A Phase I/II Trial Of Very Low to Low-Doses of Continuous Azacitidine in Combination With Standard Doses of Lenalidomide and Low-Dose Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma
Phase: PHASE1
Conditions: Refractory Multiple Myeloma
Sponsor: Case Comprehensive Cancer Center

 
 
 
 
 
 
Version: 07/16/2015 
 
 
Protocol Title: A phase I/II trial of very low to low-doses of continuous azacitidine in 
combination with standard doses of lenalidomide and low-dose dexamethasone in 
patients with relapsed or refractory multiple myeloma 
 
SPONSOR:  
Cleveland Clinic Foundation 
Institution Protocol #  
CASE1A09 CC 902 
Celgene Tracking #:  
RV-MM-PI-0507 
DATE FINAL:  
February 4, 2010 
AMENDMENT 1:   
August 26, 2010 
AMENDMENT 2:   
January 03, 2011 
AMENDMENT 3:  
May 06, 2011 
AMENDMENT 4:  
July 22, 2011 
AMENDMENT 5:  
November 11, 2011 
AMENDMENT 6:  
January 23, 2012 
AMENDMENT 7:  
April 14, 2012 
AMENDMENT 8: 
AMENDMENT 9:  
AMENDMENT 10: 
 
September 10, 2012 
September 06, 2013 
July 16, 2015 
  
 
  
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to 
the extent necessary to obtain informed consent, may not be disclosed to another party 
unless law or regulations require such disclosure.  Persons to whom the information is 
disclosed must be informed that the information is confidential and may not be further 
disclosed by them. 
 
 

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

 
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STUDY PERSONNEL 
 
Supporter: 
 
Celgene Corporation 
86 Morris Ave, 
Summit,  NJ   07901 
1-800-742-3107 
 
 
 
Study Locations: 
 
Cleveland Clinic Taussig Cancer Center, 9500 Euclid 
Ave, Cleveland, OH 44195 
 
University Hospitals, Ireland Cancer Center, 11100 
Euclid Ave, Cleveland, OH 44106  
Principal Investigator 
Cleveland Clinic: 
 
Frederic J. Reu, M.D. 
Sub-investigator 
Cleveland Clinic: 
 
Yogen Saunthararajah, M.D. 
Sub-investigator 
Cleveland Clinic: 
 
Paul Elson, Sc.D. 
Sub-investigator  
University Hospitals: 
 
 Ehsan Malek, M.D. 
Study Coordinator: 
 
Sherry Fada 
 

 
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Table of Contents 
1 
Protocol Synopsis ........................................................................................................ 6 
2 
Schedule of Study Assessments * ............................................................................. 11 
3 
Background and Rationale....................................................................................... 13 
3.1 
Lenalidomide ................................................................................................................ 13 
3.2 
Azacitidine (Vidaza®) .................................................................................................. 14 
3.3 
Rationale for Use in Relapsed or Refractory Multiple Myeloma ............................ 14 
4 
Study Objectives and Endpoints ............................................................................... 16 
4.1 
Objectives...................................................................................................................... 16 
4.2 
Endpoints ...................................................................................................................... 17 
5 
Investigational Plan .................................................................................................. 18 
5.1 
Overall Design .............................................................................................................. 18 
5.2 
Screening and Eligibility ............................................................................................. 29 
5.3 
Definition Relapsed Myeloma and Refractory Myeloma ......................................... 32 
5.4 
Visit Schedule and Assessments .................................................................................. 33 
5.5 
Correlative Science ...................................................................................................... 33 
5.6 
Drug Administration ................................................................................................... 36 
5.7 
Dose Continuation, Modification and Interruption ................................................... 39 
5.8 
Concomitant Therapy .................................................................................................. 47 
5.9 
Discontinuation of Study Treatment Including Progressive Disease Definition .... 48 
5.10 
Follow-Up...................................................................................................................... 49 
6 
Adverse Events .......................................................................................................... 49 
6.1 
Serious Adverse Event (SAE) Definition ................................................................... 49 
6.2 
Adverse Drug Reaction Reporting ............................................................................. 50 
6.3 
Investigator Reporting Responsibilities ..................................................................... 52 
6.4 
Adverse Event Updates/IND Safety Reports ............................................................. 53 
7 
Response Criteria ...................................................................................................... 53 
8 
Protocol Amendments/Deviations ............................................................................ 55 
8.1 
Protocol Amendments ................................................................................................. 55 
8.2 
Protocol Deviations ...................................................................................................... 55 
9 
Data Management .................................................................................................... 55 
9.1 
Analyses and Reporting ............................................................................................... 55 
9.2 
Data Safety Monitoring Plan ...................................................................................... 55 
9.3 
Study Auditing ............................................................................................................. 55 

 
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10 
Biostatistical Analysis ........................................................................................... 56 
10.1 
Overview ....................................................................................................................... 56 
10.2 
Datasets to be Analyzed ............................................................................................... 56 
10.3 
Statistical Methodology ............................................................................................... 58 
11 
Regulatory Considerations ................................................................................... 58 
11.1 
Institutional Review Board/Ethics Committee Approval ......................................... 58 
11.2 
Informed Consent ........................................................................................................ 59 
11.3 
Subject Confidentiality ................................................................................................ 59 
11.4 
Study Records Requirements ...................................................................................... 59 
11.5 
Premature Discontinuation of Study .......................................................................... 59 
12 
References ............................................................................................................. 60 
Appendix I: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth 
Control Methods ...................................................................................................................... 65 
Appendix II: ECOG Performance Status Scale .................................................................... 67 
Appendix III : NCI CTC Version 4.0 ..................................................................................... 67 
Appendix IV : Cockroft-Gault estimation of CrCl ............................................................... 68 
Appendix V: Bone marrow aspirations RV0507 ................................................................... 69 
Appendix VI: Blood draws for correlative science RV0507 ................................................. 70 
Appendix VII: Lenalidomide and dexamethasone drug administration diary .................. 71 

 
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1 
 
Protocol Synopsis 
PROTOCOL TITLE: A phase I/II trial of very low to low-doses of continuous 
azacitidine in combination with standard doses of lenalidomide and low-dose 
dexamethasone in patients with relapsed or refractory multiple myeloma 
DATE PROTOCOL FINAL: 
 
INDICATION:  
Relapsed or refractory multiple myeloma 
STUDY PHASE: 
Phase I/II 
BACKGROUND AND RATIONALE:  The best currently available treatment for 
patients with relapsed or refractory multiple myeloma uses regimens that include novel 
agents like lenalidomide, thalidomide, and bortezomib but still yield unsatisfactory long 
term tumor control with median remission duration not more than one year and median 
survivals ranging between 1 and 3 years in most studies (1). As myeloma progresses, 
clones emerge that have more tumor suppressor genes silenced by DNA methylation 
which may lead to resistance towards used therapies, escape from immune attack, and 
independence from the bone marrow microenvironment (2-6). In contrast to mutations 
such epigenetic changes can be corrected with aza nucleoside analogues like azacitidine, 
which inhibits the methylation of newly synthesized DNA by inhibiting DNA 
methyltransferase (DNMT) (7-9) and has been shown to improve survival in MDS and 
WHO AML compared to conventional therapy (10).  One of the most active current 
regimens for relapsed/refractory myeloma uses lenalidomide in combination with 
dexamethasone yielding a response duration of over 11 months and an overall survival of 
about 30 months (11). In the upfront therapy setting, low dose dexamethasone in 
combination with lenalidomide appears to yield at least equivalent survival rates but 
cause less toxicity than conventional dose dexamethasone (12). This regimen 
(lenalidomide 25mg day 1-21, every 28 days with dexamethasone 40mg weekly) has 
rapidly been adapted as one of the standard approaches to newly diagnosed and relapsed 
myeloma patients. By combining this regimen with azacitidine, resistant myeloma clones, 
which continue to synthesize DNA despite therapy, may become sensitive through 
reactivation of silenced tumor suppressor genes leading to a deeper and longer response. 
In vitro, non-toxic single low doses of azacitidine (1μM) can reactivate tumor suppressor 
genes in myeloma cell lines for 3-7 days (unpublished observations). Doses higher than 
2-5μM, depending on the cell type, can exert immediate toxicity likely related to 
nucleoside analogue properties of the drug. Pharmacokinetic data in humans suggest that 
a single dose of 50mg/m2 subcutaneously reaches concentrations that should be sufficient 
for DNA demethylation but could cause classical nucleoside analogue toxicity in some 
patients (2.89μM +/- 1.35 μM SD), higher doses like 75mg/m2 reach 4.88 μM +/- 1.4μM 
SD and thus almost certainly exert classic nucleoside analogue toxic effects (13). In this 
study we aim to avoid pronounced nucleoside analogue side effects while maximally 
exploiting DNA demethylating effects of azacitidine. We will therefore assess the safety 
of combination therapy with azacitidine given at low but increasing doses up to 50mg/m2 

 
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twice a week, together with standard dose lenalidomide and low dose dexamethasone in 
relapsed or refractory myeloma patients in a phase I/II study with 10 additional patients 
enrolled at the highest tolerated low azacitidine dose to obtain an initial impression of 
efficacy and to evaluate whether this dose exerts the expected pharmacodynamic effects 
in myeloma cells before a larger phase II trial may be conducted. In light of new data 
supporting use of standard-dose azacitidine in myeloid neoplasia patients with kidney 
dysfunction(14) and GFR-adjusted lenalidomide for myeloma patients(15), amendment 7 
extends the safety and preliminary efficacy evaluations to myeloma patients with GFR 
30-59 ml/min (Cockroft-Gault). Lenalidomide will be used at a fixed dose of 10mg daily 
from day 1-21 every 28 days which yielded equal AUC concentrations in myeloma 
patients with GFR 30-49m/min as 25mg daily from day 1-21 every 28 days in patients 
with GFR > 80 ml/min in a recent study(15). Only two dose levels of azacitidine will be 
tested. Dose level “CKD 1” will use azacitidine at 40 mg/m2 s.c. twice a week which has 
been found tolerable in patients with GFR > 60 ml/min; one of six patients developed a 
dose limiting toxicity, culture negative neutropenic fever at an absolute neutrophil count 
(ANC) nadir of 0.48K/mm3,.with resolution the next day at an ANC of 0.89K/mm3 
without G-CSF use. At the time of amendment 7, two patients with normal kidney 
function have completed the first cycle at dose level 5 (azacitidine 50mg/m2 s.c. twice a 
week) without dose limiting toxicities. Six patients with GFR 30-59 ml/min will be 
treated at CKD 1 if dose limiting toxicities (DLTs) do not occur in more than one patient. 
If 2 of 3 or 2 of up to six patients develop DLTs at CKD1, subsequent patients will be 
treated at “CKD -1” (30mg/m2 s.c. twice a week). Otherwise (no more than one patient 
with DLTs at CKD1), subsequent patients will receive azacitidine at 50mg/m2 s.c. twice a 
week (= dose level CKD2). Lower or higher dose levels will not be tested. This modified 
dose escalation scheme increases safety by enrolling at least 6 patients per dose level and 
guarantees that the tolerability of twice a week azacitidine in patients with GFR 30-59 
ml/min will be defined by enrolling maximally 12 additional patients. Omission of 
weekly azacitidine is based on the observation that clinical benefit response rates were 
more than twice as high with twice a week than with weekly azacitidine dosing (40% 
versus less than 15%) in patients with GFR > 60ml/min, an encouraging result taking into 
consideration that patients had received a median of  4.5 prior regimens, with myeloma 
refractory to previous lenalidomide in 88%, to previous protesome inhibitors in 81%, and 
to both lenalidomide and proteasome inhibitors in 75%. Once the highest tolerated low 
dose for patients with reduced GFR (HTLD-CKD) has been defined, enrollment at this 
dose level may contribute to the 10 patient phase II extension. Before amendment 7 
eighteen patients have started treatment, including two at dose level 5. Assuming up to 6 
patients will be enrolled per dose level; the maximal number of enrolled patients will 
therefore increase from previously estimated 40 to 44 after amendment 7. 
STUDY OBJECTIVES: 
Primary:   
• 
Define the highest tolerated low doses (HTLD and HTLD-CKD for GFR > 60 
ml/min and 30-59ml/min, respectively) and safety of azacitidine given at low but 
increasing doses up to 50mg/m2 twice a week concurrently with GFR-adjusted 
lenalidomide doses and low dose dexamethasone in patients with relapsed or 
refractory multiple myeloma. 

 
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Secondary:   
• Response according to international response criteria (>PR) and clinical benefit 
response (>minor response according to adapted EBMT criteria), see under 7 
• Correlate response with plasma activity of the azacitidine inactivating enzyme 
cytidine deaminase (CDA) 
• Progression-free survival and overall survival 
• Peripheral blood hematopoietic progenitor (CD34+) yield and time to neutrophil 
and platelet recovery in patients undergoing autologous stem cell transplantation 
• Promoter demethylation and gene reactivation in myeloma cells and 
hematopoietic progenitors treated at the HTLD / HTLD-CKD level after one 
cycle of therapy 
• Changes in global gene expression in myeloma cells treated at the HTLD / 
HTLD-CKD level after one cycle of therapy 
STUDY DESIGN: 
Two institutions phase I/II study, classical 3x3 design for patients with GFR > 60ml/min, 
modified 3x3 design for patients with GFR 30-59ml/min, with 10 additional patients 
treated at the highest tolerated low dose (HTLD / HTLD-CKD).   
Patient population: Multiple myeloma, with relapsed or refractory disease (see under 5.3). 
The Cockroft-Gault formula will be used for all GFR estimations throughout this study 
(Appendix IV). 
STUDY ENDPOINTS 
Primary: 
• The highest tolerated low dose (HTLD and HTLD-CKD for GFR > 60 ml/min 
and 30-59ml/min, respectively) of azacitidine in combination with GFR-adjusted 
lenalidomide will be defined as the dose level below which dose limiting toxicity 
(DLT) occurs during the first 28-day cycle in 2 out of three or out of up to 6 
patients. If one out of the first 3 patients with GFR > 60ml/min develops DLT, up 
to three additional patients are treated at the same dose level. In patients with 
GFR 30-59ml/min each dose level will enroll 6 patients unless more than 1 
patient develops  DLT. The dose will not be escalated above 50mg/m2 twice a 
week for reasons outlined under background and rationale of this synopsis. Any 
dose level evaluated as the possible HTLD / HTLD-CKD must include 6 patients 
assessed for DLT.  DLT is defined in Section 5.1. Toxicity according to CTCAE 
v.4.0 will be assessed with weekly CBC w. Diff and CMP during the first 6 
cycles, subsequently before each cycle, weekly history and physical during the 
first 28-day cycle, then before each cycle until cycle 12.  
 
Secondary: 
• Response will be determined monthly during the first 12 cycles and every two 
months thereafter with serum and 24hr urine protein electrophoresis, and as 
appropriate, supplemented by immunofixation, serum free light chain assay, and 

 
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bone marrow examination. Response before high dose melphalan and autologous 
stem cell transplant will also be confirmed by 2 separate blood and 24 hr urine 
tests between the last dose of combination therapy and the first dose of the 
mobilizing agent. 
• Plasma from peripheral blood draws will be used to quantify the activity of CDA 
using an HPLC method (see under 5.5.3) 
• Progression-free survival will be measured from study entry to progression as 
defined by international response criteria (see under 5.9.1) or death of any cause, 
whichever comes first.  
• Overall survival will be measured from study entry to death from any cause. 
• CD34+ cell yield will be calculated based on flow cytometry of mononuclear cells 
harvested following stem cell mobilization. Time to neutrophil (> 1,000/mm3) and 
platelet (> 100,000/mm3) recovery will be counted from the day of stem cell 
infusion (=day 0)  
• Promoter demethylation and gene reactivation will be measured at least at the 
HTLD / HTLD-CKD level using the Illumina® HumanMethylation27 BeadChip 
array on CD138 purified and CD34 purified cells obtained from bone marrow 
aspirates within 7 days before treatment start and at the end of cycle #1.RNA will 
be harvested from the same cell populations to confirm reactivation of selected 
genes identified on the array. Since the HTLD / HTLD-CKD is identified 
retrospectively DNA and RNA will be isolated from purified cell populations 
from all bone marrow aspirations before and after cycle #1.  
• The RNA harvested from myeloma cells before and after the first cycle of therapy 
at the HTLD / HTLD-CKD level will furthermore be used to identify changes in 
global gene expression using the Illumina® HT12 array.  
STUDY DURATION: 24 months 
TOTAL SAMPLE SIZE: up to 44 
patients 
DRUG SUPPLIES: 
For study participants, Celgene Corporation will provide lenalidomide at no charge 
through the RevAssist® program and azacitidine, also at no cost, via the Cleveland Clinic 
Taussig Cancer Center chemotherapy pharmacy or the pharmacy of the University 
Hospital Seidman Cancer Center.  
DOSING REGIMEN(S): 
Combination therapy (six 28-day cycles) 
GFR > 60ml/min (initial study cohort): 
All dose levels (during phase I portion of the study): 
• Lenalidomide 25mg p.o. d1-21 every 28 d 
• Dexamethasone 40mg p.o. weekly  
Azacitidine dose levels: 
1. 30mg/m2 s.c. weekly 
2. 40mg/m2 s.c. weekly 

 
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3. 30mg/m2 s.c. twice a week 
4. 40mg/m2 s.c. twice a week 
5. 50mg/m2 s.c. twice a week 
 
GFR 30-59 ml/min (amendment 7):  
All dose levels (during phase I portion of the study): 
• Lenalidomide 10mg p.o. d1-21 every 28 d 
• Dexamethasone 40mg p.o. weekly 
Azacitidine dose levels: 
CKD -1. 30mg/m2 s.c. twice a week 
CKD 1.  40mg/m2 s.c. twice a week 
CKD 2.  50mg/m2 s.c. twice a week 
 
Maintenance therapy ( 
Lenalidomide at last tolerated dose until disease progression.  
 
