in the event of grade 3 hypokalemia that is adequately treated and has 
resolved.  If the next cycle is delayed by more than 28 days due to grade 3 AE, the subject 
should be taken off maintenance. 
 
LENALIDOMIDE TREATMENT ADJUSTMENT STEPS 
Starting Dose 
25 mg D 1-21 every 28 days 
Dose Level -1* 
Maintain lenalidomide dose and add growth factor (see 
also Section 5.2) 
Dose Level -2 
15 mg daily for 21 days every 28 days 
Dose Level -3 
10 mg daily for 21 days every 28 days 
Dose Level -4 
5 mg daily for 21 days every 28 days 
 
LENALIDOMIDE DOSE MODIFICATION BASED ON ADVERSE EVENTS 
 
CTCAE Category 
At re-treatment and Day 2-
14 of cycle 
≥ Day 15 of cycle 
Sustained ( > 7 days) Grade 3 
neutropenia or ≥ Grade 3 
neutropenia associated with 
fever (temperature ≥ 38.5º C) 
or Grade 4 neutropenia  
(see section 5.3.2 if 
neutropenia is the only 
adverse event) 
 
Thrombocytopenia  
≥ Grade 3 (Plt < 50,000/mm3) 
Hold lenalidomide and 
follow CBC weekly.  If the 
toxicity resolves to 
baseline or ≤ grade 1 prior 
to Day 14, restart at next 
lower dose level and 
continue the cycle until 
Day 21. 
Omit lenalidomide for 
remainder of cycle. 
Non-blistering rash 
Grade 2 
Add Benadryl or 
comparable orally 
administered medication 
per treating physician’s 
discretion and maintain 
treatment. 
Add Benadryl or 
comparable orally 
administered medication 
per treating physician’s 
discretion and maintain 
treatment. 
Non-blistering rash 
Grade 3 
Hold lenalidomide, start 
Benadryl or comparable 
orally administered per 
treating physician’s 
Omit lenalidomide for 
remainder of cycle and 
start Benadryl or 
comparable orally 


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Investigator Protocol 19 June 2015  
 
discretion and follow.  If 
the toxicity resolves to ≤ 
grade 1 prior to Day 14, 
restart at next lower dose 
level and continue the 
cycle until Day 21. 
administered per treating 
physician’s discretion. 
 
Non-blistering rash 
Grade 4 
Discontinue lenalidomide 
and do not resume. 
Discontinue lenalidomide 
and do not resume. 
Desquamating (blistering) rash 
and Grade, or Erythema 
multiforme  
≥ Grade 3 
Discontinue lenalidomide. 
Discontinue lenalidomide 
and do not resume. 
Sinus bradycardia/other 
cardiac arrhythmia  
Grade 2 
Hold lenalidomide and 
follow.  If the toxicity 
resolves to ≤ grade 1 prior 
to Day 14, restart at next 
lower dose level and 
continue the cycle until 
Day 21. 
Omit lenalidomide for 
remainder of cycle. 
Sinus bradycardia/other 
cardiac arrhythmia  
Grade 3-4 
Discontinue lenalidomide. 
Discontinue lenalidomide 
and do not resume. 
Allergic Reaction or 
Hypersensitivity Grade 2-3 
Hold lenalidomide and 
follow.  If the toxicity 
resolves to ≤ grade 1 prior 
to Day 14, restart at next 
lower dose level and 
continue the cycle until 
Day 21. 
Omit lenalidomide for 
remainder of cycle. 
Allergic Reaction or 
Hypersensitivity Grade 4 
Discontinue lenalidomide. 
Discontinue lenalidomide 
and do not resume. 
Venous Thrombosis/embolism  
≥ Grade 3 
Hold dose of lenalidomide 
and start anticoagulation, 
restart at investigators 
discretion after adequate 
anticoagulation (maintain 
dose level). 
Omit lenalidomide for 
remainder of cycle and 
start anticoagulation.  
Restart at investigato s 
discretion after adequate 
anticoagulation (maintain 
dose level). 
Hepatic or other non-
hematologic toxicity assessed 
as lenalidomide related  
≥ Grade 3 
Hold lenalidomide and 
follow.  If the toxicity 
resolves to ≤ grade 1 prior 
to Day 14, restart at next 
 ower dose level and 
continue the cycle until 
Day 21. 
Omit lenalidomide for 
remainder of cycle. 


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Hyperthyroidism or 
Hypothyroidism 
Continue lenalidomide and 
initiate appropriate therapy 
per treating physician’s 
discretion. 
Continue lenalidomide and 
initiate appropriate therapy 
per treating physician’s 
discretion. 
 
DEXAMETHASONE  
Dexamethasone Dose Modification based on Interval Toxicity. It is expected given the low 
dose of dexamethasone that few dose modifications related to dexamethasone will be 
necessary. 
 
CTCAE Category 
Adverse Event 
Dexamethasone Treatment 
Adjustment 
Gastrointestinal 
Dyspepsia, gastric or 
duodenal ulcer, gastritis 
All patients will be treated 
with H2 Blockers, ranitidine, 
or omeprazole as per Section 
5.2.2. 
Grade 1-2 
If symptoms persist despite 
above measures, decrease 
dexamethasone dose by 50% 
permanently 
≥ Grade 3 (requiring 
hospitalization or surgery) 
Hold dexamethaso e until 
symptoms are adequately 
controlled.  Restart at 50% 
of current dose.  If 
symptoms persist, 
discontinue dexamethasone 
and do not resume.   
Acute pancreatitis 
Discontinue dexamethasone 
and do not resume. 
Cardiovascular 
Edema 
≥ Grade 3 
Diuretics as needed, and 
decrease dexamethasone 
dose by 25%, if edema 
persists despite above 
measures, decrease dose to 
50% of initial dose; 
discontinue dexamethasone 
and do not resume if 
symptoms persist despite 
50% reduction.   
Psychiatric  
Depression, anxiety, 
agitation or confusion ≥ 
Grade 2 (limiting 
instrumental ADL or self-
care ADL)  
Hold dexamethasone until 
symptoms resolve, restart at 
50% of current dose.  If 
symptoms persist despite 
above measures, discontinue 
dexamethasone and do not 


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Investigator Protocol 19 June 2015  
 
resume.   
Musculoskel tal 
Muscle Weakness ≥ Grade 2 
(symptomatic and 
interfering with function 
and/or ADLs) 
Decrease dexamethasone 
dose by 25%, if weakness 
persists despite above 
measures, decrease dose to 
50% of initial dose; 
discontinue dexamethasone 
and do not resume if 
sym toms persist despite 
50% reduction.   
Metabolic 
Hyperglycemia ≥ Grade 3 or 
higher 
Treatment with insulin or 
oral hypoglycemics as 
needed.  If uncontrolled 
despite above measures, 
decrease dose by 25% 
decrements until levels are 
satisfactory.   
 
All other treatment modifications are based on adverse events, which are possibly, probably, 
or definitely related to drug.  All adverse events should be graded according to the Common 
Terminology Criteria for Adverse Events (CTCAE, v. 4.0). 
 
