Conditions: Multiple Myeloma
Keywords: Newly Diagnosed Standard Risk Multiple Myeloma Senior Adults
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 27
Healthy volunteers: no

Brief summary:
The purpose of this research is to estimate the effectiveness of a response adapted approach with the use of the drug, lenalidomide in the treatment of older adults with newly diagnosed standard risk multiple myeloma. This means that participants will be given the study drug, lenalidomide but depending on how they respond to this drug they may also be given dexamethasone and/or prednisone to help with their treatment.

Detailed description:
Summary: Patients will be started on the study drug, lenalidomide on Day 1, Cycle 1. Lenalidomide is a capsule that is to be taken orally (by mouth). If the patient's disease progresses after 2 cycles of therapy, a low dose of dexamethasone will be added. If the patient's disease is stable after 2 cycles of therapy, the use of an alternate corticosteroid (prednisone) will be added to the lenalidomide therapy they are receiving. Dexamethasone and prednisone are in tablet form and will be taken orally (by mouth). However, if the patient has a minimal response after an additional 2 cycles of lenalidomide therapy, the therapy will be continued until their disease progresses. See the intervention descriptions for further details.

Arms:
arm 1: Lenalidomide, prednisone and dexamethasone as outlined in Intervention Descriptions.

Interventions: intervention 1: Lenalidomide intervention 2: Prednisone intervention 3: Dexamethasone
Intervention descriptions: intervention 1: * Starting Dose: 25 mg by mouth (PO) days 1-21 of a 28 days cycle;
* Dose Level -1: 15 mg PO days 1-21 of a 28 days cycle;
* Dose Level -2: 10 mg PO days 1-21 of a 28 days cycle;
* Dose Level -3: 5 mg PO days 1-21 of a 28 days cycle;
* Dose Level -4: Discontinue intervention 2: * Starting Dose: 100 mg PO days 1-5 every 28 days;
* Dose level -1: 50 mg PO days 1-5 of a 28 day cycle;
* Dose level -2: 25 mg PO days 1-5 of a 28 day cycle;
* Dose level -3: Discontinue intervention 3: * Starting Dose: 40 mg daily on days 1 - 4 every 28 days;
* Dose level -1: 20 mg daily on days 1 - 4 every 28 days;
* Dose level -1a: 40 mg daily on days 1, 2, and 3 followed by 20 mg on day 4 followed by 12 mg on day 5 followed by 8 mg on day 6;
* Dose level -2: 10 mg daily on days 1 - 4 every 28 days;
* Dose level -3: Discontinue

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
Phase II Study of Response Adapted Therapy Using Single Agent Lenalidomide in 
Older Adults with Newly Diagnosed, Standard Risk Multiple Myeloma 
 
NCT01054144 
Version 6 
April 15, 2016 


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Myeloma Program 
 
 
 
 
SPONSOR: 
H. Lee Moffitt Cancer Center 
STUDY NUMBER: MCC 16018 
CELGENE TRACKING #: 
RV-MM-PI-0454 
 
 
STUDY TITLE: Phase II Study of response adapted therapy using single agent 
lenalidomide in older adults with newly diagnosed standard risk multiple myeloma. 
 
PRINCIPAL INVESTIGATOR: Rachid Baz, MD 
STATISTICIAN: 
Hui-Yi Lin, PhD 
 
Zhenjun Ma, 
PhD 
 
SUPPORTER(S): 
Celgene Corporation 
 
CLINICAL FACILITY: 
H. Lee Moffitt Cancer Center and Research Institute 
STUDY DRUGS: 
Lenalidomide (Revlimid®) 
Prednisone 
Dexamethasone (Decadron) 
PROTOCOL VERSION: 
Version 6 (April 15, 2016) 
 
IRB APPROVAL DATE: 
12/08/2009 
 
 
 
CONFIDENTIAL 
 
This protocol is provided to you as an Investigator, potential Investigator, or consultant for review by you, your 
staff, and ethics committee/institutional review board. The information contained in this document is regarded 
as confidential and, except to the extent necessary to obtain informed consent, may not be disclosed to another 
party unless such disclosure is required by law or regulations. Persons to whom the information is disclosed 
must be informed that the information is confidential and may not be further disclosed by them. 


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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
 
 
 
 
Principal Investigator: 
Signature of Investigator 
Rachid Baz, MD 
By my signature, I agree to personally supervise the conduct of this stu
conduct in compliance with the protocol, informed consent, IRB/EC pr
instructions from Celgene representatives, the Declaration of Helsinki,
Practices guidelines, and the applicable parts of the United States Code
Regulations or local regulations governing the conduct of clinical studi 
Date 
dy and to ensure its 
ocedures, 
ICH Good Clinical 
of Federal 
es. 


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Table of Contents 
 
 
Page 
 
 
1 
Protocol Synopsis .......................................................................................... 4 
2 
Schedule of Study Assessments ................................................................... 8 
3 
Glossary of Abbreviations ............................................................................ 11 
4 
Background and Rationale ........................................................................... 15 
5. Study Endpoints. .......................................................................................... 22 
6. Investigational Plan ...................................................................................... 23 
7. Study population .......................................................................................... 26 
8. Treatments .................................................................................................. 30 
9. Safety assessments ..................................................................................... 48 
10. Protocol Amendments/Deviations ................................................................ 60 
11. Data Management ....................................................................................... 61 
12. Bio-statistical Consideration ......................................................................... 64 
13. Regulatory Considerations ........................................................................... 69 
14. Appendices .................................................................................................. 74 
15. References .................................................................................................. 85 


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1 Protocol Synopsis 
 
 
PROTOCOL  TITLE:  Phase  II  Study  of  response  adapted  therapy  using  single  agent 
lenalidomide in older adults with newly diagnosed standard risk multiple myeloma. 
PROTOCOL NUMBER: 
MCC16018 
IRB 
APPROVAL 
DATE 
OF 
PROTOCOL: 
12/08/2009 
STUDY DRUG(s): 
Lenalidomide (Revlimid®) 
Prednisone 
Dexamethasone (Decadron) 
INDICATION: 
Newly Diagnosed (standard risk) Multiple Myeloma 
with Active Disease 
STUDY PHASE: 
2 
STUDY OBJECTIVES: 
Primary: 
1-  To estimate the efficacy of a response adapted approach of treatment of older adults with 
standard risk multiple myeloma 
Secondary: 
1.  To evaluate the efficacy of single agent lenalidomide in patients with standard risk 
multiple myeloma 


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2. To evaluate the safety and efficacy of the combination of lenalidomide and prednisone in 
non responders to single agent lenalidomide 
3. To evaluate markers of lenalidomide induced tumor immunity in patients treated with 
single agent lenalidomide 
STUDY DESIGN: 
This is a multi-center, single-arm, phase 2, open-label study of lenalidomide [Revlimid® (R)] 
based therapy in older adults with standard risk multiple myeloma. After enrollment patients will 
receive single agent lenalidomide. Responders (minimal response or better) after 2 cycles will 
continue present therapy until disease progression or intolerable toxicity. Patients with stable 
disease after 2 cycles will receive prednisone (100 mg orally on days 1to 5 of each cycles) in 
addition to lenalidomide. Patients with evidence of disease progression after 2 cycles of single 
agent lenalidomide will receive low dose dexamethasone (40 mg weekly) in addition to 
lenalidomide. Patients not receiving low dose dexamethasone and with disease progression at 
any time during the study will be eligible to receive low dose dexamethasone in combination 
with lenalidomide. Patients on lenalidomide and low dose dexamethasone who experience 
disease progression at any time during the study will be taken off study and treated with 
alternative therapies.. 
STUDY ENDPOINTS 
Primary: 
1- The 12-month progression free survival (PFS) of older adults with mildly symptomatic 
multiple myeloma treated on this response adapted approach (i.e. time from lenalidomide 
start to failure of lenalidomide and low dose dexamethasone) 


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Secondary: 
1- The response rate of older adults with mildly symptomatic multiple myeloma to single 
agent lenalidomide, lenalidomide prednisone and lenalidomide low dose dexamethasone 
in patients with suboptimal responses to lenalidomide monotherapy 
2- The toxicity profile of these lenalidomide based combinations 
3- The progression free survival of patients treated with single agent lenalidomide 
4- The 1 year overall survival (OS) of older adults with mildly symptomatic multiple 
myeloma treated on this response adapted approach 
Exploratory 
1- Measure a lenalidomide induced tumor specific immune response and correlate the tumor 
specific immune response with corticosteroid use, response to therapy and duration of response 
2- To evaluate the impact of lenalidomide mono-therapy on expression of tumor suppression 
genes and cell cycle regulators 
STUDY DURATION: Patients will receive 
study therapy until evidence of disease 
progression on lenalidomide and low dose 
dexamethasone, 
unacceptable 
toxicity 
or 
withdrawal of consent 
TOTAL SAMPLE SIZE: approximately 30 
patients enrolled at Moffitt and 30 patients 
enrolled in a parallel identical design study in 
multiple sites in South Korea. 
STUDY  DRUG  SUPPLIES:  Lenalidomide capsules  will  be  supplied  by  Celgene 
Corporation at no charge through the RevAssist® program. 
Commercial supplies of dexamethasone (Decadron®) and prednisone tablets will be utilized. 
Commercial supplies of aspirin will be utilized. 


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DOSING REGIMENS: 
 
 
 Oral Lenalidomide (R) will be administered every 28 days as follows: 
 
 
 25 mg QD PO daily on Days 1-21 followed by 7 days rest (10 mg dose will be used for 
patients with a Creatinine clearance < 60 ml/min) 
 
 
 Oral Prednisone (100 mg) will be administered on days 1 to 5 of every 28 days cycle in 
patients receiving combination lenalidomide and prednisone (LP). 
 Oral  dexamethasone  (40  mg)  will  be  administered  once  a  week  in  patients  receiving 
lenalidomide and low dose dexamethasone (Ld). 
All subjects will also receive concomitant aspirin 81 mg PO daily. For patients who cannot tolerate 
aspirin, low molecular weight heparin or therapeutic doses of coumadin may be used in place of aspirin. 
 
Rationale for Amendment 6 
MCC16018 has enrolled 30 patients from 2/2010 to 6/2013. It has been closed to accrual since 
10/2013 given it met its accrual target. Currently, six patients only continue on treatment, for now 
2-4 years. We anticipate to final close the study as soon as a manuscript has been published.   
Of note, lenalidomide was approved by the FDA for newly diagnosed multiple myeloma patients in 
2/2015. MCC16018 involves lenalidomide based therapy for newly diagnosed multiple myeloma 
and is thus currently considered standard of care (although that use was considered investigational 
at the time of initiation and completion of accrual of the study). Accordingly, we propose to collect 
more limited data pertaining to the current treatment of study subject as of 2/2016 until the final 
closure of the trial. Specifically, we will only plan to capture only serious adverse events (SAE), 
response and follow up data. Patients will continue on treatment and undergo standard of care 
monitoring which is at the discretion of the treating physician.  
The changes made with this amendment will serve several purposes:  
1- Decrease the burden on patients to comply with study requirement (for example, comply 
with study visit timeframe). 
2- Decrease the number of deviations due to non-compliance with study requirements (such as 
missed 24h urine protein electrophoresis, laboratory testing outside the window).  
3- Decrease the burden to the study team which would otherwise continue to collect additional 
data which will not aid in the overall interpretation of the study results (it is unlikely that a 
new toxicity to lenalidomide will be encountered in this study population that have been on 
this treatment for now 2-4 years on average)  


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2 Schedule of Study Assessments 
 
 
Procedure 
Screening/ 
Baseline 
(-28 Days) 
Cycle 
1 
Day 
1 
Cycle 
2 day 
28 
Every 
4 
Weeks 
(1st 6 
cycles) 
Maintenance 
Addition of 
Prednisone or 
Dexamethasone 
2 months after 
Off 
Study1 
Every 3 
months 
except 
where 
the addition of 
dexamethasone 
Indicated
15 
Informed consent 
X 
- 
- 
- 
- 
- 
- 
Inclusion/exclusion criteria 
X 
- 
- 
- 
- 
- 
- 
Complete medical history 
X 
- 
- 
- 
- 
- 
- 
Confirm diagnosis and 
stage/type MM 
X 
- 
- 
- 
- 
- 
- 
Performance status (ECOG) 
X 
X 
- 
X 
 
X 
X 
Concurrent therapy 
X 
X 
- 
X 
 
X 
X 
Safety Assessments: 
- 
X 
- 
X 
X12 
X 
X12 
Adverse event query 
Concomitant Medication query 
X 
X 
- 
X 
- 
X 
X 
Vital signs/ BSA 
X 
X 
- 
X 
- 
X 
X 
12-lead ECG 
X 
- 
- 
- 
- 
- 
- 
Physical examination 
X 
X 
- 
X 
- 
X 
X 
CBC w/diff9 
X 
X9 
- 
X9 
- 
X 
X 
Serum Chemistry2 
X 
- 
X 
- 
X 
X 
TSH, T3, T43 
X 
- 
- 
X3 
- 
- 
- 
Pregnancy testing and 
X4 
X4 
- 
X4 
- 
X 
X4 
counseling4 
X 
- 
- 
X 
- 
X 
X 
Serum Free Light Chain 
X13 
- 
- 
- 
- 
- 
- 
Serum B12, RBC Folate, 
Efficacy measurements: 
X 
- 
- 
X 
X  
- 
X 
X 
-2-M 
Protein electrophoresis (serum 
X 
- 
- 
X 
- 
X 
X 
and urine) 
X 
- 
- 
X 
- 
X 
X 
Quantitative immunoglobulins 
X 
- 
- 
X 
- 
X 
X 
Immunofixation studies (serum 
X 
- 
- 
X5 
- 
X 
X 
and urine) 
Skeletal survey 
X 
- 
- 
- 
X14 
- 
- 
X 
- 
- 
X 
X 
X 
X 
Dosing: 
X 
- 
- 
X10 
- 
X 
X10 
X 
X 
X 
- -- 
- 
X 
X 
X 
X 
- 
X 
X 
Register patient into RevAssist® 
program 
Prescribe study drug10 
Count study drug returns10 
Dispense Diary Cards 
Collect Diary Cards 
Correlative testing 
Bone marrow aspiration for 
ancillary studies 
Peripheral blood collection for 
ancillary studies 
X 
X14 
X14 
X14 
X14 
X14 
X14 
Follow-up: 
Survival 
X  
X8 
 
Screening procedures must be done within 28 days of first cycle unless otherwise specified. 