 
 

 
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2 
Schedule of Study Assessments * 
 
 
Procedure 
Screening 
≤ 7 days before 
day 1, cycle 1, 
unless 
indicated 
otherwise 
Cycle 1 
Cycle 2 
Cycle 3,4,5,6 
Maintenance 
Monthly 
during first 6 
cycles, then 
every 2 
months 
 
Discontinuation 
From Protocol 
Therapy 
Follow-Up 
Phase 
Day  
1 
 
Day  
8 
Day  
15 
Day   
22 
Day   
1 
Weekly 
Day 
1 
Weekly 
Every 3 
months for 
3 years from 
entry 
Record prior medications, treatments 
X 
 
 
 
 
 
 
 
 
 
 
 
Record prior anti-cancer therapies 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, vital signs, weight 
X 
X1 
X 
X 
X 
X 
 
X 
 
X 
X 
 
ECOG performance status 
X 
X1 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Skeletal survey 2 
X  
 
 
 
 
 
 
 
 
 
 
 
Bone marrow 3 
X  
X1 
 
 
 
X 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
CBC with differential 
X 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Research blood sample (10mL EDTA, 10mL 
Heparin) 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
Calculated creatinine clearance (by 
Cockcroft-Gault)4 
X 
X1 
 
 
 
X4 
 
X4 
 
X4 
 
 
TSH5 
X5 
X1 
 
 
 
 
 
X5 
 
X5 
X5 
 
SPEP w m-spike, 24hr urine w m-spike, 
serum and urine immunofixation, serum 
quantitative immunoglobulins, serum free 
light chain assay, beta-2 microglobulin,  
X 
X1 
 
 
 
X 
 
X 
 
X 
X 
 
Complete metabolic panel 
X 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
LDH, phosphorus, uric acid 
X 
X1 
 
 
 
 
 
 
 
 
 
 
Pregnancy testing7 
X8 
X8 
X8 
X8 
X8 
X8 
 
X8 
 
X8 
X8 
 
Register patient into RevAssist® program9 
X9 
 
 
 
 
 
 
 
 
 
 
 
Prescribe lenalidomide via RevAssist®  10 
 
X10 
 
 
 
X10 
 
X10 
 
X10 
 
 
Azacitidine administration 
 
X11 
X11 
X11 
X11 
X11 
X11 
X11 
X11 
 
 
 
Dexamethasone prescription 
 
X12 
 
 
 
X12 
 
X12 
 
 
 
 
Response assessment 13 
 
 
 
 
 
X 
 
X 
 
X 
X 
 
Record adverse events14 
 
 
X 
X 
X 
X 
 
X 
 
X 
X14 
 
Record concomitant therapies/procedures 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
 
Obtain Follow-Up anti-cancer treatments 
 
 
 
 
 
 
 
 
 
 
 
X 
Obtain Follow-Up survival information 
 
 
 
 
 
 
 
 
 
 
 
X 
 
* Variations of ± 3 days of the scheduled visit are permitted.   
If Physical examination, vital signs, weight and ECOG performance status were done within 7 days of Day 1, they do not need to be repeated at Study Day 
1. 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. 

 
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1 If screening assessments were done within 7 days of Day 1, they do not need to be repeated at Study Day 1. 
2 A skeletal survey may be obtained up to 28 days before day 1, cycle 1. It will be repeated every 12 months or earlier if symptoms suggest bony 
progression. 
3 With each bone marrow aspiration two 20mL samples, each containing 2mL of heparin, will be obtained for correlative studies in addition to routine 
clinical analyses as indicated. In addition to defined times, a bone marrow examination is required to confirm complete response and before high dose 
melphalan in patients who choose to undergo autologous stem cell transplantation. In patients who have measurable disease only in the bone marrow, the 
bone marrow biopsy and aspiration will be performed every three cycles (+/- 7 days) while on combination therapy and every six cycles (+/- 7 days) while 
on maintenance. 
4 Calculated creatinine clearance (by Cockcroft-Gault) at baseline and before dosing at the start of each cycle until cycle 12, then every two cycles. 
5 To include Thyroid Stimulating Hormone (TSH) at screening, at least every 16 weeks and at treatment discontinuation. To facilitate monitoring in the 
maintenance phase it is recommended to obtain TSH at day 1 of cycle 1, 4, 8, 12, 16, and so on. T3 and T4 levels may be assessed as clinically indicated. 
6 If patients undergo stem cell transplantation before completion of six cycles, SPEP w m-spike, 24hr urine w m-spike, serum and urine immunofixation, 
and serum free light chain assay should be repeated before mobilization begins for confirmation of their pre-transplant response.  
7 Pregnancy tests for females of childbearing potential.  A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not undergone 
a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any 
time in the preceding 24 consecutive months). 
8 Pregnancy tests must occur within 10 – 14 days and again within 24 hours prior to prescribing lenalidomide (prescriptions must be filled within 7 days).  
FCBP with regular or no menstruation must have a pregnancy test weekly for the first 28 days and then every 28 days while on therapy (including breaks 
in therapy); at discontinuation of lenalidomide and at Day 28 post the last dose of lenalidomide.  Females with irregular menstruation must have a 
pregnancy test weekly for the first 28 days and then every 14 days while on therapy (including breaks in therapy), at discontinuation of lenalidomide and at 
Day 14 and Day 28 post the last dose of lenalidomide (see Appendix I: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth 
Control Methods).    
9 Lenalidomide must be prescribed through and in compliance with the RevAssist® program of Celgene Corporation.  Prescriptions must be filled within 7 
days.   
10  Consideration should be given to prescribing lenalidomide 5 to 7 days in advance of Day 1 of each cycle to allow time for required patient and 
prescriber surveys, and drug shipment to patient.  Any unused Revlimid® (lenalidomide) should be returned to the patient for disposition in accordance 
with the RevAssist® program. Lenalidomide will be taken by patients from day 1-21 of the 28 day cycle as outlined under 5.6. 
11 Azacitidine will be administered at the Taussig Cancer Institute and Case Medical Center as outlined under 5.6, with weekly dosing for dose levels 1 and 
2, and twice-a-week administration for dose levels 3 to 5.  
12 Dexamethasone will be taken by patients weekly during cycle 1 to 6 as outlined under 5.6. At day one of each cycle it should be ascertained that 
patients have an active prescription. 
13 Response according international uniform response criteria, outlined in section 7. If PD is suspected, response may be re-assessed through repeat of 
relevant lab tests at any time before the next planned assessment for confirmation.  
14 An additional safety assessment will be done 28 days (+/- 2 days) following the last dose of protocol therapy. 

 
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3 
Background and Rationale 
3.1 
Lenalidomide 
3.1.1 Introduction  
Lenalidomide is a proprietary IMiD™ compound of Celgene Corporation.  IMiD™ 
compounds have both immunomodulatory and anti-angiogenic properties which could 
confer anti-tumor and anti-metastatic effects.  Lenalidomide has been demonstrated to 
possess anti-angiogenic activity through inhibition of bFGF, VEGF and TNF-alpha 
induced endothelial cell migration, due at least in part to inhibition of Akt 
phosphorylation response to bFGF (16).  In addition, lenalidomide has a variety of 
immunomodulatory effects.  Lenalidomide stimulates T cell proliferation, and the 
production of IL-2, IL-10 and IFN-gamma, inhibits IL-1 beta and IL-6 and modulates IL-
12 production(17).  Upregulation of T cell derived IL-2 production is achieved at least in 
part through increased AP-1 activity(18). 
Although the exact anti-tumor mechanism of action of lenalidomide is unknown, a 
number of mechanisms are postulated to be responsible for lenalidomide’s activity 
against multiple myeloma.  Lenalidomide has been shown to increase T cell proliferation, 
which leads to an increase in IL-2 and IFN-gamma secretion.  The increased level of 
these circulating cytokines augment natural killer cell number and function, and enhance 
natural killer cell activity to yield an increase in multiple myeloma cell lysis(19).  In 
addition, lenalidomide has direct activity against multiple myeloma and induces 
apoptosis or G1growth arrest in multiple myeloma cell lines and in multiple myeloma 
cells of patients resistant to melphalan, doxorubicin and dexamethasone(20).   
3.1.2 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. 
3.1.3 Adverse Events 
Most frequently reported adverse events reported during clinical studies with 
lenalidomide in oncologic and non-oncologic indications, regardless of presumed 
relationship to study medication include: anemia, neutropenia, thrombocytopenia and 
pancytopenia, abdominal pain, nausea, vomiting and diarrhea, dehydration, rash, itching, 
infections, sepsis, pneumonia, UTI, upper respiratory infection, cellulites, 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. 

 
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Complete and updated adverse events are available in the Investigational Drug Brochure 
and the IND Safety Letters. 
3.2 
Azacitidine (Vidaza®) 
3.2.1 Introduction 
Azacitidine is an azanucleoside analogon, which was developed in the early 1960s as a 
cytotoxic agent(21). A number of studies have looked at different parenteral doses and 
schedules of azacitidine, finding maximum tolerated doses of up to 500 mg/m2 when 
administered weekly(22). Almost 20 years after the original development, azacitidine was 
found to inhibit the methylation of newly synthesized DNA by inhibiting DNA 
methyltransferase (DNMT)(7-9), leading to differentiation of human cell lines(23) and 
reversing oncogenic silencing of tumor suppressor genes(24). Early trials used high doses 
of the drug that predominantly had nucleoside analogue-type cytotoxic effects  but in 
recent years lower doses, that can induce DNA demethylation in vivo (25)have been used 
successfully in MDS and AML, improving survival compared to conventional care 
regimens in high risk MDS and WHO AML patients in a recent phase III trial(10).  
3.2.2 INDICATIONS AND USAGE 
Azacitidine is indicated for treatment of patients with the following French-American-
British (FAB) myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory 
anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or 
requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia 
with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia 
(CMMoL).  
3.2.3 Adverse Events 
The most frequently reported adverse events reported during clinical studies with 
azacitidine, regardless of presumed relationship to study medication include: 
Gastrointestinal events (nausea, vomiting, diarrhea, constipation, and anorexia), 
neutropenia, febrile neutropenia, thrombocytopenia, injection site events, arthralgia, 
dizziness, dyspnea, cough, and myalgia. 
 
Complete and updated adverse events are available in the Investigational Drug Brochure 
and the IND Safety Letters. 
3.3 
Rationale for Use in Relapsed or Refractory Multiple Myeloma 
With an incidence of 5.6/100,000 multiple myeloma is the second most common 
hematologic malignancy after Non-Hodgkin lymphomas (SEER 2001-2005). It remains 
an incurable disease and in the setting of second line or later treatment the progression-
free survival ranged between 6-12 months with an overall survival between 1.5 and 3 
years in recent trials(1). One of the most successful regimens combined lenalidomide at 
25mg on 21 days of a 28 day cycle with dexamethasone in pulse fashion at 40mg day 1-4, 
9-12, 17-20 of the first 4 cycles followed by administration from day 1-4 only in US 

 
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patients (11). The majority of patients in this trial had been treated with at least 2 prior 
regimens. The median time to progression was 11.1 months in patients treated with the 
combination compared to 4.7 month with dexamethasone alone. Although the majority of 
dexamethasone-only treated patients received lenalidomide at relapse, the median overall 
survival was superior in the group randomly assigned to combination therapy (29.6 
months versus 20.2 months). In Europe and Australia this regimen yielded similar 
results(26) leading to approval of lenalidomide in combination with dexamethasone for 
patients with myeloma who have been treated with at least one prior regimen in the US 
and Europe and for relapsed or refractory myeloma in Australia. A more recent trial 
randomly assigned newly diagnosed myeloma patients to a lower dexamethasone dose 
(40mg weekly) or to pulsed dexamethasone in combination with lenalidomide (Rd vs. 
RD, respectively) and found an improved 2 year overall survival (p=0.006) of 87% (Rd) 
vs. 75% (RD) at the most recently published analysis(12), suggesting at least equivalent 
outcome 
with 
a 
trend 
for 
lower 
toxicity, 
especially 
regarding 
venous 
thromboembolism(27). This finding was rapidly translated into clinical practice in the 
front-line and relapsed setting and is the regimen used in ongoing clinical trials (FIRST 
trial, SO777).  
To further improve the outcome of patients with relapsed and/or refractory multiple 
myeloma, resistance mechanisms towards available therapies and immune surveillance 
need to be overcome. In the course of myeloma progression genetic and epigenetic 
changes accumulate(2-4, 6, 28-34). The latter are most stable if mediated by DNA 
methylation of promoter regions which confers heritable silencing of tumor suppressor 
genes favoring apoptosis resistance, cell cycle dysregulation, and immune escape(2-6, 
28-32, 35-41). Azacitidine can reverse such silencing and has been shown to have anti-
myeloma activity in vitro and in mouse xenografts as a single agent and in combination 
therapy by overcoming apoptosis resistance as exemplified in a myeloma cell line with a 
silenced pro-apoptotic gene, called XAF-1(35, 42). The genome wide activity of DNA 
methyltransferase I (DNMT1) inhibitors like azacitidine offers a mechanism to overcome 
apoptosis resistance mediated by silencing of diverse tumor suppressor genes in different 
myeloma clones of individual patients and patient populations as illustrated by in vitro 
studies of resistance to interferon-induced apoptosis in kidney cancer cell lines(37). 
Reactivation of tumor antigens and immunomodulatory genes by DNMT1 inhibition (37) 
may further increase the activity of immunomodulatory drugs and intrinsic immune 
responses as suggested by an encouraging 31% response rate of melanoma patients 
treated with decitabine, the in vivo DNA demethylating metabolite of azacitidine, and 
interleukin-2 in a phase I trial(43). After prolonged exposure to low doses of aza 
nucleosides in vitro, cancer cells may undergo cell death via differentiation, senescence, 
or direct apoptosis, likely depending on the methylation profile. Interestingly, healthy 
human hematopoietic stem cells can be expanded in vitro by decitabine(44, 45). Indirect 
evidence for expansion of the healthy stem cell pool in vivo comes from the observation 
that overall survival can be extended independent of a complete response in MDS(10), a 
disease that can be fatal due to a lack of normal hematopoietic stem cells. Such an 
expansion of healthy stem cells would have added benefit in myeloma patients who 
undergo hematopoietic stem cell harvesting for high dose chemotherapy and autologous 
stem cell rescue.   

 
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In MDS azacytidine at 75mg/m2 d1-5 every 28 days or 50mg/m2 d1-5 and 8-12 every 28 
days was relatively well tolerated in combination with lenalidomide 5-10mg daily and 
showed promising activity with an overall response rate of 71% and a complete response 
rate of 41%, suggesting the two drugs can be combined synergistically without excess 
toxicity(46). The FDA approved regimen of azacitidine, 75mg/m2 day 1-7 every 28 days 
for the treatment of MDS leads to maximal blood concentrations that, while lower than in 
the original studies, are still directly cytotoxic in vitro(47) which could limit the tumor 
suppressor gene reactivating function by inhibiting DNA duplication which is required 
for DNA demethylation. It furthermore likely contributes to side effects that make a 
treatment interruption of three weeks necessary to allow for recovery when the standard 
MDS schedule is used (75mg/m2 d1-7 every 28 days). Unfortunately this also leads to 
DNA re-methylation before a new cycle begins (25, 48, 49). Furthermore, in diseases 
with a lower proliferative rate, like multiple myeloma, only a minority of cells would be 
expected to reactivate tumor suppressor genes if the drug was only given on one out of 
four weeks. In vitro, non-toxic single low doses of azacitidine (1μM) can reactivate tumor 
suppressor genes in myeloma cell lines for 3-7 days (unpublished observations). Doses 
higher than 2-5μM, depending on the cell type, can exert immediate toxicity likely related 
to nucleoside analogue properties of the drug. Pharmacokinetic data in humans suggest 
that a single dose of 50mg/m2 subcutaneously reaches concentrations that should be 
sufficient for DNA demethylation but could cause classical nucleoside analogue toxicity 
in some patients (2.89μM +/- 1.35 μM SD), higher doses like 75mg/m2 reach 4.88 μM 
+/- 1.4μM SD and thus almost certainly exert classic nucleoside analogue toxic effects 
(13). In this study we aim to avoid pronounced nucleoside analogue side effects while 
maximally exploiting DNA demethylating effects of azacitidine. We will therefore assess 
the safety of combination therapy with azacitidine given at low but increasing doses up to 
50mg/m2 twice a week, together with standard dose lenalidomide and low dose 
dexamethasone in relapsed or refractory myeloma patients in a phase I/II study with 10 
additional patients enrolled at the highest tolerated low azacitidine dose to obtain an 
initial impression of efficacy and to evaluate whether this dose exerts the expected 
pharmacodynamic effects in myeloma cells before a larger phase II trial may be 
conducted.   
4 
Study Objectives and Endpoints 
4.1 
Objectives 
4.1.1 Primary Objective 
• Define the highest tolerated low doses (HTLD and HTLD-CKD for GFR > 60 
ml/min and 30-59ml/min, respectively) and safety of azacitidine given at low but 
increasing doses up to 50mg/m2 twice a week concurrently with GFR-adjusted 
lenalidomide doses and low dose dexamethasone in patients with relapsed or 
refractory multiple myeloma. 