5.4 
Duration of Treatment 
In arm A, therapy will be given through 4 cycles followed by melphalan-based autologous 
peripheral blood stem cell transplant if CR or PR is achieved after the 4 cycles.  In arm A, 
lenalidomide maintenance will begin between day 90 and 110 following PSCT for a 
maximum of 24 months or until disease progression.  Therapy will be given in arm B, per 
schema to include 8 cycles lenalidomide and dexamethasone followed by maintenance 
lenalidomide for a maximum of 24 months or until disease progression.  Patients who 
progress in either arm may be offered to end protocol treatment and proceed to alternate 
therapy.  Patients who progress in arm B will be off treatment and have the option ultimately 
to undergo autologous peripheral blood stem cell transplant.  Patients will come off 
treatment for unacceptable toxicity, withdrawal of consent, non-compliance, and completion 
of protocol therapy.    
 
5.5 
Duration of Follow Up 
Patients will be followed for response until disease progression and death.  Duration of 
follow up will vary according to the overall survival of the patient or, at the most, 5 years 
from randomization.  All patients must also be followed through completion of all protocol 
therapy.  For patients randomized to Arm A, it is recommended that a bone marrow 
biopsy/aspiration be performed between day  80-100 following autologous PBSCT.  Patients 
removed from study for unacceptable adverse events will be monitored until resolution or 
stabilization of the adverse event.  At treatment discontinuation, subjects will undergo a 
safety assessment approximately 30 days post the last dose of protocol therapy.    Safety 
assessments can occur by phone contact or office visit per treating physician’s discretion. 


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6 
STUDY CALENDAR 
 
The pre-study bone marrow aspirate/biopsy and bone survey may be done up to 6 weeks 
before registration.  Pre-study CBC (with differential and platelet count) and all required 
pre-study chemistries will be done < 4 weeks prior to registration.  If any required lab values 
are abnormal, they should be repeated < 48 hours prior to registration. Assessments can be 
performed on day 22 through day 1 of the planned cycle.  Cycle four bone marrow biopsy 
should be performed days 14-21 of cycle four for subject participating in correlative studies. 
Cycles will be counted consecutively through maintenance phase. Stem Cell Harvest and 
Stem Cell transplant will not be counted as a cycle.   
 
Study Parameters:  
Arm A  
(All assessments 
can be done +/- 2 
days except cycle 
4)  
 
Baseline 
 
Cycle 1-3 
(day 22 to 
day1 of next 
cycle) 9 
Cycle 
4 9 
Stem cell 
harvest 
and 
transplant 
Post   
SCT  
(day 
80 to 
100) 
Maintenance  
phase   
(day 22 to day1 of 
next cycle) 9  
(start at day 90-110) 
16 
Discontinuation 
of therapy 8 
History & Physical 
Examination 
X 
X 
X 
 
X 
X 
X 
Vital Signs, Adverse 
Events assessment 
X 
X 
X 
 
X 
X 
X 
Response Assessment  
X 
X 
X 
 
X 
X 
X 
Performance Status 
X 
X 
X 
 
X 
X 
X 
CBC (with diff and 
platelets)1 
X 
X 
X 
 
X 
X 
X 
Calcium, Electrolytes, 
serum creatinine, 
BUN 
X 
X 
X 
 
X 
X 
X 
TSH 
X 
X 
X 
 
X 
X 
X 
Glucose 
X 
X 
X 
 
X 
X 
X 
Total Bilirubin, LDH 
X 
X 
X 
 
X 
X 
X 
AST/ALT 
X 
X 
X 
 
X 
X 
X 
Alkaline Phosphatase 
X 
X 
X 
 
X 
X 
X 
Albumin 
X 
X 
X 
 
X 
X 
X 
SPEP including M-
spike, FLC 
X 
X 
X 
 
X 
X 
X 
UPEP 
X 
X 
X 
 
X 
X 
X 
24 hour urine 
collection for total 
protein, quantitative 
light chains 
X 
X 
X 
 
X 
 
X 
Immunofixation of 
serum and urine 
X6 
X6 
X6 
 
X6 
 
X6 
Bone Marrow 
Aspirate/Biopsy 
X7 
 
X7 
 
X7 
 
X7, 8 
Beta 2 Microglobulin,  X 
X 
X 
 
X 
X 
X 
Ig A, G, M 
X 
X 
X 
 
X 
X 
X 


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Investigator Protocol 19 June 2015  
 
Cytogenetics (bone 
marrow) 
X 
 
X 
 
 
 
 
Skeletal Survey3 
X 
 
X 
 
 
 
 
Pregnancy test4,  
X4 
X4,  
X4 
 
X4,  
X4 
X4 
 Stem Cell Harvest14 
 
 
 
X 
 
 
 
 Stem Cell 
Transplant15 
 
 
 
X 
 
 
 
Register patient into 
Revlimid REMS® 
program 
X 
 
 
 
 
 
 
Prescribe 
lenalidomide 
 
X11 if 
applicable 
X11 
 
X11 
X11 
 
 
 
Study 
Parameters: 
Arm B  
(All assessments 
can be done +/- 
2 days except 
cycle 4 and 5)  
 
Baseline 
 
Cycle 1-3 
(day 22 to day1 
of next cycle) 9 
Cycle 
4 9 
Stem 
cell 
harvest  
Post 
Stem 
Cell 
Harvest 
visit 
(Within 
7 days 
of 
C5D1) 
Cycle 
5-8  
Maintenance  
phase 16  (start 
at day 90-110) 
(day 22 to day1 of 
next cycle) 9 
Discontinuation 
of therapy 8 
History & 
Physical 
Examination 
X 
X 
X 
 
x 
X 
X 
X 
VS, AE 
assessment 
X 
X 
X 
 
x 
X 
X 
X 
Response 
Assessment  
X 
X 
X 
 
 
X 
X 
X 
Performance 
Status 
X 
X 
X 
 
x 
X 
X 
X 
CBC (with diff 
and platelets)1 
X 
X 
X 
 
x 
X 
X 
X 
Calcium, 
Electrolytes, 
serum 
creatinine, BUN 
X 
X 
X 
 
x 
X 
X 
X 
TSH 
X 
X 
X 
 
 
X 
X 
X 
Glucose 
X 
X 
X 
 
x 
X 
X 
X 
Total Bilirubin, 
LDH 
X 
X 
X 
 
x 
X 
X 
X 
AST/ALT 
X 
X 
X 
 
x 
X 
X 
X 
Alkaline 
Phosphatase 
X 
X 
X 
 
x 
X 
X 
X 
Albumin 
X 
X 
X 
 
x 
X 
X 
X 
SPEP including 
M-spike, FLC 
X 
X 
X 
 
x 
X 
X 
X 
UPEP 
X 
X 
X 
 
X 
X 
X 
X 
24 hour urine 
collection for 
total protein, 
quantitative 
light chains 
X 
X 
X 
 
X 
X 
 
X 
Immunofixation 
of serum and 
urine 
X6 
X6 
X6 
 
X6 
X6 
 
X6 


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Investigator Protocol 19 June 2015  
 
Bone Marrow 
Aspirate/Biopsy 
X7 
 
X7 
 
 
X7 
 
X7, 8 
Beta 2 
Microglobulin,  
X 
X 
X 
 
X 
X 
X 
X 
Ig A, G, M 
X 
X 
X 
 
X 
X 
X 
X 
Cytogenetics 
(bone marrow) 
X 
 
X 
 
 
 
 
 
Skeletal Survey3 
X 
 
X 
 
 
 
 
 
Pregnancy test4,  
X4 
X4,  
X4 
 
x 
X4,  
X4 
X4 
 Stem Cell 
Harvest14 
 
 
 