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Starting with Cycle 1, Day 1, and all tests must be done +/- 7 business days of the treatment 
visit day. However, pregnancy testing must be done strictly as scheduled in footnote #4 
below and in sections 6.5.1 and 6.7 without an allowance of +/- 7 days. 
 
* An unscheduled visit can occur at any time during the study. Source must be maintained for these unscheduled 
visits. The date for the visit and any data generated must be recorded on the appropriate CRF. Source documents for 
these unscheduled visits must also be maintained. 
 
1 All subjects are to have the designated tests performed upon discontinuation of study drug. 
 
 
2 Clinical laboratory examinations include: total protein, albumin, calcium, , glucose, total bilirubin, alkaline 
phosphatase, AST (SGOT), ALT (SGPT), sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, 
creatinine, and LDH. 
 
3 Serum TSH, (Thyroid Stimulating Hormone), T3 and T4 levels every 3 months 
 
4 Pregnancy testing for females of child bearing potential. A female of childbearing potential (a woman of 
childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral 
oophorectomy or 2) who has not been postmenopausal for at least 24 consecutive months [i.e., who has had menses 
at any time in the preceding 24 consecutive months]). Pregnancy testing must be performed 10 to 14 days and again 
within 24 hours prior to prescribing lenalidomide for Cycle 1. (prescriptions must be filled within 7 days). FCBP 
with regular or no menstruation must have a pregnancy test weekly for the first 4 weeks and then every 28 days  
while on therapy (including breaks in therapy); at discontinuation of lenalidomide and at Day 28 post the last dose of 
lenalidomide. Females with irregular menstruation must have a pregnancy test weekly for the first 4 weeks and then 
every 14 days while on therapy (including breaks in therapy), at discontinuation of lenalidomide and at Day 14 and 
Day 28 post the last dose of lenalidomide. (see Appendix VIII: Risks of Fetal Exposure, Pregnancy Testing 
Guidelines and Acceptable Birth Control Methods). 
 
5 Skeletal survey is to be performed at baseline, upon addition of corticosteroids (prednisone and / or 
dexamethasone) , discontinuation, and when clinically indicated. 


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6 Bone marrow biopsy is to be performed at baseline, after 2 cycles of single agent lenalidomide therapy, to confirm 
CR, at the time of addition of corticosteroids (prednisone and / or dexamethasone), discontinuation, and when 
clinically indicated. 
 
8 Survival follow-up to be completed every 3 months. 
 
 
9 CBC with diff. is required on Day 1Cycle 1 (unless baseline done within 7 days of Day 1), then every 2 weeks for 
the first 4 weeks of therapy. After the first 4 weeks of therapy, if the patient required a dose reduction of 
lenalidomide (Revlimid®) or the addition of cytokine support due to neutropenia encountered during the previous 
cycle, CBC with diff. is required at least every 2 weeks during the next cycle, otherwise CBC with diff. is required 
at least every 4 weeks.   More frequent CBCs may be obtained at the investigator’s discretion. After 4/2016, 
laboratory testing is at the discretion of the treating physician and in accordance with lenalidomide package insert. 
CBC will not be collected for the purpose of the trial but could be ordered per standard practise 
10 Lenalidomide must be prescribed through and in compliance with Celgene’s RevAssist® Program. Prescriptions 
must be filled within 7 days. Drug returned from the previous cycle will be counted, recorded in the patient’s CRF. 
Patients must be instructed to return all bottles (whether empty, partial or full) at each visit. Unused lenalidomide 
should be returned to the patient for disposition in accordance with the RevAssist® program. After April 2016, 
diaries and pill counts will not be performed.  
11. During maintenance, patients will have laboratory testing per institutional standard of care approximately  
e v e r y  3  m o n t h s .   
12 After April 2016, only serious adverse events SAE will be collected. 
 
13 At the initiation of study and yearly thereafter. 
 
14 Ancillary bone marrow aspiration will be obtained at baseline and after 2 months of lenalidomide monotherapy. 
Ancillary peripheral blood samples will be obtained at baseline, after 2 months of lenalidomide monotherapy and 
after 2 month of addition of dexamethasone .see section 9.7.4 for details regarding ancillary studies. 
15. Patients who complete the first 6 cycles of therapy, are on a stable dose of lenalidomide for more than 2 cycles and 
are responding to therapy are eligible for entering a maintenance schedule of visits where office visits will be every 3 
months and monitoring will be pre institutional standard of care Patient will continue to be followed for disease 
progression per standard clinical practice.  


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3 
Glossary of Abbreviations 
 
 
2-M 
Beta2-microblogulin 
 
 
-hCG 
Beta - Human chorionic gonadotropin 
 
 
AE 
Adverse event 
 
 
ALT (SGPT) 
Alanine transaminase (serum glutamate pyruvic transaminase) 
AST (SGOT) 
Aspartate transaminase (serum glutamic oxaloacetic transaminase) 
Bid 
Twice per day 
BM 
Bone marrow 
 
 
BMSC 
Bone marrow stromal cells 
 
 
BUN 
Blood urea nitrogen 
 
 
CBC 
Complete blood count 
 
 
CFR 
Code of Federal Regulations 
 
 
CR 
Complete response 
 
 
CRF 
Case report form 
 
 
CTC 
Common toxicity criteria 
 
 
DLT 
Dose-limiting toxicity 
 
 
DSMP 
Data Safety Monitoring Plan 
 
 
DVT 
Deep vein thrombosis 
 
 
EC 
Ethics Committee 


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ECG 
Electrocardiogram 
 
 
ECHO 
Echocardiogram 
 
 
EGR1 
Early Growth Response 1 
 
 
EGR2 
Early Growth Response 2 
 
 
EGR3 
Early Growth Response 3 
 
 
FDA 
Food and Drug Administration 
 
 
GCP 
Good clinical practice 
 
 
G-CSF 
Granulocyte colony stimulating factor 
 
 
GM-CSF 
Granulocyte macrophage colony stimulating factor 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
 
 
IFN- 
Interferon-alpha 
 
 
IL 
Interleukin 
 
 
IMiD 
Immunomodulatory drug 
 
 
IMWG 
International Myeloma Working Group 
 
 
IND 
Investigational New Drug 
 
 
IRB 
Institutional Review Board 
 
 
IVP 
Intravenous push 
 
 
LDH 
Lactate dehydrogenase 
 
 
mAbs 
Monoclonal antibodies 


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MM 
Multiple myeloma 
 
 
MTD 
Maximum tolerated dose 
 
 
NCI 
National Cancer Institute 
 
 
NK cells 
Natural Killer Cells 
 
 
PBMC 
Peripheral blood mononuclear cells 
 
 
PD 
Progressive disease 
 
 
PCR 
Polymerase chain reaction 
 
 
PDE-4 
Phosphodiesterase 4 
 
 
PO 
Per orum – by mouth 
 
 
PR 
Partial Response 
 
 
PS 
Performance status 
 
 
SAE 
Serious adverse event 
 
 
Q.D. 
Every day 
 
 
Q-PCR 
Quantitative Polymerase Chain Reaction 
SPARC 
Secreted Protein Acidic and Rich in Cysteine 
SD 
Stable disease 
SWOG 
Southwest Oncology Group 
 
 
TCR 
T-cell receptor 
 
 
TGF 
Tumor growth factor beta 
 
 
TNF 
Tumor necrosis factor 


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TPP 
Therapeutics Product Programme 
 
 
TSH 
Thyroid-stimulating hormone 
 
 
ULN 
Upper limit of normal 
 
 
VEGF 
Vascular endothelial growth factor 
 
 
WBC 
White blood cell 
 
 
WCBP 
Women of child bearing potential 
 
 
WHO 
World Health Organization 


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4 
Background and Rationale 
 
 
 
4.1. 
Multiple Myeloma 
 
 
Multiple myeloma is a plasma cell neoplasm characterized by an infiltrate of monoclonal plasma 
cells in the bone marrow which results in the production of a monoclonal protein. Multiple 
myeloma accounts for approximately 10% of hematologic malignancies and about 1% of 
malignancies overall[1]. Approximately 19,000 patients will be diagnosed with multiple 
myeloma in 2007 in the United States and the median age at the time of diagnosis is 70 years 
(hence most patients with multiple myeloma are older than 65 years)[1]. Bone marrow 
involvement may result in cytopenias, painful skeletal lytic lesions and systemic symptoms 
(fevers, sweats, anorexia and weight loss); while the paraprotein may cause renal dysfunction, 
neuronal damage, amyloid deposition, and rarely hyperviscosity. The cornerstone of therapy of 
multiple myeloma has traditionally included the use of corticosteroids (prednisone or 
dexamethasone). However, these agents have substantial toxicities especially in the multiple 
myeloma patient population which tends to be particularly vulnerable to those side effects 
(namely fluid retention, non neutropenic infections and venous thromboembolic events). The 
past 5 years has witnessed the introduction of novel agents (lenalidomide, thalidomide and 
bortezomib) with considerable efficacy especially when combined with corticosteroids[2-4]. 
While these novel agents have considerably changed the outlook of multiple myeloma patients, 
the toxicity of therapy remains significant and attempts to reduce the toxicity of therapy by 
minimizing corticosteroid exposure remains a significant priority. 


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4.2. 
Lenalidomide 
 
 
 
4.2.1  Preclinical evaluation of lenalidomide 
 
 
Lenalidomide is a proprietary IMiD® compound of Celgene Corporation, which markedly 
stimulate T-cell proliferation, as well as IL-2 and IFN-production, but do not inhibit 
phosphodiesterase 4 (PDE-4)[5]. Lenalidomide (Revlimid®) is 50 to 2000 times more potent 
than thalidomide in stimulating T-cell proliferation triggered via the T-cell receptor (TCR), and 
50 to 100 times more potent than thalidomide in augmenting IL-2 and IFN-production. In 
addition, Lenalidomide triggers dose-dependent decreased secretion of TNF-, IL-1, and IL-6; 
and triggers increased secretion of IL-10. The IC50 of Lenalidomide for inhibiting LPS induced 
TNF-secretion by PBMC is ~100 nM (25.9 ng/mL), whereas thalidomide has an IC50 of ~194 
µM (50.2 µg/mL)[6]. Lenalidomide decreases binding of MM cells to bone marrow stromal cells 
 
(BMSCs); inhibits the production in the BM milieu of cytokines (IL-6, VEGF, TNF-) 
mediating growth and survival of MM cells; blocks angiogenesis; and stimulates host anti-MM 
NK cell immunity[7, 8]. These preclinical studies suggest that Lenalidomide may overcome drug 
resistance, even to thalidomide, in MM cells. 
 
4.2.2. Lenalidomide in relapsed refractory multiple myeloma 
 
 
The immunomodulator lenalidomide has considerable activity in multiple myeloma. Early phase 
I study of single agent lenalidomide in relapsed refractory multiple myeloma have shown a 
response rate of approximately  30%[9, 10]. This  single agent activity  was confirmed in a 
subsequent phase II study evaluating two different doses of lenalidomide (15 mg once daily or 
15 mg twice daily) for 21 of a 28 days cycle[9]. High dose dexamethasone (40 mg orally on days 
1-4, 9-12, and 17-20) was added after 2 or 4 cycles in the event of disease progression or stable 


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Version. 5.1 date 6/25/2014 
 
 
disease respectively. Of 83 evaluable patients, 5 had a complete remission, 15 a partial 
remission, 14 had a minimal response, 39 had stable disease and the remainder had progressive 
disease. The rate of minimal response or better was 40%[9]. Dexamethasone was added to 
lenalidomide therapy in 30 non-responders, and resulted in a response in 10 patients (30% added 
response rate)[9]. The combination of lenalidomide and high dose dexamethasone was compared 
to high dose dexamethasone in two phase III trials in relapsed refractory multiple myeloma[11, 
12]. This combination resulted in an overall response rate of approximately 60% and a complete 
response rate of 25% which was statistically superior to high dose dexamethasone[11, 12]. More 
importantly, the combination of lenalidomide and high dose dexamethasone resulted in an 
overall survival benefit compared to high dose dexamethasone[11, 12]. These results have led to 
the approval of lenalidomide by the Food and Drug Administration for the treatment of relapsed 
or refractory multiple myeloma. 
 