 
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4.1.2 Secondary Study Objectives 
• Response according to international response criteria (>PR) and clinical benefit 
response (>minor response according to adapted EBMT criteria), see under 7 
• Correlate response with plasma activity of the azacitidine inactivating enzyme 
cytidine deaminase (CDA) 
• Progression-free survival and overall survival 
• Peripheral blood hematopoietic progenitor (CD34+) yield and time to neutrophil 
and platelet recovery in patients undergoing autologous stem cell transplantation 
• Promoter demethylation and gene reactivation in myeloma cells and 
hematopoietic progenitors treated at the HTLD / HTLD-CKD level after  cycle 1 
• Changes in global gene expression in myeloma cells treated at the HTLD / 
HTLD-CKD level after cycle 1  
 
4.2 
Endpoints 
4.2.1 Primary Endpoint 
• The highest tolerated low dose (HTLD and HTLD-CKD for GFR > 60 ml/min 
and 30-59ml/min, respectively) of azacitidine in combination with GFR-adjusted 
lenalidomide will be defined as the highest dose level studied (up to 50mg/m2 
twice a week) at which dose limiting toxicity (DLT) occurs during the first 28-day 
cycle in ≤ 1 out of 6 patients.  If one out of the first 3 patients with GFR > 
60ml/min develops DLT, up to three additional patients are treated at the same 
dose level. In patients with GFR 30-59ml/min each dose level will enroll 6 
patients unless more than 1 patient develops  DLT..  Any dose level evaluated as 
the possible HTLD / HTLD-CKD must include 6 patients assessed for DLT.  DLT 
is defined in Section 5.1. Toxicity according to CTCAE v.4.0 will be assessed 
with weekly CBC w. Diff and CMP during the first 6 cycles, then before each 
cycle, weekly history and physical during the first 28-day cycle, then before each 
cycle until cycle 12.  
 
4.2.2 Secondary Endpoints 
• Response will be determined monthly during the first 12 cycles and every two 
months thereafter with serum and 24hr urine protein electrophoresis, and as 
appropriate, supplemented by immunofixation, serum free light chain assay, and 
bone marrow examination. Response before high dose melphalan and autologous 
stem cell transplant will also be confirmed by two separate  blood and 24 hr urine 
tests between the last dose of combination therapy and the first dose of the 
mobilizing agent. 

 
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• Plasma from peripheral blood draws will be used to quantify the activity of CDA 
using an HPLC method (see under 5.5.3) 
• Progression-free survival will be measured from study entry to progression as 
defined by international response criteria (see under 5.9.1) or death of any cause, 
whichever comes first.  
• Overall survival will be measured from study entry to death from any cause. 
• CD34+ cell yield will be calculated based on flow cytometry of mononuclear cells 
harvested following stem cell mobilization. Time to neutrophil (> 1,000/mm3) and 
platelet (> 100,000/mm3) recovery will be counted from the day of stem cell 
infusion (=day 0)  
• Promoter demethylation and gene reactivation will be measured at least at the 
HTLD / HTLD-CKD level using the Illumina® HumanMethylation27 BeadChip 
array on CD138 purified and CD34 purified cells obtained from bone marrow 
aspirates within 7 days before treatment start and at the end of cycle #1.RNA will 
be harvested from the same cell populations to confirm reactivation of selected 
genes identified on the array. Since the HTLD / HTLD-CKD is identified 
retrospectively DNA and RNA will be isolated from purified cell populations 
from all bone marrow aspirations before and after cycle #1.  
• The RNA harvested from myeloma cells before and after the first cycle of therapy 
at the HTLD / HTLD-CKD level will furthermore be used to identify changes in 
global gene expression using the Illumina® HT12 array. 
5 
Investigational Plan 
5.1 
Overall Design 
This phase I/II trial will use a classical 3x3 design to determine the highest tolerated low 
dose (HTLD) for patients with GFR > 60 ml/min (Cockroft-Gault) and a modified 3x3 
design to identify the highest tolerated low dose for patients with GFR 30-59 ml/min 
(HTLD-CKD) with additional enrollment of 10 patients at the highest tolerated low doses 
(HTLD / HTLD-CKD) of azacitidine.   
 
Dose levels are outlined under 5.6.2.3. 
Dose limiting toxicity (DLT) is defined as one of the following drug-related toxicities 
occurring during the first 28-day cycle (if a DLT is attributed to progressive disease, it 
will not be counted as a DLT): 
• Any CTCAE v.4.0 grade >3 non hematologic toxicity (including febrile 
neutropenia) 
o For nausea, vomiting, or diarrhea, subjects must have a Grade 3 or 4 
event that persists at this level despite the use of optimal symptomatic 
treatment, in order for these events to be considered a DLT 

 
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o Grade 4 transaminitis (serum transaminase > 20 x upper limit of normal 
[ULN]) is a DLT, while Grade 3 transaminitis (serum transaminase > 5 x 
and ≤ 20 x ULN) must be present for ≥ 7 days to be considered a DLT  
o Grade 3 or 4 venous thromboembolic events are not considered to be 
DLTs as long as anticoagulant therapy can be administered (see Section 
6.5.3 and 6.6.2) 
o Grade 3 or 4 hypokalemia, hypophosphatemia, hypomagnesemia or 
hyponatremia that responds to electrolyte supplementation within 7 days 
would not qualify as a DLT.  
 
• CTCAE v.4.0 grade > 4 neutropenia or thrombocytopenia that does not resolve to 
grade < 3 within seven days of holding azacitidine and lenalidomide. While 
platelet transfusions are allowed at the discretion of the treating physician to 
maintain 100% dose level, any grade > 4 thrombocytopenia that is followed by 
platelet transfusion prior to resolution to grade < 3 will be counted as DLT. 
 
Dose escalation for patients with GFR > 60ml/min: 
At least 3 patients will be treated in each dose level tested beginning with dose level 1. At 
any dose level, if none of the first 3 evaluable patients experience DLT in the first 28 day 
cycle, the next three patients will be treated at the next dose level. At any dose level, if 
DLT occurs in one out of three patients during the first 28 day cycle, up to 3 additional 
patients will be treated at the same dose level. If no DLT occurs in the additional 3 
patients, subsequent 3 patients will be treated at the next dose level. Once DLT occurs in 
2 patients treated at a given dose level no further patients will be accrued at this dose 
level but patients already on treatment will continue according to study protocol. If DLT 
occurs in 2 patients treated at a given dose level, the next lower dose level will be 
evaluated as the possible HTLD, and if only 3 patients had been enrolled at this dose 
level, an additional 3 patients will enrolled to properly assess this dose level as the 
possible HTLD.  The dose level at which DLT occurs in ≤ 1 out of 6 patients will be 
defined as the highest tolerated low dose (HTLD) and ten more patients will be accrued 
at this dose level.  Six evaluable patients must be assessed for DLT at any dose level that 
is being considered as the HTLD.  Patients experiencing a DLT during their first 28-day 
cycle may remain on study with appropriate dose reduction  (5.7.3). 
 
Dose escalation for patients with GFR 30-59ml/min: 
Only two dose levels of azacitidine will be tested in combination with fixed dose 
lenalidomide. Starting with dose level “CKD 1” (DL CKD1), 3 patients will initially be 
enrolled and if no more than 1 experience DLT, 3 additional patients will be enrolled at 
the same dose level. If no more than 1 out of 6 patients treated at DL CKD1 develop 
DLT, subsequent patients will be enrolled at DL CKD2. Once 2 of 3 or 2 of up to 6 
patients treated at a given dose level develop DLT, no further patients will be enrolled at 
that dose level. If this occurs at DL CKD1, subsequent patients will be enrolled at DL 
CKD-1. If it occurs at DL CKD2, DL CKD1 will be defined as HTLD-CKD. If 2 of 3 or 
2 of up to 6 patients treated at DL CKD-1 develop DLT, the tested azacitidine / 
lenalidomide / dexamethasone regimen will be considered intolerable for patients with 

 
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GFR 30-59 ml/min. The highest dose level that causes DLT in no more than 1 out of 6 
evaluable patients will be considered the HTLD-CKD and once this is defined additional 
patients treated at this dose level may contribute to the 10 patient phase II extension.  
Patients experiencing a DLT during their first 28-day cycle may remain on study with 
appropriate dose reduction (5.7.3). 
 
Patients that are not evaluable for DLT throughout the first 28 day cycle of the dose 
escalation portion of the study due to progressive disease or for other reasons, will be 
replaced.  
 
5.1.1 Protocol Therapy  
5.1.1.1 
Lenalidomide Description 
REVLIMID®  (lenalidomide), a thalidomide analogue, is an immunomodulatory agent 
with anti-angiogenic properties.  The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -
2H-isoindol-2-yl) piperidine-2,6-dione and it has the following chemical structure:  
Chemical Structure of Lenalidomide 
 
N
N
H
O
O
O
NH2
 
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione 
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 
259.3.  
Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic 
solvent/water mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in 
organic solvents and low pH solutions. Solubility was significantly lower in less acidic 
buffers, ranging from about 0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon 
atom and can exist as the optically active forms S(-) and R(+), and is produced as a 
racemic mixture with a net optical rotation of zero. 
5.1.1.2 CLINICAL PHARMACOLOGY 
Mechanism of Action:  
The mechanism of action of lenalidomide remains to be fully characterized. 
Lenalidomide 
possesses 
immunomodulatory 
and 
anti-angiogenic 
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 

 
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Manawa cells (a human B cell lymphoma cell line with a deletion of one chromosome 5) 
but was much less effective in inhibiting growth of KG-1 cells (human myeloblastic cell 
line, also with a deletion of one chromosome 5) and other cell lines without chromosome 
5 deletions.  Lenalidomide inhibited the expression of cyclooxygenase-2 (COX-2) but not 
COX-1 in vitro.   
5.1.1.3 Pharmacokinetics and Drug Metabolism: 
Absorption: 
Lenalidomide, in healthy volunteers, is rapidly absorbed following oral administration 
with maximum plasma concentrations occurring between 0.625 and 1.5 hours post-dose. 
Co-administration with food does not alter the extent of absorption (AUC) but does 
reduce the maximal plasma concentration (Cmax) by 36%. The pharmacokinetic 
disposition of lenalidomide is linear. Cmax and AUC increase proportionately with 
increases in dose. Multiple dosing at the recommended dose-regimen does not result in 
drug accumulation. 
Pharmacokinetic 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(50).  
Exposure (AUC) in multiple myeloma patients is 57% higher than in healthy male 
volunteers(51).  
 
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. Renal 
impairment increases the area under the curve (AUC) and increases half-life to 9-10 
hours with moderate to severe renal dysfunction and to more than 15hours in ESRD 
making dose adjustments necessary(52). A study presented at ASH 2011 determined 
lenalidomide AUC concentrations in 37 multiple myeloma patients with various 
glomerular filtration rates (Cockroft-Gault) who were treated with lenalidomide dosing 
schedules predicted to yield equal AUCs based on pharmacokinetic data obtained in 
patients without cancer diagnosis but with chronic kidney disease (CKD)(15). Ten 

 
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myeloma patients with GFR > 80ml/min were treated with standard lenalidomide 25mg 
day 1-21 every 28 days and served as comparison for patients with GFR 50-80 ml/min 
(n=10), GFR 30-49 ml/min (n=7), GFR < 30 ml/min (n=5), and patients on chronic 
hemodialysis (n=5), who received 25mg daily, 10mg daily, 15mg every other day, and 
5mg daily, respectively, from day 1-21 every 28 days. All patients received 
dexamethasone 40mg once a week but no other antimyeloma drugs. Average daily AUC 
values of patients with CKD were between 103-149% of the ones in patients with GFR > 
80 ml/min and essentially identical for patients with GFR 30-49 (103%). The renal 
function remained stable in all patients. Severe adverse events occurred in 60% of 
patients on dialysis and 45% of remaining patients (p=0.3), overall comparable to 
reported results(11, 26), as were response rates of around 70% in these patients who had 
received a minimum of one prior myeloma regimen. In summary, GFR-adjusted 
lenalidomide dosing achieved appropriate drug exposure and was safe and effective(15). 
 
5.1.1.4 Supplier(s) 
Celgene Corporation will supply Revlimid® (lenalidomide) to study participants at no 
charge through the RevAssist® program.   
5.1.1.5 Dosage form 
Lenalidomide will be supplied as capsules for oral administration.   
5.1.1.6 Packaging 
Lenalidomide will be shipped directly to patients.   Bottles will contain a sufficient 
number of capsules for one cycle of dosing.    
5.1.1.7 Storage 
Lenalidomide should be stored at room temperature away from direct sunlight and 
protected from excessive heat and cold.     
5.1.1.8 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. 
 

 
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5.1.1.9 Azacitidine Description 
VIDAZA (azacitidine for injection) contains azacitidine, which is a pyrimidine 
nucleoside analog of cytidine. Azacitidine is 4-amino-1-β-D-ribofuranosyl-s-
triazin-2(1H)-one. The structural formula is as follows: 
  
The empirical formula is C8H12N4O5. The molecular weight is 244. Azacitidine is a 
white to off-white solid. Azacitidine was found to be insoluble in acetone, ethanol, and 
methyl ethyl ketone; slightly soluble in ethanol/water (50/50), propylene glycol, and 
polyethylene glycol; sparingly soluble in water, water saturated octanol, 5% dextrose in 
water, N-methyl-2-pyrrolidone, normal saline and 5% Tween 80 in water; and soluble in 
dimethylsulfoxide (DMSO).  
The finished product is supplied in a sterile form for reconstitution as a suspension for 
subcutaneous injection or reconstitution as a solution with further dilution for intravenous 
infusion. Vials of VIDAZA contain 100 mg of azacitidine and 100 mg mannitol as a 
sterile lyophilized powder. 
5.1.1.10 CLINICAL PHARMACOLOGY 
Mechanism of Action:  
VIDAZA is a pyrimidine nucleoside analog of cytidine. VIDAZA is believed to exert its 
anti-neoplastic effects by causing hypomethylation of DNA and direct cytotoxicity on 
abnormal hematopoietic cells in the bone marrow. The concentration of azacitidine 

 
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required for maximum inhibition of DNA methylation in vitro does not cause major 
suppression of DNA synthesis. Hypomethylation may restore normal function to genes 
that are critical for differentiation and proliferation. The cytotoxic effects of azacitidine 
cause the death of rapidly dividing cells, including cancer cells that are no longer 
responsive to normal growth control mechanisms. Non-proliferating cells are relatively 
insensitive to azacitidine(51). 
5.1.1.11 Pharmacokinetics and Drug Metabolism: 
The pharmacokinetics of azacitidine were studied in 6 MDS patients following a single 
75 mg/m
2 
subcutaneous (SC) dose and a single 75 mg/m
2 
intravenous (IV) dose. 
Azacitidine is rapidly absorbed after SC administration; the peak plasma azacitidine 
concentration of 750 ± 403 ng/ml occurred in 0.5 hour. The bioavailability of SC 
azacitidine relative to IV azacitidine is approximately 89%, based on area under the 
curve. Mean volume of distribution following IV dosing is 76 ± 26 L. Mean apparent SC 
clearance is 167 ± 49 L/hour and mean half-life after SC administration is 41 ± 8 
minutes(52). In a more recent trial the cytidine deaminase inhibitor tetrahydrouridine 
(THU) was added to collected blood samples to  avoid enzymatic breakdown of 
azacitidine in vitro. This trial suggested that maximal azacitidine blood concentrations 
after s.c. administration were about 50% higher, 1192.8 +/- 342.4 ng/mL(13). 
 