X 
 
 
 
 
Register patient 
into Revlimid 
REMS® 
program 
X 
 
 
 
 
 
 
 
Prescribe 
lenalidomide 
 
X11 if 
applicable 
X11 
 
x 
X11 
X11 
 
 
1  CBC (with differential and platelet count) should be performed <48 hours prior to the chemotherapy treatment cycle and 
must be performed within 7 days of start of chemotherapy treatment cycle.  CBC can be ordered more than once per cycle 
per physician discretion and this data should be entered into the eCRFs. 
3 Skeletal survey should be repeated as physician’s discretion to determine the response or if clinically indicated. 
4 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).  
Pregnancy tests must occur within 10 – 14 days and again within 24 hours prior to prescribing lenalidomide (prescriptions 
must be filled within 7 days).  FCBP with regular or no menstruation must have a pregnancy test weekly for the first 28 
days and then every 28 days while on therapy (including breaks in therapy), at discontinuation of lenalidomide and at Day 
28 post the last dose of lenalidomide.   
Females with irregular menstruation must have a pregnancy test weekly for the first 28 days and then every 14 days while 
on therapy (including breaks in therapy ), at discontinuation of lenalidomide and at Day 14 and Day 28 post the last dose of 
lenalidomide (see Appendix: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control 
Methods). 
6  Required only to document complete response; if complete response, repeat to confirm response at ≥ 4 weeks.  
7  To be performed in all the patients of both arms during cycle number 4 and before starting maintenance to assess for 
remission.  In the case of a subject from Arm A for this protocol, a biopsy should be performed on Day 80-100  following 
autologous PBSCT.  All subjects will have bone marrow biopsy at end of lenalidomide therapy.  At PI’s discretion an 
additional bone marrow aspiration may be done to confirm complete response, progressive disease or relapse.  
 8 After discontinuation of therapy, subjects should be followed every 3 months for the first two years, every 6 months for 
years 2-5, and annually thereafter. Follow up will be for time to next treatment and then for survival for subjects who 
received maintenance.  For subjects not receiving maintenance, follow up will include standard of care labs until 
progression, then time to next treatment, then survival.  
 9 Each cycle consists of 28 days.   In cycle 4, physical exam can be done 2 weeks after finishing cycle 4 and with transplant 
physical exam. All labs can be done the same time with BM biopsy between days 15 and 28 of cycle 4. Per transplant 
physician discretion, the cycle 4 studies can also occur within 2 weeks after completion of cycle 4 if needed to correctly 
assess response.  
11 Lenalidomide must be prescribed through and in compliance with the Revlimid REMS® program of Celgene 
Corporation.  Prescriptions must be filled within 7 days.  Consideration should be given to prescribing lenalidomide 5 to 7 
days in advance of Day 1 of each cycle to allow time for required patient and prescriber surveys, and drug shipment to 
patient.  Any unused Revlimid® (lenalidomide) should be returned to the patient for disposition in accordance with the 
Revlimid REMS® program    
14 Stem cell harvest can be done up to 6 weeks after finishing cycle  4. 
15  Stem cell  transplant  can be done up to 8 weeks after finishing cycle 4. 
16 Maintenance phase is for a maximum of 24 months.  
 
7 
MEASUREMENT OF EFFECT 
 
7.1 
Definitions 


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Definitions of response are based on those of the International Response Criteria as 
published in  Leukemia in 2006.24  
M-protein 
Synonyms include M-spike, monoclonal protein and myeloma protein, monoclonal 
paraprotein, M-component. 
Response terms 
The following response terms will be used: stringent complete response (sCR), complete 
response (CR), very good partial response (VGPR), partial response (PR), stable disease 
(SD), plateau, and progression or relapse (PD). See section 7.3 for Response Criteria. 
Measurable disease 
Patients who have one of the following three measurements: serum M-protein >1 g/dL, urine 
M-protein >200 mg/24hr, serum FLC assay with involved FLC level > 10mg/dL (>100 mg/l 
provided serum FLC ration is abnormal.  
Non-measurable disease 
Patients who do not meet any of the criteria for measurable disease as listed above.  Patients 
who do not meet any of the criteria for measurable disease as listed above can only be 
assessed for stringent CR, and cannot be assessed for any of the other response categories. 
Non-secretory myeloma 
Patients with multiple myeloma who have never had a detectable serum or urine M-
component or an abnormal serum FLC ratio.  The baseline bone marrow must have >10% 
clonal plasma cells.  
 
7.2 
Guidelines for Evaluation of Measurable Disease 
Bone radiographs 
These are not required to document response. If bone radiographs are obtained, their findings 
must be consistent with the bone response criteria. 
Bone progression 
Caution must be exercised to avoid rating progression or relapse on the basis of variation of 
radiologic technique alone. Compression fracture does not exclude continued response and 
may not indicate progression. When progression is based on skeletal disease alone, it should 
be discussed with the study chair before removing the patient from the study. 
Clarification of test indications 
Patients with “measurable disease’ as defined above need to be followed by both SPEP and 
UPEP for response assessment and categorization.  Except for assessment of CR, patients 
with measurable disease restricted to the SPEP will need to be followed only by SPEP; 
correspondingly, patients with measurable disease restricted to the UPEP will need to be 
followed only by UPEP.  Patients with measurable disease in either SPEP or UPEP or both 
will be assessed for response only based on these two tests and not by the FLC assay.  FLC 
response criteria are only applicable to patients without measurable disease in the serum or 
urine, and to fulfill the requirements of the category of stringent CR. 
Laboratory tests for measurement of M-protein 
Serum M-protein level is quantified using densitometry on SPEP except in cases where the 
SPEP is felt to be unreliable such as in patients with IgA monoclonal proteins migrating in 
the beta region.  If SPEP is not available or felt to be unreliable (e.g., in some cases of IgA 
myeloma) for routine M-protein quantitation during therapy, then quantitative 
immunoglobulin levels on nephelometry or turbidimetry can be accepted.  However, this 


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must be explicitly reported, and only nephelometry can be used for that patient to assess 
response and SPEP and nephelometric values cannot be used interchangeably. 
 
7.3 
Response Criteria 
Stringent Complete Response (sCR) 
CR as defined below plus normal FLC ratio and absence of clonal cells in bone marrow by 
immunohistochemistry or immunofluorescence. 
Complete Response (CR) 
Negative immunofixation on the serum and urine and disappearance of any soft tissue 
plasmacytomas and <5% plasma cell in bone marrow. 
Note that patients who do not meet any of the criteria for measurable disease as listed above 
in the definition can only be assessed for stringent CR, and cannot be assessed for any of the 
other response categories. 
Very Good Partial Response (VGPR) 
Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% 
or greater reduction in serum M-protein plus urine M-protein level <100 mg/24hr. 
Partial Response (PR) 
Requires all of the following:  
≥50% reduction of the serum M-protein. 
Reduction in 24-hour urinary M-protein by >90% or to <200 mg/24hr. 
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. 
If serum and urine M-protein are unmeasurable, and serum free light chain assay is also 
unmeasurable, a >50% reduction in plasma cells is required in place of M-protein, provided 
baseline bone marrow plasma cell percentage was >30%. 
In addition to the above criteria, if present at baseline, a >50% reduction in the size of soft 
tissue plasmacytomas is also required.  
Stable disease (STAB) 
Not meeting criteria for CR, VGPR, PR or progressive disease. 
Disease Plateau (Note: plateau is not a distinct response category) 
A patient in sCR, CR, VGPR, or PR (see sections above) will be further classified as being 
in plateau if the following criteria are met: 
Serum and/or urine M-protein values and/or serum FLC ratio must be stable for a period of 
at least 12 weeks. Stable values are defined as a continued CR or in the case of patients with 
residual M-protein, absence of progression. 
Any patient with measurable disease who is continuing to have "improvement" in serum or 
urine response criteria would not be considered in plateau. "Improvement" is defined as a 
decrease in the serum or urine M spike by > 25% He or she might be approaching a better 
level of response, and therefore, should not yet be deemed in plateau until the improvement 
has leveled off. 
DATE of plateau will be the first date of suspected plateau. Date cannot be assigned until 
CONFIRMATION that the patient is in plateau (that is at least 12 weeks later).  
Progressive Disease (PD) 
To be used for calculation of time to progression and progression-free survival end points for 
all patients including those in CR (including primary progressive disease and disease 
progression on or off therapy) 