4.2.3 INDICATIONS AND USAGE: 
 
 
Revlimid® (lenalidomide) is indicated for the treatment of patients with transfusion-dependent 
anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes associated with a deletion 
5q cytogenetic abnormality with or without additional cytogenetic abnormalities. Revlimid® is 
also approved in combination with dexamethasone for the treatment of patients with multiple 
myeloma that have received at least one prior therapy. 
 
4.2.4 Adverse Events 
 
 
Most frequently reported adverse events reported during clinical studies with lenalidomide in 
oncologic and non-oncologic indications, regardless of presumed relationship to study 
medication include: anemia, neutropenia, thrombocytopenia and pancytopenia, abdominal pain, 


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nausea, vomiting and diarrhea, dehydration, rash, itching, infections, sepsis, pneumonia, UTI, 
Upper respiratory infection, atrial fibrillation, congestive heart failure, myocardial infarction, 
chest pain, weakness, hypotension, hypercalcemia, hyperglycemia, back pain, bone pain, 
generalized pain, dizziness, mental status changes, syncope, renal  failure, dyspnea, pleural 
effusion, pulmonary embolism, deep vein thrombosis, CVA, convulsions, dizziness, spinal cord 
compression, syncope, disease progression, death not specified and fractures. 
 
Complete and updated adverse events are available in the Investigational Drug Brochure and the 
IND Safety Letters. 
 
4.2.5 Lenalidomide in newly diagnosed multiple myeloma 
 
 
The phase II experience of lenalidomide and high dose dexamethasone in newly diagnosed 
multiple myeloma resulted in a response rate of 91% and generated interest in larger randomized 
studies evaluating this combination in this patient population[3]. The Eastern Cooperative 
Oncology Group randomized patients with newly diagnosed multiple myeloma to lenalidomide 
and low dose dexamethasone or lenalidomide and high dose dexamethasone[13]. The patients 
who received high dose dexamethasone in combination with lenalidomide had a superior 
response rate after 4 cycles of therapy (82% compared to 70% with low dose dexamethasone and 
lenalidomide, p<0.01), but had an inferior 1 year overall survival rate (87% versus 96%, 
p<0.001) and had a higher induction mortality (5% versus 0.5%, p=0.006)[13]. In addition, the 
patients who received high dose dexamethasone and lenalidomide had a higher rate of toxicity in 
the form of venous thromboembolic events, infectious complications, and neutropenia[13]. From 
these clinical observations, one can conclude that a better tolerated less intensive therapy will 
result in better survival (long term) outcomes in older adults with multiple myeloma. 


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4.2.6 Rationale for the evaluation of single agent lenalidomide in newly diagnosed 
mildly symptomatic multiple myeloma 
 
While corticosteroids have been shown to result in apoptosis and decreased proliferation of 
multiple myeloma cells, they have also been noted to inhibit the stimulatory effects of 
lenalidomide on T cell and NK cell[14]. Hence, a lenalidomide based therapeutic approach 
excluding corticosteroids would take better advantage of the immunomodulatory effects of 
lenalidomide. In addition, clinical results corroborate such an approach: E4A03 study suggest 
that a lower dose of dexamethasone is associated with a superior survival outcome compared to 
higher dose of dexamethasone. These findings were more striking in older adults who are more 
vulnerable to the toxicities of dexamethasone (greater than 65 years of age)[13]. Accordingly, we 
propose to evaluate single agent lenalidomide in patients with newly diagnosed multiple 
myeloma who are only mildly symptomatic from their disease but who fulfill the requirement for 
active treatment initiation. This would be expected to result in better tolerance to therapy, less 
toxicity but more potential for eliciting the immunomodulatory effects of lenalidomide. 
 
4.2.7 Measuring lenalidomide induced humoral immune response 
 
 
Immunomodulation is one of the proposed mechanisms of action of lenalidomide and 
thalidomide in multiple myeloma. Because most of the clinical evaluations of lenalidomide in 
multiple myeloma have included concomitant corticosteroid use, firm evidence of 
immunomodulation and a lenalidomide induced tumor specific immune response has not been 
demonstrated in vivo. Noonan et al. have recently demonstrated enhanced humoral response to 
pneumococcal vaccination in multiple myeloma patients who received lenalidomide prior to 
vaccination as compared to patients receiving vaccination prior to lenalidomide therapy[15]. This 
data suggests an enhanced humoral immune response during lenalidomide therapy. Accordingly, 


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we propose to evaluate the impact of lenalidomide monotherapy on the development of a 
humoral immune response directed to common tumor antigens. 
 
4.2.7.1          Serametrix® serum profiling assay 
 
 
The Serametrix serum profiling assay enables the multiplex detection of serum antibodies to key 
tumor antigens. The assay utilizes a proprietary protein microarray that contains protein antigens 
that are known to be immunogenic in cancer. The use of automated liquid handling equipment 
ensures high reproducibility, high throughput and low sample volumes. The assay has sufficient 
sensitivity and dynamic range to measure physiological levels of serum antibody and is therefore 
an effective tool in the measurement of humoral immune responses in cancer. 
The Serametrix protein microarray contains approximately 100 tumor antigens. Each antigen is 
derived from sequence-verified full-length human clones. These are expressed in insect cells and 
the consequent eukaryotic glycosylation helps to ensure authentic epitopes are maintained. The 
proteins were selected from published scientific literature in consultation with leading academic 
tumor immunologists. The criteria for selection included demonstrable immunogenicity, 
association with cancer and suitability for use as biomarker. 
 
 
 
4.2.8  Lenalidomide induced expression of tumor suppressor genes 
 
A number of mechanisms of actions have been postulated to account for lenalidomide activity in 
multiple myeloma including direct tumor growth inhibition, upregulation of tumor suppressor 
genes and immunomodulation. Lenalidomide has been shown to induce the expression of various 
tumor suppressor genes (EGR1, EGR2, EGR3, p15, p21, p27 and SPARC) in multiple myeloma 
cells lines[14, 16, 17]. These studies have not been replicated in samples from patients and 
induction of these tumor suppressors could be an early predictor of response to lenalidomide. As 


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such, we propose to evaluate the expression of the above tumor suppressor genes after treatment 
of patients with single agent lenalidomide and correlate the induction of the tumor suppressor 
genes to clinical responses. 
 
 
 
4.3.    Corticosteroids in induction therapy for multiple myeloma. 
 
The optimal dosage of corticosteroids in combination with lenalidomide in patients with newly 
diagnosed myeloma has not clearly been established. In older adults with multiple myeloma, 
several groups have attempted to investigate the optimal corticosteroid in induction therapy 
stemming from the lower tolerance to dexamethasone of older adults with multiple myeloma. 
One such investigation conducted by the national cancer institute of Canada compared induction 
therapy in older newly diagnosed multiple myeloma patients with melphalan and prednisone to 
therapy with melphalan and dexamethasone[18]. They noted a higher rate of grade 3 and 4 
infections in the dexamethasone arm without a response or survival benefit to that agent[18]. 
Similar findings were reported by investigators of the Intergroupe Francais du Myelome (IFM) 
who compared induction therapy with melphalan and prednisone compared to dexamethasone 
based therapy in older adults with multiple myeloma[19]. These results prompted us to evaluate 
prednisone as the corticosteroid partner of lenalidomide in  patients who do not achieve a 
response after 2 cycles of single agent lenalidomide and yet have not evidence of disease 
progression. This combination was safely delivered as reported in two investigations where 
lenalidomide and alternate day prednisone were used as maintenance therapy in relapsed and 
newly diagnosed patients[20]. 


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5. 
Study Endpoints 
 
 
Primary: 
 
1- The 12-month progression free survival (PFS) of older adults with mildly symptomatic 
multiple myeloma treated on this response adapted approach (i.e. time from start of 
lenalidomide to failure of lenalidomide and low dose dexamethasone) 
Secondary: 
 
 
1- The response rate of older adults with mildly symptomatic multiple myeloma to single 
agent lenalidomide, lenalidomide prednisone and lenalidomide low dose dexamethasone 
in patients with suboptimal responses to lenalidomide monotherapy 
2- The toxicity profile of these lenalidomide based combinations 
 
3- The progression free survival of patients treated with single agent lenalidomide 
 
4- The 1 year overall survival (OS) of older adults with mildly symptomatic multiple 
myeloma treated on this response adapted approach 
 
 
 
Exploratory 
 
1- 
Measure a lenalidomide induced tumor specific immune response and correlate the tumor 
specific immune response with corticosteroid use, response to therapy and duration of response 
2- 
To  evaluate  the  impact  of  lenalidomide  mono-therapy  on  expression  of  tumor 
suppression genes and cell cycle regulators 


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6. 
Investigational Plan 
 
 
 
6.1. 
Overall design 
 
 
This is a phase 2 trial evaluating a lenalidomide based response adapted strategy in older adults 
with newly diagnosed multiple myeloma. Subjects will be started on single agent lenalidomide. 
In the event of disease progression, low dose dexamethasone will be added (see diagram below). 
In the event of stable disease after 2 cycles of therapy, the use of an alternate corticosteroid 
(prednisone) will be added to lenalidomide therapy (see diagram below). In the event of a 
minimal response after 2 cycles of single agent lenalidomide therapy, such therapy will be 
continued until disease progression (see diagram below). 


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Newly diagnosed multiple 
myeloma 
Mildly symptomatic* 
 
 
 
 
 
Lenalidomide 25 mg PO 
days 1-21 of a 28 day cycle 
 
 
 
 
 
Response after 2 cycles 
MR± or better 
Stable disease after 2 cycles 
Progressive disease within 2 
cycles 
 
 
 
 
 
Continue present therapy as 
long as response maintained. 
Addition of Prednisone 
100 mg PO on days 1-5 
Addition of 
Dexamethasone 40 mg PO 
days 1, 8, 15, 22 
 
 
 
 
Progressive disease: add 
dexamethasone 40 mg PO 
days 1, 8, 15, 22 of the 
cycle 
Response after 2 cycles: 
continue above therapy 
Stable or progressive 
disease after 2 cycles: 
Discontinue Prednisone 
Add Dexamethasone 40 mg 
PO days 1,8,15, 22 
No progression after 2 
cycles: 
Continue above therapy 
Progressive disease: off 
study 
 
 
 
Subject replacement and evaluable patients 
 
 
Subjects who discontinue study drug, other then for progression, prior to completing one cycle of 
therapy will be replaced. 
 
6.2. 
Discussion of design 
 
 
Older adults or subjects not willing or eligible for post induction high dose therapy and stem cell 
transplantation will be offered participation into this study. This is in line with findings from the 
ECOG E4A03 study which noted a decreased survival among patients receiving higher dose 
dexamethasone compared to low dose dexamethasone specifically in the subgroup of patients 
older than 65 years of age[13]. In addition, patients enrolled on this response adapted clinical 


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trial would be either not willing or ineligible to undergo immediate (post 4 cycles of induction) 
high dose therapy and stem cell transplantation. The rationale underlying this exclusion criterion 
related to the fact that patients wishing to undergo immediate (post induction) high dose therapy 
usually are treated with more aggressive front line regimens. 
Mildly symptomatic patients will be selected for participation in this study. The rationale for the 
selection of this population lies in the fact that patients with aggressive disease at presentation 
(patients with significant symptoms) are probably best treated with combination therapy in order 
to achieve a higher likelihood of response (as evidenced by E4A03 where patients receiving 
higher dose dexamethasone in combination with lenalidomide had a higher response rate than 
patients receiving a lower dose of dexamethasone in combination with lenalidomide)[13]. 
Empirically, defining this patient population objectively can be difficult but we propose the 
following definition of mildly symptomatic disease: good performance status (ECOG 0-1), 
absence of severe cytopenias or renal failure, as well as low risk as defined by β2-microglobulin 
level and lack of adverse cytogenetic features[21]. 
In addition, this study will evaluate the role of an alternative corticosteroid in combination with 
lenalidomide. Prednisone is known to be a better tolerated corticosteroid than dexamethasone 
without a compromise in the efficacy. This was seen in a recent report of a clinical trial by the 
national cancer institute of Canada study comparing melphalan prednisone to melphalan 
dexamethasone (grade 3 and 4 infections; 9 versus 15%, p=0.03)[18]. In addition, the 
intergroupe francais du myelome (IFM) had noted similar finding in older adults with newly 
diagnosed myeloma randomized to melphalan prednisone or dexamethasone based 
induction[19]. Both trials did not note a superiority of dexamethasone based induction to the 
prednisone based induction. 


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The primary endpoint of this study will be the progression free survival of patients treated with 
this response  adapted  approach.  This is  defined  as  the  time from enrollment to failure of 
lenalidomide and low dose dexamethasone. Outcomes of this cohort of patients treated with this 
response adapted approach would be compared to patients treated with lenalidomide and low 
dose dexamethasone. If this response adapted approach results in similar or improved outcomes 
compared to therapy with lenalidomide and low dose dexamethasone, this approach would be 
favored since it likely result in less toxicity by using an overall lower dosage of corticosteroid. 
 
 
7. Study population 
 
 
Male and female subjects with documented newly diagnosed multiple myeloma who meet all of 
the eligibility criteria in Section 7.1.1 below will be enrolled into the study. 
 