While deamination by cytidine deaminase in plasma appears to be the main mode of 
inactivation, urinary excretion is the primary route of elimination of azacitidine and its 
metabolites. Following IV administration of radioactive azacitidine to 5 cancer patients, 
the cumulative urinary excretion was 85% of the radioactive dose. Fecal excretion 
accounted for <1% of administered radioactivity over 3 days. Mean excretion of 
radioactivity in urine following SC administration of 
14
C-azacitidine was 50%. The 
mean elimination half-lives of total radioactivity (azacitidine and its metabolites) were 
similar after IV and SC administrations, about 4 hours(52).  
Special Populations  
The effects of renal or hepatic impairment, gender, age, or race on the pharmacokinetics 
of azacitidine have not been studied prospectively but investigators at MD Anderson 
Cancer Center have recently reviewed their experience with the use of azacitidine and 
decitabine in 41 patients with myeloid malignancies and kidney dysfunction(14). The 
GFR was between 30 and 59ml/min in 29 patients and below 30ml/min in 12 patients. 
Eleven patients were treated with standard-dose azacitidine (75mg/m2 for 7 days every 
28 days), 10 patients SC, one IV, and three of the eleven patients had GFRs below 
30ml/min. Overall, adverse events to decitabine and azacitidine were not felt to be more 
frequent than in historical controls for patients with GFR > 30ml/min but more severe 
kidney dysfunction appeared to increase risk for hematologic and non-hematologic 
toxicities leading to more frequent dose reduction or treatment delay. Response rates and 
survival was similar to historical controls. Results thus support the use of azacitidine and 
decitabine at standard doses, at least in patients with GFR > 30ml/min(14). 
Drug-Drug Interactions  

 
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Drug interaction studies with azacitidine have not been conducted.  
An in vitro study of azacitidine incubation in human liver fractions indicated that 
azacitidine may be metabolized by the liver. Whether azacitidine metabolism may be 
affected by known microsomal enzyme inhibitors or inducers has not been studied.  
The potential of azacitidine to inhibit cytochrome P450 (CYP) enzymes is not known. In 
vitro studies with human cultured hepatocytes indicate that azacitidine at concentrations 
of  
1.0 μM to 100 μM does not induce CYP 1A2, 2C19, or 3A4/5. 
 
5.1.1.12 NONCLINICAL TOXICOLOGY  
Carcinogenesis, Mutagenesis, Impairment of Fertility  
The potential carcinogenicity of azacitidine was evaluated in mice and rats. Azacitidine 
induced tumors of the hematopoietic system in female mice at 2.2 mg/kg (6.6 mg/m
2
, 
approximately 8% the recommended human daily dose on a mg/m
2 
basis) administered 
IP three times per week for 52 weeks. An increased incidence of tumors in the 
lymphoreticular system, lung, mammary gland, and skin was seen in mice treated with 
azacitidine IP at 2.0 mg/kg (6.0 mg/m
2
, approximately 8% the recommended human 
daily dose on a mg/m
2 
basis) once a week for 50 weeks. A tumorigenicity study in rats 
dosed twice weekly at 15 or 60 mg/m
2 
(approximately 20-80% the recommended human 
daily dose on a mg/m
2 
basis) revealed an increased incidence of testicular tumors 
compared with controls.  
The mutagenic and clastogenic potential of azacitidine was tested in in vitro bacterial 
systems Salmonella typhimurium strains TA100 and several strains of trpE8, 
Escherichia coli strains WP14 Pro, WP3103P, WP3104P, and CC103; in in vitro 
forward gene mutation assay in mouse lymphoma cells and human lymphoblast cells; 
and in an in vitro micronucleus assay in mouse L5178Y lymphoma cells and Syrian 
hamster embryo cells. Azacitidine was mutagenic in bacterial and mammalian cell 
systems. The clastogenic effect of azacitidine was shown by the induction of 
micronuclei in L5178Y mouse cells and Syrian hamster embryo cells.  

 
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Administration of azacitidine to male mice at 9.9 mg/m
2 
(approximately 9% the 
recommended human daily dose on a mg/m
2 
basis) daily for 3 days prior to mating with 
untreated female mice resulted in decreased fertility and loss of offspring during 
subsequent embryonic and postnatal development. Treatment of male rats 3 times per 
week for 11 or 16 weeks at doses of 15-30 mg/m
2 
(approximately 20-40%, the 
recommended human daily dose on a mg/m
2 
basis) resulted in decreased weight of the 
testes and epididymides, and decreased sperm counts accompanied by decreased 
pregnancy rates and increased loss of embryos in mated females. In a related study, male 
rats treated for 16 weeks at 24 mg/m
2 
resulted in an increase in abnormal embryos in 
mated females when examined on day 2 of gestation. 
 
5.1.1.13 
Adverse Events in Clinical Trials 
In addition to hematologic toxicities the most frequent side effects and discomforts 
reported for azacitidine are nausea, vomiting and diarrhea. Infrequent side effects include 
neuromuscular aches, liver enzyme abnormalities, and renal tubular acidosis (the kidneys 
excrete too much bicarbonate and/or not enough hydrogen ions).   
 
The azacitidine injection may result in redness and inflammation at the injection site. 
 
5.1.1.14 Supplier(s) 
Celgene Corporation will supply VIDAZA® (azacitidine) to study participants at no 
charge through the Cleveland Clinic Taussig Cancer Center chemotherapy pharmacy or 
the pharmacy of the University Hospital Ireland Cancer Center.   
.   
5.1.1.15 
Dose Preparation and Storage of Azacitidine (VIDAZA®) 
VIDAZA is a cytotoxic drug and, as with other potentially toxic compounds, caution 
should be exercised when handling and preparing VIDAZA suspensions (see 5.1.1.24). 
 
If reconstituted VIDAZA comes into contact with the skin, immediately and thoroughly 
wash with soap and water.  If it comes into contact with mucous membranes, flush 
thoroughly with water. 
 
The VIDAZA vial is single-use and does not contain any preservatives. Unused portions 
of each vial should be discarded properly.  See Handling and Disposal (5.1.1.24). Do 
not save any unused portions for later administration.   
 

 
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5.1.1.16 
Storage   
Store unreconstituted vials at 25º C (77º F); excursions permitted to 15º-30º C (59º-86º 
F).  There is no need to protect azacitidine from exposure to light. 
 
5.1.1.17 Dosage Form 
Azacitidine will be supplied as a lyophilized powder in 100mg single-use vials for 
subcutaneous administration.   
 
5.1.1.18 
Preparation for Subcutaneous Administration 
VIDAZA should be reconstituted aseptically with 4 mL sterile water for injection.  The 
diluent should be injected slowly into the vial.  Vigorously shake or roll the vial until a 
uniform suspension is achieved.  The suspension will be cloudy. The resulting suspension 
will contain azacitidine 25 mg/mL.  
 
5.1.1.19 
Preparation for Immediate Subcutaneous  Administration  
Doses greater than 4 mL should be divided equally into 2 syringes. The product may be 
held at room temperature for up to 1 hour, but must be administered within 1 hour after 
reconstitution.  
5.1.1.20 
Preparation for Delayed Subcutaneous  Administration  
The reconstituted product may be kept in the vial or drawn into a syringe. Doses greater 
than 4 mL should be divided equally into 2 syringes. The product must be refrigerated 
immediately, and may be held under refrigerated conditions (2ºC–8ºC, 36ºF–46ºF) for up 
to 8 hours. After removal from refrigerated conditions, the suspension may be allowed to 
equilibrate to room temperature for up to 30 minutes prior to administration.  
 
5.1.1.21 
Subcutaneous Administration 
To provide a homogeneous suspension, the contents of the syringe must be re-suspended 
by inverting the syringe 2–3 times and vigorously rolling the syringe between the palms 
for 30 seconds immediately prior to administration.  
 
VIDAZA suspension is administered subcutaneously. Doses greater than 4 mL should be 
divided equally into 2 syringes and injected into 2 separate sites. Rotate sites for each 
injection (thigh, abdomen, or upper arm). New injections should be given at least 1 inch 
from an old site and never into areas where the site is tender, bruised, red, or hard. 
 

 
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5.1.1.22 
Suspension Stability  
VIDAZA reconstituted for subcutaneous administration may be stored for up to 1 hour at 
25°C (77°F) or for up to 8 hours between 2°C and 8°C (36°F and 46°F).   
5.1.1.23 Packaging 
Azacitidine will be shipped to the Cleveland Clinic Foundation Taussig Cancer Center 
chemotherapy pharmacy and the pharmacy of the University Hospital Ireland Cancer 
Center.   
.    
5.1.1.24 
Handling and Disposal  
Procedures for proper handling and disposal of anticancer drugs should be applied.  
5.1.1.25 Prescribing Information  
Azacitidine (VIDAZA®) will be provided to research subjects for the duration of their 
participation in this trial at no charge to them or their insurance providers.   
 
5.1.1.26 Dexamethasone  Description 
Glucocorticoids are adrenocortical steroids, both naturally occurring and synthetic, which 
are readily absorbed from the gastrointestinal tract. Dexamethasone, a synthetic 
adrenocortical steroid, is a white to practically white, odorless, crystalline powder. It is 
stable in air. It is practically insoluble in water. It is designated chemically as 9-fluoro- 
11β, 17,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione. The structural formula is 
represented below: 
 
 
 
C22H29FO5 MW 392.47 
 
The tablets, for oral administration are available at 0.25 mg, 0.5 mg, 0.75 mg, 1.5 mg, 4 
mg or 6 mg strength of dexamethasone. The 4mg tablet will be used in this study. 
 
Each tablet contains the following inactive ingredients: Anhydrous lactose, 
croscarmellose sodium, magnesium stearate, microcrystalline cellulose and stearic acid.  
 

 
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5.1.1.27 CLINICAL PHARMACOLOGY 
Pharmacokinetics and Mechanism of Action  
Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids that are 
readily absorbed from the gastrointestinal tract. Glucocorticoids cause varied metabolic 
and immune effects after binding to cytoplasmic glucocorticoid receptors with 
subsequent translocation into the nucleus, where they affect gene expression. Naturally 
occurring glucocorticoids (hydrocortisone and cortisone), which also have sodium-
retaining properties, are used as replacement therapy in adrenocortical deficiency states. 
At equipotent anti-inflammatory doses, the synthetic analogue Dexamethasone almost 
completely lacks the sodium-retaining property of hydrocortisone and closely related 
derivatives of hydrocortisone. Dexamethasone, when used at relatively high doses, can 
directly inhibit growth of myeloma cells and cause apoptosis. In numerous clinical trials 
increases of response rate have been observed by the addition of dexamethasone to 
standard chemotherapeutics and novel myeloma drugs.  
5.1.1.28 Expected Side Effects:  
Common side effects of dexamethasone include anxiety, mood alteration/lability, 
potassium loss, hypokalemic alkalosis, peptic ulcer with possible perforation and 
hemorrhage, impaired wound healing, menstrual irregularities, hyperglycemia, increased 
intraocular pressure, weight gain, nausea, headache, insomnia, peripheral edema, 
myopathy (with chronic use), acne, hirsutism. 
No drug interactions that raise additional concerns are known or postulated between 
azacitidine, lenalidomide and dexamethasone. 
5.1.1.29 Dosage Form 
Dexamethasone will be prescribed as tablets of 4mg strength for oral administration.   
5.1.1.30 Storage 
Dexamethasone tablets should be stored at room temperature away from direct sunlight 
and protected from excessive heat and cold.     
5.1.1.31 Prescribing Information  
Dexamethasone will be prescribed according to standard practices and charged to the 
patient’s insurance. 
5.2 
Screening and Eligibility 
The Investigator is responsible for keeping a record of all subjects who sign an Informed 
Consent Form for entry into the study.  All subjects will be screened for eligibility.  
Screening procedures are outlined in Section 2, Schedule of Study Assessments and 
unless otherwise specified, must take place within 28 days prior to initiation of therapy.  
Approximately 100 subjects with relapsed or refractory myeloma will be screened for 
enrollment and must meet the eligibility criteria below. 

 
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5.2.1 Inclusion Criteria 
Subjects must meet the following inclusion/exclusion criteria to be eligible for the study. 
Inclusion Criteria  
1. Understand and voluntarily sign an informed consent form. 
2. Age ≥18 years at the time of signing the informed consent form. 
3. Able to adhere to the study visit schedule and other protocol requirements. 
4. Refractory or relapsed multiple myeloma (see under 5.3.) 
5. Measurable disease defined as at least one of the following: Serum m-spike > 
1g/dL, urine m-spike > 200mg/24hrs, serum free light chains > 100mg/L 
(provided the kappa/lambda ratio is abnormal), or bone marrow plasma cells > 
30%. 
6. Previous therapy with IMiD™ compounds (thalidomide, lenalidomide, 
pomalidomide), 
proteasome 
inhibitors 
(bortezomib, 
carfilzomib), 
and 
corticosteroids must be discontinued at least 14 days before entry onto this study. 
7. Previous cytotoxic chemotherapy (e.g. alkylating chemotherapy, anthracyclines, 
and vinca alkaloids), radiation therapy to the pelvis, and any experimental therapy 
other than carfilzomib or pomalidomide must have been discontinued at least 28 
days prior to entry onto this study.  
8. ECOG performance status of ≤ 2 at study entry (see Appendix II). 
9. Laboratory test results within these ranges: 
• Absolute neutrophil count ≥ 1,500 /mm³  
• Platelet count ≥ 75,000/mm³  
• Calculated creatinine clearance (Cockroft-Gault) ≥ 30ml/min.   
• Total bilirubin ≤ 1.5 x ULN 
• Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase 
[AST]) and serum glutamic-pyruvic transaminase (SGPT) (alanine 
aminotransferase [ALT]) levels ≤2 x ULN  
10. All study participants must be registered into the mandatory RevAssist® program, 
and be willing and able to comply with the requirements of RevAssist®. 
11. Females of childbearing potential (FCBP)† must have a negative serum or urine 
pregnancy test with a sensitivity of at least 50 mIU/mL within 10 – 14 days prior 
to and again within 24 hours of prescribing lenalidomide (prescriptions must be 
filled within 7 days) and must either commit to continued abstinence from 
                                                
 
† A female of childbearing potential is a sexually mature woman who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). 
 
 

 
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heterosexual intercourse or begin TWO acceptable methods of birth control, one 
highly effective method and one additional effective method AT THE SAME 
TIME, at least 28 days before she starts taking lenalidomide.  FCBP must also 
agree to ongoing pregnancy testing.  Men must agree to use a latex condom 
during sexual contact with a FCBP even if they have had a successful vasectomy.  
See Appendix: Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods. 
12. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients 
intolerant to ASA may use warfarin or low molecular weight heparin) if no 
additional risk factor for VTE other than myeloma diagnosis according to IMW 
guidelines(55) and as specified for this study under Section 5.6.2.5. 
13. Able to take low molecular weight heparin or warfarin if >1 additional risk factor 
for VTE according to IMW guidelines(55) and as specified for this study under 
Section 5.6.2.5. 
 
5.2.2 Exclusion Criteria   
1. Any serious medical condition, laboratory abnormality, or psychiatric illness that 
would prevent the subject from signing the informed consent form. 
2. Pregnant or breast feeding females. (Lactating females must agree not to breast 
feed while taking lenalidomide or azacitidine). 
3. Any condition, including the presence of laboratory abnormalities, which places 
the subject at unacceptable risk if he/she were to participate in the study or 
confounds the ability to interpret data from the study. 
4. Use of any experimental drug or therapy other than carfilzomib and 
pomalidomide within 28 days of treatment start on this protocol. 
5. Neuropathy > Grade 2 
6. Known hypersensitivity to thalidomide, lenalidomide, azacitidine, or mannitol. 
7. The development of erythema nodosum if characterized by a desquamating rash 
while taking thalidomide or lenalidomide drugs. 
8. Concurrent use of other anti-cancer agents or treatment or concurrent radiation to 
the pelvis. Palliative radiation to areas outside the pelvis is allowed. 
9. Previous inability to tolerate full-dose lenalidomide, adjusted to creatinine 
clearance (CrCl) according to Cockroft-Gault at the time of previous lenalidomide 
treatment (25mg day 1-21 every 28 days if CrCl > 60ml/min, 10mg lenalidomide 
d1-21 every 28 days if CrCl < 60mL/min but > 30mL/min, lenalidomide 15mg 
every 48 h d1-21 every 28 days if CrCl < 30mL/min but not requiring dialysis, 
lenalidomide 5mg daily, day 1-21 every 28 days if CrCl < 30mL/min and 
requiring dialysis).  
 