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Requires any or more of the following: 
Increase of >25% from baseline in: 
Serum M-component and/or (the absolute increase must be >0.5 g/dl) 
Urine M-component and/or (the absolute increased must be > 200mg/24hr) 
Only in patients without measurable serum and urine M-protein levels:  the difference 
between involved and uninvolved FLC levels.  The absolute increase must be >10 mg/dl. 
Bone marrow plasma cell percentage:  the absolute % must be 10%. 
Definite development of new bone lesions or soft tissue plasmacytomas or definite increase 
in the size of existing bone lesions or soft tissue plasmacytomas. 
Development of hypercalcemia (corrected serum calcium >11.5 mg/dl or 2.65 mmol/l) that 
can be attributed solely to the plasma cell proliferative disorder. 
Clinical Relapse 
Requires one or more of the following: 
Direct indicators of increasing disease and/or end organ dysfunction.  It is not used in 
calculation of time to progression or progression-free survival but is listed here as something 
that can be reported optionally o for use in clinical practice. 
Development of new soft tissue plasmacytomas or bone lesions 
Definite increase in the size of existing plasmacytomas or bone lesions.  A definite increase 
is defined as a 50% (and at least 1 cm) increase as measured serially by the sum of the 
products of the cross-diameters of the measurable lesion. 
Hypercalcemia (11.5 mg/dl) [2.65 mmol/l] 
Decrease in hemoglobin > 2g/dl [1.25 mmol/l] not attributed to lenalidomide treatment.   
Rise in serum creatinine by 2 mg/dl or more [177 μmol/l or more] 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression, even after discontinuation of treatment. 
Relapse from CR (To be used only if the end point studied is DFS) 
Any one or more of the following: 
Reappearance of serum or urine M-protein by immunofixation or electrophoresis 
Development of >5% plasma cells in the bone marrow.  Note the 5% cutoff versus 10% for 
other categories of relapse. 
Appearance of any other sign of progression (i.e., new plasmacytoma, lytic bone lesion, or 
hypercalcemia. 
 
7.4 
Confirmatory Measurement and Duration of Response 
Confirmed response 
In order to be classified as a response, confirmation of serum and urine monoclonal protein 
results and serum free light chain levels must be made by verification on two consecutive 
determinations 4-6 weeks apart. 
For patients with non-secretory myeloma only, a bone marrow is required to document all 
response categories; however, a second confirmatory bone marrow is not required to confirm 
response. 
Bone marrow aspirate and biopsy are not required to document or confirm response. 
Exception: for patients with non-secretory myeloma only, a bone marrow is required to 
document all response categories including progression. 


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Investigator Protocol 19 June 2015  
 
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are met for 
achieving at least partial response to the time of disease progression, with deaths owing to 
causes other than progression not counted, but censored.   The duration of overall CR is 
measured from the time measurement criteria are first met for CR until the first date that 
recurrent disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest measurements recorded since the treatment started. 
Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or death. 
 
7.5 
Response Review 
The CUMC Data Safety and Monitoring Plan includes provisions for independent review 
and confirmation of responding patients on clinical trials.  All reported responders on this 
trial will be subject to independent review and confirmation.   
 
8 
CORRELATIVE STUDIES 
 
Part of the blood and bone marrow samples obtained during this trial will be used for 
correlative studies.  Patients will be informed of these studies during the informed consent 
process. 
 
9 
REGULATORY OBLIGATIONS 
 
9.1 
Adverse Event Reporting 
 
Serious Adverse Drug Experience 
Only Serious Adverse Event (SAE) which meets the definition of an Unanticipated Problem 
Involving Risks to Subjects or Others will be reported promptly but no later than one week 
to the CUMC IRB. 
 
“Adverse Event” is any untoward or unfavorable medical occurrence in a human subject, 
including any abnormal sign, symptom or disease, temporally associated with the subject’s 
participation in research, whether or not considered related to the subject’s participation in 
the research. 
 
“Monitoring Entity” is the group that is responsible for overseeing the safety of all subjects 
enrolled in the study in accordance with the protocol (e.g., a Data Safety Monitoring Board 
(DSMC), a Data Monitoring Committee (DMC), a coordinating or statistical center, or a 
sponsor).  
 
“Unanticipated Problem” is any incident, experience or outcome involving risk to subjects or 
others in any human subjects research that meets all of the following criteria: 
▪ Unexpected (in terms of nature, severity or frequency) given (a) the research procedures 


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Investigator Protocol 19 June 2015  
 
that are described in the IRB-approved protocol and informed consent document, and (b) the 
characteristics of the subject population.  
▪ Related or possibly related to participation in such research (i.e. there is a reasonable 
possibility that the incident, experience or outcome may have been caused by the procedures 
involved in such research); and  
▪ Suggests that the research places subjects or other at a greater risk of harm (including 
physical, psychological, economic or social harm) than was previously known or recognized. 
 
Any adverse drug experience occurring at any dose that results in any of the following 
outcomes: Death, a life-threatening adverse drug experience, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant disability/incapacity, a 
congenital anomaly/birth defect or a suspected positive pregnancy, Important medical events 
that may not result in death, be life-threatening, or require hospitalization may be considered 
a serious adverse drug experience when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.   
 
Unexpected Drug Adverse Experience 
Any adverse drug experience, the specificity or severity of which is not consistent with the 
current investigator brochure; or, if an investigator brochure is not required or available, the 
specificity or severity of which is not consistent with the risk information described in the 
general investigational plan or elsewhere in the current application, as amended.   
Associated with the use of the drug: There is a reasonable possibility that the experience may 
have been caused by the drug. 
 
Disability 
A substantial disruption of a person's ability to conduct normal life functions. 
 
Life-threatening adverse drug experience 
Any adverse drug experience that places the patient or subject, in the view of the 
investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction that, had it occurred in a more severe form, might have caused death. 
 
Medical Event 
Medical 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  
 
Scoring 


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Investigator Protocol 19 June 2015  
 
Toxicity will be scored using CTCAE Version 4.0 for toxicity and adverse event reporting.  
A copy of the CTCAE Version 4.0 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 4.0.  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. 
 
Reporting 
Only events which meet the definition of an Unanticipated Problem (UP) and are considered 
possibly related to lenalidomide need to be reported to the CUMC IRB after day 31+ of 
induction.  All other unrelated events or events related to the SOC transplant process should 
be documented, but do not need to be submitted to the CUMC IRB.  Starting at Day 1 of 
maintenance lenalidomide, all events which meet the definition of an UP need to be reported 
to the CUMC IRB. 
 
ADVERSE EVENT REPORTING 
TO: COLUMBIA UNIVERSTIY MEDICAL CENTER IRB 
The investigator must inform CUMC Institutional Review Board (IRB) in accordance with 
their guidelines.   
Provide the IRB with a copy of the MedWatch 3500A form within one week of the onset 
and assessment of the event. 
 
TO SUPPORTER: CELGENE CORPORATION 
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 
date of awareness should be noted on the report.  The written report must be completed and 
supplied to Celgene by facsimile within 24 hours/1 business day at the latest on the 
following working day.  The initial report must be as complete as possible, including details 
of the current illness and (serious) adverse event, and 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 
received after the report) must be documented on a follow-up report.  A final report to 
document resolution of the SAE is required.  The Celgene tracking number (RV-MM-PI-
0385) and the institutional protocol number should be included on SAE reports (or on the 
fax cover letter) sent to Celgene.  A copy of the fax transmission confirmation of the SAE 
report to Celgene should be attached to the SAE and retained with the subject records. 
 
 
PREGNANCY 
Pregnancy of a female subject or the female partner of a male subject while the subject is on 
lenalidomide or within 4 weeks after the subject’s last dose of lenalidomide are considered 


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Investigator Protocol 19 June 2015  
 
expedited reportable events.  If the subject is on lenalidomide, it is to be discontinued 
immediately and the subject is to be instructed to return any unused portion of lenalidomide 
to the Investigator.  The pregnancy must be reported to Celgene Drug Safety within 24 hours 
of the Investigator’s knowledge of the pregnancy by phone and facsimile using the SAE 
Form. 
 
The Investigator will follow the subject until completion of the pregnancy, and must notify 
Celgene Drug Safety of the outcome as specified below.  The Investigator will provide this 
information as a follow-up to the initial SAE. 
 
If the outcome of the pregnancy meets the criteria for immediate classification as a SAE 
(i.e., spontaneous abortion [any congenital anomaly detected in an aborted fetus is to be 
documented], stillbirth, neonatal death, or congenital anomaly), the Investigator should 
follow the procedures for Expedited Reporting of SAEs to Celgene (i.e., report the event to 
Celgene Drug Safety by facsimile within 24 hours of the Investigator’s knowledge of the 
event). 
 
Any suspected fetal exposure to lenalidomide must be reported to Celgene within 24 hours 
of being made aware of the event.  The patient should be referred to an 
obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and 
counseling. 
 
All neonatal deaths that occur within 30 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 30 days that the Investigator suspects 
is related to the in utero exposure to lenalidomide should also be reported. 
 
In the case of a live “normal” birth, Celgene Drug Safety should be advised as soon as the 
information is available. 
Celgene Drug Safety Contact Information: 
Celgene Corporation      
Global Drug Safety and Risk Management    
Connell Corporate Park      
300 Connell Dr.  Suite 6000     
Berkeley Heights, NJ  07922        
Fax: 
 
(908) 673-9115 
E-mail:  
drugsafety@celgene.com 
 
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 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 


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Investigator Protocol 19 June 2015  
 
AE(s) or significant risks to subjects. 
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). 
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.  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 received after the report) must be 
documented on a follow-up report.  A final report to document resolution of the SAE is 
required.  The Celgene tracking number (RV-MM-PI-0385) and the institutional protocol 
number should be included on SAE reports (or on the fax cover letter) sent to Celgene.  A 
copy of the fax transmission confirmation of the SAE report to Celgene should be attached 
to the SAE and retained with the patient records. 
 
9.2 
Data and Safety Monitoring Plan 
The data and safety monitoring plan for this study consists of monitoring safety issues in the 
form of adverse events occurring at this site as well as safety reports regarding external 
events received from Celgene. All such events that meet the reporting guidelines of 
Columbia University Medical Center IRB are submitted on an ongoing basis throughout the 
renewal interval. Events that do not meet the reporting guidelines are reviewed and placed in 
the regulatory file for this study. All reportable events are entered into Velos eResearch and 
submitted to the HICCC Data and Safety Monitoring Committee (DSMC) for review. Study 
progress is also assessed by the study team on a monthly basis during the conduct of this 
trial. This assessment includes discussion of recruitment, screening and accrual issues as 
well as study conduct (dosing, study tests and procedures, response data, patient follow-up, 
deviations, confidentiality, etc.). In addition, new scientific publications or data that suggest 
changes to the current trial may be warranted will be discussed should they arise. Both safety 
and study progress assessments are summarized monthly and reported to the HICCC DSMC, 
which provides oversight to this and all HICCC trials. This cumulative data and safety 
monitoring plan ensures that the risk-to-benefit ratio will be closely monitored for any 
changes. Once all patients are off active study treatment (i.e., are on follow-up only), the 
data and safety monitoring reviews will occur every 6 months rather than monthly. At the 
time of IRB renewal, the data and safety monitoring activities outlined above will be 
summarized and included in the IRB renewal report. 
 
The Data and Safety Monitoring Committee (DSMC) is composed of medical and statistical 
independent reviewers and will meet to review the efficacy and safety data and determine a 
risk/benefit analysis in this subject population.  The purpose of the DSMC is to advise on 
serious safety considerations, lack of efficacy and any other considerations within the charge 
to the Committee.  The DSMC may request additional meetings or safety reports as deemed 
necessary upon discussion with Celgene and its representatives.  The DSMC may stop the 


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Investigator Protocol 19 June 2015  
 
study following review of results from each interim analysis.  The first interim analysis will 
examine only safety information; the second interim, conducted when the database is more 
mature, will examine both safety and efficacy.  Appropriate efficacy and safety data 
summaries will be provided to the DSMC after each interim analysis. 
 
9.3 
Record Retention 
According to 21 CFR 312.62(c), the investigator/sponsor shall retain required records for a 
period of 2 years following the date a marketing application is approved for the drug for the 
indication for which it is being investigated. If no application is to be filed or if the 
application is not approved for such indication, the investigator shall retain these records 
until 2 years after the investigation is discontinued (IND is withdrawn) and the FDA is 
notified. 
 
The investigator/sponsor must retain protocols, amendments, IRB/IBC approvals, copies of 
the Form FDA 1572, completed, signed, dated consent forms, patient source documents, 
case report forms, quality monitoring reports, drug accountability records and all documents 
of any nature regarding the study or patients enrolled. All records will be maintained under 
restricted access by Columbia University’s Clinical Research Management Office while the 
study remains active. Records will be placed in long-term storage after the study is 
completed. The location of long-term storage will be secure and easily accessed for 
regulatory purposes. 
 
9.4 
Protocol Amendments and Deviations 
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.   
 
9.5 
Study Monitoring and Auditing 
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 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 audits 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. 
 


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9.6 
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. 
 
9.7 
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 
representatives of Celgene Corporation 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. 
 
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. 
 
 
10 
STATISTICAL CONSIDERATIONS 
 
10.1 Study Objectives and Endpoints 
The primary objectives of this trial are to estimate and compare the complete response rate in 
newly diagnosed multiple myeloma patients receiving autologous peripheral blood stem cell 
transplant after undergoing 4 cycles of lenalidomide and low-dose dexamethasone (Arm A) 
vs. in those receiving 8 cycles of lenalidomide and low-dose dexamethasone until plateau of 
best response (Arm B).  
  
The secondary objectives are to estimate duration of complete response, objective response 
rate (complete response rate plus partial response rate), progression free survival, overall 
survival, time to progression, time to transplant in both arms and toxicity of the two 
treatments. 
 
Objective response is based on the definitions of complete response, partial response, 
minimal response, and progression as outlined by the IBMTR/ABMTR (Blade 1998). 
 
Target enrollment for this study is 60 patients. 50 patients have been enrolled at the 
University of Pittsburg Cancer Institute, and expected enrollment at the Columbia University 
Medical Center is 10 patients.  
 
Adverse events are evaluated by NCI common toxicity criteria for adverse events (CTCAE) 
v4.0. Toxicity is defined as any adverse event that is probably, possibly, or definitely 
attributable to the regimen.  
 


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Investigator Protocol 19 June 2015  
 
Duration of complete response is calculated as the time interval between the date when a 
confirmed complete response is first documented and the documented date of disease 
progression or death. For an alive and progression free patient, duration of complete 
response is censored by the last follow-up date when patient is documented to be progression 
free. 
 
Progression free survival (PFS) is calculated as the time interval between the treatment start 
date and the documented date of disease progression or death. For an alive and progression 
free patient, PFS is censored by the last follow-up date when patient is documented to be 
progression free.  
 
Time to progression (TTP) is calculated as the time interval between the treatment start date 
and the documented date of disease progression. For a progression-free patient, TTP is 
censored by the date of death or by the last follow-up date when that patient is documented 
to be progression free.  
 
Overall survival (OS) is calculated as the time interval between the treatment start date and 
the documented date of death. For a surviving patient, OS is censored by the last follow-up 
date when that patient is documented to be alive. 
 
Evaluable patients will be used for both efficacy and safety analysis. Evaluable patients are 
patients who meet the protocol inclusion/exclusion criteria, sign the consent form, and 
receive at least one dose of lenalidomide or dexamethasone. 
 
10.2 Statistical Analysis 
Descriptive statistics will be provided for age, gender, race, disease stage at enrollment etc. 
 
We will estimate the complete response rates in both Arms A and B, and construct exact 
95% confidence intervals. We hypothesize that the response rate among patients receiving 8 
cycles lenalidomide/dexamethasone (Arm B) is not worse than that that in Arm A.  We will 
use one-sided binomial test at significance level 0.05 to compare the complete response rates 
between the two arms. 
 
In preliminary results, among 19 patients who assigned to Arm A, none of them had 
complete response; while 3 out of 20 patients in Arm B achieved complete response. 
Assuming the actual response rate among patients in Arm A is 1% and actual complete 
response rate in Arm B is 17%, with total sample size 60 patients and 1:1 randomization 
scheme, we have 80.8% power to detect such difference at 5% significance level.  
 
The accrual rate is estimated to be 15 patients per year in both centers UPMC and CUMC.   
The overall duration of accrual is expected to be 2 – 3 years. The remaining duration of 
accrual is expected to be 12-18 months. 
 
Adverse events will be tabulated by the type, grade, and treatment arm. Fisher exact test or 
Chi-square test will be used to compare severity of different type of adverse event across two 
arms. For any observed serious adverse events (SAEs), its attribution to regimen (unrelated, 


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Investigator Protocol 19 June 2015  
 
unlikely, possible, probable, or definite) will be reported. The observed proportion of 
regiment-related SAEs (number of patients experienced regiment-related SAEs / total 
number of patients treated), along with a 95% confidence interval will be calculated by 
treatment arms.  
 
Duration of complete response, progression free survival, time to progression and overall 
survival curves will be estimated by Kaplan-Meier method. Median PFS, TTP, OS and 
corresponding 95% confidence interval will be reported by treatment arms. Log rank test 
will be used to compare the duration of complete response, progression free survival, time to 
progression and overall survival curves across two treatment arms. 
 
10.3 Interim Analysis 
An interim analysis is planned when each treatment arm has at least 25 patients evaluated for 
objective response (yes or no). The objective response rate and toxicity will be summarized 
by treatment arms.  
 
The toxicity will be continuously monitored. We expect some toxicity with these two 
regimens, and have set up some rules for holding doses and dose de-escalation in the events 
of selected toxicities (section 5.3). Lenalidomide, dexamethasone and autologous stem cell 
transplant for multiple myeloma are approved by food and drug administration (FDA). If the 
observed proportion of SAEs for those 25 patients in each arm is much higher than the FDA 
reported rate of SAE for the corresponding treatment, the enrollment of the study will be 
suspended pending review by data safety and monitoring committee (DSMC) at the 
Columbia University Medical Center.  
 
If the underlying complete response rate in the treatment arm (Arm B) is 30%, the 
probability of observing 3 or less complete responses out of 25 treated patients in arm B is 
0.10. Therefore, if there are 3 or less complete responses out of 25 treated patients in arm B, 
i.e. the observed complete response rate is 10% or less, the trial will be stopped early for 
lack of efficacy. Table 1 lists the probability of stopping the study early under different 
underlying but unknown complete response rate in arm B. 
 
Table 1: Probability of stopping the study early due to lack of efficacy 
Underlying but unknown complete response rate in arm B 
Pr(Early stop)* 
30% 
0.03 
25% 
0.10 
20% 
0.23 
15% 
0.47 
10% 
0.76 
6% 
0.94 
*: Stopping rule: 3 or less complete responses out of 25 treated patients in arm B. 
 
11 
PREMATURE DISCONTINUATION OF STUDY 
 
The Principal Investigator, institution and Celgene have the right to discontinue this study at 


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Investigator Protocol 19 June 2015  
 
any time for reasonable medical or administrative reasons.  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. 
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.). 
 
12 
REFERENCES 
 
1. 
Rajkumar SV, Hayman SR, Lacy MQ, et al. Combination therapy with lenalidomide 
plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood. 2005;106:4050-4053. 
2. 
Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of 
autologous bone marrow transplantation and chemotherapy in multiple myeloma. 
Intergroupe Francais du Myelome. N Engl J Med. 1996;335:91-97. 
3. 
Fermand J-P, Ravaud P, Chevret S, et al. High-dose therapy and autologous 
peripheral blood stem cell transplantation in multiple myeloma: Up-front or rescue 
treatment?  Results of a multicenter sequential randomized clinical trial. Blood. 
1998;92:3131-3136. 
4. 
Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic 
stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348:1875-1883. 
5. 
Blade J, Rosinol L, Sureda A, et al. High-dose therapy intensification compared with 
continued standard chemotherapy in multiple myeloma patients responding to the initial 
chemotherapy: long-term results from a prospective randomized trial from the Spanish 
cooperative group PETHEMA. Blood. 2005;106:3755-3759. 
6. 
Palumbo A, Dimopoulos MA, Delforge M, et al. A Phase III Study to Determine the 
Efficacy and Safety of Lenalidomide in Combination with Melphalan and Prednisone (MPR) 
in Elderly Patients with Newly Diagnosed Multiple Myeloma. ASH Annual Meeting 
Abstracts. 2009 114:# 613. 
7. 
Richardson P, Schlossman R, Weller E, et al. Immunomodulatory drug CC-5013 
overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. 
Blood. 2002;100:3063-3067. 
8. 
Lentzsch S, LeBlanc R, Podar K, et al. Immunomodulatory analogs of thalidomide 
inhibit growth of Hs Sultan cells and angiogenesis in vivo. Leukemia. 2003;17:41-44. 
9. 
Zangari M, Tricot G, Zeldis J, Eddlemon P, Saghafifar F, Barlogie B. Results of 
phase I study of CC-5013 for the treatment of multiple myeloma (MM) patients who relapse 
after high dose chemotherapy (HDCT). Blood. 2001:775a (A3226). 
10. 
Richardson P, Jagannath S, Schlossman R, etal. A multi-center, randomized, phase 2 
study to evaluate the efficacy and safety of 2 CC-5013 dose regimens when used alone or in 
combination with dexamethasone (Dex) for the treatment of relapsed or refractory multiple 
myeloma (MM). Blood. 2003;102:235a. 
11. 
Hideshima T, Chauhan D, Shima Y, et al. Thalidomide and its analogs overcome 
drug resistance of human multiple myeloma cells to conventional therapy. Blood. 
2000;96:2943-2950. 


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Investigator Protocol 19 June 2015  
 
12. 
Mitsiades N, Mitsiades CS, Poulaki V, et al. Apoptotic signaling induced by 
immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic 
implications. Blood. 2002;99:4525-4530. 
13. 
Hideshima T, Chauhan D, Podar K, Schlossman RL, Richardson P, Anderson KC. 
Novel therapies targeting the myeloma cell and its bone marrow microenvironment. Semin 
Oncol. 2001;28:607-612. 
14. 
Davies FE, Raje N, Hideshima T, et al. Thalidomide and immunomodulatory 
derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood. 
2001;98:210-216. 
15. 
Dimopoulos MA, Spencer A, Attal M, et al. Study of lenalidomide plus 
dexamethasone versus dexamethasone alone in relapsed or refractory multiple myeloma 
(MM); results of a phase 3 study (MM-010). Blood. 2005:106:106a (abstract). 
16. 
Weber DM, Chen D, Niesvizky R, et al. Lenalidomide plus high-dose 
dexamethasone provides improved overall survival compared to high-dose dexamethasone 
alone for relapsed or refractory multiple myeloma (MM): results of a North American phase 
III study (MM-009). Journal of Clinical Oncology, 2006 ASCO Annual Meeting 
Proceedings. 2006;24:Abstract #7521. 
16-2.   Palumbo A, Delforge M, Catalano J, et al. A Phase III evaluating efficacy and safety 
of Lenalidomide combined with Melphalan and Prednisone in patients>65 years with newly 
diagnosed Multiple Myeloma (NDMM): Continuous use of lenalidomide vs fixed-duration 
regimens. Blood. 2010;116(21). ASH Annual Meeting Abstracts. 2010: # 622 
17. 
Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR. Phase III clinical trial of 
thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed 
multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J 
Clin Oncol. 2006;24:431-436. 
18. 
Rajkumar SV, Jacobus S, Callander NS, et al. Phase III trial of lenalidomide plus 
high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly 
diagnosed multiple myeloma (E4A03): a trial coordinated by the Eastern Cooperative 
Oncology Group. ASCO Annual Meeting. 2007:Abstract LBA8025. 
19. 
Moreau P, Facon T, Attal M, et al. Comparison of 200 mg/m(2) melphalan and 8 Gy 
total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral 
blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final 
analysis of the Intergroupe Francophone du Myelome 9502 randomized trial. Blood. 
2002;99:731-735. 
20. 
Knight R, DeLap RJ, Zeldis JB. Lenalidomide and venous thrombosis in multiple 
myeloma. N Engl J Med. 2006;354:2079-2080. 
21. 
Rajkumar SV, Blood E. Lenalidomide and venous thrombosis in multiple myeloma. 
N Engl J Med. 2006;354:2079-2080. 
22. 
Zonder JA, Barlogie B, Durie BG, McCoy J, Crowley J, Hussein MA. Thrombotic 
complications in patients with newly diagnosed multiple myeloma treated with lenalidomide 
and dexamethasone: benefit of aspirin prophylaxis. Blood. 2006;108:403; author reply 404. 
23. 
Palumbo A, Dimopoulos M, San Miguel J, et al. Risk factors for venous 
thromboembolism during lenalidomide plus dexamethasone treatment. 12th Congress of the 
European Hematology Association, Vienna, Austria. 2007;June 7-10, 2007. 
24. 
Blade J, Samson D, Reece D, et al. Criteria for evaluating disease response and 
progression in patients with multiple myeloma treated by high-dose therapy and 


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haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European 
Group for Blood and Marrow Transplant. Br J Haematol. 1998;102:1115-1123. 
25. 
Moreau P, Facon T, Attal M, et al. Comparison of 200 mg/m(2) melphalan and 8 Gy 
total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral 
blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final 
analysis of the Intergroupe Francophone du Myelome 9502 randomized trial. Blood. 
2002;99:731-735. 
26. 
Knight R, DeLap RJ, Zeldis JB. Lenalidomide and venous thrombosis in multiple 
myeloma. N Engl J Med. 2006;354:2079-2080. 
27. 
Rajkumar SV, Blood E. Lenalidomide and venous thrombosis in multiple myeloma. 
N Engl J Med. 2006;354:2079-2080. 
28. 
Zonder JA, Barlogie B, Durie BG, McCoy J, Crowley J, Hussein MA. Thrombotic 
complications in patients with newly diagnosed multiple myeloma treated with lenalidomide 
and dexamethasone: benefit of aspirin prophylaxis. Blood. 2006;108:403; author reply 404. 
29. 
Durie BG, Harousseau JL, Miguel JS, et al.  International uniform response criteria 
for mulitple myeloma.  Leukemia. 2006; 20: 1467-1473. 
30. 
Palumbo A, Dimopoulos M, San Miguel J, et al. Risk factors for venous 
thromboembolism during lenalidomide plus dexamethasone treatment. 12th Congress of the 
European Hematology Association, Vienna, Austria. 2007;June 7-10, 2007. 
31. 
Blade J, Samson D, Reece D, et al. 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. 1998;102:1115-1123. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix A Subject Medication Diary 
 
Subject Name 
 
Sequence Number 
 
Cycle 
 
 
Please use this diary to record the medication you take for the protocol.  Use the space 
marked comments to make notes about things you would like to tell the study doctor 
(including symptoms you experience, and anything else you think would be of interest). 
 
DAY 
DATE 
LENALIDOMIDE 
DOSE TAKEN 
DEXAMETHASONE 
DOSE TAKEN 
OTHER  
MEDICATIONS 
COMMENTS 
Example 
 
_ mg 
40 mg 
Aspirin at least 81 
mg, Ranitidine 2 
tablets 
Skin rash 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
 
10 
 
 
 
 
 
11 
 
 
 
 
 
12 
 
 
 
 
 
13 
 
 
 
 
 
14 
 
 
 
 
 
15 
 
 
 
 
 
16 
 
 
 
 
 
17 
 
 
 
 
 
18 
 
 
 
 
 
19 
 
 
 
 
 
20 
 
 
 
 
 
21 
 
 
 
 
 
22 
 
 
 
 
 
23 
 
 
 
 
 
24 
 
 
 
 
 
25 
 
 
 
 
 


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Investigator Protocol 19 June 2015  
 
26 
 
 
 
 
 
27 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
Appendix B Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, 
able to carry on all pre-
disease performance without 
restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal 
activity; minor signs or 
symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry 
out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry 
on normal activity or to do 
active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry 
out any work activities.  Up 
and about more than 50% of 
waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable 
assistance and frequent medical 
care. 
3 
In bed >50% of the time.  
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking 
hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated.  
Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on 
any self-care.  Totally 
confined to bed or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 


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Appendix C Impaired Renal Function Dosing Schedule 
 
Recommended dose adjustments during lenalidomide therapy in patients with impaired renal 
function. 
 
Renal function (CLCr) 
 
Lenalidomide dose adjustment 
Mild renal impairment (CLCr ≥ 50 ml/min) 
25 mg once daily 
Moderate renal impairment (30 ≤ CLCr < 50 ml/min) 
10 mg once daily* 
Severe renal impairment (CLCr < 30 ml/min, not 
requiring dialysis 
15 mg every other day* 
End-stage renal disease (CLCr < 30 ml/min, requiring 
dialysis 
15 m g 3 times per week 
following each dialysis 
 
*The dose may be escalated to 15 mg once daily after 2 cycles if the patient is not 
responding to, but is tolerating, the treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix D Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth 
Control Methods 
 
RISKS ASSOCAITED 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. 
 
Study participants must follow pregnancy testing requirements as outlined in the Revlimid 
REMS® program material. 
 
All study participants must be registered into the mandatory Revlimid REMS® program, and 
be willing and able to comply with the requirements of Revlimid REMS®. 
 
CRITERIA for Females of Childbearing Potential (FCBP) 
This protocol defines a female of childbearing potential as a sexually mature female who: 1) 
has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally 
postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the 
preceding 24 consecutive months). 
The investigator must ensure that: 
▪ Females of childbearing potential comply with the conditions for pregnancy risk 
minimization, including confirmation that she has an adequate level of understanding 
▪ Females NOT of childbearing potential acknowledge that she understands the hazards and 
necessary precautions associated with the use of lenalidomide 
▪ Males taking lenalidomide acknowledge that he understands that traces of lenalidomide 
have been found in semen, that he understands the potential teratogenic risk if engaged in 
sexual activity with a female of childbearing potential, and that he understands the need for 
the use of a condom even if he has had a vasectomy, if engaged in sexual activity with a 
female of childbearing potential.   
 
CONTRACEPTION 
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two 
reliable forms of contraception simultaneously or to practice complete abstinence from 
heterosexual intercourse during the following time periods related to this study: 1) for at 
least 28 days before starting lenalidomide; 2) throughout the entire duration of lenalidomide 
treatment; 3) during dose interruptions; and 4) for at least 28 days after lenalidomide 


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discontinuation.  
 
The two methods of reliable contraception must include one highly effective method and one 
additional effective (barrier) method. FCBP must be referred to a qualified provider of 
contraceptive methods if needed. The following are examples of highly effective and 
additional effective methods of contraception:   
▪ Highly effective methods: 
▪ Intrauterine device (IUD) 
▪ Hormonal (birth control pills, injections, implants) 
▪ Tubal ligation 
▪ Partner’s vasectomy 
▪ Additional effective methods: 
▪ Male condom 
▪ Diaphragm 
▪ Cervical Cap 
 
Because of the increased risk of venous thromboembolism in patients with multiple 
myeloma taking lenalidomide and dexamethasone, combined oral contraceptive pills are not 
recommended. If a patient is currently using combined oral contraception the patient should 
switch to one of the effective method listed above. The risk of venous thromboembolism 
continues for 4−6 weeks after discontinuing combined oral contraception. The efficacy of 
contraceptive steroids may be reduced during co-treatment with dexamethasone. 
 
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased 
risk of infection at the time of insertion and irregular vaginal bleeding. Prophylactic 
antibiotics should be 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 
FCBP must have two negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to 
prescribing lenalidomide.  The first pregnancy test must be performed within 10-14 days 
prior to prescribing lenalidomide and the second pregnancy test must be performed within 24 
hours prior to prescribing lenalidomide.  The patient may not receive lenalidomide until the 
Investigator has verified that the results of these pregnancy tests are negative. 
 
Male 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 


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lenalidomide discontinuation, even if he has undergone a successful vasectomy.   
 
DURING STUDY PARTICIPATION AND FOR 28 DAYS FOLLOWING LENALIDOMIDE 
DISCONTINUATION  
 
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.   
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.   
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 
Both female and male subjects should be instructed never to give lenalidomide to another 
person. 
Female subjects should not donate blood during therapy and for at least 28 days following 
discontinuation of lenalidomide. 
Male subejcts should not donate blood, semen or sperm during therapy or for at least 28 days 
following discontinuation of lenalidomide. 
Only enough lenalidomide for one cycle of therapy may be prescribed with each cycle of 
therapy.  
 
 
 
 
 


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Appendix E Staging of Myeloma: Durie-Salmon System and International Staging System 
 
The staging system most widely used since 1975 has been the Durie-Salmon system, in 
which clinical stage of disease (stage I, II, or III) is based on four measurements: levels of M 
protein, the number of lytic bone lesions, hemoglobin values, and serum calcium levels. 
Stages are further divided according to renal function.  
There is somewhat of an overlap between the various myeloma categories and stages. For 
example, both patients with smoldering myeloma and patients with Stage I disease do not 
require immediate treatment, and patients with Stage II and III disease have active, 
symptomatic myeloma. Increasingly, physicians are relying less on the Durie-Salmon 
staging system and more on biologically relevant markers as prognostic indicators when 
making treatment choices. 
A new, simpler, more cost-effective alternative is the International Staging System (ISS). 
The ISS is based on the assessment of two blood test results, beta 2-microglobulin (ß2-M) 
and albumin, which together showed the greatest prognostic power for multiple myeloma. 
This system has only recently been developed, but has already been proven more sensitive in 
discriminating between three stages of the disease, which indicate different levels of 
projected survival and suggest increasingly more aggressive treatment strategies.  
 
The following table summarizes the staging criteria. 
Stage 
Durie-Salmon Criteria 
ISS Criteria 
I 
All of the following: 
Hemoglobin value >10 g/dL 
Serum calcium value normal 
Bone x-ray, normal bone structure (scale 0) or 
solitary bone plasmacytoma only 
Low M-component production rate - IgG value <5 
g/dL; IgA value <3 g/dL  
Bence Jones protein <4 g/24 h 
ß2-M   3.5 mg/L and album n ≥3.5 
g/ L  
II* 
Neither stage I nor stage III 
*Stage II =( ß2-M <3.5 g/dL &  
albumin <3.5) OR  (ß2-M 3.5 - 5.5 
mg/dL,)  
III 
One or more of the following: 
Hemoglobin value <8.5 g/dL 
Serum calcium value >12 mg/dL 
Advanced lytic bone lesions (scale 3) 
High M -component production rate - IgG value 
>7 g/dL; IgA value >5 g/dL - Bence Jones protein 
>12 g/24 h  
ß2-M ≥ 5.5 mg/L 
Durie-Salmon sub classifications (either A or B) 


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A: Relatively normal renal function (serum creatinine value <2.0 mg/ L  
B: Abnormal renal function (serum creatinine value =2.0 mg/dL