7.1. 
Inclusion and exclusion criteria 
 
 
Subjects are to be assessed for suitability for entry into the study based on the following 
inclusion and exclusion criteria. 
 
7.1.1. Inclusion criteria 
 
 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study: 
1. Understand and voluntarily sign an informed consent form. 
 
2. Age 65 years or not eligible for high dose therapy and autologous stem cell transplant. 
 
3. Able to adhere to the study visit schedule and other protocol requirements. 


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4. Diagnosed with multiple myeloma and be considered to have active disease. Patients 
must not have received an active chemotherapy regimen or Dexamethasone. Patients may 
have received palliative radiotherapy at least 2 weeks prior to the study start. 
5. Measurable myeloma paraprotein levels in serum (≥ 0.5 g/dL), urine (≥ 0.2 g excreted in 
a 24-hour urine collection sample) or by serum free light chains (involved free light chain 
greater than 100mg/L) 
6. Eastern Cooperative Group (ECOG) Performance Status of 0 or 1. 
 
7. Serum bilirubin levels 1.5 times the upper limit of the normal range for the laboratory 
(ULN). 
8. Serum AST or serum ALT] levels 2 x ULN 
 
9. Must have adequate bone marrow function: 
 
a. Absolute neutrophil count > 1,000 cells/mm3 (1.0 x 109/L). 
 
b. Platelets 100,000 /mm3. 
 
10. Hemoglobin > 8 g/dL 
 
 
11. Must have adequate renal function: Renal function assessed by calculated creatinine 
clearance as follows (see Appendix VI: Cockcroft-Gault estimation of CrCl): 
 
a. Calculated creatinine clearance ≥ 30ml/min by Cockcroft-Gault formula. See 
section below, “Prescribing Information”, regarding lenalidomide dose 
adjustment for calculated creatinine clearance 30ml/min and < 60ml/min. 
12. Low risk myeloma is defined as the absence of the following adverse features[21] 
 
i. t(4;14) by FISH or metaphase cytogenetics 
 
ii. t(14,16) or t(14;20) by FISH or metaphase cytogenetics 
 
iii. Deletion 17q13 by FISH 
 
iv. Deletion 13 by metaphase analysis 
 
v. Aneuploidy by metaphase analysis 


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vi. Β2 microglobulin > 5.5 
 
 
13. Able to tolerate one of the following thromboprophylactic strategies:  aspirin,  low 
molecular weight heparin or warfarin (coumadin). 
14. All study participants must be registered into the mandatory RevAssist® program, and be 
willing and able to comply with the requirements of RevAssist®. 
15. 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 and again 
within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled 
within 7 days) and must either commit to continued abstinence from heterosexual 
intercourse or begin TWO acceptable methods of birth control, one highly effective 
method and one additional effective method AT THE SAME TIME, at least 4 weeks 
before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy 
testing. Men must agree to use a latex condom during sexual contact with a female of 
child bearing potential even if they have had a successful vasectomy.   See Appendix 
VIII:  Risks  of  Fetal  Exposure,  Pregnancy  Testing  Guidelines  and  Acceptable  Birth 
Control Methods. 
 
7.1.2. Exclusion criteria 
 
 
The presence of any of the following will exclude a subject from study enrollment: 
 
1. Ongoing severe infection requiring intravenous antibiotic treatment. 
 
2. Life expectancy of less than 3 months. 
 
 
 
† A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy 
or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has 
had menses at any time in the preceding 24 consecutive months). 


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3. Performance status of 2, 3 or 4 
 
4. Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, 
in-situ cervical cancer, or other cancer from which the subject has been disease-free for at 
least 2 years. 
5. Solitary bone or solitary extramedullary plasmacytoma as the only evidence of plasma 
cell dyscrasia. 
6. Uncontrolled medical problems such as diabetes mellitus, congestive heart failure, 
coronary artery disease, hypertension, unstable angina, arrhythmias), pulmonary, hepatic 
and renal diseases unless renal insufficiency is felt to be secondary to multiple myeloma. 
7. Any serious medical condition, laboratory abnormality, or psychiatric illness that would 
prevent the subject from signing the informed consent form. 
8. Pregnant or lactating females. 
 
9. 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. 
 
10. Known hypersensitivity to thalidomide. 
 
11. Use of any other experimental drug or therapy within 28 days of baseline. 
 
12. The development of erythema nodosum if characterized by a desquamating rash while 
taking thalidomide or similar drugs. 
 
13. Any prior use of lenalidomide. 
 
14. Concurrent use of other anti-cancer agents or treatments. 
 
15. Known seropositive for or active viral infection with human immunodeficiency virus 
(HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are seropositive 
because of hepatitis B virus vaccine are eligible. 


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8. Treatments 
 
 
 
8.1.1. Investigational drug and reference therapy 
 
 
 
8.1.1.1. 
Supplier(s) 
 
 
Celgene Corporation will supply Revlimid® (lenalidomide) to study participants at no charge 
through the RevAssist® program. 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 Celgene’s RevAssist® program. 
 
Commercial supplies of dexamethasone, prednisone, low molecular weight heparin, coumadin 
and aspirin will be used for this study. 
 
8.1.1.2. 
Lenalidomide Description 
 
 
REVLIMID® (lenalidomide), a thalidomide analogue, is an immunomodulatory agent with anti- 
angiogenic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -2H-isoindol-2-yl) 
piperidine-2,6-dione and it has the following chemical structure: 
 
Chemical Structure of Lenalidomide 
 
 
O 
O 
H 
N 
N 
O 
 
 
NH2 
 
 
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione 
 
 
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 259.3. 


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Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic solvent/water 
mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic solvents and 
low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 
0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon atom and can exist as the optically 
active forms S(-) and R(+), and is produced as a racemic mixture with a net optical rotation of 
zero. 
 
Clinical pharmacology 
Mechanism of Action: 
The mechanism of action of lenalidomide remains to be fully characterized. Lenalidomide 
possesses immunomodulatory and antiangiogenic properties. Lenalidomide inhibited the 
secretion of pro-inflammatory cytokines and increased the secretion of anti-inflammatory 
cytokines from peripheral blood mononuclear cells. Lenalidomide inhibited cell proliferation 
with varying effectiveness (IC50s) in some but not all cell lines. Of cell lines tested, 
lenalidomide was effective in inhibiting growth of Namalwa cells (a human B cell lymphoma 
cell line with a deletion of one chromosome 5) but was much less effective in inhibiting growth 
of KG-1 cells (human myeloblastic cell line, also with a deletion of one chromosome 5) and 
other cell lines without chromosome 5 deletions. Lenalidomide inhibited the expression of 
cyclooxygenase-2 (COX-2) but not COX-1 in vitro. 
 
Pharmacokinetics and Drug Metabolism: 
Absorption: 
Lenalidomide, in healthy volunteers, is rapidly absorbed following oral administration with 
maximum plasma concentrations occurring between 0.625 and 1.5 hours post-dose. 


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Co-administration with food does not alter the extent of absorption (AUC) but does reduce the 
maximal plasma concentration (Cmax) by 36%. The pharmacokinetic disposition of 
lenalidomide is linear. Cmax and AUC increase proportionately with increases in dose. Multiple 
dosing at the recommended dose-regimen does not result in drug accumulation. 
 
Pharmacokinetic analyses were performed on 15 multiple myeloma patients treated in the phase I 
studies. Absorption was found to be rapid on both Day 1 and Day 28 with time to maximum 
blood levels ranging from 0.7 to 2.0 hours at all dose levels (5mg, 10mg, 25mg, and 50mg). No 
plasma accumulation was observed with multiple daily dosing. Plasma lenalidomide declined in 
a monophasic manner with elimination half-life ranging from 2.8 to 6.1 hours on both Day 1 and 
28 at all 4 doses. Peak and overall plasma concentrations were dose proportional over the dosing 
range of 5mg to 50mg. Exposure (AUC) in multiple myeloma patients is 57% higher than in 
healthy male volunteers. 
 
Pharmacokinetic Parameters: 
Distribution: 
In vitro (14C)-lenalidomide binding to plasma proteins is approximately 30%. 
 
 
Metabolism and Excretion: 
 
 
The metabolic profile of lenalidomide in humans has not been studied. In healthy volunteers, 
approximately two-thirds of lenalidomide is eliminated unchanged through urinary excretion. 
The process exceeds the glomerular filtration rate and therefore is partially or entirely active. 
Half-life of elimination is approximately 3 hours. 


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Dosage form 
 
 
Lenalidomide will be supplied as capsules for oral administration. Lenalidomide will be supplied 
as 5 mg and 25 mg capsules for oral administration. 
 
Prescribing Information 
 
 
Lenalidomide (Revlimid®) will be provided to research subjects for the duration of their 
participation in this trial at no charge to them or their insurance providers. Lenalidomide will be 
provided in accordance with the RevAssist® program of Celgene Corporation. Per standard 
RevAssist® requirements all physicians who prescribe lenalidomide for research subjects 
enrolled into this trial, and all research subjects enrolled into this trial, must be registered in and 
must comply with all requirements of the RevAssist® program. Prescriptions must be filled 
within 7 days. Only enough lenalidomide for one cycle of therapy will be supplied to the 
patient each cycle. 
 
The planned dose of lenalidomide for investigation is 25 mg/day, orally on days 1 - 21 followed 
by 7 days rest (28 day cycle). Dosing will be based on CrCl: 
Lenalidomide will be given at a dose of 25 mg once daily on days 1 to 21, every 28 days for 
those patients with a subjects with a creatinine clearance of ≥ 60 mL/min by Cockroft-Gault 
formula. 
Subjects with a creatinine clearance of ≥ 30 mL/min but < 60 mL/min by Cockroft-Gault 
formula will begin lenalidomide at 10 mg once daily on days 1 to 21, every 28 days. 
The lenalidomide dose may be increased to dose 15 mg at the start of Cycle 3 if hematologic 
toxicities have not occurred. 


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Dosing will be in the morning at approximately the same time each day.  Lenalidomide capsules 
should be swallowed whole, and should not be broken, chewed or opened. 
 
If a dose of lenalidomide is missed, it should be taken as soon as possible on the same day. If it 
is missed for the entire day, it should not be made up. 
 
Patients who take more than the prescribed dose of lenalidomide should be instructed to seek 
emergency medical care if needed and contact study staff immediately. 
 
Special Handling Instructions 
 
 
Females of childbearing potential should not handle or administer lenalidomide unless they are 
wearing gloves. 
 
8.1.1.3. 
Study Drug Storage 
 
 
 
Lenalidomide 
 
 
Lenalidomide should be stored at room temperature away from direct sunlight and protected 
from excessive heat and cold. 
 
Dexamethasone and prednisone 
 
 
Dexamethasone should be stored at room temperature away from direct sunlight and protected 
from excessive heat and cold. 
 
8.1.1.4. 
Record of administration 
 
 
Subjects will receive diary cards to record when medications are taken. Diary cards will be 
collected at the end of each cycle or every 3 cycles in maintenance. 


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Accurate records will be kept in the source documents of all drug administration (including 
prescribing and dosing). After April 2016, diary card will no longer be used 
 
Dexamethasone 
 
 
Commercial dexamethasone is available as 4 mg tablets for oral administration. 
 
 
Prednisone 
 
 
Commercial prednisone is available as 50 mg tables for oral administration 
 
 
Low Molecular Weight Heparin, Coumadin or Aspirin: 
 
 
Commercial low molecular weight heparin, coumadin or aspirin for oral administration will be 
utilized. 
 
8.1.2. Treatment assignments 
 
 
Subjects will be entered in to the study sequentially in the order they are registered. 
 
 
 
8.1.3. Prior/Concomitant therapy 
 
 
All medications (prescription and non-prescription), treatments and therapies taken from 28 days 
prior to the start of study drug, Lenalidomide, through to the last dose of study drug, must be 
recorded on the appropriate page of the data collection system. Subjects will be supplied a diary 
to record their concomitant medications. After April 2016, diary card will no longer be used. 
 
8.1.3.1. 
Allowed concomitant therapy 
 
 
The use hematopoietic growth factors for subjects in this study are permitted when used to treat 
neutropenia and anemia. In addition, low dose prednisone (up to 10 mg/day) may be used for the 
treatment and prevention of lenalidomide induced neutropenia. Therapies considered necessary 


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for the subject’s well being may be administered at the discretion of the Investigator. These 
therapies may include bisphosphonates, palliative radiation therapy, antibiotics, analgesics, 
antihistamines, or other medications as well as transfusions of red blood cells, platelets, or fresh 
frozen plasma given to assist in the management of complications associated with multiple 
myeloma. Low dose corticosteroid therapy, (the equivalent up to 10 mg a day of prednisone) for 
the treatment of the patient existing autoimmune, rheumatologic or inflammatory conditions is 
allowed. 
 
8.1.3.2. 
Prohibited concomitant therapy 
 
 
Concomitant use of other anti-myeloma therapy while the subject is on study drug is prohibited. 
No new investigational therapies shall be initiated while the subject is on study drug. 
 
8.1.4. Treatment compliance 
 
 
To monitor treatment compliance, reconciliation of Lenalidomide capsules will be done at each 
study visit. Subject diaries will be provided to assist in the collection of dosing information 
between study visits. After April 2016, diary card will no longer be used and reconciliation of 
lenalidomide capsule will not be performed.  
 
8.1.5. Dose modification or interruption 
 
 
Subjects will be evaluated for adverse events at each visit using the National Cancer Institute 
Common Toxicity Criteria (NCI CTCAE) version 4.0 to grade severity. All subjects who are 
discontinued due to an adverse event should be followed for as long as necessary to document 
the resolution or stabilization of the event. 
 
8.1.5.1. 
Dose Reduction Steps for Lenalidomide 


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Table 1: Lenalidomide dose levels 


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Starting Dose 
Dose level –1 
Dose Level -2 
Dose Level –3 
Dose Level -4 
25 mg PO days 
1-21 of a 28 days 
cycle 
15 mg PO days 
1-21 of a 28 days 
cycle 
10 mg PO days 
1-21 of a 28 days 
cycles 
5 mg PO days 1- 
21 of a 28 days 
cycles 
Discontinue 
 
 
Lenalidomide dose reductions will be done as per the instruction below and as illustrated in the 
following example. 
 
Example 1: A patient is being treated with lenalidomide 25mg daily on Days 1-21 every 28 days 
and requires a lenalidomide dose reduction per Table 1. The patient will start their next cycle of 
therapy with lenalidomide 15 mg daily on Days 1-21 every 28 days. 
 
Lenalidomide will always be dosed daily on Days 1-21 every 28 days. The minimum 
lenalidomide dose is 5 mg/day on days 1 – 21 every 28 days. If this dose is not tolerated, 
lenalidomide must be discontinued. 
 
 
 
Table 2: Dose Modification Guidelines for Lenalidomide 
 
 
 
 
CTCAE CATEGORY 
ADVERSE EVENT 
CTCAE 
GRADE 
TREATMENT ADJUSTMENT 
Maintenance Phase 
Neutropenia 
Grade 3 with 
fever 
grade 4 
Hold lenalidomide for remainder of cycle 
if the toxicity occurs in the latter 2 weeks 
of the cycle and resume the next cycle at 
the dose detailed below. Alternatively if 
the toxicity occurred during the first 2 


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weeks of the cycle, then hold lenalidomide 
until the toxicity improves to ≤ grade 2 
and resume lenalidomide as detailed 
below. 
First occurrence: when resolved to ≤ grade 
2 begin next cycle with one dose level 
reduction of lenalidomide or continue 
same dose with cytokine or low dose 
prednisone support. 
Second occurrence: when resolved to ≤ 
grade 2 begin next cycle with one level 
dose reduction of lenalidomide or 
continue same dose with cytokine support 
if not already implemented. 
Subsequent dose reductions of 
lenalidomide are permitted at the 
investigators discretion. 
Thrombocytopenia 
Grade 4 
Hold lenalidomide for remainder of cycle 
if the toxicity occurs in the latter 2 weeks 
of the cycle and resume the next cycle 
with one dose level reduction in 
lenalidomide. Alternatively if the toxicity 
occurred during the first 2 weeks of the 


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cycle, then hold lenalidomide until the 
toxicity improves to ≤ grade 2 and resume 
lenalidomide with one dose level 
reduction . . 
Cardiac toxicity 
Arrhythmia > 
grade 2 
Hold lenalidomide until resolved to < 
grade 1. Resume at one dose level 
reduction of lenalidomide. 
Arrhythmia > 
grade 3 
Discontinue protocol therapy. 
Congestive 
heart failure > 
grade 2 
Discontinue lenalidomide at the 
investigators discretion. 
Hyperthyroidism/ 
Hypothyroidism 
Any grade 
Hold lenalidomide and evaluate patient. 
May resume therapy at the same dose 
once patient is stable at investigators 
discretion. 


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Non desquamating rash 
Grade 2 
Hold lenalidomide for remainder of cycle 
if the toxicity occurs in the latter 2 weeks 
of the cycle and resume the next cycle 
with one dose level reduction in 
lenalidomide if the toxicity resolves to less 
than grade 2. Alternatively if the toxicity 
occurred during the first 2 weeks of the 
cycle, then hold lenalidomide until the 
toxicity improves to < grade 2 and resume 
lenalidomide with one dose level  
reduction .. 
Grade 3 or 4 
Discontinue protocol therapy. 
Desquamating rash or Erythema 
Multiforme 
Any grade 
Discontinue protocol therapy. 


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Allergic reaction or 
hypersensitivity 
Grade 2 or 3 
Hold lenalidomide for remainder of cycle 
if the toxicity occurs in the latter 2 weeks 
of the cycle and resume the next cycle 
with one dose level reduction in 
lenalidomide if the toxicity improves to 
less than grade 2. Alternatively if the 
toxicity occurred during the first 2 weeks 
of the cycle, then hold lenalidomide until 
the toxicity improves to less than grade 2 
and resume lenalidomide with one dose 
level reduction. 
Grade 4 
Discontinue lenalidomide 
Venous thrombosis/embolism 
≥ Grade 3 
Hold (interrupt) dose, consider therapeutic 
anticoagulation; restart at investigator’s 
discretion (maintain dose level) 


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Other non-hematologic toxicity 
except those events specifically 
attributed to dexamethasone as 
outlined in table 4. 
Grade 3 / 4 
Hold lenalidomide for remainder of cycle 
if the toxicity occurs in the latter 2 weeks 
of the cycle and resume the next cycle 
with one dose level reduction in 
lenalidomide. Alternatively if the toxicity 
occurred during the first 2 weeks of the 
cycle, then hold lenalidomide until the 
toxicity improves to ≤ grade 2 and resume 
lenalidomide with one dose level 
reduction. 
 
 
 
8.1.5.2. 
Dose reduction steps for corticosteroids 
 
 
For patients assigned to receive corticosteroids as part of the trial therapy, dose reduction steps 
for prednisone and dexamethasone should follow the guidelines in the following tables. Table 2 
refers to dose levels for the corticosteroids used on this clinical trial: prednisone and 
dexamethasone. Table 3 suggests dose reduction schema dictated by specific adverse events. 
 
Table 3: Dose Reduction Steps for Dexamethasone and / or Prednisone 
 
 
Starting Dose 
Dose level –1 
Dose Level -2 
Dose Level –3 
40 mg daily on days 1 
– 4 every 28 days 
20 mg daily on days 1 
– 4 every 28 days 
Dose level -1a 
10 mg daily on days 1 
– 4 every 28 days 
Discontinue 


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40 mg daily on days 
1, 2, and 3 followed 
by 20 mg on day 4 
followed by 12 mg on 
day 5 followed by 8 
mg on day 6 
Prednisone 100 mg 
PO days 1-5 every 28 
days 
50 mg PO days 1-5 of 
a 28 day cycle 
25 mg PO days 1-5 of 
a 28 day cycle 
Discontinue 


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Table 3: Dose Modification Guidelines for corticosteroids (Dexamethasone and / or 
Prednisone) 
 
CTCAE 
CATEGORY 
ADVERSE 
EVENT 
ADVERSE EVENT 
TREATMENT ADJUSTMENT 
Gastrointestinal 
Dyspepsia, gastric or duodenal 
ulcer, gastritis 
Grade 1-2 
Treat with H2 blockers, sucralfate, or 
Omeprazole. If symptoms persist despite 
above measures, decrease corticosteroid 
dose by 2 dose levels permanently 
> Grade 3 
Hold corticosteroids until symptoms are 
adequately controlled. Reduce by 2 dose 
levels along with concurrent therapy with 
H2 blockers, sucralfate, or omeprazole. If 
symptoms persist despite above measures, 
discontinue corticosteroids and do not 
resume. 
Acute pancreatitis 
Discontinue corticosteroids and do not 
resume 
Cardiovascular 
Edema 
> Grade 3 
Diuretics as needed, and decrease 
corticosteroids dose by 1 dose level; if 
edema persists despite above measures 


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decrease dose by 2 dose levels from the 
initial dose; discontinue corticosteroids and 
do not resume if symptoms persist despite 
reduction. 
Neurology 
Confusion or Mood alteration 
> Grade 2 (interfering with 
function 
+/- interfering with activities of 
daily 
living) 
Hold corticosteroids until symptoms 
resolve to < grade1. Reduce dose by 2 dose 
levels from current dose. 
If symptoms persist despite above 
measures, discontinue corticosteroids and 
do not resume. 
Musculoskeletal 
Muscle weakness 
> Grade 2 (symptomatic and 
interfering with function +/- 
interfering with activities of 
daily 
living) 
Decrease corticosteroids dose by 1 dose 
level; If weakness persists despite above 
measures decrease dose by 2 dose levels 
from the initial dose. Discontinue 
corticosteroids and do not resume if 
symptoms persist despite reduction. 
Metabolic 
Hyperglycemia 
> Grade 3 or higher 
Treatment with insulin or oral 
hypoglycemics as needed. If uncontrolled 
despite above measures, 
decrease dose by 1 dose level decrements 
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8.1.6. Initiation of a new cycle of therapy 
 
 
A new course of treatment may begin on the scheduled Day 1 of a new cycle if: 
 
 
 
Absolute neutrophil count > 500 cells/mm3 
 
 
 
Thrombocytopenia ≤ grade 2 and there is no bleeding; 
 
 
 
Any therapy-related rash, allergic reaction/hypersensitivity, sinus bradycardia or other 
cardiac arrhythmia, or confusion/mood-alteration adverse event that may have occurred 
has resolved to ≤ Grade 1 severity 
 
 
Any other therapy-related adverse event that may have occurred has resolved to ≤ Grade 
2 severity. 
If these conditions are not met on Day 1 of a new cycle, evaluate the subject weekly through an 
exam and relevant evaluations by the Investigator. A new cycle of lenalidomide treatment will 
not be initiated until the toxicity has resolved as described above. If a new cycle is delayed for > 
4 weeks, the Principal Investigator will be notified. The above criteria will not be used after April 
2016, a new cycle of therapy may be initiated per the treating physician discretion consistent 
with standard of care use of lenalidomide. 
 
8.1.7. Discontinuation from treatment 
 
 
The following events are considered sufficient reasons for discontinuing a subject from study 
drug: 
 
 
Subject declines further study participation. 
 
 
 
Adverse event(s) (AEs) that, in the judgment of the Investigator, may cause severe or 
permanent harm or which rule out continuation of study drug. 
 


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 
Major violation of the study protocol. 
 
 
 
Progression of disease/unsatisfactory therapeutic effect 


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 
Death 
 
 
 
Pregnancy or a positive pregnancy test 
 
 
 
Discontinuation of lenalidomide for any reason 
 
 
 
Subject lost to follow-up 
 
 
 
If for any other reason, must be specified in the data collection system. 
Study Closure 
Reasons for discontinuation should be recorded in the data collection system and in the 
subject’s medical records. 
 
8.2.     Visit schedule and assessments 
 
 
The Investigator is responsible for keeping a record of all subjects who sign an Informed 
Consent Form and are screened for entry into the study. For those subjects who fail screening 
the reason(s) for exclusion must be recorded in the subject’s source documents. 
 
A schedule of the assessments can be found in Section 2, Schedule of Study Assessments. All 
scheduled visits will have a ±7-day window unless otherwise stated. 
 
An unscheduled visit can occur at any time during the study. The date for the visit and any data 
generated must be recorded on the data collection system. Source documents for these 
unscheduled visits must also be maintained. 
 
All study participants must be registered into the mandatory RevAssist® program, and be willing 
and able to comply with the requirements of RevAssist®. 
After April 2016 patients will be followed per standard of care at the discretion of the treating 
physician.


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9. Safety assessments 
 
 
The following safety assessments will be done at baseline and at scheduled intervals throughout 
the duration of the study (see Section 2, Schedule of Study Assessments). Unless otherwise 
noted, all laboratory testing will be conducted in the local laboratory. After April 2016, safety 
assessments will not be mandated by the trial but rather will be at the discretion of the treating 
physician in accordance with standard of care management of multiple myeloma patients on 
lenalidomide. 
 
9.1. 
Physical examination 
 
 
Routine physical examination including vital signs (blood pressure, pulse, temperature), height, 
and weight. Height is only collected at the baseline physical examination. 
 
9.2. 
Clinical laboratory evaluations 
 
 
 
General Laboratory Testing 
 
 
Serum chemistries 
 
 
Total protein, albumin, calcium, phosphate, glucose, uric acid, total bilirubin, alkaline 
phosphatase, AST (SGOT), ALT (SGPT), sodium, potassium, chloride, carbon dioxide, 
blood urea nitrogen, creatinine, and LDH. 
 
Hematology 
 
 
Red blood cell (RBC) count, hemoglobin, hematocrit, MCV, MCH, MCHC, white blood 
cell (WBC) count and differential, absolute neutrophil count (ANC), and platelet count. 
 
Specific Laboratory Testing 
 
 


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Myeloma Specific 
 
 
SPEP, 24 hour UPEP, 2 microglobulin, serum and urine immunofixation, serum free 
light chain 


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Supportive 
 
 
Serum B12, RBC Folate, Ferritin, ESR 
 
 
Thyroid-stimulating hormone, total triiodothyronine (T3) and total thyroxine (T4). 
 
 
 
9.3. 
Pregnancy testing for FCBP - -hCG 
 
 
Serum or urine pregnancy testing β-hCG with a sensitivity of at least 50 mIU/mL is to be done 
on FCBP only per Appendix VIII. 
 
 
9.4. 
Electrocardiogram (ECG) 
 
 
12-lead electrocardiogram. 
 
 
 
9.5. 
Prior/Concomitant therapy 
 
 
All concomitant therapies (prescription and non-prescription) taken 28 days prior to the start of 
study drug, Lenalidomide, and during the course of the study (from start of study drug until the 
last dose of study drug) will be collected. All therapies taken while the subject is on study drug 
will be recorded in the subject’s data collection system. After April 2016, concomitant therapy 
will not be collected 
 
9.6. 
Adverse events 
 
 
 
All serious adverse events must be reported to Celgene Clinical Affairs within 24 hours of the 
investigational staff’s knowledge; this includes any event that occurs during the participation of 
the trial regardless of associated therapy, severity or relationship 
 
9.6.1. Serious Adverse Event (SAE) Definition 
 


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A serious adverse event is one that at any dose (including overdose): 


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<         Results in death 
 
 
<         Is life-threatening1 
 
 
<         Requires inpatient hospitalization or prolongation of existing hospitalization 
 
 
<         Results in persistent or significant disability or incapacity2 
 
 
<         Is a congenital anomaly or birth defect 
 
 
<         Is an important medical event3 
 
 
<         Pregnancy 
 
1“Life-threatening” means that the subject was at immediate risk of death at the time of the serious 
adverse event; it does not refer to a serious adverse event that hypothetically might have caused death if it 
were more severe. 
 
2“Persistent or significant disability or incapacity” means that there is a substantial disruption of a person’s 
ability to carry out normal life functions. 
3Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in situations where none of the outcomes listed above occurred.  Important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient 
or may require intervention to prevent one of the other outcomes listed in the definition above should also 
usually be considered serious. Examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. A new diagnosis of cancer during 
the course of a treatment should be considered as medically important. 
 
9.6.2. Adverse Event Reporting 
 
 
Lenalidomide was approved by the FDA for newly diagnosed multiple myeloma patients in 
2/2015. MCC16018 involves lenalidomide based therapy for newly diagnosed multiple myeloma 
and is thus currently considered standard of care (although that use was considered investigational 


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at the time of initiation and completion of accrual of the study). Moreover, the adverse event 
profile of lenalidomide is now well established. Finally, as of April 2016, all the current study 
patients have been on present therapy for a minimum of 2 years and a continued collection of all 
adverse events will not leads to a meaningful change in the adverse event profile of lenalidomide. 
Accordingly, as of April 2016, we will only collect serious adverse events (SAE) and will no 
longer collect other adverse events encountered after that time.  
 
9.6.3. Pregnancies 
 
 
Pregnancy of a female subject or the female partner of a male subject occurring while the subject 
is on study drug or within 4 weeks after the subject’s last dose of study drug are considered 
expedited reportable events. If the subject is on study drug the study drug is to be discontinued 
immediately and the subject is to be instructed to return any unused portion of the study drug to 
the Investigator. Within 24 hours of the investigator’s knowledge, all pregnancies must be 
reported to Celgene Corporation World Wide Safety Surveillance (WWDSS) by phone and 
facsimile. 
 
The Investigator will follow the pregnant female until completion of the pregnancy, and must 
notify Celgene Corporation Worldwide Drug Safety Surveillance (WWDSS) of the outcome as 
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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 reporting SAEs (i.e., report the event to  Celgene Corporation 
Worldwide Drug Safety Surveillance (WWDSS) 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 pregnant female should be referred to an 
obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and 
counseling. 
All neonatal deaths that occur within 30 days of birth should be reported, without 
regard to causality, as SAEs. In addition, any infant death after 30 days that the 
investigator suspect is related to the in utero exposure to the study drug should also be 
reported. 
 
In the case of a live “normal” birth, Celgene Corporation Worldwide Drug Safety 
Surveillance (WWDSS) should be advised as soon as the information is available. 
9.6.4. Celgene 
Drug 
Safety 
Contact 
Information: 
 
Celgene Corporation  
Worldwide Drug Safety Surveillance (WWDSS) 
 86 Morris Avenue 
Summit, NJ 07901 
Toll Free:      (800) 640-7854 
Phone:           (908) 763-9667  
Fax: 
(908) 673-9115 
E-mail: 
drugsafety@celgene.com 


 
 
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9.7. 
Investigator Reporting Responsibilities 
 
 
The conduct of the study will comply with all FDA safety reporting requirements. Given 
that the FDA has granted an IND exemption for this study, an annual report is not 
required. 
 
 
All adverse experience reports must include the patient number, age, sex, weight, severity 
of reaction (mild, moderate, severe), relationship to study drug (probably related, 
unknown relationship, definitely not related), date and time of administration of test 
medications and all concomitant medications, and medical treatment provided. The 
investigator is responsible for evaluating all adverse events to determine whether criteria 
for “serious” and as defined above are present. The investigator is responsible for 
reporting adverse events to Celgene as described below. 
 
9.7.1. Expedited reporting by investigator to Celgene 
 
 
Serious adverse events (SAE) are defined above. The investigator should inform Celgene 
of any SAE within 24 hours of being aware of the event. This must be documented on 
Celgene SAE form, an acceptable institution SAE from or a FDA 3500 or MEDWATCH 
form. This form must be completed and supplied to Celgene within 24 hours of the 
investigator’s knowledge of the event.. The date of awareness should be noted on the 
report. 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), if available.  Information not available at the 
 
 
 
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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 MEDWATCH. A final 
report to document resolution of the SAE is required. The Celgene protocol number 
(RV-MM-PI-0454) should be included on SAE reports 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. 
 
 
Moffitt Cancer Center will only be responsible to report to Celgene those events 
that occur at Moffitt. 
 
9.7.2. Report of Adverse Events to the Institutional Review Board 
 
 
The principal Investigator is required to notify his/her Institutional Review Board (IRB) 
of a serious adverse event according to institutional policy. 
 
9.7.3. Investigator Reporting to the FDA 
 
 
Adverse drug reactions that are Serious, Unlisted/unexpected, and at least possibly 
associated to the drug, and that have not previously been reported in the Investigators 
brochure, or reference safety information document should be reported promptly to the 
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in clinical research.   A clear description of the suspected reaction should be provided 
along with an assessment as to whether the event is drug or disease related. 
 
 
 
Adverse event updates/IND safety reports 
 
 
Celgene for lenalidomide shall notify the Investigator via an IND Safety Report of the 
following information: 
 
 
Any AE associated with the use of study drug in this study or in other studies that 
is both serious and unexpected. 
 
 
Any finding from tests in laboratory animals that suggests a significant risk for 
human 
subjects 
including 
reports 
of 
mutagenicity, 
teratogenicity, 
or 
carcinogenicity. 
 
The Investigator shall notify his/her IRB/EC promptly of these new serious and 
unexpected AE(s) or significant risks to subjects. 
 
The Investigator must keep copies of all AE information, including correspondence with 
Celgene and the IRB/EC, on file (see Section 13.4 Study records requirements). 
 
9.7.4. Efficacy assessments 
 
 
 
9.7.4.1. 
Myeloma paraprotein 
 
 
Serum and urine protein electrophoresis, quantitative immunoglobulins, serum and urine 
immunofixation studies (see Section 2, Schedule of Study Assessments). Response will 
be assessed using the Uniform response criteria set forth by the International myeloma 
working group (IMWG) (See Appendix II). Response will be assessed at least every 3 
months in the maintenance setting. 


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As of April 2016, given all patients are in maintenance, patients will be followed for follow up and 
survival. Response assessment is not mandated per the trial and per institutional standard of care and 
to occur at a minimum of every 3 months.  


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9.7.4.2. 
Bone marrow aspiration/ biopsy 
 
 
At baseline, after 2 cycles of lenalidomide monotherapy, at the end of study, to confirm 
complete response, and as clinically indicated (see Section 2, Schedule of Study 
Assessments). 
 
9.7.4.3. 
Skeletal survey 
 
 
Radiographic assessment of the bones to be done at baseline, end of study, to confirm 
complete response, and as clinically indicated (see Section 2, Schedule of Study 
Assessments). 
 
9.7.5. Correlative and translational studies 
 
 
All patients will be encouraged to participate in the correlative / translational studies 
outlined below. However, patients will have the option to decline such participation and 
still be eligible for inclusion in the study if they meet all other requirements and 
assessments. Correlatives / translational studies will involve additional bone marrow 
aspiration specimen (optimally up to 20 cc additional aspiration needed) and peripheral 
blood specimens. Bone marrow plasma cells from patients with multiple myeloma will be 
isolated with CD138 positive beads. RNA will be extracted and expression of tumor 
suppression genes will be assayed by real time reverse transcriptase polymerase chain 
reaction (RT-PCR) at baseline and after 2 cycles of mono-therapy with lenalidomide. 
 
9.7.5.1. 
Effects of Lenalidomide Monotherapy on Tumor Suppressor Genes 
 
 
CD138 positive plasma cell will be isolated from the bone marrow aspirate of 
patients at diagnosis and after 2 cycles of lenalidomide using CD138 positive 
selection. RNA will be extracted. Quantitative PCR (Q-PCR) will be performed to 


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assay the expression of the following target genes: EGR1, EGR2, EGR3, p15, 
p21, p27 and SPARC. These studies will be performed by the Moffitt Core Lab 
under the direction of Christopher Cubitt. We estimate 15 paired samples will be 
obtained to compare the expression of the above mentioned genes pre and post 2 
cycles of lenalidomide monotherapy. 
 
9.7.5.2. 
Demonstration of Lenalidomide Induced Humoral Immune Response 
 
 
Peripheral blood will be collected at the time of study start (C1D1), after 2 cycles 
of lenalidomide monthotherapy, at the time of addition of dexamethasone, and 2 
cycles after the addition of dexamethasone. Serum will be used for the detection 
of lenalidomide induced humoral immune response using the serametrix assay. 
Samples will be stored at -20ºC prior to assay in the lab of Dr. Javier Pinilla. 
 
9.7.5.3. 
Effects of lenalidomide monotherapy and in combination with corticosteroids 
on T cells subsets 
 
Peripheral blood collected at the time of study start (C1D1), after 2 cycles of 
lenalidomide monthotherapy, at the time of addition of dexamethasone, and 2 
cycles after the addition of dexamethasone will be used for the determination of 
changes in T cell subsets with lenalidomide monotherapy and after the addition of 
dexamethasone. The determination of T cell subset will be performed by flow 
cytometry. Samples will be collected, processed (ficoll separation and slow freeze 
at -120ºC ) and stored under the care of Dr. Javier Pinilla. A total of 5 green top 
tube per sample will be obtained. 


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9.7.5.4. 
Effects of single agent lenalidomide on global gene expression profile of 
malignant plasma cells. 
 
RNA extracted from CD138 positive cells isolated from the bone marrow aspirate 
of patients with myeloma at baseline and after 2 cycles of lenalidomide 
monotherapy will be subjected to affymatrix array for global gene expression 
profiling and changes in gene expression before and after treatment will be 
correlated. 
 
9.7.5.5. 
Significance of Notch signaling in myeloma 
 
 
RNA will be isolated form CD138 positive cells and the expression of notch 
receptors, ligants and targets by Q-pCR will be compared among responder and 
non responders to lenalidomide. These experiments will be performed by Dr. 
Yulia Nefedova. 
 
9.7.5.6. 
Post Translational modification of protein drug targets in myeloma using mass 
spectrometry 
 
Cell pellets of comprised of CD138 positive cells will be used for proteomic 
studies. Using quantitative mass spectrometry, protein expression and selected 
post-translational modifications will be monitored for apoptotic proteins, nuclear 
factor kappa B survival signaling, and existing drug targets. The impact of 
exposure to lenalidomide on the malignant cell proteome will thus be examined. 
These studies will be performed by Dr. John Koomen. 
 
9.7.5.7. 
Prioritization of samples for correlative/translational studies 


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Recognizing that not all patients will consent to the ancillary studies noted above and for 
some of the patients who do consent, the quantity of quality sample might not be 
sufficient for all experiments above, the following priority for sample usage for 
correlative studies is proposed (mainly applicable to bone marrow aspiration samples): 
 
1- induction of tumor suppressor genes by lenalidomide 
 
 
2- Post translational modification of protein drug targets in myeloma using mass 
spectrometry 
 
3- Significance of Notch signaling in myeloma 
 
 
4- Differential gene expression profile of malignant plasma cell treated in vivo 
with lenalidomide as monotherapy 
 
 
10. Protocol Amendments/Deviations 
 
 
 
10.1. Protocol amendments 
 
 
Any amendment to this protocol must be agreed to by the Principal Investigator and 
reviewed by Celgene. Amendments should only be submitted to IRB/EC after 
consideration of Celgene review. Written verification of  IRB/EC approval will be 
obtained before any amendment is implemented. 
 
10.2. Protocol deviations 
 
 
When an emergency occurs that requires a deviation from the protocol for a subject, a 
deviation will be made only for that subject. The physician in attendance in such an 
emergency will, if circumstances and time permit, contact Principal Investigator (Rachid 


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Baz, MD) prior to the deviation immediately by telephone. If time does not allow for 
this, the Investigator will notify Dr. Baz of the deviation as soon as possible in writing 
and by phone. 
 
Such contacts will be made as soon as possible to determine whether or not the subject 
(for whom the deviation from protocol was effected) is to continue in the study. The 
subject’s medical records will completely describe the deviation from the protocol and 
state the reasons for such deviation and document the contact or attempted contact with 
Dr. Baz. In addition, the Investigator will notify the IRB/EC in writing of such deviation 
from protocol. 
 
Non-emergency minor deviations from the protocol will be permitted only with prior 
agreement from the Principal Investigator. 
 
 
11. Data Management 
 
 
 
11.1. Study monitoring and auditing 
 
 
 
11.2. Scientific Review Committee (SRC) 
 
The Cancer Center maintains two full board Scientific Review Committees (SRC), 
meeting every other week (the first Wednesday and third Thursday of every month) as 
well as one Behavioral Ad-Hoc SRC. 
 
Each SRC conducts a formal internal peer review of all clinical protocols and 
general scientific oversight of interventional clinical research. Protocols are reviewed for 
scientific merit, adequate study design, safety, availability of targeted study population, 
and feasibility of timely completion of all proposed research projects to be conducted by 


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its assigned programs at the Cancer Center. Each SRC is responsible for evaluating the 
risk/benefit assessment and corresponding data and safety monitoring plan as part of the 
scientific review and approval process. The SRC will refer any potential conflicts of 
interest identified in the proposed research to the Conflict Committee. 
 
11.3. PI Responsibility 
 
 
The PI of each study is ultimately responsible for every aspect of the design, conduct and 
actions of all members of the research team. This includes the final analysis of the 
protocol. The PI is responsible for ensuring that: 
 
 All protocols include a DSMP and procedures for its implementation commensurate 
with the risk and complexity of the study. The DSMP must include a structured 
adverse event determination, monitoring and reporting system, including standardized 
forms and procedures for referring and/or treating subjects experiencing adverse 
events. The plan must include data and safety-monitoring procedures for subjects 
enrolled who may be receiving a part of their protocol-required treatment at 
community sites. 
 
 In all cases, the PI of the study will have primary responsibility for ensuring that the 
protocol is conducted as approved by the SRC and IRB. The PI will ensure that the 
monitoring plan is followed, that all data required for oversight of monitoring are 
accurately reported to a DSMB and/or to the PMC and IRB as required, that all 
adverse events are reported according to protocol guidelines, and that any adverse 
actions reflecting patient safety concerns are appropriately reported. 
 
 
 


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11.4. The Protocol Monitoring Committee (PMC)   
 
The PMC monitors its assigned ongoing research protocols for: adverse event reporting, 
data and safety monitoring, and internal audit findings. The PMC, upon review of any 
agenda item, may approve the study for continuation, require revisions, suspend or close 
a protocol. 
 
Investigators of studies, which are designated to be reviewed by the PMC for data and 
safety monitoring, shall provide a statistical report of the study’s progress and summary 
of adverse events and deviations based on the phase of the study and the associated risk 
of the study or more often if applicable. The external DSMB (if applicable) shall forward 
its report for high-risk studies designated for external review at least annually or more 
often if applicable. 
 
11.5. Research Compliance Division (RCD) 
 
 
RCD of the Corporate Compliance Office is the coordinating center for internal audits of 
clinical trials conducted at the Cancer Center. The audit procedure is a formal, 
comprehensive, source document review of all clinical trials. External audit reports that 
meet the criteria of the internal audit may be accepted in lieu of an internal audit. 
 
The (RCD) shall provide a report to the PMC of internal audit findings for PMC action. 
A representative of the RCD will be present to discuss the audits with the PMC. For 
cause audits will be discussed during an executive session of the PMC. Only members 
(voting and ex-officio) may attend this session. 
 
 
 


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11.6. Investigator responsibilities 
 
 
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice 
and in the US Code of Federal Regulations. 
Investigators, or designee, must enter study data onto a 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, and TPP), providing direct 
access to the facilities where the study took place, to source documents, to the data 
collection system, 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 any visits and be made available to the Celgene representatives so that the accuracy 
and completeness may be checked. 
 
This study may be subject to an independent audit at the investigational site, which will 
be conducted by Celgene’s Quality Assurance personnel or designee. Full consultation 
with appropriate personnel will be made prior to and during such an audit. The 
Investigator must be available during the audit. 
 
If the Investigator is contacted by any regulatory authority regarding an audit for this 
study or any other study, the Investigator is to contact Celgene immediately. 
 
12. Bio-statistical Consideration 
 
This is a phase 2 trial evaluating a lenalidomide based response adapted strategy in 
older adults with newly diagnosed multiple myeloma. Descriptive statistics will be 


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used to summarize patients’ demographic and clinical characteristics collected at each 
visit. Mean, standard deviation and range will be calculated for continuous variables, 
and frequency and percentage will be generated for categorical variables. The 
distribution (frequency and percentage) of patients treated with single agent 
lenalidomide, lenalidomide + prednisone, and lenalidomide+low dose dexamethasone 
will be presented. 
 
12.1. Sample size: 
 
 
The primary endpoint is 12-month PFS for the overall response adaptive approach. Based on 
the E4A03 and SWOG 2032 studies, the 12-month PFS is approximately 70% for patients 
treated with lenalidomide low dose dexamethasone. The sample size determination is 
primarily based on the consideration of providing an estimate of the 12-month PFS with 
reasonable precision. We estimate the 12-month PFS in the response adapted approach is 
85%. With a sample size of 60 evaluable patients (30 from Moffitt and 30 from sites in South 
Korea), its 95% confidence interval is 73.4-92.9%. 
 
12.2. Efficacy evaluation 
 
 
 
12.2.1 Primary efficacy analysis 
 
 
Progression free survival (PFS) is defined as the time from start of lenalidomide 
monotherapy to the first occurrence of disease progression or death on study from 
any cause, whichever occurs earlier. All treated patients will be included in efficacy 
endpoint analysis. Those patients who are treated on this trial but have not had a 
relevant event at the time of last follow-up will be included in the analyses of these 
endpoints as censored observations. 
 


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The primary endpoint is the point estimate of the 12-month PFS rate for the overall 
response adaptive approach. Number and percentage of patients who survived greater or 
equal to 365 days without disease progression will be summarized. The 95% confidence 
interval will be calculated using the exact binominal method. The PFS curves will be 
estimated by the Kaplan-Meier method. Median and its 95% confidence intervals will be 
estimated. 
 
12.2.2 Secondary efficacy analysis 
 
 
Response will be assessed using the Uniform response criteria set forth by the 
International myeloma working group (IMWG)  (See  Appendix II). Frequencies and 
percentages will be used to summarize for all response categories. The response in this 
trial is defined as complete remission (CR), stringent complete remission (SRC), very 
good partial remission (VGPR) and partial remission (PR). The response rate for patients 
treated with single agent lenalidomide, lenalidomide and prednisone and lenalidomide 
and low dose dexamethasone will be calculated as the percentage of responders, and the 
95% confidence interval will be calculated using the exact binominal method. Logistic 
regression will be used to investigate relationships of the response rates with baseline and 
other relevant covariates, if appropriate. 
 
Overall survival (OS) is defined as the time from study entry to death of any cause. The 
OS curves will be estimated by the Kaplan-Meier method. Median and its 95% 
confidence intervals will be estimated. The effect of baseline and other relevant 
covariates will be investigated with Cox regression models, when appropriate. 
Confidence intervals for the survival probabilities at different points will be constructed 
as needed. The PFS curve for the patients treated with single agent lenalidomide will also 


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be calculated using the Kaplan-Meier method. 
 
12.2.3 Safety analysis 
 
 
The following safety analyses will be performed using data from all subjects who receive 
any study drug. Adverse events will be classified using the MedDRA classification 
system. The severity of the toxicities will be graded according to the NCI CTCAE v 4.0 
whenever possible. 
 
In the by-subject analysis, a subject having the same event more than once will be 
counted only once. Adverse events (AE) will be summarized by worst NCI CTCAE 
grade. The patient incidence of AEs will be summarized by system organ class, preferred 
term, severity and relationship to study drug. Adverse events leading to death or to 
discontinuation from treatment, events classified as NCI CTCAE v 4.0 grade 3 or higher, 
study-drug-related events, and serious adverse  events will be  listed  separately. 
Laboratory data will be graded according to NCI CTCAE v 4.0 severity grade. Cross 
tabulations will be provided to summarize frequencies of abnormalities. The physical 
examine results (such as blood pressure, pulse, temperature) at each visit will be 
summarized using descriptive statistics. 
 
12.2.4 Evaluation of the group difference between participants from Moffitt and 
South Korea 
 
The study participants will be enrolled half from Moffitt and half from multiple sites in 
South Korea. The important demographic and clinical characters associated with the 
endpoints were addressed in the inclusion and exclusion criteria so these two groups 
should be comparable at baseline. Although there are currently no reports suggesting a 
difference tolerance or response in Korean patients to lenalidomide as compared to 


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European / North American patients, we will evaluate the ethnic effect for our study 
endpoints for conservative purpose. For survival endpoints (PFS and OS), the log-rank 
test will be applied to evaluate the ethnic effect. For response rate and adverse event 
proportion, the Fisher’s exact test will be applied for testing the ethnic effect. If there are 
no significant differences between these two groups, we will provide the overall results 
using the combined data sources. If ethnic effects are observed for some endpoints, 
statistical models will be applied for adjusting the ethnic effect. Cox regression models 
and logistic models will be applied for adjusting the ethnic effect for the survival and 
binary endpoints, respectively. 
 
12.2.5 Analysis on exploratory aims 
 
 
The first exploratory aim is to measure a lenalidomide induced tumor specific immune 
response and correlate the tumor specific immune response with corticosteroid use 
(addition of dexamethasone or prednisone), response to therapy and duration of response. 
Antibody titer, measurement of tumor specific immune response, will be obtained at 4 
different time points: at baseline, after 2 cycles of lenalidomide monthotherapy, at the 
time of addition of dexamethasone, and 2 cycles after the addition of dexamethasone. 
Descriptive statistics (mean, standard deviation, median, and inter-quartile range) will be 
used to describe antibody titer distributions for the overall response adaptive approach 
and by treatment in different time points. For evaluating lenalidomide effect on immune 
response, the antibody titer change from baseline to after 2 cycles of lenalidomide 
monthotherapy will be summarized using descriptive statistics. For evaluating 
corticosteroid effect on immune response, the antibody titer change from baseline to 
either time of addition of dexamethasone or 2 cycles after the addition of dexamethasone 
will be summarized. These lenalidomide and corticosteroid effect will be analyzed using  


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either the pair t-test if the original or transformed data are normally distributed, or the 
Wilcoxon sign rank test whenever the normality assumption cannot be justified. The 
antibody titer change will also be compared between response to therapy (yes/no) using 
either the student’s t-test or Wilcoxon rank sum test. Duration of response is defined as 
the time from study start to the time of disease progression on lenalidomide and 
dexamethasone. Cox regression model will be applied to evaluate the association between 
antibody titer change and duration of response. 
The second exploratory aim is to evaluate the impact of lenalidomide mono-therapy on 
expression of tumor suppression genes and cell cycle regulators. The expressions of 
interest are in the following target genes: EGR1, EGR2, EGR3, p15, p21, p27 and 
SPARC. The 15 paired samples will be obtained pre and post 2 cycles of lenalidomide 
monotherapy. The gene expression data will be pre-processed using appropriate 
background correction, normalization, and transformation. The processed expression data 
will be used for further analyses. For each gene expression, the expression differences 
between pre and post 2 cycles of lenalidomide monotherapy will be described using 
descriptive statistics and the impact of lenalidomide mono-therapy will be evaluated  
using either the paired t-test or Wilcoxon sign rank test. 
 
 
13. Regulatory Considerations 
 
 
 
13.1. Institutional review board/ethics committee approval 
 
 
The protocol for this study has been designed in accordance with the general ethical 
principles outlined in the Declaration of Helsinki. The review of this protocol by the 
IRB/EC and the performance of all aspects of the study, including the methods used for 


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obtaining informed consent, must also be in accordance with principles enunciated in the 
declaration, as well as ICH Guidelines, Title 21 of the Code of Federal Regulations 
(CFR), Part 50 Protection of Human Subjects and Part 56 Institutional Review Boards. 
 
The Investigator will be responsible for preparing documents for submission to the 
relevant IRB/EC and obtaining written approval for this study. The approval will be 
obtained prior to the initiation of the study. 
 
A copy of the IRB/EC approval for the protocol and the Informed Consent is to be 
provided to Celgene. The approval for both the protocol and informed consent must 
specify the date of approval, protocol number and version, or amendment number. 
 
Any amendments to the protocol after receipt of IRB/EC approval must be submitted by 
the Investigator for review to Celgene, and then to the IRB/EC for approval. The 
Investigator is also responsible for notifying the IRB/EC of any serious deviations from 
the protocol, or anything else that may involve added risk to subjects. 
 
Any advertisements used to recruit subjects for the study must be reviewed and approved 
by the IRB/EC prior to use. 
 
13.2. Informed consent 
 
 
The Investigator must obtain informed consent of a subject or his/her designee prior to 
any study related procedures as per Good Clinical Practices (GCP) 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 


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the subject prior to the subject’s entry into the study, must be maintained in the 
Investigator’s study files. 
 
A sample of the informed consent to be used in the study is to be forwarded to Celgene 
prior to submitting it to the IRB/EC for approval. 
 
13.3. Subject confidentiality 
 
 
Celgene affirms the subject’s right to protection against invasion of privacy. In 
compliance with United States federal regulations, Celgene requires the Investigator to 
permit Celgene representatives and, when necessary, representatives of the FDA or other 
regulatory authorities to review and/or copy any medical records relevant to the study in 
accordance with local laws. 
 
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. 
 
13.4. Study records requirements 
 
 
The Investigator must ensure that the records and documents pertaining to the conduct of 
the study and the distribution of the study drug, that is copies of data collection and 
source documents (original documents, data, and records [e.g., hospital records; clinical 
and office charts; laboratory notes; memoranda; subject’s diaries or evaluation checklists; 
pharmacy dispensing records; recorded data from automated instruments; copies or 
transcriptions certified after verification as being accurate copies; microfiches; 
photographic negatives, microfilm, or magnetic media; x-rays; subject files; and records 
kept at the pharmacy, at the laboratories, and at medico-technical departments involved in 


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the clinical study; documents regarding subject treatment and study drug accountability; 
original signed informed consents, etc.]) be retained by the investigator for as long as 
needed to comply with national and international regulations (generally 2 years after 
discontinuing clinical development or after the last marketing approval). The 
Investigator agrees to adhere to the document/records retention procedures by signing the 
protocol. 
 
Premature discontinuation of study 
 
 
 
13.4.1. Single center 
 
 
The responsible local clinical Investigator as well as Celgene have the right to 
discontinue this study at any time for reasonable medical or administrative reasons in any 
single center. Possible reasons for termination of the study could be but are not limited 
to: 
 
 
Unsatisfactory enrollment with respect to quantity or quality. 
 
 
 
Inaccurate or incomplete data collection. 
 
 
 
Falsification of records. 
 
 
 
Failure to adhere to the study protocol. 
 
 
 
13.4.2. Study as a whole 
 
 
Any possible premature discontinuation would have to be documented adequately with 
reasons being stated, and information would be issued according to local requirements 
after discussions and agreement between the PI’s sponsor (s) and regulatory authorities at 
the institutions (e.g., IRB/EC, regulatory authorities, etc.). 
 


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14. Appendices 
 
 
 
Appendix I: Classification of the plasma cell dyscrasias[22] & 
International Staging System (ISS)[23] 
 
MGUS 
Asymptomatic multiple 
myeloma 
Symptomatic multiple 
myeloma 
Serum M protein < 30g/L & 
Clonal bone marrow 
plasmacytosis <10% 
No other B cell 
lymphoproliferative disorder 
No related organ and tissue 
impairment 
Serum M protein ≥ 30g/L or 
Clonal bone marrow 
plasmacytosis ≥ 10% 
No related organ and tissue 
impairment 
M protein in the serum or urine 
& 
Clonal bone marrow 
plasmacytosis or plasmacytoma 
Related organ and tissue 
impairment* 
 
*Related Organ Tissue Impairment 
 
 
• 
Hypercalcemia 
 
 
• 
Renal dysfunction 
 
 
• 
Anemia: hemoglobin 2 g/dL below the lower limit of normal 
 
• 
Lytic bone lesions (solitary plasmacytoma requires >30% PC) 
 
 
 
• 
Symptomatic hyperviscosity 
 
 


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• 
Amyloidosis (requires >30% PC) 
 
 


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• 
 
 
 
 
• 
Recurrent bacterial infections (>2/year) 
 
 
 
 
 
International Staging System[23]: 
 
 
I 
β2m < 3.5 mg/dL 
Albumin≥3.5g/dL 
II 
5.5> β2m ≥ 3.5 mg/dL 
Or 
Albumin <3.5g/dL and β2m < 3.5 mg/dL 
III 
β2m ≥ 5.5 mg/dL 
 
 


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Appendix II: Uniform Response Criteria as defined by the International 
Myeloma Working Group[22] 
All relapse categories require two consecutive assessments made at anytime 
before classification as relapse or disease progression and/or the institution of 
any new therapy. 
Measurable disease is defined as: 
 
Complete remission 
• Negative immunofixation on the serum and urine, and 
• Disapppearance of any soft tissue plasmacytomas , and 
• ≤5% plasma cells in the bone marrow (confirmation with repeat bone marrow 
is not needed) 
Stringent Complete 
remission 
• CR as defined above, and 
• Normal free light chain (FLC) ratio, and 
• Absence of clonal cells in the bone marrow by immunohistochemistry or 
immunofluorescence, based on a κ/λ ratio of > 4:1 or < 1:2 performed on a 
minimum of 100 plasma cells (confirmation with repeat bone marrow is not 
needed) 
Very Good Partial 
Remission 
• 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 of < 
100 mg per 24 hours 
Partial Remission 
• ≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein 
by ≥90%, or to <200mg per 24 h 
• 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 
• In addition to the above listed criteria, if present at baseline, a ≥50% 
reduction in the size of soft tissue plasmacytomas is also required 
Minimal remission 
• 25-49% reduction of serum M-protein and reduction in 24-h urinary M-
protein by ≥50% but less than 90% 
• In addition to the above listed criteria, if present at baseline, a ≥25% 
reduction in the size of soft tissue plasmacytomas is also required 
Stable Disease 
• Not meeting criteria for CR, VGPR, PR or progressive disease 


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Progressive Disease 
V. 3 12/06/2010 
Increase of ≥25% from baseline in serum M-component, and the absolute 
increase must be ≥0.5 g/dl. If the starting M-component is ≥5 g/dl, increases 
≥1 g/dl are sufficient to define relapse. 
• Increase of ≥25% from baseline in urine M-component, and the absolute 
increase must be ≥200 mg/24 hours 
• Only in patients without measurable serum and urine M-protein levels: 
Increase of ≥25% from baseline in the difference between involved and 
uninvolved FLC levels, and the absolute difference must be >10 mg/dl 
• Increase of ≥25% from baseline in bone marrow plasma cell percentage, and 
the absolute % must be ≥10% (relapse from CR has the 5% cutoff versus 10% 
for other categories of relapse) 
• 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. 
 
 
- Serum M-protein ≥ 1 g/dl (≥ 10 gm/l) [10 g/l] 
 
- Urine M-protein ≥ 200 mg/24h 
 
Serum FLC assay: Involved FLC level ≥ 100 mg/dl (≥ 100 mg/l) provided serum FLC 
ratio is abnormal 
 
 
 


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


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Appendix IV: Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods 
Risks Associated with Pregnancy 
The use of lenalidomide in pregnant females and nursing mothers has not been studied 
nor has the effect of the lenalidomide on human eggs and sperm. Lenalidomide is 
structurally related to thalidomide. Thalidomide is a known human teratogenic active 
substance that causes severe life-threatening birth defects. An embryofetal development 
study in animals indicates that lenalidomide produced malformations in the offspring of 
female monkeys who received the drug during pregnancy. The teratogenic effect of 
lenalidomide in humans cannot be ruled out. Therefore, a risk minimization plan to 
prevent pregnancy must be observed.The risks to a fetus are not known. However, 
because lenalidomide is related to thalidomide, and thalidomide is known to cause severe 
birth defects, the following requirements must be observed. 
All study participants must be registered into the mandatory RevAssist® program, and be 
willing and able to comply with the requirements of RevAssist®. 
Criteria for females of childbearing potential (FCBP) 
 
This protocol defines a female of childbearing potential as a sexually mature female who: 
1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been 
naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any 
time in the preceding 24 consecutive months). 
The investigator must ensure that: 
 Females of childbearing potential comply with the conditions for pregnancy risk 
minimization, including confirmation that she has an adequate level of 
understanding 
 
 Females NOT of childbearing potential acknowledge that she understands the 
hazards and necessary precautions associated with the use of lenalidomide 
 
 Male patients taking lenalidomide acknowledge that he understands that traces of 
lenalidomide have been found in semen, that he understands the potential 
teratogenic risk if engaged in sexual activity with a female of childbearing 
potential, and that he understands the need for the use of a condom even if he has 
had a vasectomy, if engaged in sexual activity with a female of childbearing 
potential. 


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Contraception 
 
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two 
reliable forms of contraception simultaneously or to practice complete abstinence from 
heterosexual intercourse during the following time periods related to this study: 1) for at 
least 28 days before starting lenalidomide; 2) throughout the entire duration of 
lenalidomide treatment; 3) during dose interruptions; and 4) for at least 28 days after 
lenalidomide discontinuation. 
 
The two methods of reliable contraception must include one highly effective method and 
one additional effective (barrier) method. FCBP must be referred to a qualified provider 
of contraceptive methods if needed. The following are examples of highly effective and 
additional effective methods of contraception: 
 
o Highly effective methods: 
 
 Intrauterine device (IUD) 
 
 Hormonal (birth control pills, injections, implants) 
 
 Tubal ligation 
 
 Partner’s vasectomy 
 
o Additional effective methods: 
 
 Male condom 
 
 Diaphragm 
 
 Cervical Cap 
 
Because of the increased risk of venous thromboembolism in patients with multiple 
myeloma taking lenalidomide and dexamethasone, combined oral contraceptive pills are 
not recommended. If a patient is currently using combined oral contraception the patient 
should switch to one of the effective method listed above. The risk of venous 
thromboembolism continues for 4−6 weeks after discontinuing combined oral 
contraception. The efficacy of contraceptive steroids may be reduced during co-treatment 
with dexamethasone. 
 
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. 


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Pregnancy testing 
 
Medically supervised pregnancy tests with a minimum sensitivity of 50 mIU/mL must be 
performed for females of childbearing potential, including females of childbearing 
potential who commit to complete abstinence, as outlined below. 
 
Before starting lenalidomide 
 
Female Patients: 
 
FCBP must have two negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to 
prescribing lenalidomide. The first pregnancy test must be performed within 10-14 days 
prior to prescribing lenalidomide and the second pregnancy test must be performed 
within 24 hours prior to prescribing lenalidomide. The patient may not receive 
lenalidomide until the Investigator has verified that the results of these pregnancy tests 
are negative. 
 
Male Patients: 
 
Must agree to practice complete abstinence or agree to use a condom during sexual 
contact with pregnant females or females of childbearing potential throughout the entire 
duration of lenalidomide treatment, during dose interruptions and for at least 28 days 
following lenalidomide discontinuation, even if he has undergone a successful 
vasectomy. 
 
During study participation and for 28 days following lenalidomide discontinuation 
 
Female Patients: 
 
 FCBP with regular or no menstrual cycles must agree to have pregnancy tests 
weekly for the first 28 days of lenalidomide treatment, including dose 
interruptions and then every 28 days throughout the remaining duration of 
lenalidomide 
treatment, 
including 
dose 
interruptions, 
at 
lenalidomide 
discontinuation, and at Day 28 following lenalidomide  discontinuation.  If 
menstrual cycles are irregular, the pregnancy testing must occur weekly for the 
first  28 days of lenalidomide treatment, including dose interruptions, and then 
every  14 days throughout the remaining duration  of  lenalidomide  treatment, 
including dose interruptions, at lenalidomide discontinuation, and at Day 14 and 
Day 28 following lenalidomide discontinuation. 
 At each visit, the Investigator must confirm with the FCBP that she is continuing 
to use two reliable methods of birth control at each visit during the time that birth 
control is required. 
 If pregnancy or a positive pregnancy test does occur in a study patient, 
lenalidomide must be immediately discontinued. 
 


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 Pregnancy testing and counseling must be performed if a patient misses her period 
or if her pregnancy test or her menstrual bleeding is abnormal. Lenalidomide 
treatment must be temporarily discontinued during this evaluation. 
 
 Females must agree to abstain from breastfeeding during study participation and 
for at least 28 days after lenalidomide discontinuation. 
 
Male Patients: 
 
 Must practice complete abstinence or use a condom during sexual contact with 
pregnant females or females of childbearing potential throughout the entire 
duration of lenalidomide treatment, during dose interruptions and for at least 28 
days following lenalidomide discontinuation, even if he has undergone a 
successful vasectomy. 
 
 If pregnancy or a positive pregnancy test does occur in the partner of a male study 
patient during study participation, the investigator must be notified immediately. 
 
Additional precautions 
 
 Patients should be instructed never to give lenalidomide to another person. 
 
 Female patients should not donate blood during therapy and for at least 28 days 
following discontinuation of lenalidomide. 
 
 Male patients should not donate blood, semen or sperm during therapy or for at 
least 28 days following discontinuation of lenalidomide. 
 
 Only enough lenalidomide for one cycle of therapy may be prescribed with each 
cycle of therapy. 
 
 
 


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Appendix V NCI CTC Version 4.0 
 
 
Toxicity will be scored using NCI CTC Version 4.0 for toxicity and adverse event 
reporting. A copy of the NCI CTC Version 4.0 can be downloaded from the CTEP 
homepage: (http://ctep.info.nih.gov). All appropriate treatment areas have access to a 
copy of the CTC Version 
 
 
 


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Appendix VI: Cockcroft-Gault estimation of CrCl: 
 
 
 
Cockcroft-Gault estimation of creatinine clearance (CrCl): 
(Cockcroft, 1976; Luke 1990) 
 
 
CrCl (mL/min) = 
 (140 –age) x (weight, kg) 
(Males) 
72 x (serum creatinine, mg/dL) 
 
 
CrCl (mL/min) = 
(140 –age) x (weight, kg)_   x 0.85 
(Females) 
72 x (serum creatinine, mg/dL) 
 
 
 


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