 
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5.3 
Definition Relapsed Myeloma and Refractory Myeloma 
A recent ASH/FDA panel has recommended to include clinical criteria to define relapsed 
myeloma and to separately analyze data for the relapsed as opposed to the refractory 
group of patients (56). In accordance with this consensus statement, International 
Myeloma Working Group diagnostic criteria (57), and the international uniform response 
criteria (58) the following definitions will be used: 
 
5.3.1 Refractory Myeloma. 
Biochemical or clinical evidence of loss of disease control within 90 days after the last 
therapy. Any of the following defines refractory myeloma: 
1. Progressive disease (see 5.8.1) on prior therapy 
2. Best response to prior therapy was stable disease (see under 7) 
3. Progressive disease (see 5.8.1) within 90 days of the last therapy 
 
5.3.2 Relapsed Myeloma. 
Not fulfilling criteria for refractory disease and at least one biochemical and at least one 
clinical criterion fulfilled indicating recurrence of disease more than 90 days after the last 
therapy:  
One or more biochemical criteria for recurrent disease: 
An increase of 25% from lowest response value in any one or more of the following, 
verified on two consecutive measurements: 
1. Serum M-component (absolute increase must be >0.5 g/100 ml) * 
2. Urine M-component (absolute increase must be >200mg per 24 h) 
3. Only in patients without measurable serum and urine M-protein levels: the 
difference between involved and uninvolved FLC levels (absolute increase must 
be >100 mg/l) 
4. Bone marrow plasma cell percentage (absolute % must be >10%) 
 
AND one or more clinical criteria for recurrent disease: 
Any of the following: 
1. Definite development of new bone lesions or soft tissue plasmacytomas 
2. Definite increase in the size of existing bone lesions or soft tissue plasmacytomas. 
A definite increase is defined as a 50% (and at least 1 cm) increase as measured 
serially by the sum of the products of the cross-diameters of each measurable 
lesion 
3. Development of hypercalcemia (corrected serum calcium >11.5mg / 100ml) that 
can be attributed solely to the plasma cell proliferative disorder 
4. Decrease of hemoglobin by at least 2g/dL below the best independent value 
(without ESA or blood transfusion for at least 28 days) since the  end of previous 

 
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therapy or new decrease in HgB below 10g/dL or to 2g/dL below the lower limit 
of normal 
5. New increase in serum creatinine to > 2mg/dL, or increase by 2mg/dL attributed 
to myeloma progression 
 
*: If the starting serum m-protein level is >5g/dL an absolute increase of >1g/dL, 
verified on two consecutive measurements, is sufficient as a biochemical criterion 
for recurrent disease. 
5.4 
Visit Schedule and Assessments 
Screening assessments and all on study scheduled visits and assessments are outlined in 
Section 2 Table of Study Assessments.  
At treatment discontinuation, subjects will undergo off study evaluations per the 
Schedule of Assessments, Section 2.   In addition, a safety assessment will be done 
approximately 28 days post the last dose of protocol therapy.  Follow-Up contact with the 
subjects should occur at a minimum of every three months for three years from study 
entry.  
5.5 
Correlative Science 
Azacitidine has been shown to reactivate expression of tumor suppressor genes silenced 
by DNA methylation of their promotors in multiple cell lines, animal experiments, and 
clinical trials, but so far this has not been demonstrated in myeloma cells of patients 
treated with azacitidine. Lenalidomide has pleiotropic effects that can include selective 
reactivation of SPARC in 5q- but not cytogentically normal erythroid progenitors (59).  
The two drugs might therefore act in concert, reactivating tumor suppressor genes 
silenced in myeloma cells. With the proposed studies we will investigate baseline DNA 
methylation and gene expression of myeloma cells and if silenced tumor suppressor 
genes can be reactivated using the proposed regimen.  Effects on normal CD34+ 
hematopoietic progenitors will be investigated as well.   
5.5.1 Sample Handling and Processing 
All samples obtained at the Cleveland Clinic will be picked up and processed by staff of 
Dr. Reu’s laboratory (R4-035) the same day they are obtained. The personnel obtaining 
the sample (bone marrow technicians and phlebotomists) will be given a sheet (appendix 
V, VI) specifying what tubes are to be used and who to page (81077) upon sample 
acquisition.  
 
Samples obtained at University Hospitals will be shipped by same-day courier service at 
room temperature to: 
Frederic J. Reu, MD 
Cleveland Clinic Taussig Cancer Institute, R4-035 
9500 Euclid Ave 

 
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Cleveland, OH 44195  
Phone: 216 636 0200; Cell: 216 312 9596; Email: reuf@ccf.org 
Please either page or email Dale Grabowski when sample is shipped.  Email: 
grabowd@ccf.org 
Paging: 216-444-4000 – 81077 followed by # sign – enter call back number followed by 
# sign 
 
Bone marrow samples from University Hospitals will also be processed the same day by 
staff of Dr. Reu’s laboratory, peripheral blood samples may be stored at 4-8°C and 
processed the following day if the sample arrives late.   
5.5.2 Bone Marrow Examinations 
Two 20mL syringes, each pre-filled under sterile conditions with 2mL heparin will be 
used to obtain 40mL bone marrow aspirate on day 1 (or up to 7 days prior) of the first 
cycle and on day 1 of the second cycle, each time before drug administration. After 
isolation of mononuclear cells using the Ficoll TM method, CD34+ cells and CD138+ 
cells will be purified using 2 purification steps with Miltenyi columns followed by flow 
cytometric assessment of achieved purity. Samples of at least 70% purity will be used to 
assess DNA demethylation and mRNA reactivation. DNA and RNA of purified cells will 
be harvested using the Qiagen AllPrep DNA/RNA mini kit TM, which allows for column-
based isolation of DNA and RNA from the same sample. Isolated RNA and DNA will be 
stored at -80°C. Within 30 days (once a month) RNA samples will be transcribed into 
cDNA using Superscript III (Invitrogen TM), then stored at -80°C until further analysis. 
The Illumina® HT12 array will be used to analyze global gene expression in CD138+ 
cells. DNA methylation profiling will be performed using the Illumina® 
HumanMethylation27 BeadChip array in CD138+ and CD34+ cells according to the 
manufacturer’s instructions including bisulfite modification using ZymoTM kits. For 
approximately 10 selected sample genes, changes in expression after cycle one will be 
confirmed using real-time RT-PCR (TaqMan, Applied Biosystems TM).  
5.5.3 Blood Studies 
EDTA blood samples (10mL purple top) obtained at day one of week 1,2,3,4 and day one 
of cycle 2,3,4,6 will be used to obtain buffy coats for DNMT1 immunohistochemistry 
with Q-dot® (Invitrogen TM) analysis, according to a protocol that has been validated in 
samples of AML and MDS patients treated with decitabine in the laboratory of Dr. 
Saunthararajah. Briefly, cytospin slides of buffy coats will be prepared and cells fixed 
and permeabilized with 10% formalin and 0.25% triton. Non specific binding sites will 
be blocked with 10% normal goat serum and 6% BSA. Slides will be incubated overnight 
with mouse anti-DNMT1 antibody (Abcam catalog number ab13537) (diluted 1:500 in 
blocking solution), followed by a 655 nm Quantum DotsTM-conjugated goat anti-mouse 
antibody (Invitrogen catalog number Q11022MP) (diluted 1:500). Finally, cells will be 
stained with 3 μM DAPI for 5 min before dehydration in graded alcohols and toluene 
before mounting on QmountTM QdotTM mounting media (Invitrogen), which provides 

 
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Qdot emission stability for up to 8 months.  Images will be obtained the next working 
day.   
Heparin tubes (10mL) from the same time points (day one of week 1,2,3,4 and day one of 
cycle 2,3,4,6) will be used to isolate whole blood DNA using the DNA blood and tissue 
mini kit® from Qiagen TM. This DNA will be stored at -80°C and may later be used to 
investigate whether genes identified as hypermethylated on the methylation array can be 
detected in the peripheral blood using pyrosequencing of bisulfite modified DNA . A 
PyroMark Q24® sequencer in Dr Reu’s laboratory will be used for these studies. 
Plasma from heparin tubes will be collected and frozen at -80°C for later determination of 
the activity of the azacitidine inactivating enzyme cytidine deaminase (CDA). This will 
be performed by an HPLC method optimized in Dr. Saunthararajah’s laboratory, which 
quantifies deamination of added cytidine. The enzymatic activity is determined by 
comparison of cytidine deamination achieved by plasma samples with deamination 
achieved by incubation of cytidine with dilutions of pure CDA enzyme standards. 
5.5.4 Data Analysis 
Promoter demethylation after cycle 1 in bone marrow cells enriched either for CD138 or 
for CD34 expression will be measured using Illumina TM array technology. The 
IlluminaTM bead array software assigns each CpG region tested a number between 0 and 
1.0 representing the degree of DNA methylation from 0 to 100%. The number of genes 
changing their methylation status significantly according to Illumina TM Bead Studio 
software, version 3 and the number of genes changing their methylation score by at least 
0.2 points absolute will be analyzed and will be made publicly available. Dr. Mohammed 
Orloff will assist in the analysis and if necessary, additional help will be obtained from 
the Cleveland Clinic department of quantitative health sciences. If differences in purity 
occur between pre-and post-treatment samples this will be taken into account in the 
statistical analysis. 
Changes in global gene expression (Illumina® HT12 array) after cycle one of therapy at 
the HTLD / HTLD-CKD in bone marrow cells enriched for CD138 will analyzed by the 
Illumina TM Bead Studio software, version 3. Genes statistically significantly up- or 
downregulated at least 2, 5, and 10 fold will be analyzed for each patient and will be 
made publicly available. Dr. Mohammed Orloff will assist in the analysis and if 
necessary, additional help will be obtained from the Cleveland Clinic department of 
quantitative health sciences. If differences in purity occur between pre-and post-treatment 
samples this will be taken into account in the statistical analysis. 
To confirm reactivation of about 10 selected sample genes in CD138+ and CD34+ cells, 
real-time RT-PCR will be performed in triplicates and reported for each gene analyzed 
with mean and standard deviation of expression after compared to before cycle one. 
DNMT1 suppression will be analyzed after above outlined immunohistochemistry 
protocol. Image files will be loaded into the Image-Pro Plus environment and individual 
cells will be segmented for quantification of fluorescence signal with the "count/size" 
function of Image-Pro Plus. Precise segmentation will be achieved by setting a lower 
threshold just above background emission. A filter will then be set for an area of whole 

 
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cells to exclude fluorescent fragments from the measurement. Image-Pro Plus generates a 
high-content array of measurements that include event number, area, mean of pixel 
intensities, and maximum and minimum pixel intensities. These scores will be integrated 
into a mean intensity fluorescence (MIF) score using the Image-Pro Plus software. The 
mean and standard deviation of reduction in MIF scores after treatment with azacitidine 
at the studied time points will be reported for all tested dose levels.  
5.6 
Drug Administration 
5.6.1 
Treatment Assignments 
The first three patients will be treated at dose level 1. Subsequent increases in dose level 
will occur as outlined under 5.1. after approval by the PI. 
5.6.2 
Dosing Regimen 
The trial will use a classical 3x3 phase I design for patients with GFR > 60ml/min and a 
modified 3x3 design for patients with GFR 30-59ml/min with enrollment of ten 
additional patients at the highest tolerated low dose (HTLD / HTLD-CKD) of azacitidine 
as outlined under 5.1. The dosing schedule is outlined below. Assigned combination 
treatment with lenalidomide, azacitidine, and dexamethasone will be continued for six 
28-day cycles followed by maintenance treatment with lenalidomide single agent at the 
last tolerated dose until disease progression with adjustment of dose as outlined under 
5.7.1 and 5.7.3.  
 
Peripheral blood stem cell harvesting and high dose chemotherapy therapy may be 
performed at any point after treatment cycle #2. In such patients protocol therapy will be 
permanently discontinued at least five days before stem cell mobilization begins but in 
addition to the basic follow up outlined under 2, schedule of study assessments, their 
peripheral blood stem cell yield and engraftment will be documented.  
5.6.2.1 Special Handling Instructions 
Females of childbearing potential should not handle or administer lenalidomide and 
azacitidine unless they are wearing gloves. 
5.6.2.2 Record of administration 
Accurate records will be kept in the source documents of all drug administration 
(including prescribing and dosing).   
 
5.6.2.3 Combination Therapy 
 
Dosing Schedule for Patients with GFR > 60ml/min (Cockroft-Gault) 
  
Dose 
level 
Azacitidine (s.c.)* 
Starting day 1 
Lenalidomide (p.o.) 
Starting day 1 
Dexamethasone (p.o.) 
 

 
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1 
30mg/m2 once a week1 
25mg d1-21 every 28d3 
40mg p.o. once a week4  
2 
40mg/m2 once a week1 
25mg d1-21 every 28d3 
40mg p.o. once a week4 
3 
30mg/m2 s.c. twice a week2 25mg d1-21 every 28d3 
40mg p.o. once a week4 
4 
40mg/m2 s.c. twice a week2 25mg d1-21 every 28d3 
40mg p.o. once a week4 
5 
50mg/m2 s.c. twice a week2 25mg d1-21 every 28d3 
40mg p.o. once a week4 
* After highest tolerated low dose (HTLD) of azacitine  determination, azacitidine 
starting dose will be at the HTLD 
 
Dosing Schedule for Patients with GFR 30-59ml/min (Cockroft-Gault) 
  
Dose 
level 
Azacitidine (s.c.)* 
Starting day 1 
Lenalidomide (p.o.) 
Starting day 1 
Dexamethasone (p.o.) 
 
-1 
30mg/m2 s.c. twice a week2 10mg d1-21 every 28d3 
40mg p.o. once a week4 
1 
40mg/m2 s.c. twice a week2 10mg d1-21 every 28d3 
40mg p.o. once a week4 
2 
50mg/m2 s.c. twice a week2 10mg d1-21 every 28d3 
40mg p.o. once a week4 
* After highest tolerated low dose (HTLD-CKD) of azacitidine determination, azacitidine 
starting dose will be at the HTLD-CKD 
 
1 Ideally, azacitidine is administered on the same day each week, but +/- up to two days is 
allowed, individual doses should be at least 5 days apart. Rotation of injection sites is 
obligatory. 
 
2 Azacitidine should be administered on the same days each week, +/- one day is allowed 
but there should be at least 48hrs between doses. The following schedules are 
recommended: Monday-Thursday, Monday-Friday, Tuesday-Friday, Tuesday-Saturday. 
Rotation of injection sites is obligatory 
3: Lenalidomide dosing will be in the evening at approximately the same time each day.  
Prescriptions must be filled within 7 days. 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. 
 
4: Dexamethasone dosing, independent of age, will be in the morning with breakfast. 
Dexamethasone should be taken at least 24h after and not less than 24h before azacitidine 
to maximize the s-phase specific epigenetic effects of azacitidine. 
 
5.6.2.4 
Lenalidomide Maintenance Treatment and Guidelines for Re-
Introduction of Azacitidine and Dexamethasone 
After six 28-day cycles on combination therapy, dexamethasone and azacitidine will be 
discontinued and lenalidomide will be continued as a single agent at the last tolerated 
dose until disease progression.  At physician discretion, for patients with response < PR 
after six 28-day cycles on combination therapy, the dose of lenalidomide may be 

 
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escalated during maintenance treatment to a maximum dose of 25mg daily on Days 1-21 
of each 28-day cycle.  Lenalidomide dose titration may only occur at the start of a new 
cycle of maintenance one dose level at a time, and only in patients who completed the 
previous treatment cycle without dose modifications or treatment delays due to toxicity.  
Lenalidomide dose titration may occur NOT more frequently than once every 28 days.  
After 12 months since initiation of protocol therapy, no further lenalidomide dose 
titration is permitted.  Also for patients with response < PR after six 28-day cycles on 
combination therapy, dexamethasone and/or azacitidine may be continued or restarted (if 
it had been discontinued) at physician discretion.  In particular, patients with response < 
PR after six 28-day cycles on combination therapy that have not shown sufficient signs of 
end organ improvement should be considered for lenalidomide dose titration and/or 
additional dexamethasone and/or azacitidine as outlined above. Similarly, patients who 
have achieved disease control (stable disease or better) during the first six 28-day cycles 
of combination therapy and who’s myeloma progresses on maintenance therapy may be 
restarted on lenalidomide, azacitidine, and dexamethasone combination therapy at the last 
tolerated dose at physician discretion. 
 
 
5.6.2.5 
Anticoagulation 
Throughout the study, patients who receive lenalidomide (not while the drug is held for 
high dose chemotherapy and ASCT), who have none of the following risk factors for 
VTE will receive aspirin 81-325mg daily. If patients have one or more risk factors as 
outlined below, more intensive prophylaxis should be considered with enoxaparin, 40mg 
s.c. daily if their GFR (according to Cockroft-Gault, Appendix IV) is > 30ml/min and 
30mg s.c. daily if it is < 30ml/min. Alternatively, full anticoagulation with warfarin to a 
target INR of 2.0-3.0 may be used if > 1 risk factor is present. Enoxaparin or warfarin at 
above doses may also be used for patients with no risk factor if aspirin is not tolerated. 
Risk factors: 
• Previous venous thromboembolism 
• Central venous catheter 
• Cardiac pacemaker 
• Chronic kidney disease as defined by a GFR < 30ml/min lasting > 28 days 
• Symptomatic coronary artery disease or heart failure with a left ventricular 
ejection fraction < 30%  
• Diabetes mellitus (unless controlled with diet alone)  
• Acute infection, necessitating hospitalization 
• Immobility with bed rest > 50% of daytime (ECOG PS >3) due to any reason 
while on study 
• General surgery or anesthesia 

 
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• Treatment with erythropoiesis stimulating agents 
• Hereditary hypercoagulability 
• Symptomatic hyperviscosity 
 
Subjects experiencing adverse events may need study treatment modifications (See 
section 5.7). 
5.7 
Dose Continuation, Modification and Interruption    
Subjects will be evaluated for AEs at each visit with the NCI CTCAE v.4.0 (Appendix 
III: NCI CTCAE v.4.0) used as a guide for the grading of severity.  Sections below 
describe recommended dose reduction steps, instructions for initiation of a new cycle of 
therapy and dose modifications during a cycle of therapy. Clinical judgment may be used 
when deciding which drug to hold or modify in scenarios that are not covered below. 
Patients encountering a dose-limiting toxicity during their first cycle may remain on 
study with appropriate  reduction steps.  
5.7.1 Dose Modification Steps and Dose Re-Escalation Guidelines 
5.7.1.1 Dose Modification Steps 
 
Table 1: Lenalidomide dose modification steps for all toxicities listed in Table 5 EXCEPT 
for renal impairment or toxicities in the presence of renal impairment* 
Current Lenalidomide Dose 
One Level Dose Reduction 
25 mg daily on Days 1-21 every 28 days 
20 mg daily on Days 1-21 every 28 days 
20 mg daily on Days 1-21 every 28 days 
15 mg daily on Days 1-21 every 28 days 
15 mg daily on Days 1-21 every 28 days 
10 mg daily on Days 1-21 every 28 days 
10 mg daily on Days 1-21 every 28 days 
5 mg daily on Days 1-21 every 28 days 
5 mg daily on Days 1-21 every 28 days 
Discontinue lenalidomide  
* Renal impairment is defined as calculated creatinine clearance ≥ 30mL/min but < 60mL/min 
(see Table 2 below for lenalidomide dosing) 
 
 

 
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Table 2: Lenalidomide dose modification steps for renal impairment (see Table 5) and for 
other toxicities which occur after dose reduction for renal impairment* 
Current Lenalidomide Dose 
One Level Dose Reduction 
25 mg daily on Days 1-21 every 28 days 
10 mg daily on Days 1-21 every 28 days 
10 mg daily on Days 1-21 every 28 days 
15 mg every 48 hours during Days 1-21 
every 28 days 
15 mg every 48 hours during Days 1-21 every 
28 days 
5 mg daily on Days 1-21 every 28 days 
5 mg daily on Days 1-21 every 28 days 
Discontinue lenalidomide  
* Renal impairment is defined as calculated creatinine clearance ≥ 30mL/min but < 60mL/min 
 
Table 3: Azacitidine Dose Adjustment Steps  
Dose Level +2 
100 mg/m2 SC twice a week (only for patients on 
twice a week azacitidine who tolerated azacitidine 
75mg/m2 SC twice a week but did not respond, see 
under 5.7.1.2) 
Dose Level +1 
75 mg/m2 SC twice a week (only for patients on 
twice a week azacitidine who tolerated their full 
azacitidine starting dose but did not respond, see 
under 5.7.1.2) 
Dose Level 0 
Starting azacitidine dose (differs depending on 
cohort during phase I part, see 5.6.2.3) 
Dose Level -1  
Reduce dose by 50%, maintain frequency of 
administration 
Dose Level -2  
Discontinue azacitidine 
 
 
Table 4: Dexamethasone Dose Reduction Step 
Dose Level – 1 
Reduce each dexamethasone dose by 50% 
Dose Level – 2 
Discontinue dexamethasone 
 
5.7.2 Intra-Individual Dose Escalation of Azacitidine Beyond Starting 
Dose 
In patients treated with twice a week azacitidine we have measured the plasma activity of 
the azacitidine inactivating enzyme cytidine deaminase (CDA) by an HPLC method that 
quantifies deamination of added cytidine. Responders had significantly lower plasma 
CDA activities than non-responders suggesting that destruction of azacitidine precluded 
response (submitted to ASH 2012). Patients who do not achieve a reduction of 
monoclonal proteins to MR range after the first cycle or to PR range after the second 
cycle and who have tolerated the previous cycle at their full starting dose of azacitidine 
twice a week without dose reduction or delay due to toxicities may therefore be treated 
with 75mg/m2 azacitidine in the next cycle and if an entire cycle at this dose level is 

 
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tolerated without the need for dose reduction or delay due to toxicities but monoclonal 
proteins are still not in MR range after one cycle or PR range after two cycles at this 
azacitidine dose, the dose of azacitidine may further be increased to 100mg/m2. There 
will be no intra-individual dose escalation of azacitidine beyond 100mg/m2. 
 
5.7.3 Dose Re-Escalation Guidelines 
Dose Re-Escalation Upon Recovery from Hematologic Adverse Events 
 
If the dose of lenalidomide or azacitidine was reduced due to dose limiting hematologic 
toxicity and continued treatment results in improvement of bone marrow function, dose 
increases by one dose level and drug at a time may be performed if the ANC is ≥ 1000 
/mm³ and platelets are ≥ 50,000 /mm³ at day one of the respective cycle if the previous 
cycle was completed without dose modifications due to toxicity (regardless of type).  If 
patient’s myeloma has previously been refractory to lenalidomide consideration should 
be given to increase azacitidine first, otherwise lenalidomide should be increased first. In 
general, drug dosing increases should alternate between lenalidomide and azacitidine 
until target doses of both drugs are reached or toxicity occurs but the treating physician 
may use clinical judgment and first increase one drug to target dose.  After 12 months 
since initiation of protocol therapy, no further lenalidomide dose titration is permitted.   
Dose Re-Escalation Upon Recovery of Kidney Function 
If the patient’s GFR increases from 30-59ml/min at enrollment to > 60ml/min at the start 
of a cycle and the previous cycle was tolerated without need for dose reduction of 
lenalidomide due to any adverse event and no G-CSF or platelet transfusions were 
required, the dose of lenalidomide may be increased by one dose level according to table 
2. If the dose of lenalidomide or azacitidine was reduced due to renal impairment on 
study, and continued treatment results in calculated creatinine clearance ≥ 60ml/min (by 
Cockroft-Gault), the dose of lenalidomide and azacitidine can be increased by one dose 
level each at the start of each cycle until the target dose of both drugs is reached provided 
the calculated creatinine clearance remains ≥ 60ml/min (by Cockroft-Gault) and no 
relationship between study drugs and renal impairment was suspected. If a relationship 
between study drugs and renal impairment is considered possible, drug increases should 
be done one drug at a time and alternating between lenalidomide and azacitidine, starting 
with lenalidomide. Doses may be increased only in patients who completed the previous 
treatment cycle without dose modifications or treatment delays due to toxicity (regardless 
of type).  Dose increases may occur NOT more frequently than once every 28 days. If the 
current dose of lenalidomide is 15 mg every 48 hours during Days 1-21 every 28 days, or 
5 mg daily on Days 1-21 every 28 days, the first dose increase would be to 10 mg daily 
on Days 1-21 every 28 days.  Additional dose increases if warranted would be in 5 mg 
increments.  After 12 months since initiation of protocol therapy, no further lenalidomide 
dose titration is permitted.   
  

 
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5.7.4 Instructions for Initiation of a New Cycle  
A new course of treatment may begin on the scheduled Day 1 of a new cycle if: 
• The ANC is ≥ 1000/mm³ (G-CSF is allowed to achieve this threshold) 
• The platelet count is ≥ 50,000/mm³ (During the first 4 cycles platelet transfusions 
are allowed to achieve this threshold) 
• Any new drug-related neuropathy or rash other than injection site reaction that 
may have occurred has resolved to ≤ grade 1 severity; 
• Any bicarbonate decrease below 20mEq/L that may have occurred has resolved to 
baseline. 
• Calculated creatinine clearance ≥ 30ml/min (by Cockroft-Gault), after 12 cycles 
on therapy, determining the creatinine clearance every 2 months will suffice 
• Any other drug-related adverse events that may have occurred have resolved to ≤ 
grade 2 severity.  Physician discretion may be used in initiating the next cycle of 
treatment if the only toxicities that have not resolved to ≤ grade 2 severity are 
dexamethasone-related toxicities. 
If these conditions are not met on Day 1 of a new cycle, the subject will be evaluated 
weekly and a new cycle of treatment will not be initiated until the toxicity has resolved as 
described above.  If criteria to initiate a new cycle are not met by 21 days after the 
planned start of a new cycle patients go off study. If a lenalidomide or azacitidine dose 
reduction was taken during the previous cycle, and the cycle was completed without 
requiring further dose modification, then the next cycle will start at the same reduced 
dose.  If lenalidomide and / or azacitidine dosing was omitted for the remainder of 
the previous cycle or if the new cycle is delayed due to toxicity newly encountered on 
the scheduled Day 1, then the new cycle will be started with a one-level dose reduction 
of lenalidomide and/or azacitidine as appropriate.  Dose reductions should generally be 
taken one drug at a time based on attribution of toxicity to one of the drugs unless 
otherwise indicated in Section 5.7.3.   
5.7.5 Instructions for Dose Modifications or Interruption During a Cycle 
Table 5 outlines instructions for dose reductions of study drugs for specific toxicities. 
Study drugs may be temporarily or permanently dose reduced using doses outlined in 
table 1-4 or temporarily discontinued in other situations where their continued 
administration according to protocol is felt unsafe by the treating physician. 
 

 
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Table 5: Dose Modifications Azacitidine and Lenalidomide  
NCI CTC Toxicity 
Grade 
Dose Modification Instructions 
Grade 3 neutropenia 
associated with fever 
(temperature ≥ 38.5º 
C) or Grade 4 
neutropenia 
• Hold (interrupt) lenalidomide and, while on combination, also 
azacitidine dose. 
• Follow CBC weekly. 
• During combination therapy with lenalidomide and azacitidine: 
o 
 If neutropenia has resolved to ≤ grade 2 prior to Day 21 of 
the current cycle, restart azacitidine at the next lower dose 
level and continue lenalidomide at the same dose level if the 
patient’s myeloma has not previously been refractory to 
lenalidomide, otherwise maintain azacitidine dose level and 
reduce lenalidomide by one dose level (if the patient is only 
on one of these drugs reduce its dose by one level) and 
continue treatment through the scheduled end of the cycle.  
Otherwise, omit treatment for the remainder of the cycle and 
reduce dose levels in the same way at the start of the next 
cycle.  Omitted doses are not made up.   
o 
If neutropenia is the only toxicity for which a dose reduction 
is required (no fever or other reason to reduce doses), G-
CSF should be considered instead of a dose reduction.     
• 
During maintenance therapy with lenalidomide: 
o 
If neutropenia has resolved to ≤ grade 2 prior to Day 21 of 
the current cycle, restart lenalidomide at the next lower dose 
level, and continue through the scheduled end of the cycle.  
Otherwise, omit lenalidomide for the remainder of the cycle 
and reduce lenalidomide by 1 dose level at the start of the 
next cycle.  Omitted doses are not made up. 

 
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Table 5: Dose Modifications Azacitidine and Lenalidomide  
NCI CTC Toxicity 
Grade 
Dose Modification Instructions 
Thrombocytopenia 
≥Grade 3 (platelet 
count < 50,000/mm³) 
• During the first 4 cycles platelet transfusions may be used at the 
discretion of the treating physician to achieve platelet counts > 
50,000/mm3 on post-transfusion CBCs and thereby maintain the 
current dose level of lenalidomide and azacitidine. If platelet 
transfusions are administered, the CBC should be monitored at 
least twice a week. 
• For thrombocytopenia > grade 3 (< 50,000/mm3) after platelet 
transfusion or if platelet transfusions are not used hold (interrupt) 
lenalidomide and, while on combination, also azacitidine dose. 
• If thrombocytopenia > grade 4 (< 25,000/mm3) on a pre-platelet 
transfusion CBC or if platelet transfusions are not used hold 
prophylactic anticoagulation  
• Follow CBC weekly, if given platelet transfusions twice a week. 
• If thrombocytopenia resolves to < grade 4 (> 25,000/mm3) and last 
platelet 
transfusion 
> 
7 
days 
ago 
resume 
prophylactic 
anticoagulation. 
• During combination therapy with lenalidomide and azacitidine: 
o 
 If thrombocytopenia resolves to ≤ grade 2 (with or without 
the use of platelet transfusions) prior to Day 21 of the current 
cycle, restart azacitidine at the next lower dose level and 
lenalidomide at the same dose level if the patient’s myeloma 
has not previously been refractory to lenalidomide, otherwise 
maintain azacitidine dose level and reduce lenalidomide by 
one dose level (if the patient is only on one of these drugs 
reduce its dose by one level). Otherwise, omit treatment for 
remainder of cycle and reduce dose levels in the same way 
at the start of the next cycle. Omitted doses are not made up. 
• 
During maintenance therapy with lenalidomide: 
o 
If thrombocytopenia has resolved to ≤ grade 2 prior to Day 
21 of the current cycle, restart lenalidomide at the next lower 
dose level, and continue through the scheduled end of the 
cycle.  Otherwise, omit lenalidomide for the remainder of the 
cycle and reduce lenalidomide by 1 dose level at the start of 
the next cycle.  Omitted doses are not made up. 
Non-blistering rash 
 
Grade 3 
 
 
 
 
 
 
              
Grade 4 
 
• If Grade 3, hold (interrupt) lenalidomide and, while on combination, 
also azacitidine dose. 
• Follow weekly. 
• If the toxicity resolves to ≤ grade 1 prior to Day 21 of the current 
cycle, restart lenalidomide at next lower lenalidomide dose level 
and continue azacitidine at the same dose level through the 
scheduled end of the cycle.  Otherwise, omit treatment for 
remainder of cycle and reduce the lenalidomide dose by 1 dose 
level and maintain the current azacitidine dose at the start of the 
next cycle.  Omitted doses are not made up. 
 
 
• If Grade 4, discontinue lenalidomide and azacitidine.  Remove 
patient from study. 

 
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Table 5: Dose Modifications Azacitidine and Lenalidomide  
NCI CTC Toxicity 
Grade 
Dose Modification Instructions 
Desquamating 
(blistering) rash- any 
Grade  
• Discontinue lenalidomide and azacitidine.  Remove patient from 
study. 
Injection site reaction 
Grade 1 (pain, 
itching, erythema) 
 
Grade  2 (pain or 
swelling with 
inflammation or 
phlebitis) 
 
Grade 3 (ulceration or 
necrosis that is 
severe, operative 
intervention 
indicated) 
• Unless > Grade 3 maintain azacitidine dose 
• For 
Grade 
1-2 
use 
post-injection 
hydrocortisone 
cream 
(recommended strength: 2.5%) until resolution. Make sure injection 
sites are rotated. 
 
 
 
 
 
 
• If grade 3 discontinue azacitidine. Remove patient from study. 
Neuropathy 
 
Grade 3 
 
 
 
 
 
 
Grade 4 
 
• If Grade 3, hold (interrupt) lenalidomide dose and, while on 
combination, also azacitidine dose.  Follow at least weekly. 
• If the toxicity resolves to ≤ grade 1 prior to Day 21 of the current 
cycle, restart lenalidomide at next lower lenalidomide dose level, 
restart azacitidine at the current dose and continue treatment 
through the scheduled end of the cycle.  Otherwise, omit treatment 
for remainder of cycle and reduce the dose of lenalidomide by 1 
lenalidomide dose level and maintain the current azacitidine dose 
at the start of the next cycle.  Omitted doses are not made up. 
 
• If Grade 4, discontinue lenalidomide.  Remove patient from study. 
Venous 
thrombosis/embolism 
≥ Grade 3 
• Hold (interrupt) lenalidomide and start anticoagulation; restart 
lenalidomide at investigator’s discretion (maintain dose level). 
• Omit lenalidomide for remainder of cycle. See Anticoagulation 
(Section 5.8.1.2) 
Hyperthyroidism or 
hypothyroidism 
• Omit lenalidomide for remainder of cycle, evaluate etiology, and 
initiate appropriate therapy.  
• See Instructions for Initiation of a New Cycle and reduce the dose 
of lenalidomide by 1 lenalidomide dose level. 
Bicarbonate - low 
(CO2 below 20mEq/L) 
• If unexplained hold azacitidine  and lenalidomide  
• Check weekly 
• Upon recovery to baseline restart azacitidine at next lower dose 
level and restart lenalidomide at the current dose.  If recovery to 
baseline occurs prior to Day 21 of the current cycle, restart as 
instructed above and continue treatment through the scheduled 
end of the cycle.  Otherwise, omit treatment for remainder of cycle 
and reduce the dose of azacitidine by 1 dose level and maintain 
the current dose of lenalidomide at the start of the next cycle.  
Omitted doses are not made up. 

 
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Table 5: Dose Modifications Azacitidine and Lenalidomide  
NCI CTC Toxicity 
Grade 
Dose Modification Instructions 
Renal impairment 
 
(Calculated creatinine 
clearance ≥ 30ml/min 
< 60ml/min) 
 
 
 
 
(Calculated creatinine 
clearance < 
30ml/min) 
 
 
 
 
 
 
 
 
 
 
• Maintain current dosing schedule, but reduce lenalidomide by 1 
dose level (see Section 5.7.1, Table 2).  If lenalidomide dose had 
been ≥ 15mg, reduce to 10mg daily on Days 1-21 of each 28-day 
cycle. 
 
 
 
 
 
• Hold lenalidomide and, while on combination, also azacitidine 
• Check weekly 
• Upon recovery to calculated creatinine clearance ≥ 30ml/min 
restart at next lower dose level for both lenalidomide and 
azacitidine (see Section 5.7.1, Table 2 and Table 3).  If 
lenalidomide dose had been ≥ 15mg, reduce to 10mg daily on 
Days 1-21 of each 28-day cycle.  If recovery occurs prior to Day 21 
of the current cycle, restart as instructed above and continue 
treatment through the scheduled end of the cycle.  Otherwise, omit 
treatment for remainder of cycle and reduce the dose of azacitidine 
by 1 dose level and reduce the dose of lenalidomide by 1 dose 
level at the start of the next cycle (see Section 5.7.1, Table 2 and 
Table 3).  If lenalidomide dose had been ≥ 15mg, reduce to 10mg 
daily on Days 1-21 of each 28-day cycle.  Omitted doses are not 
made up. 
other non-
hematologic toxicity 
≥ Grade 3 
• In general hold (interrupt) lenalidomide and, while on combination, 
also azacitidine dose but clinical discretion may be used to only 
hold the most likely causative agent. 
• Follow at least weekly. 
• If the toxicity resolves to ≤ grade 2 prior to Day 21 of the current 
cycle, restart lenalidomide and azacitidine and continue through 
the scheduled end of the cycle.  Otherwise, omit treatment for 
remainder of cycle.  Omitted doses are not made up.  For toxicity 
attributed to lenalidomide, reduce the lenalidomide dose by 1 
lenalidomide dose level when restarting lenalidomide. For toxicities 
attributed to azacitidine, reduce dose by one azacitidine dose level 
when restarting azacitidine. 
 

 
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Table 6: Dose Modifications Dexamethasone  
NCI CTC Toxicity 
Grade 
Dose Modification Instructions 
Dyspepsia 
Grade 1-2 
• Maintain dose  
• Add proton pump inhibitor or H2 blocker 
Dyspepsia 
Grade > 3 
• Hold dose  
• Add proton pump inhibitor or H2 blocker 
• When symptoms controlled decrease one dose level and restart. 
Omitted doses are not made up 
Edema 
> Grade 3 
• Use diuretics as needed and decrease by one dose level 
Confusion or mood 
alteration 
> Grade 2 
• Hold dose until symptoms resolve. When restarting decrease one 
dose level. 
Muscle weakness 
(steroid myopathy) 
> Grade 2 
 
 
• Hold dose until muscle weakness < Grade 1. When restarting 
decrease one dose level. 
Hyperglycemia 
≥ Grade 3 
• Decrease dose by one dose level. Treat with insulin or oral 
hypoglycemic agent. 
Acute pancreatitis 
• Discontinue dexamethasone 
 
5.7.6 Treatment Compliance 
Research center personnel will review the dosing instructions with subjects. Subjects will 
be asked to maintain a diary to record the drug administration (appendix VII). Subjects 
will be asked to bring any unused drug and empty drug containers to the research center 
at their next visit.  Research personnel will count and record the number of used and 
unused drug at each visit and reconcile with the patient diary.  Azacitidine will be 
administered at the Taussig Cancer Center and at University Hospital Ireland cancer 
Center, compliance will be assessed by review of medication administration reports. 
Any unused Revlimid® (lenalidomide) should be returned to the patient for disposition in 
accordance with the RevAssist® program. 
5.8 
Concomitant Therapy   
5.8.1 Recommended Concomitant Therapy   
Subjects should receive full supportive care, including transfusions of blood and blood 
products, antibiotics, and antiemetics when appropriate.  
 
5.8.1.2 Anticoagulation   
Lenalidomide increases the risk of thrombotic events in patients who are at high risk or 
with a history a thrombosis, in particular when combined with other drugs known to 
cause thrombosis. When lenalidomide is combined with other agents such as steroids 

 
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(e.g. dexamethasone, prednisone), anthracyclines (Doxil, Adriamycin) and erythropoietin 
the risk of thrombosis is increased.  
Prophylactic anticoagulation is mandatory on this trial according to guidelines outlined 
under 5.6.2.5 with holding and restarting parameters as per Table 5 (hold for plts < 
25,000/mm3, restart once plts > 25,000/mm3 and platelet transfusion independent for > 7 
days).  
In case of documented deep venous thrombosis or embolism standard anticoagulation 
with subcutaneous low molecular weight heparin or intravenous heparin with conversion 
to warfarin will be started. Full anticoagulation will be maintained for at least 12 months 
while patients are on lenalidomide and at least 6 months if they have gone off trial and 
the DVT was below the knee (distal to the popliteal vein).  
5.8.1.3 Concomitant Therapy with Azacitidine 
5HT3 serotonin receptor antagonists should be administered at least 30min prior to each 
azacitidine dose. If constipation or headache limits the use of HT3 antagonists, 
metoclopramide may be used. 
 
Rotation of azacitidine injection sites is obligatory. Patients who nevertheless experience 
grade 1-2 injection site reactions should be treated with topical hydrocortisone (2.5% 
cream recommended) until resolution.  
5.8.2 Prohibited Concomitant Therapy 
Concomitant use of other anti-cancer therapies, thalidomide, or other investigational 
agents is not permitted while subjects are receiving protocol therapy on this study.  
Palliative radiation (with the exception of pelvic radiation) is permitted.  
5.9 
Discontinuation of Study Treatment Including Progressive Disease Definition  
Treatment will be discontinued in case of: 
• Progressive Disease (see under 5.9.1) 
• Adverse event(s) that, in the judgment of the Investigator, may cause severe or 
permanent harm or which rule out continuation of the treatment regimen. 
• Delay of the start of a new cycle by more than 21 days due insufficient recovery 
from toxicity 
• Permanent discontinuation of lenalidomide for any reason  
• Major violation of the study protocol 
• Withdrawal of consent 
• Lost to follow up 
• Death 
• Suspected pregnancy or positive pregnancy 

 
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5.9.1 
Progressive Disease 
Progressive disease (PD) is defined according to the international uniform response 
criteria (Durie et al. Leukemia 20:1467-73, 2006, ERRATUM Durie et al. Leukemia 
21:1134, 2007) and requires any of the following, confirmed on two consecutive 
assessments: 
An increase of 25% from lowest response value in any one or more of the following: 
• Serum M-component (absolute increase must be >0.5 g/100 ml) * 
• Urine M-component (absolute increase must be >200mg per 24 h) 
• Only in patients without measurable serum and urine M-protein levels: the 
difference between involved and uninvolved FLC levels (absolute increase must 
be >100 mg/l) 
• Bone marrow plasma cell percentage (absolute % must be >10%) 
 
And / or: 
• 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/100 ml) that 
can be attributed solely to the plasma cell proliferative disorder 
 
*: If the starting serum m-protein level is >5g/dL an absolute increase of >1g/dL, verified 
on two consecutive measurements, is sufficient to define progressive disease. 
 
The decision as to when to repeat the assessment to document progressive disease will be 
left at the discretion of the treating physician, there is no need to wait until the next 
scheduled response assessment.  
 
5.10 Follow-Up   
Subjects who discontinue treatment for any reason, will be followed every 3 months for 3 
years from study entry (if patients are no longer treated at this Institution attempts will be 
made to obtain information over the phone as per Schedule of Assessments, Section 2). 
Patients, who stay on protocol therapy will be followed at least every 2 months according 
to schedule of study assessments (2) for 3 years from study entry. At treatment 
discontinuation, off study evaluations per the Schedule of Assessments, Section 2, will be 
done.  In addition, subjects will undergo a safety assessment approximately 28 days post 
the last dose of protocol therapy. 
6 
Adverse Events 
6.1 
Serious Adverse Event (SAE) Definition  
A serious adverse event is one that at any dose (including overdose): 
• Results in death 
• Is life-threatening1 

 
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• 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.  
6.2 
Adverse Drug Reaction Reporting 
Toxicity will be scored using CTCAE Version 4.0 for toxicity and adverse event 
reporting.  A copy of the CTCAE Version 4.0 can be downloaded from the CTEP 
homepage (HTTP://CTEP.INFO.NIH.GOV).  All appropriate treatment areas should 
have access to a copy of the CTCAE Version 4.0.  All Grade 3 and 4 adverse clinical 
experiences, whether observed by the investigator or reported by the patient, must be 
recorded, with details about the duration and intensity of each episode, the action taken 
with respect to the test drug, and the patient’s outcome.  The investigator must evaluate 
each adverse experience for its relationship to the test drug and for its seriousness. 
 
The investigator must appraise all abnormal laboratory results for their clinical 
significance.  If any abnormal laboratory result is considered clinically significant, the 
investigator must provide details about the action taken with respect to the test drug and 
about the patient’s outcome. 
 

 
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6.2.1 
Dose Limiting Toxicity Reporting 
Dose limiting toxicity (DLT) is defined as one of the following drug-related toxicities 
occurring during the first 28-day cycle (if a DLT is attributed to progressive disease, it 
will not be counted as a DLT): 
• Any CTCAE v.4.0 grade >3 non hematologic toxicity (including febrile 
neutropenia)  
o For nausea, vomiting, or diarrhea, subjects must have a Grade 3 or 4 
event that persists at this level despite the use of optimal symptomatic 
treatment, in order for these events to be considered a DLT 
o Grade 4 transaminitis (serum transaminase > 20 x upper limit of normal 
[ULN]) is a DLT, while Grade 3 transaminitis (serum transaminase > 5 x 
and ≤ 20 x ULN) must be present for ≥ 7 days to be considered a DLT  
o Grade 3 or 4 venous thromboembolic events are not considered to be 
DLTs as long as anticoagulant therapy can be administered (see Section 
6.5.3 and 6.6.2) 
o Grade 3 or 4 hypokalemia, hypophosphatemia, hypomagnesemia or 
hyponatremia that responds to electrolyte supplementation within 7 days 
would not qualify as a DLT.  
 
• CTCAE v.4.0 grade > 4 neutropenia or thrombocytopenia that does not resolve to 
grade < 3 within seven days of holding azacitidine and lenalidomide.  
 
The PI has to be informed about the occurrence of DLT within one working day after the 
sub investigator or nurse becomes aware of it. The PI may not allow further accrual at a 
given dose level once two patients have developed DLT. The PI has to inform Celgene 
within 5 working days of any DLT with a brief description of the nature of the DLT. 
 
6.2.2 
Pregnancies 
Pregnancy of a female subject or the female partner of a male subject occurring while the 
subject is on lenalidomide or azacitidine or within 4 weeks after the subject’s last dose of 
lenalidomide or azacitidine are considered expedited reportable events.  If the subject is 
on lenalidomide or azacitidine, both drugs are to be discontinued immediately and the 
subject is to be instructed to return any unused portion of lenalidomide to the 
Investigator.  The pregnancy must be reported to Celgene Drug Safety within 24 hours of 
the Investigator’s knowledge of the pregnancy by phone and facsimile using the SAE 
Form. 
 
The Investigator will follow the pregnant female until completion of the pregnancy, and 
must notify Celgene Drug Safety of the outcome as specified below.  The Investigator 
will provide this information as a follow-up to the initial SAE. 
 

 
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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 Expedited Reporting of SAEs to Celgene (i.e., report the event 
to Celgene Drug Safety by facsimile within 24 hours of the Investigator’s knowledge of 
the event). 
 
Any suspected fetal exposure to lenalidomide or azacitidine 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 
suspects is related to the in utero exposure to lenalidomide or azacitidine should also be 
reported. 
 
In the case of a live “normal” birth, Celgene Drug Safety should be advised as soon as the 
information is available. 
 
6.2.3 Celgene Drug Safety Contact Information: 
 
Celgene Corporation 
Drug Safety 
86 Morris Avenue 
Summit, N.J. 07901 
 
Toll Free:   
(800)-640-7854 
Phone:  
(908) 673-9667 
Fax: 
 
(908) 673-9115 
e-mail:  
drugsafety@celgene.com 
 
 
6.3 
Investigator Reporting Responsibilities 
The conduct of the study will comply with all FDA safety reporting requirements.   
 
All adverse experience reports must include the patient number, age, sex, weight, severity 
of reaction (e.g. mild, moderate, severe), relationship to drug (e.g. probably related, 
unknown relationship, definitely not related), date and time of administration of test 
medications and all concomitant medications, and medical treatment provided.   The 
investigator is responsible for evaluating all adverse events to determine whether criteria 
for “serious” and as defined above are present.  The investigator is responsible for 
reporting adverse events to Celgene as described below. 

 
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6.3.1 Expedited Reporting by Investigator to Celgene 
Serious adverse events (SAE) are defined above.  The investigator must inform Celgene 
in writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 
24 hours of being aware of the event.  The written report must be completed and supplied 
to Celgene by facsimile within 24 hours/1 business day.  The initial report must be as 
complete as possible, including an assessment of the causal relationship between the 
event and the investigational product(s), if available.  Information not available at the 
time of the initial report (e.g., an end date for the adverse event or laboratory values 
received after the report) must be documented on a follow-up report.  A final report to 
document resolution of the SAE is required.  The Celgene tracking number (RV-MM-PI-
0507) and the institutional protocol number should be included on SAE reports (or on the 
fax cover letter) sent to Celgene.  A copy of the fax transmission confirmation of the SAE 
report to Celgene should be attached to the SAE and retained with the patient records. 
 
SAEs occurring in patients treated at a participating study site must be reported to 
Celgene by the respective site investigator within 24h of awareness as outlined above. 
Copies should be sent at the same time to the principal investigator.  
6.3.2 Report of Adverse Events to the Institutional Review Board 
The principal Investigator is required to notify his/her Institutional Review Board (IRB) 
of a serious adverse event according to institutional policy.   
6.4 
Adverse Event Updates/IND Safety Reports 
Celgene shall notify the Investigator via an IND Safety Report of the following 
information: 
 
• Any AE associated with the use of 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 11.4 for records retention information). 
7 
Response Criteria 
Baseline assessments must occur within ≤ 7 days of protocol therapy initiation as 
indicated in Section 2, Schedule of Study Assessments. 
Efficacy assessments are scheduled to occur monthly, beginning at Cycle 3 Day 1, during 
the first 12 cycles, then every two months.  

 
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All response categories (60)require two consecutive blood and urine assessments (bone 
marrow biopsies do not need to be repeated) and no evidence for progressive or new bone 
lesions if radiographic studies were performed. Radiographic studies are not required for 
response assessment but should be obtained when there is clinical suspicion for 
progressive bone disease.  
 
Complete response (CR) 
Negative immunofixation of serum and urine (or 
normal sFLC ratio if the only measurable disease 
outside of the bone marrow is by sFLCs) and 
disappearance of any soft tissue plasmacytomas, 
and <5% plasma cells in bone marrow 
 
Stringent CR (sCR) 
 
CR as defined above plus normal sFLC ratio and 
absence of clonal cells in bone marrow by 
immunohistochemistry or immunofluorescence 
 
Very good partial response (VGPR) Serum and urine M-component detectable by 
immunofixation but not on electrophoresis or 
>90% or greater reduction in serum M-component 
plus urine M-component <100mg per 24 h or >90% 
reduction in the difference between involved and 
uninvolved serum free light chains if this is the only 
measurable disease outside of the bone marrow 
 
Partial response (PR)  
>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 sFLC levels is 
required in place of the M protein criteria, if the 
only measurable disease is in the bone marrow, a 
>50% reduction in bone marrow plasma cells is 
required, provided the baseline percentage was 
>30%. In addition to the above criteria, if present at 
baseline, a >50% reduction in the size of soft tissue 
plasmacytomas is required. 
 
Minor response (MR) 
>25% but <49% reduction of serum M protein and 
reduction in 24 h urine M protein by 50–89%, 
which still exceeds 200mg per 24 h. In addition to 
the above criteria, if present at baseline, 25–49% 
reduction in the size of soft tissue plasmacytomas is 
also required. No increase in size or number of lytic 
bone lesions (development of compression fracture 
does not exclude response). 

 
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Stable disease (SD)  
Not meeting criteria for sCR, CR, VGPR, PR, MR, 
or progressive disease (see under 5.9.1). 
8 
Protocol Amendments/Deviations 
8.1 
Protocol Amendments 
Any amendment to this protocol must be agreed to by the Principal Investigator and 
reviewed by Celgene.  Amendments should only be submitted to IRB/EC after 
consideration of Celgene review.  Written verification of IRB/EC approval will be 
obtained before any amendment is implemented.   
8.2 
Protocol Deviations 
When an emergency occurs that requires a deviation from the protocol for a subject, a 
deviation will be made only for that subject.  A decision will be made as soon as possible 
to determine whether or not the subject (for whom the deviation from protocol was 
effected) is to continue in the study.  The subject’s medical records will completely 
describe the deviation from the protocol and state the reasons for such deviation.  In 
addition, the Investigator will notify the IRB/EC in writing of such deviation from 
protocol. 
Non-emergency minor deviations from the protocol will be permitted with approval of 
the Principal Investigator.  
9 
Data Management 
9.1 
Analyses and Reporting 
Oncore will be used for data entry and analysis. Data will be analyzed and reported after 
the last patient has been on trial for at least three 28 day cycles. All subsequent data 
collected will be analyzed and reported in a follow-up clinical report.  
9.2 
Data Safety Monitoring Plan 
Twice a month the data safety and toxicity committee of the joint Comprehensive Cancer 
Center of the Cleveland Clinic Foundation and Case Western Reserve University Cancer 
Centers reviews all hematologic and oncologic trials run at either institution to ensure the 
safety of patients, validity of data, and appropriate termination of trials should undue 
risks be discovered or if the trial can not be successfully completed.    
9.3 
Study Auditing 
9.3.1 Investigator Responsibilities 
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice 
(GCP) and in the US Code of Federal Regulations. 

 
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Investigators must enter study data onto CRFs or other data collection system.  The 
Investigator will permit study-related audits by Celgene or its representatives, IRB/EC 
review, and regulatory inspection(s) (e.g., FDA, EMEA, TPP), providing direct access to 
the facilities where the study took place, to source documents, to CRFs, and to all other 
study documents. 
The Investigator, or a designated member of the Investigator’s staff, must be available at 
some time during audits to review data and resolve any queries and to allow direct access 
to the subject’s records (e.g., medical records, office charts, hospital charts, and study 
related charts) for source data verification.  The data collection must be completed prior 
to each visit and be made available to the Celgene representative so that the accuracy and 
completeness may be checked. 
 
10 Biostatistical Analysis 
10.1 
Overview 
The phase I 3x3 design with 10 additional patients at the highest tolerated low dose 
(HTLD / HTLD-CKD) of azacitidine as a small phase II extension will lead to a patient 
accrual of up to 44 patients if the highest dose level is reached. Safety, efficacy, and 
mechanism of action will be analyzed. Dr. Paul Elson will perform the statistical analysis 
of all clinical endpoints outlined below. The correlative science will be analyzed utilizing 
the Illumina Bead Studio TM software version 3 with support from Dr. Mohammed 
Orloff. 
10.2 
Datasets to be Analyzed 
10.2.1 Dose Limiting Toxicity 
Dose limiting toxicity is defined as any one of the following drug-related toxicities 
occurring during the first 28-day cycle (if a DLT is attributed to progressive disease, it 
will not be counted as a DLT): 
• Any CTCAE v.4.0 grade >3 non hematologic toxicity (including febrile 
neutropenia)  
o For nausea, vomiting, or diarrhea, subjects must have a Grade 3 or 4 
event that persists at this level despite the use of optimal symptomatic 
treatment, in order for these events to be considered a DLT 
o Grade 4 transaminitis (serum transaminase > 20 x upper limit of normal 
[ULN]) is a DLT, while Grade 3 transaminitis (serum transaminase > 5 x 
and ≤ 20 x ULN) must be present for ≥ 7 days to be considered a DLT  
o Grade 3 or 4 venous thromboembolic events are not considered to be 
DLTs as long as anticoagulant therapy can be administered (see Section 
6.5.3 and 6.6.2) 

 
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o Grade 3 or 4 hypokalemia, hypophosphatemia, hypomagnesemia or 
hyponatremia that responds to electrolyte supplementation within 7 days 
would not qualify as a DLT. 
• CTCAE v.4.0 grade > 4 neutropenia or thrombocytopenia that does not resolve to 
grade < 3 within seven days of holding azacitidine and lenalidomide 
Dose limiting toxicity will be assessed weekly during the first cycle. The highest 
tolerated low dose will be determined as described in Section 5.1.  
10.2.2 Safety 
Data from all subjects who receive any protocol therapy will be included in the safety 
analyses. Subjects who entered the study and did not receive any protocol therapy and 
had this confirmed, will not be evaluated for safety. Adverse events will be recorded 
during the first 12 cycles, graded according to CTCAE v.4.0 whenever possible, and 
reported for the time points day 1 of cycle 2, 3, 6, 9, and 12 according to dose level 
treated. Additionally, worst overall toxicity will be reported at each publication.  
 
10.2.3  Response 
The response rate (RR= sCR+CR+VGPR+PR) and clinical benefit response rate 
(CBRR=sCR+CR+VGPR+MR) will be analyzed for the entire study group, and for the 
16-22 patients treated at the HTLD / HTLD-CKD according to whether patients had 
relapsed or refractory disease at study entry. All response categories require two 
consecutive assessments but the time a response is first reached will be used to calculate 
response rates after 6 and 12 cycles. Additionally, best response will be reported. If one 
or more patients on this trial elect to undergo stem cell transplantation, response before 
mobilization will be reported.  
10.2.4 Progression-free Survival 
Progression-free survival will be calculated from the time of enrollment until the 
development of progressive disease or death from any cause, whichever occurs first. 
Patients who elect to undergo high dose chemotherapy followed by autologous stem cell 
transplantation will not be included in an analysis of progression-free survival.  
10.2.5 Overall Survival 
Overall survival will be calculated from the time of study entry until the date of death 
from any cause. Patients who elect to undergo high dose chemotherapy followed by 
autologous stem cell transplantation will not be included in an analysis of overall 
survival.   

 
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10.2.6 Autologous Stem Cell Transplantation 
In patients who elect to undergo stem cell harvesting, high dose chemotherapy, and 
autologous peripheral blood stem cell transplantation, CD34+ yield and time to 
neutrophil and platelet engraftment (counted from the day of stem cell infusion = day 0) 
will be reported. 
10.2.7 Pharmacodynamics 
See under correlative science (5.5). 
  
10.3 
Statistical Methodology 
The Kaplan-Meier method will be used to report progression free survival and overall 
survival for patients treated at the HTLD / HTLD-CKD and for the entire study cohort 
but excluding patients who elect to undergo high dose chemotherapy and autologous stem 
cell transplantation. For statistical methods pertaining to pharmacodynamic analyses 
please see under correlative science (5.5).  
 
11 Regulatory Considerations 
 
11.1 
Institutional Review Board/Ethics Committee Approval 
The protocol for this study has been designed in accordance with the general ethical 
principles outlined in the Declaration of Helsinki.  The review of this protocol by the 
IRB/EC and the performance of all aspects of the study, including the methods used for 
obtaining informed consent, must also be in accordance with principles enunciated in the 
declaration, as well as ICH Guidelines, Title 21 of the Code of Federal Regulations 
(CFR), Part 50 Protection of Human Subjects and Part 56 Institutional Review Boards. 
The Investigator will be responsible for preparing documents for submission to the 
relevant IRB/EC and obtaining written approval for this study.  The approval will be 
obtained prior to the initiation of the study. 
The approval for both the protocol and informed consent must specify the date of 
approval, protocol number and version, or amendment number. 
Any amendments to the protocol after receipt of IRB/EC approval must be submitted by 
the Investigator to the IRB/EC for approval.  The Investigator is also responsible for 
notifying the IRB/EC of any serious deviations from the protocol, or anything else that 
may involve added risk to subjects. 
Any advertisements used to recruit subjects for the study must be reviewed and approved 
by the IRB/EC prior to use. 

 
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11.2 
Informed Consent 
The Investigator must obtain informed consent of a subject or his/her designee prior to 
any study related procedures as per GCPs as set forth in the CFR and ICH guidelines. 
Documentation that informed consent occurred prior to the subject’s entry into the study 
and the informed consent process should be recorded in the subject’s source documents.  
The original consent form signed and dated by the subject and by the person consenting 
the subject prior to the subject’s entry into the study, must be maintained in the 
Investigator’s study files. 
11.3 
Subject Confidentiality 
Celgene affirms the subject’s right to protection against invasion of privacy.  In 
compliance with United States federal regulations, Celgene requires the Investigator to 
permit representatives of Celgene Corporation and, when necessary, representatives of 
the FDA or other regulatory authorities to review and/or copy any medical records 
relevant to the study in accordance with local laws. 
Should direct access to medical records require a waiver or authorization separate from 
the subject’s statement of informed consent, it is the responsibility of the Investigator to 
obtain such permission in writing from the appropriate individual. 
11.4 
Study Records Requirements 
The Investigator must ensure that the records and documents pertaining to the conduct of 
the study and the distribution of the protocol therapy, that is copies of CRFs and source 
documents (original documents, data, and records [e.g., hospital records; clinical and 
office charts; laboratory notes; memoranda; subject’s diaries or evaluation checklists; 
SAE reports, pharmacy dispensing records; recorded data from automated instruments; 
copies or transcriptions certified after verification as being accurate copies; microfiches; 
photographic negatives, microfilm, or magnetic media; x-rays; subject files; and records 
kept at the pharmacy, at the laboratories, and at medico-technical departments involved in 
the clinical study; documents regarding subject treatment and 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. 
11.5 
Premature Discontinuation of Study 
The Principal Investigator, institution and Celgene have the right to discontinue this study 
at any time for reasonable medical or administrative reasons.  Possible reasons for 
termination of the study could be but are not limited to: 
• Unsatisfactory enrollment with respect to quantity or quality. 
• Inaccurate or incomplete data collection. 
• Falsification of records. 

 
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• Failure to adhere to the study protocol. 
Any possible premature discontinuation would be documented adequately with reasons 
being stated, and information would have to be issued according to local requirements 
(e.g., IRB/EC, regulatory authorities, etc.). 
 
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Appendices 
 
Appendix I: 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.  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®. 
Females of childbearing potential (FCBP)† must agree to use two reliable forms of 
contraception simultaneously or to practice complete abstinence from heterosexual 
intercourse during the following time periods related to this study: 1) for at least 28 days 
before starting lenalidomide; 2) while participating in the study; and 3) for at least 28 
days after discontinuation from the study. The two methods of reliable contraception 
must include one highly effective method (i.e. intrauterine device (IUD), hormonal [birth 
control pills, injections, or implants], tubal ligation, partner’s vasectomy) and one 
additional effective (barrier) method (i.e. latex condom, diaphragm, cervical cap).  FCBP 
must be referred to a qualified provider of contraceptive methods if needed.   
Because of the increased risk of venous thromboembolism in patients with multiple 
myeloma taking lenalidomide and dexamethasone, combined oral contraceptive pills are 
not recommended with regimens combining lenalidomide and dexamethasone.  If a 
patient is being treated with a regimen combining lenalidomide and dexamethasone and 
is currently using combined oral contraception, the patient should switch to one of the 
other highly effective contraceptive methods listed above.  The risk of venous 
thromboembolism continues for 4−6 weeks after discontinuing combined oral 
contraception.  The efficacy of contraceptive steroids may be reduced during co-
treatment with dexamethasone. 
 
 
Before starting lenalidomide:   
Female Subjects:   
• FCBP must have two negative pregnancy tests (sensitivity of at least 50 mIU/mL) 
prior to prescribing lenalidomide.  The first pregnancy test must be performed 
within 10-14 days prior to prescribing lenalidomide and the second pregnancy test 
                                                
 
† A female of childbearing potential is a sexually mature woman who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). 
 
 

 
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must be performed within 24 hours prior to prescribing lenalidomide 
(prescriptions must be filled within 7 days).  The subject may not receive 
lenalidomide until the Investigator has verified that the results of these pregnancy 
tests are negative. 
 
Male Subjects:   
• Must agree to use a latex condom during sexual contact with females of 
childbearing potential while participating in the study and for at least 28 days 
following discontinuation from the study even if he has undergone a successful 
vasectomy.  
During study participation and for 28 days following discontinuation from the 
study: 
All Subjects: 
• If pregnancy or a positive pregnancy test does occur in a study subject or the 
partner of a male study subject during study participation, lenalidomide must be 
immediately discontinued. 
Female Subjects:   
• FCBP with regular or no menstrual cycles must agree to have pregnancy tests 
weekly for the first 28 days of study participation and then every 28 days while on 
study, at study discontinuation, and at day 28 following discontinuation from the 
study. If menstrual cycles are irregular, the pregnancy testing must occur weekly 
for the first 28 days and then every 14 days while on study, at study 
discontinuation, and at days 14 and 28 following discontinuation from the study.   
• In addition to the required pregnancy testing, the Investigator must confirm with 
FCBP that she is continuing to use two reliable methods of birth control at each 
visit.   
• Pregnancy testing and counseling must be performed if a subject misses her 
period or if her pregnancy test or her menstrual bleeding is abnormal.  
Lenalidomide treatment must be discontinued during this evaluation. 
Male Subjects: 
• Must agree to use a latex condom during sexual contact with females of 
childbearing potential while participating in the study and for at least 28 days 
following discontinuation from the study even if he has undergone a successful 
vasectomy. 
 

 
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Appendix II: ECOG Performance Status Scale 
 
 
SCORE 
DESCRIPTION 
0 
Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of a light or sedentary nature, e.g., light 
house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry 
out any work activities.  Up and about more than 50% of 
waking hours. 
3 
Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair. 
5 
Dead. 
 
 
 
 
 
 
 
 
 
 
 
Appendix III : 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 IV : Cockroft-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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Appendix V: Bone marrow aspirations RV0507 
Date: 
 
Patient study number: 
Aspiration sequence 
1. Two 20mL heparin syringes, each pre-filled with 2mL of heparin 
2. One 10mL heparin syringe pre-filled with 1mL heparin 
 
Distribution 
1. Page 81077 for pick-up of the two 20mL syringes and this sheet 
2. Send the 10mL syringe to pathology for cytogenetics and FISH (both Mayo send-
out, sent by our pathology department) 
 
Outside CCF: 
Please either page or email Dale Grabowski when sample is shipped: 
Email: grabowd@ccf.org 
Paging: 216-444-4000 – 81077 followed by the # sign – enter call back number followed 
by # sign 

 
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Appendix VI: Blood draws for correlative science RV0507 
 
Date: 
 
Patient study number: 
 
 
Obtain 10mL heparin (green top tube) and 10mL EDTA (two purple top tubes) 
 
Page 81077 for sample pickup 
 
Outside CCF: 
Please either page or email Dale Grabowski when sample is shipped: 
Email: grabowd@ccf.org 
Paging: 216-444-4000 – 81077 followed by the # sign – enter call back number followed 
by # sign 
 
 
 

 
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Appendix VII: Lenalidomide and dexamethasone drug administration diary 
 
Cycle # : 
 
Date of day 1 of above cycle:  
 
Patient study number: 
 
Revlimid® (lenalidomide) should be taken from day 1-21 and dexamethasone on day 1, 8, 
15, and 22. On the table “R” represents Revlimid® and “D” represents dexamethasone. 
 
Please call you study nurse when you take the 21st dose of Revlimid®, to allow time for 
the next order and ensure you have Revlimid® on time for the next cycle. 
 
Please cross out the R if you took Revlimid® and cross out the D if you took 
dexamethasone on the indicated days. Please leave blank if you did not take the indicated 
drugs on the respective day, irrespective of the reason, whether you were advised by your 
physician or simply forgot.   
 
Day 1 
R 
Day 2 
RD 
Day 3 
R 
Day 4 
R 
Day 5 
R 
Day 6 
R 
Day 7 
R 
Day 8 
R 
Day 9 
RD 
Day 10 
R 
Day 11 
R 
Day 12 
R 
Day 13 
R 
Day 14 
R 
Day 15 
R 
Day 16 
RD 
Day 17 
R 
Day 18 
R 
Day 19 
R 
Day 20 
R 
Day 21 
R (call) 
Day 22 
 
Day 23 
D 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
Received by study nurse on:   
 
(date as MM/DD/YY) 
Name of study nurse:   
 
 
Signature of study nurse: