Randomized Phase III Trial of Lenalidomide Versus Observation Alone in Patients With Asymptomatic High-Risk Smoldering Multiple Myeloma
Phase: PHASE3
Conditions: Light Chain Deposition Disease, Smoldering Multiple Myeloma
Sponsor: National Cancer Institute (NCI)

i 
28 State Street, Suite 1100, Boston, MA 02109 
p: 857.504.2900 
f: 617. 589.0914 
ecog-acrin.org 
 
September 26, 2019  
 
Martha Kruhm, MS RAC 
Head, Protocol and Information Office 
Quality Assurance Section 
CTEP, DCT, NCI 
6130 Executive Blvd, EPN Room 7000 
Bethesda, MD   20892 
Dear Ms. Kruhm: 
Enclosed is Addendum #14 to E3A06, Randomized Phase III Trial of Lenalidomide Versus 
Observation Alone in Patients with Asymptomatic High-Risk Smoldering Multiple Myeloma. 
This addendum is in response to a Lenalidomide request for amendment from Dr. Streicher, 
August 13, 2019. 
There are no revisions to the case report forms as a result of this amendment. 
Please replace your current copy of the protocol and Informed Consent document with these 
updated versions.  We recommend that each institution maintain a file containing the original 
protocol, Informed Consent, and all subsequent revisions/versions. 
IRB Review Requirements: 
Full IRB review of this addendum is recommended, however, ECOG-ACRIN will accept the 
method of review determined by the standard operating procedures for the IRB of record for this 
protocol. [If changes have been made to the consent, insert the following sentence here:  It is 
the decision of the local IRB whether or not subjects are to be re-consented]. This addendum 
must be submitted and reviewed by your IRB within 90 days of receipt of this notice, unless your 
local IRB has different written SOPs, which must be available at future ECOG-ACRIN audits. 
 
Sites using the CIRB as their IRB of record: The protocol and/or informed consent form 
changes have been approved by the CIRB and must be activated within 30 days of the CIRB 
posting of this notice.  
 
Sites not using the NCI CIRB: Per CTMB Guidelines, the protocol updates and/or informed 
consent changes must be approved by local IRBs within 90 days of distribution of this notice. If 
your local IRB has different SOPs, they must be available at future E-A audit. 
I. Recommendations: 
# 
Section 
Comments 
1. 
5.5.2.3 
Please replace the 2 remaining mentions of “LCP” with “CPPCP”. 
Response: This has been completed 
2. 
Appendix VI 
1) Please delete “sexually mature” from the definition of FCBP. 
2) In section 1.3.1, the italicized paragraph regarding dexamethasone-
containing lenalidomide regimens can be deleted. 
Response: This has been completed 

ii 
# 
Section 
Comments 
3. 
Appendix VII 
1) Please delete “sexually mature” from the definition of FCBP. 
2) Please add back the following text in red in the “male” section: Do not 
donate blood, semen or sperm 
Response: This has been completed 
4. 
9.9 
NCI and the CTSU would be happy to have a call with the E-A to brainstorm 
strategies to increase awareness of the importance of outreach to Black or African 
American patients and physicians to consider participation in this trial given their 
higher incidence rates of multiple myeloma . Contact Andrea Denicoff at: 
denicofa9@mail.nih.gov' 
Response: This is no longer applicable to the study  
5. 
9 
Accrual 
The investigators state that the plan is to increase accrual of Black or African 
American patients and operationally close the trial to non-AA patients when they 
reach 150 non-AA patients. 
A revised plan that changes the study number to 150 should be included in the 
statistical section, study design, and consent An explanation of why this is being 
done should be included in the background section.  
Section 9.8.3 indicates accrual will continue to 180 patients. Which would seem to 
include 150 patients and 30 AA patients. These numbers however do not include 
the AA patients included in the first 150. Is the intent to include 30 additional 
randomized patients, to complete a total of 30 patients, or to a total of 21 as 
indicated in the table 9.9.  The intent to increase the total AA accrual to 21 needs 
to be clarified described if in fact the study will remain open to accrue these 
patients. Will this continue in a randomized fashion? Will an analysis plan be 
included? 
The total number of participants in the consent 224 does not match any of these 
numbers. Please clarify.  
Response: This is no longer applicable to the study 
The following revisions to E3A06 protocol have been made in this addendum: 
 
Section 
Change 
1. 
Cover Page 
Updated Version Date 
2. 
Contacts Page 
Updated Madhav Dhodapkar, MD contact information  
3. 
5.2.3 
Updated the AE team at ECOG-ACRIN and NCI fax phone numbers  
4. 
5.3 
Updated the Lenalidomide CAEPR list with version 2.8, June 27, 2019. 
5. 
5.5.2.3 
Replaced the 2 remaining mentions of “LCP” with “CPPCP”. 
6. 
Appendix VI 
Deleted “sexually mature” from the definition of FCBP. 
The italicized paragraph regarding dexamethasone-containing 
lenalidomide regimens has been deleted.  
7. 
Appendix VII 
Deleted “sexually mature” from the definition of FCBP. 
Added back the following text in red in the “male” section: Do not donate 
blood, semen or sperm 
8. 
Appendix XIII 
Clarified what needs to be reported in female patients and CTEP’s phone 
number  

iii 
The following revisions to E3A06 Informed Consent Document have been made in this 
addendum: 
 
Section 
Change 
1. 
Cover Page  
Updated Version Date  
2. 
Risks and side effects 
related to the 
lenalidomide include: 
Updated Lenalidomide risk list to version 2.8 from June 27, 2019.  
If you have any questions regarding this addendum, please contact Camilla Abreu at 
cabreu@ecog-acrin.org or 857-504-2900. 
We request review and approval of this addendum to E3A06, so ECOG-ACRIN may activate it 
promptly.  Thank you. 
Sincerely, 
Pamela Cogliano 
Senior Director, Protocol Development Enclosure 
 
CC: Sagar Lonial MD  
Matthias Weiss, MD  
Susanna Jacobus, MS. 
S. Vincent Rajkumar, MD  
Matthias Weiss, MD  
Madhav Dhodapkar, MD  
Bruce Giantonio, MD 
Donna Marinucci 
Peter J. O’Dwyer, MD 
Carol Chami, RN 
Melinda Flood 
Jean MacDonald 
Kerry Higgins 
Matthew Shimizu 
Kevin Pollard 
Camilla Abreu  
Sarah Archambault  
 
 
 

E3A06 
 
1 
Randomized Phase III Trial of Lenalidomide Versus 
Observation Alone in Patients with Asymptomatic High-
Risk Smoldering Multiple Myeloma 
 
STUDY CHAIR: 
Sagar Lonial MD 
 
STUDY CO-CHAIR: 
Matthias Weiss, MD 
 
STUDY STATISTICIAN: 
Susanna Jacobus, MS 
 
DISEASE-ORIENTED COMMITTEE CHAIR: 
S. Vincent Rajkumar, MD  
 
QOL CO-CHAIR: 
Matthias Weiss, MD 
 
SWOG CO-CHAIR: 
Madhav Dhodapkar, MD 
 
LABORATORY CO-CHAIRS: 
Joshua Epstein, D.Sc. 
Rafael Fonesca, MD 
Madhav V. Dhodapkar, MD 
 
Version Date:  September 26, 2019 
NCI Update Date:  February 3, 2016 
 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
ALLIANCE / Alliance for Clinical Trials in 
Oncology 
NRG / NRG Oncology Foundation, Inc  
SWOG / SWOG 
 
October 5, 2010 
Addendum #1: Incorporated prior to activation 
Addendum #2: 6/11 
Addendum #3: 8/11 
Addendum #4: 10/11 
 
 
Addendum #5: 2/12 
NOTE: This study is supported by the NCI 
Cancer Trials Support Group (CTSU). 
Institutions not aligned with ECOG-
ACRIN will participate through the CTSU 
mechanism (please see Section 4 for 
details). 
 
Addendum #6: 9/12 
Addendum #7: 7/13 
Addendum #8: 12/13 
Addendum #9: 7/14 
Addendum #10: 10/14 
 
 
Addendum #11: 1/16 
 
 
Update #1: 2/16 
 
 
Addendum #12: 7/16 
 
 
Addendum #13 
 
 
Addendum #14 
 
Agents 
IND# 
NSC# 
Supply 
Lenalidomide 
 
NSC 703813 
NCI-supplied 
 
 
 
 
 
Rev. 8/11 
Rev. 7/13 

ECOG-ACRIN 
E3A06 
Cancer Research Group 
Version Date: September 26, 2019 
 
NCI Update Date: February 3, 2016 
2 
Table of Contents 
Schema ...................................................................................................................... 7 
1. Introduction ........................................................................................................ 8 
1.1 Multiple Myeloma (MM) ........................................................................... 8 
1.2 Smoldering Multiple Myeloma (SMM) ..................................................... 8 
1.3 Targeted Patient Population ..................................................................... 9 
1.4 Lenalidomide ............................................................................................. 9 
1.5 Rationale and Hypothesis for Current Study .......................................... 10 
1.6 Quality of Life Assessment ...................................................................... 12 
1.7 Correlative Studies .................................................................................. 13 
2. Objectives ......................................................................................................... 16 
2.1 Phase II .................................................................................................... 16 
2.2 Phase III ................................................................................................... 16 
2.3 Quality of Life Assessment Objectives .................................................... 17 
3. Selection of Patients ......................................................................................... 18 
3.1 Eligibility Criteria ..................................................................................... 18 
4. Registration Procedures.................................................................................... 22 
4.1 Pre-Registration ...................................................................................... 24 
4.2 Registration ............................................................................................. 25 
4.3 Eligibility Verification .............................................................................. 26 
4.4 Additional Requirements ........................................................................ 26 
4.5 Stratification Factors ............................................................................... 26 
4.6 Instructions for Patients who Do Not Start Assigned Protocol Treatment26 
5. Treatment Plan ................................................................................................. 27 
5.1 Administration Schedule ......................................................................... 27 
5.2 Adverse Event Reporting Requirements ................................................. 27 
5.3 Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Lenalidomide (CC-5013, NSC 703813) .................................................... 35 
5.4 Dose Modifications ................................................................................. 43 
5.5 Supportive Care ....................................................................................... 45 
5.6 Duration of Therapy ................................................................................ 46 
5.7 Duration of Follow Up ............................................................................. 47 
6. Measurement of Effect ..................................................................................... 48 
6.1 Response Considerations ........................................................................ 48 
6.2 Response Categories ............................................................................... 50 
6.3 Quality of Life Measurement .................................................................. 52 
7. Study Parameters for Arm A and Arm B ........................................................... 54 
7.1 Therapeutic Parameters (for both arms of the study) ............................ 54 
7.2 Biological Sample Submissions ............................................................... 57 
8. Drug Formulation and Procurement ................................................................. 58 
8.1 Lenalidomide (NSC 703813), (IND) ......................................................... 58 

ECOG-ACRIN 
E3A06 
Cancer Research Group 
Version Date: September 26, 2019 
 
NCI Update Date: February 3, 2016 
3 
9. Statistical Considerations .................................................................................. 63 
9.1 Introduction ............................................................................................ 63 
9.2 Accrual ..................................................................................................... 63 
9.3 Phase II Study .......................................................................................... 64 
9.4 Primary Clinical Endpoint ........................................................................ 64 
9.5 Secondary Clinical Endpoints .................................................................. 66 
9.6 Stem Cell Mobilization ............................................................................ 67 
9.7 Quality of Life .......................................................................................... 67 
9.8 Correlative Studies .................................................................................. 70 
9.9 Gender and Ethnicity .............................................................................. 73 
9.10 Study Monitoring .................................................................................... 73 
10. Correlative Studies ............................................................................................ 75 
10.1 Bone Marrow and Peripheral Blood for Laboratory Studies at Mayo 
Clinic ........................................................................................................ 75 
10.2 Bone Marrow for Gene Expression Profiling (GEP) – University of 
Arkansas .................................................................................................. 78 
10.3 Specimens for Immunology Testing – Yale University ............................ 81 
10.4 Banking .................................................................................................... 83 
10.5 ECOG-ACRIN Sample Tracking System .................................................... 83 
10.6 Sample Inventory Submission Guidelines ............................................... 84 
10.7 Lab Data Transfer Guidelines .................................................................. 84 
11. Records to Be Kept ............................................................................................ 85 
11.1 Records Retention ................................................................................... 85 

ECOG-ACRIN 
E3A06 
Cancer Research Group 
Version Date: September 26, 2019 
 
NCI Update Date: February 3, 2016 
4 
12. Patient Consent and Peer Judgment ................................................................ 85 
13. References ........................................................................................................ 85 
Appendix I  Informed Consent Template for Cancer Treatment Trials (English 
Language) [Deleted in Addendum #7] .............................................................. 91 
 Appendix II  Patient Thank You Letter .................................................................... 92 
Appendix III  Myeloma Tumor Biology Kit ............................................................... 93 
Appendix IV  Bone Marrow Aspirate Kit – University of Arkansas .......................... 96 
Appendix V  Patient Pill Diary .................................................................................. 97 
Appendix VI  Risks Associated with Pregnancy ....................................................... 98 
Appendix VII  Lenalidomide Education and Counseling Guidance Document ...... 102 
Appendix VIII  Lenalidomide Information Sheet ................................................... 105 
Appendix IX  Cooperative Research and Development Agreement (CRADA/CTA)107 
Appendix X  Bone Marrow Aspirate and Peripheral Blood Kit — Yale University . 109 
Appendix XI  Bone Marrow Core Biopsy Kit—University of Arkansas ................... 110 
Appendix XII  Celgene Pregnancy Prevention & Counseling Program Site Counselor 
Identification Form ......................................................................................... 111 
 Appendix XIII  Instructions for Reporting Pregnancies on a Clinical Trial ............. 112 
 
 
 
Rev. 8/11 
Rev. Add14 

ECOG-ACRIN 
E3A06 
Cancer Research Group 
Version Date: September 26, 2019 
 
NCI Update Date: February 3, 2016 
5 
STUDY CHAIR 
Sagar Lonial, MD 
Winship Cancer Institute 
1365 Clifton Rd 
Building C, Room 4004 
Atlanta, GA 30322 
Phone: 404-778-3921 
FAX 404-778-5530 
E-mail: sloni01@emory.edu 
 
STUDY CO-CHAIR 
Matthias Weiss, MD 
Marshfield Clinic 
1000 North Oak Avenue 
Marshfield, WI 54449-5777 
Phone: 715-358-1296 
FAX 715-389-7555 
E-mail: weiss.matthias@marshfieldclinic.org 
 
SWOG CO-CHAIR 
Madhav Dhodapkar, MD 
Dhodapkar Lab of Emory University 
Health Sciences Research Building Room E369 
1760 Haywood Drive, NE 
Atlanta GA 30322 
Lab contact: Rituparna Das 
E-mail: rituparna.das@emory.edu 
 
STUDY CHAIR LIASON (SCL) 
Cathy Sharp RN, MN, OCN 
Clinical Research Nurse IV, Supervisor 
Winship Cancer Institute of Emory University 
1365C Clifton Rd. NE, Ste 3012 
Atlanta, GA 30322 
Phone: 404-778-3811 
Fax: 404-778-4389 
E-mail: cathysharp@emory.edu 
 
 
NOTE: 
Please refer to Section 4 for CTSU registration guidelines. 
Rev. 8/11 
Rev. 7/13 
Rev. 1/16 

ECOG-ACRIN 
E3A06 
Cancer Research Group 
Version Date: September 26, 2019 
 
NCI Update Date: February 3, 2016 
6 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site registration 
documents: 
For patient enrollments:  
Submit study data directly to the 
Lead Cooperative Group unless 
otherwise specified in the protocol:  
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206 
Email: 
CTSURegulatory@ctsu.coccg.org 
(for submitting regulatory 
documents only) 
Please refer to the patient 
enrollment section of the 
protocol for instructions on 
using the Oncology Patient 
Enrollment Network (OPEN) 
which can be accessed at 
https://www.ctsu.org/OPEN_SY
STEM/ or 
https://OPEN.ctsu.org. 
Contact the CTSU Help 
Desk with any OPEN-related 
questions at 
ctsucontact@westat.com. 
ECOG-ACRIN Operations Office - 
Boston, 
FSTRF, 900 Commonwealth Avenue 
Boston, MA 02215 
(ATTN: DATA). 
Phone # 617-632-3610 
Fax # 617-632-2990 
Data should be sent via postal mail 
(preferred), however fax is accepted. 
Do not submit study data or forms to 
CTSU Data Operations. Do not copy 
the CTSU on data submissions.   
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ websiteis managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. 
For clinical questions (i.e. patient eligibility or treatment-related)  contact the Study PI of the 
Coordinating Group 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail: CTSU General Information Line – 1-888-
823-5923, or ctsucontact@westat.com. All calls and correspondence will be triaged to the appropriate 
CTSU representative.  
For detailed information on the regulatory and monitoring procedures for CTSU sites please 
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website   
https://www.ctsu.org  > education and resources tab > CTSU Operations Information >CTSU Regulatory 
and Monitoring Policy 
The CTSU Web site is located at   https://www.ctsu.org 
 
Rev. 7/14 

ECOG-ACRIN 
E3A06 
Cancer Research Group 
Version Date: September 26, 2019 
 
NCI Update Date: February 3, 2016 
7 
Schema 
Arm A1
Lenalidomide 25 mg by 
mouth  days 1-21 every 
28 days and aspirin 325 
mg by mouth3 days 1-28
R
E
G
I
S
T
E
R
Continue 
treatment until 
disease 
progression or  
toxicity2
R
A
N
D
O
M
I
Z
E
Before a patient 
registers, they must 
have a confirmed 
diagnosis of 
asymptomatic high-risk 
smoldering multiple 
myeloma. See Section 
3 of the protocol.
Continue treatment until 
disease progression or  
toxicity2
Arm A1
Lenalidomide 25 mg by 
mouth days 1-21 every 
28 days and aspirin by 
mouth3 days 1-28
Arm B1
Observation
Phase II
Ph II Accrual= 44 patients
Ph III Accrual= 180 patients
Accrual = 224 patients
Cycle= 28 days
Phase III
1. Enrollment will be suspended for a phase II safety analysis when the phase II accrual goal is met. Once that has happened, the randomized portion of the trial will begin. 
2. Mobilize stem cells following 4-6 cycles of therapy. While stem cell collection following 4-6 cycles of therapy is suggested strongly, it is not required for protocol participation.
3. Patients are to receive aspirin or an alternative as outlined in Sections 5.1.1 and 5.5.2.1. The suggested dose is 325 mg/day however the dose is at the discretion of the treating physician. Alternative dosing of 75 mg/
day or higher is acceptable provided the patient is at low risk of thrombosis.
4. Submission of pre-study specimens per patient consent.
Continue observation 
until disease 
progression2
Rev. 2/12, 7/13
Rev.7/13
Rev. 7/13
Rev.
7/13
Stratify:
· Time since 
Smoldering 
Multiple Myeloma 
diagnosis 
(   1yr vs. > 1yr)
Rev.
12/13
P
R
E
-
R
E
G
I
S
T
R
A
T
I
O
 N4
Rev.6/14
Rev.6/14
Rev.11/15
 

ECOG-ACRIN 
E3A06 
Cancer Research Group 
Version Date: September 26, 2019 
 
NCI Update Date: February 3, 2016 
8 
1. 
Introduction 
1.1 
Multiple Myeloma (MM) 
Multiple myeloma (MM) accounts for 10% of all hematologic malignancies (1-3). 
For many years, autologous stem cell transplantation (ASCT), alkylator-based 
chemotherapy, and corticosteroids had been the mainstay of therapy for the 
disease. Recently, thalidomide, bortezomib, and lenalidomide have emerged as 
effective single-agents, demonstrating significant clinical activity in relapsed and 
refractory MM (4-6). The discovery of these drugs has been accompanied by a 
growing awareness of the importance of bone marrow microenvironmental 
changes such as induction of angiogenesis, suppression of cell-mediated 
immunity, and expression of various adhesion molecules and cytokines in 
disease progression (7,8). The present challenge is to determine how best to 
incorporate thalidomide, bortezomib and lenalidomide into the therapeutic 
strategy for myeloma. ECOG has conducted randomized phase III trials 
incorporating thalidomide and lenalidomide as part of the initial therapy for newly 
diagnosed symptomatic MM. 
1.2 
Smoldering Multiple Myeloma (SMM) 
Approximately 15-20% of patients with MM are asymptomatic at presentation (9-
12).  These patients are usually referred to smoldering multiple myeloma (SMM) 
(2). They are to be distinguished from patients with monoclonal gammopathy of 
undetermined significance (MGUS) (13, 14). The current definitions of these 
disorders are described in the Table below.  
Criteria for the diagnosis of MGUS, SMM and MM (15-17) 
MGUS Serum monoclonal protein < 3 g/dl and bone marrow plasma cells < 10% and 
absence of anemia, renal failure, hypercalcemia and lytic bone lesions 
SMM Serum monoclonal protein  3 g/dl and/or bone marrow plasma cells  10% and 
absence of anemia, renal failure, hypercalcemia and lytic bone lesions 
MM Presence of a serum/urine monoclonal protein, bone marrow plasmacytosis and 
anemia, renal failure, hypercalcemia, or lytic bone lesions; patients with primary 
systemic amyloidosis and 30% bone marrow plasma cells are considered to have both 
multiple myeloma and amyloidosis 
Abbreviations: MGUS, monoclonal gammopathy of undetermined significance; SMM, 
smoldering multiple myeloma; MM, multiple myeloma. 
Patients with SMM have a much higher risk of transformation to overt 
symptomatic myeloma than patients with MGUS. Most patients with SMM 
progress eventually to symptomatic MM, and the risk of progression is 
substantially higher than with MGUS (10-20% per year for SMM versus 1% per 
year from MGUS) (9). The time to progression (TTP) to symptomatic disease is 
approximately 2-4 years, but differs greatly depending on the definition used for 
SMM (18). In SMM patients having bone marrow plasma cells (BMPC)  10%, 
the median time to progression is approximately 2-3 years (19). In a large study 
by Kyle and colleagues, using the current criteria for SMM the risk of progression 
was approximately 10% per year, a rate much higher than observed with MGUS 
(12).  
Rev. 12/13 

ECOG-ACRIN 
E3A06 
Cancer Research Group 
Version Date: September 26, 2019 
 
NCI Update Date: February 3, 2016 
9 
1.3 
Targeted Patient Population 
The above points support the use of lenalidomide as the experimental arm. The 
current standard of care for SMM is observation alone with no therapy (1), 
justifying observation as the control arm. Additionally, in the current trial, we 
propose to evaluate those patients with SMM who have the highest risk of 
progression to symptomatic MM. Based upon published data by Kyle et al 
(12)and Dispenzieri et al (23), we propose to limit eligibility to the highest risk 
smoldering myeloma patients. Kyle’s study cohort (12) is classified into three 
prognostic groups as follows: high-risk ≥ 10% BMPC and serum M-protein ≥ 3 
gm/dl, intermediate-risk ≥ 10% BMPC and serum M-protein < 3 gm/dl and low-
risk < 10% BMPC and serum M-protein < 3 gm/dl. 
Dispenzieri et al (23) further divided patients based on the free light chain (FLC) 
ratio. The normal reference range for FLC ratio is 0.26-1.65. In the Dispenzieri 
study, 90% of patients were abnormal based on this definition. To discern 
whether the extent to which FLC ratio was abnormal had an impact, they 
evaluated the prognostic effect of continuous FLC ratio and found an optimal 
breakpoint of the FLC ratio was < 0.125 or > 8.0. With this range, 60% of patients 
were abnormal. Risk of progression was approximately 35% at 2 years and 60% 
at 5 years. This is slightly higher than the risk of progression using the < 0.26  
or > 1.65 of 32.5% and 52.6%, respectively. They then constructed a risk 
stratification model including three risk factors: ≥ 10% bone marrow plasma cells, 
serum M-protein ≥ 3 gm/dl and FLC ratio less than 0.125 or greater than 8. For 
our trial, high- and intermediate-risk patients based on the Kyle stratification are 
eligible for entry in the study if they also have an abnormal free light chain ratio 
defined as < 0.26 or > 1.65. Given the published natural history of these patients, 
it will be easier to show benefit for these patients, and they have the highest risk 
of progression to symptomatic myeloma. 
1.4 
Lenalidomide 
Single agent lenalidomide has shown responses in approximately one-third of 
patients with advanced MM, even if patients had previously failed thalidomide 
(36). In combination with dexamethasone, lenalidomide was active in 
approximately 60% of patients with advanced relapsed MM (37, 38), and over 
90% of patients with newly diagnosed symptomatic MM (30-32). Thus, the drug 
is likely to have significant activity in patients with asymptomatic MM who are at 
an earlier stage the disease. This hypothesis has been previously tested with 
thalidomide, where the activity observed with thalidomide in relapsed MM did 
translate into significant activity in the asymptomatic stage (25,39). Lenalidomide 
is a safer and more potent analog of thalidomide, and there is no reason to 
believe that the drug will fail to act in the asymptomatic stage.  Additionally, for 
patients who achieve long lasting and deep responses to lenalidomide based 
therapy, there is a history of chronic administration of lenalidomide for periods far 
longer than other therapies in the setting of relapsed and newly diagnosed 
myeloma. The net result of these observations is that lenalidomide is an active 
agent with a good safety profile in the acute and chronic administration setting, 
and is an ideal agent to test in a patient population that is at high risk of 
progression to symptomatic myeloma, yet to date has not proven to benefit from 
early therapy. 
Rev. 7/13, 12/13 
Rev. 7/13 
Rev. 12/13 

ECOG-ACRIN 
E3A06 
Cancer Research Group 
Version Date: September 26, 2019 
 
NCI Update Date: February 3, 2016 
10 
In a phase II trial of 122 patients with relapsed myeloma, approximately 25% 
responded to single-agent lenalidomide therapy (40). This trial included several 
patients who had earlier failed thalidomide. Typical dosing for lenalidomide is 25 
mg per day on days 1-21 of a 28 day cycle. The most common adverse effects 
are thrombocytopenia and neutropenia. Side effects such as sedation, 
constipation, and neuropathy appear to be less common with lenalidomide. 
The clinical efficacy of lenalidomide was established in two recent phase III trials, 
where patients with relapsed refractory MM had superior response rates, TTP 
and overall survival with lenalidomide plus dexamethasone compared to 
dexamethasone/placebo (37,38).  
In a trial among newly diagnosed MM patients, the combination of lenalidomide 
plus dexamethasone has shown remarkable activity with responses in more than 
90% of patients (30,31).  
Additional rationale for the current trial was generated when the closely related 
analogue thalidomide was shown to improve TTP in another trial of SMM, but its 
use was limited by the development of peripheral neuropathy (25).  
The risk of deep vein thrombosis (DVT) with lenalidomide is one concern; 
however this risk appears to be limited to patients receiving high dose 
dexamethasone plus lenalidomide;(41) the risk does not seem to be increased 
when lenalidomide is used as a single-agent (42) or when the drug is used in 
combination with lower doses of dexamethasone (41).  
Lenalidomide has anti-angiogenic and immunomodulatory properties (43). 
Therapy targeted against angiogenesis presents an exciting, new and possibly 
less toxic way to treat malignant disease. There is evidence that increased bone 
marrow angiogenesis occurs in myeloma and is correlated with the plasma cell 
labeling index (PCLI; a measure of plasma cell proliferative activity) (44,45). 
Angiogenesis has also been shown to be a powerful prognostic factor in newly 
diagnosed MM, and it increases as patients progress from asymptomatic to 
symptomatic disease (24,46,47). 
To better study the risks of lenalidomide in this asymptomatic patient population, 
we have built in a pilot phase prior to the start of the randomized phase of the 
trial. 
1.5 
Rationale and Hypothesis for Current Study 
Over the years due to lack of effective therapy, patients with SMM have been 
observed without therapy. However, with the discovery of new active agents, the 
time has come to test therapeutic intervention in asymptomatic MM with the goal 
of delaying progression to symptomatic MM because of the following reasons:  
i) Once symptomatic, MM is incurable, and symptoms from MM such as bone 
fractures can be debilitating. Patients with asymptomatic MM who will be 
considered for this study will be at high risk of progression to symptomatic 
MM. The median time to progression is approximately 18 months in patients 
who have no bony lesions.(19) The presence of bone lesions on skeletal 
survey or magnetic resonance imaging greatly increases the risk of 
progression in asymptomatic MM.(9, 20-22) Patients with abnormal 
peripheral blood monoclonal plasma cell studies defined as an increase in the 
number or proliferative rate of circulating plasma cells by immunofluorescent 
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assays are at higher risk for earlier progression to myeloma. In a study of 57 
patients, we found the median time to progression was 9 months for those 
with abnormal peripheral blood monoclonal plasma cell studies versus 30 
months for those with normal studies.(P <0.01)) (19). More recently, the 
serum free light chain (FLC) ratio has been shown to be a significant adverse 
predictor of outcome, and the test is widely available. Patients with bone 
marrow plasma cells 10% or more and an abnormal FLC ratio have a median 
progression free survival (PFS) of 2.3 years, and a 2 year PFS rate of 58.5% 
(23). 
ii) As discussed later, progression to symptomatic MM likely involves an 
angiogenic switch, similar to the progression of in-situ carcinomas to an 
invasive phenotype (8, 24). Thus there is mechanistic rationale for anti-
angiogenic agents such as lenalidomide to delay progression. 
iii) There is strong preliminary data from a phase II trial at Mayo Clinic that the 
related agent thalidomide is effective in asymptomatic MM with evidence 
suggesting a delay in time to progression based on historical controls (25). 
iv) Single agent lenalidomide is an attractive new option that is ideally suited for 
testing in asymptomatic MM (6, 26).  The drug does not appear to have much 
of the non-hematologic side-effects that have been a problem with the use of 
thalidomide in this population such as peripheral neuropathy (6,27,28). It has 
shown remarkable activity in relapsed and newly diagnosed MM (29,30). 
Lenalidomide is orally administered making it convenient for long term 
therapy in an asymptomatic population. Incidentally, there is remarkable 
interest in this agent as initial therapy as evidenced by the rapid accrual to 
ECOG E4A03 trial with lenalidomide in newly diagnosed MM. 
v) There is evidence from Mayo and ECOG studies that therapy with 
lenalidomide does not adversely affect stem cell collection (30-32). Some 
reports have found problems with stem cell mobilization with growth factors 
alone (33), which is resolved with the use of growth factor plus 
cyclophosphamide (34). This appears to be an effect of lenalidomide on 
adhesion molecules, rather than toxicity to stem cells since patients can 
successfully mobilize with cyclophosphamide (34, 35).  
vi) Given the toxicity of stem cell transplantation and current MM therapy, and 
given the destructive bone lesions that characterize MM, there is a strong 
patient demand for novel therapeutic options that would delay progression to 
symptomatic MM, rather than observation without therapy. 
Patients and physicians alike desire a way to delay progression in patients with 
SMM. Currently, such patients are observed without therapy even though the risk 
of progression is high. Symptomatic MM has a median survival of 3–4 years and 
is associated with significant morbidity from destructive bone lesions, renal 
failure, and infections. Therapy includes aggressive chemotherapy regimens 
including stem cell transplantation, but is not curative. With the advent of new, 
non-cytotoxic agents with novel mechanisms of action that target critical steps in 
MM pathogenesis, there is a great need for clinical trials using these agents. 
There is little question whether lenalidomide can induce responses in patients 
with SMM. The more important end-point is demonstration of a superior PFS with 
lenalidomide compared to observation, especially considering the costs and 
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necessary. Overall survival differences between lenalidomide and observation 
need to be studied; however, overall survival as a primary end-point has become 
unrealistic given the rapid advances in new therapeutic options available to 
patients at the time of relapse, and the protracted time it would take to complete 
in patients with SMM in which the median overall survival is likely to be in excess 
of seven years. 
We are confident that this phase III trial will be successful in improving 
progression-free survival of SMM (the primary endpoint), and further, will have 
the potential to effect a paradigm shift in the treatment of early stage MM. If the 
endpoints of the trial are successfully met, the benefits of therapy far outweigh 
the risks. There is strong preliminary data supporting a role for use of 
lenalidomide in this setting, a therapy that overcomes much of the limitations 
previously seen with agents like thalidomide, melphalan, or corticosteroids. In 
sum, per detailed discussions with NCI/CTEP and various cooperative groups, 
this trial is felt to be of major importance and will be done collaboratively by 
ECOG-ACRIN and SWOG. 
1.5.1 
Modifications in Addendum #8: 
In Addendum #8, we are modifying the inclusion criteria in response 
to emerging data in the smoldering MM arena. The first modification is 
to relax the free light entry criteria. We are continuing to exclude 
patients with a normal free light ratio as they have a very low risk of 
conversion. However, we are now amending to allow any free light 
chain abnormality (abnormal ratio) to enroll. This change is being 
made to allow further exploration of the potential benefit of early 
treatment among patients with abnormal but not at the extremes free 
light chain ratio. The second change is to allow for patients diagnosed 
with smoldering MM to be enrolled if within 5 years of diagnosis of 
smoldering MM as opposed to 1 year. This modification is to bring our 
trial into more alignment with what is being reported by the PETHEMA 
group in their current high risk smoldering clinical trial. Research on 
the natural history of SMM published by Kyle et al (12) in an 
unselected SMM cohort show the risk of progression over the first 5 
years is 10% per year, approximately 3% per year for the next 5 years 
and 1% per year for the last 10 years. This suggests that broadening 
eligibility by years since diagnosis from 1 to 5 likely will not have a 
significant impact on PFS estimates. Additionally, patients will be 
stratified at randomization according to time since diagnosis of SMM: 
(  1 year vs. > 1 year). 
1.6 
Quality of Life Assessment  
1.6.1 
Background and Significance 
The Quality of Life (QOL) of MM patients is determined by disease 
specific symptoms and treatment specific side-effects. Patients with 
SMM participating in E3A06 are required to be asymptomatic from 
disease and must be MM specific treatment naive. Patient reported 
outcome (PRO) assessment as part of E3A06 is designed to describe 
symptoms of MM specific disease progression as well as potential 
side-effects from treatment intervention. The PRO instrument chosen 
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consists of the Functional Well Being (FWB) and Physical Well Being 
(PWB) components of the Functional Assessment of Cancer Therapy 
- General (FACT-G) (48).  This instrument has been validated 
extensively and has been incorporated into our ongoing E1A05 and 
E1A06 phase III MM treatment trials. For the purpose of a 
comprehensive, disease specific QOL assessment in symptomatic 
MM patients we will also utilize the Multiple Myeloma Subscale 
(MMS). This MM specific novel instrument, as described in detail in 
6.3.1, has been developed by interviewing MM patients, describing 
and quantifying their disease and treatment specific symptoms as well 
as by incorporating the cumulative experience of MM expert 
physicians.  
1.6.2 
Hypothesis 
We hypothesize that the combination of the functional well-being 
(FWB) and physical well-being (PWB) components of the FACT-G (14 
questions) will assess the overall functional and physical well-being 
and serious toxicities experienced by SMM patients and correlate with 
the impact of a specific treatment intervention in terms of progression 
free survival. The primary endpoint for this quality of life assessment 
is best assessed at the end of cycle 24 treatment since at this point 
patients will have experienced both acute and chronic toxicities, if any, 
and beyond two years, more and more patients will drop out due to 
disease progression. 
1.7 
Correlative Studies  
1.7.1 
Background 
Samples will be collected as in previous studies (E1A00 and E4A03) 
using the ECOG-ACRIN myeloma tumor biology kit at time of study 
entry and at time patient goes off-study. Further samples will be 
collected by SWOG (University of Arkansas and Yale University). 
Since laboratory correlative studies and sample submission are 
routinely done with ECOG-ACRIN and SWOG myeloma studies, we 
have a well organized system for sample submission and processing. 
Studies will be supported by existing ECOG-ACRIN R01 grants to 
Drs. Rajkumar and Fonseca, and existing SWOG laboratory grants. 
Correlative studies will be headed by Madhav Dhodapkar and Joshua 
Epstein from SWOG (immune function studies and GEP studies), and 
Rafael Fonseca from ECOG-ACRIN (IgH translocations). As 
discussed earlier, we have shown that certain biologic characteristics 
such as angiogenesis are increased in MM,(8, 46) and decreases with 
response following thalidomide therapy (49).  We have shown myeloma 
cells express the various cytokines such as basic fibroblast growth 
factor (bFGF) and vascular endothelial growth factor (VEGF) (50,51). 
We have also found that response to thalidomide may be determined 
by underlying specific cytogenetic abnormalities (primary IgH 
translocations) (52). We have expertise with the assays planned 
including GEP studies, studies of immune function, detecting IgH 
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immunohistochemistry, quantitative RT-PCR and Western blotting, and 
FISH (8, 46, 50, 51, 53-59).  
The slide based bone marrow plasma cell labeling index (PCLI) is 
now being determined by a cytometric flow procedure (PCPRO). This 
technique provides identification of clonal plasma cells and cells in S-
phase of the cell cycle. 
Circulating plasma cells will be assessed by a CD38/CD45 
immunofluorescence flow cytometry assay. 
The Beta-2-Microglobulin levels are ascertained using an automated 
system based on nephelometry. 
1.7.2 
Gene Expression Profiling 
Studies from the Epstein lab have shown that GEP of tumor cells can 
provide valuable insights into the genetic heterogeneity in MM. Three 
aspects of these studies are of particular interest in this trial 
(57,58,60):  
· 
GEP based Molecular subtypes of MM (60) 
· 
MGUS-Like versus non-MGUS-Like subtype of MM (58) 
· 
MM associated microenvironment genes (58) 
Preliminary studies from Little Rock have identified genes differentially 
expressed in the microenvironment between MGUS and MM, and 
differential response to therapy based on baseline GEP subtype. The 
GEP obtained at baseline will be used to assess whether specific 
subtypes of MM are more or less likely to achieve clinical response to 
lenalidomide therapy.  
1.7.3 
Immune Function 
This trial provides an important opportunity to evaluate the changes in 
immune function as a result of lenalidomide therapy in early myeloma. 
Lenalidomide was developed in part due to its capacity to mediate 
greater co-stimulation of T cells compared to the parent compound, 
thalidomide. Several groups have now documented that progression 
of MGUS to MM is associated with changes in the function of both 
innate as well as adaptive immune effector cells. The underlying 
hypothesis is that lenalidomide will favorably impact these responses 
and this will correlate with clinical benefit in terms of PFS. Analyses of 
immune function will be carried out in the Dhodapkar lab, which has 
considerable experience with such studies. Certain aspects of 
immune response are of particular interest in this trial: 
· 
Changes in NK and NKT number and activation 
· 
Changes in effector (Th1, Th17), and regulatory (FOXP3+ tregs) T 
cells 
· 
Changes in antigen specific immunity, particularly against stem 
cell associated antigens (e.g., SOX-2), shown to correlate with 
favorable outcome in these patients 
· 
Changes in dendritic cell subsets 
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1.7.4 
Radiologic Studies (MRI) 
Historical experience dictates the use of skeletal surveys as baseline 
radiological evaluation for patients with plasma cell disorders. While 
these studies are useful in some patients, their overall sensitivity is 
not as good as that seen with CT scans, MRI, or PET scans. Because 
one of the criteria for having symptomatic myeloma is based upon the 
presence of bone disease, more sensitive testing may be of value. 
Additionally, it is important to distinguish between patients that have 
bone marrow involvement from SMM or MM vs. bone involvement 
from MM. Data from the Arkansas group has demonstrated that the 
presence of focal MRI lesions that harbor residual disease has 
independent prognostic implications.  However, an analysis from 
Dimopolus et al demonstrated that even if the bone marrow signal 
was evaluated (focal vs. diffuse involvement) there were prognostic 
implications for patients with symptomatic myeloma. These 
observations suggest that there may be clinical utility to evaluating the 
role of MRI in predicting outcome among a group of asymptomatic 
myeloma patients. 
1.7.5 
Cytogenetic Abnormalities 
It is our hypothesis that the different genetic subtypes of the disease 
will be associated with differential risk of progression from SMM to 
MM. In general, the high-risk genetic categories in MM fall into one of 
three genetic subtypes: t(4;14)(p16;q32), t(14;16)(q32;q23), and those 
having 17p deletions. These three groups we have collectively called 
“High-Risk MM” (HR-MM). Patients with HR-MM tend to be slightly 
younger in age and present with less bone disease, and more 
frequently IgA subtype MM (a known predictor of progression from 
MGUS to MM). It is then that we believe that HR-MM genetic 
changes, when present in MGUS or SMM, will dictate a slightly higher 
risk of progression per year. Over the course of several years, this 
might dictate that HR-MM genetic lesions in SMM dictate progression 
earlier in life, and hence the younger age of presentation for MM with 
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2. 
Objectives 
2.1 
Phase II 
2.1.1 
Primary Objective 
2.1.1.1 
To study the risk of grade 3 adverse events that effect vital 
organ function (such as cardiac, hepatic or 
thromboembolic) or any grade 4 or higher non-hematologic 
adverse events among patients receiving lenalidomide as 
treatment for high-risk asymptomatic, smoldering multiple 
myeloma.  
2.1.2 
Secondary Objectives 
2.1.2.1 
To assess the response to therapy of patients treated with 
lenalidomide as treatment for asymptomatic, smoldering 
multiple myeloma.  
2.1.3 
Correlative Objectives 
2.1.3.1 
To describe the cohort in terms of GEP and cytogenetic 
risk classification and evaluate baseline immune and MRI 
parameters. 
2.2 
Phase III 
2.2.1 
Primary Objectives 
2.2.1.1 
To compare progression free survival where failure is 
defined as death or the development of symptomatic 
myeloma indicating treatment between patients receiving 
lenalidomide versus observation alone in high-risk 
asymptomatic, smoldering multiple myeloma. 
2.2.2 
Secondary Objectives  
2.2.2.1 
To determine and compare the response rate, time to 
progression, 1-year progression-free survival probability, 
and overall survival between patients randomized to 
receive lenalidomide or observation in the setting of 
asymptomatic myeloma.     
2.2.2.2 
To estimate the incidence of adverse events in patients 
receiving lenalidomide therapy for early-stage multiple 
myeloma. 
2.2.3 
Correlative Objectives  
2.2.3.1 
To evaluate the impact of therapy within GEP-defined risk 
groups and GEP as a prognostic marker. 
2.2.3.2 
To study the effects of lenalidomide on laboratory markers 
of immune function. 
2.2.3.3 
To study the prognostic value of MRI detected 
asymptomatic bone disease on clinical outcome. 
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2.2.3.4 
To evaluate the prognostic effect of baseline high-risk 
cytogenetic abnormalities on clinical outcome. 
2.3 
Quality of Life Assessment Objectives  
2.3.1 
To compare QOL change between treatment and observation arms 
based on the functional (FWB) and physical (PWB) well-being 
components of the FACT-General (G) patient-reported outcome 
(PRO) measure from registration (prior to initiation of treatment) up to 
cycle 24. 
2.3.2 
To examine the impact of differential treatment response (PFS), if 
observed, on QOL based on the FACT FWB+PWB up to cycle 48. 
2.3.3 
To obtain prospective data on Myeloma specific QOL attributes, 
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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date _________________________________________ 
NOTE: 
All questions regarding eligibility should be directed to the study chair or 
study chair liaison. 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician.  
NOTE: 
This study involves pre-registration (see Section 4).  Bone marrow and 
peripheral blood specimens are to be submitted for defined laboratory 
research studies and future undefined research studies as outlined in Section 
10 per patient consent. 
3.1 
Eligibility Criteria 
3.1.1 
Age ≥ 18 years. 
3.1.2 
Patients must be diagnosed with asymptomatic high-risk smoldering 
multiple myeloma (SMM) within the past 60 months, as confirmed by 
both of the following: 
1) Bone marrow plasmacytosis with ≥ 10% plasma cells or sheets of 
plasma cells at any time before initiating study treatment, including 
a marrow which must be obtained by bone marrow aspiration 
and/or biopsy within 4 weeks prior to randomization.  
If plasmacytosis, % plasma cells: _____ Date: ___________  
If sheets of plasma cells, Date: _____________  
2) Abnormal serum free light chain ratio (< 0.26 or > 1.65) by serum 
FLC assay. FLC assay must be performed within 28 days of 
randomization.   
Serum Free Light Chain Ratio ________ Date of Test _________ 
3.1.3 
Patients must have measurable levels of monoclonal protein (M-
protein): ≥ 1g/dL on serum protein electrophoresis or ≥ 200 mg of 
monoclonal protein on a 24 hour urine protein electrophoresis which 
must be obtained within 4 weeks prior to randomization.  
Both SPEP and UPEP are required to be performed within 28 days 
prior to randomization.  
Serum M-protein by SPEP __________ (g/dL) Date of Test:________ 
______ 
______ 
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Urine M-protein light chain excretion by UPEP_____(mg/24hr)  
Date of Test: ________  
NOTE: 
UPEP (on a 24-hour collection) is required, no substitute 
method is acceptable. Urine must be followed monthly if 
the baseline urine M-spike is ≥ 200 mg/24 hr. Please note 
that if both serum and urine M-components are present, 
both must be followed in order to evaluate response. 
3.1.4 
Patients must have no lytic lesions on skeletal surveys and no 
hypercalcemia (i.e., ≥ 11 mg/dL). 
3.1.5 
The following laboratory levels must be obtained within four weeks 
prior to randomization:  
3.1.5.1 
 Hemoglobin ≥ 11 g/dL.  
Hemoglobin: __________Date:__________ 
3.1.5.2 
Platelet count ≥ 100,000 cells/mm3. 
Platelet:__________ Date:__________ 
3.1.5.3 
Absolute neutrophil count ≥ 1500 cells/mm3.  
ANC:__________ Date:__________  
3.1.5.4 
Calculated creatinine clearance ≥ 30 mL/min.  
Creatinine clearance:__________ Date:__________  
3.1.5.5 
Bilirubin   1.5 mg/dL.  
Bilirubin:__________ Date:__________  
3.1.5.6 
SGPT (ALT) and SGOT (AST)   2.5 times the upper limit 
of normal.  
SGPT (ALT):________ ULN:_________ Date:__________ 
SGOT (AST):________ ULN:________ Date:__________ 
3.1.6 
No prior or concurrent systemic or radiation therapy for the treatment 
of myeloma.  
3.1.7 
Concurrent use of bisphosphonates is not permitted. However, prior 
bisphosphonates or once-a-year intravenous bisphosphonate given 
for the treatment of osteoporosis is permitted. 
3.1.8 
Prior or concurrent use of erythropoietin is disallowed. 
3.1.9 
Prior glucocorticosteroid therapy for the treatment of multiple 
myeloma is not permitted.  
3.1.10 
Prior systemic glucocorticosteroid use for the treatment of non-
malignant disorders is permitted; concurrent use after registration on 
the study should be restricted to the equivalent of prednisone 10 mg 
per day.  
3.1.11 
Prior or concurrent topical or localized glucocorticosteroid therapy to 
treat non-malignant comorbid disorders is permitted.  
3.1.12 
Patients must not have active, uncontrolled seizure disorder. Patients 
must have had no seizures in the last 6 months. 
______ 
______ 
______
______
______
______
______
______
______ 
______ 
______
______
______
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3.1.13 
Patients must not have uncontrolled intercurrent illness including 
uncontrolled hypertension, symptomatic congestive heart failure, 
unstable angina, uncontrolled cardiac arrhythmia, uncontrolled 
psychiatric illness or social situation that would limit compliance with 
the study, or a prior history of Stevens Johnson Syndrome. 
3.1.14 
ECOG performance status 0, 1, or 2. 
3.1.15 
Patients must not have baseline bone lesions or plasmacytomas. 
3.1.16 
Patients with monoclonal gammopathy of undetermined significance 
are not eligible. 
3.1.17 
Patients must not have Grade 2 or higher peripheral neuropathy. 
3.1.18 
Patients must not have active, uncontrolled infection. 
3.1.19 
Patients may have a history of current or previous deep vein 
thrombosis or pulmonary embolism but are required to take some 
form of anti-coagulation as prophylaxis if they are not currently on full-
dose anticoagulation. 
3.1.20 
Patients should not have New York Heart Association classification III 
or IV heart failure. 
3.1.21 
Patients with a history of prior malignancy are eligible provided they 
were treated with curative intent and have been free of disease for the 
time period considered appropriate for cure of the specific cancer. For 
most diseases this time frame is 5 years. 
3.1.22 
Patients should not be felt to have an immediate need for 
chemotherapy. 
3.1.23 
Females of childbearing potential (FCBP) must have a negative 
serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL 
within 10 – 14 days prior to and again within 24 hours of starting cycle 
1 of lenalidomide and must either commit to continued abstinence 
from heterosexual intercourse or begin TWO acceptable methods of 
birth control, one highly effective method and one additional effective 
method AT THE SAME TIME, at least 28 days before she starts 
taking lenalidomide. FCBP must also agree to ongoing pregnancy 
testing. Men must agree to use a latex condom during sexual contact 
with a FCBP even if they have had a successful vasectomy. 
A FCBP 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).  All 
patients must be counseled by a trained counselor every 28 days 
about pregnancy precautions and risks of fetal exposure. (See 
Appendix VI: Risks Associated with Pregnancy and also Appendix 
VII: Lenalidomide Education and Counseling Guidance Document). 
Female of childbearing potential (Y/N)? _______   
Date of Test: _________ 
______ 
______ 
______ 
______ 
______ 
______ 
______ 
______ 
______ 
______ 
______ 
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3.1.24 
HIV infection is not excluded. HIV+ patients must meet the following 
criteria: 
· 
CD4 cell count ≥ 350/mm3 
· 
No history of AIDS-related illness 
· 
Not currently prescribed zidvoudine or stavudine 
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4. 
Registration Procedures 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all investigators participating in any NCI-sponsored clinical trial to register 
and to renew their registration annually. 
Registration requires the submission of: 
· 
a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature 
· 
a current Curriculum Vitae (CV) 
· 
a completed and signed Supplemental Investigator Data Form (IDF) 
· 
a completed Financial Disclosure Form (FDF) with an original signature 
Fillable PDF forms and additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>.  For 
questions, please contact the CTEP Investigator Registration Help Desk by email at 
<pmbregpend@ctep.nci.nih.gov>. 
CTEP Associate Registration Procedures / CTEP-IAM Account 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) application is a web-based application intended for use by both Investigators (i.e., 
all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates 
(i.e., all staff involved in the conduct of NCI-sponsored clinical trials). 
Associates will use the CTEP-IAM application to register (both initial registration and 
annual re-registration) with CTEP and to obtain a user account. 
Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering with 
CTEP as an Investigator, which must be completed before a CTEP-IAM account can be 
requested.) 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU 
(Cancer Trials Support Unit) websites and applications, including the CTSU members’ 
website. 
Additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>.  For questions, 
please contact the CTEP Associate Registration Help Desk by email at 
<ctepreghelp@ctep.nci.nih.gov>. 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients. Study centers can 
check the status of their registration packets by querying the Regulatory Support System 
(RSS) site registration status page of the CTSU member web site by entering credentials 
at https://www.ctsu.org. For sites under the CIRB initiative, IRB data will automatically 
load to RSS.Submitting Regulatory Documents 
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Downloading Site Registration Documents:   
Site registration forms may be downloaded from the E3A06 protocol page located on the 
CTSU members’ website.   
· 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
· 
Click on the Protocols tab in the upper left of your screen 
· 
Click on the ECOG-ACRIN link to expand, then select trial protocol E3A06 
· 
Click on the Site Registration Documents link 
Requirements for E3A06 site registration: 
· 
CTSU IRB Certification (for sites not participating via the NCI CIRB) 
· 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the 
NCI CIRB) 
Submitting Regulatory Documents 
Submit completed forms along with a copy of your IRB Approval and Model Informed 
Consent to the CTSU Regulatory Office, where they will be entered and tracked in the 
CTSU RSS. 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone: 1-866-651-2878 
FAX: (215) 569-0206 
E-mail: CTSURegulatory@ctsu.coccg.org (for regulatory document 
submission only) 
Required Protocol Specific Regulatory Documents 
1. 
CTSU Regulatory Transmittal Form. 
2. 
Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information 
concerning risks or alternative procedures contained in the 
sample informed consent document must be justified in writing 
by the investigator and approved by the IRB. 
3. 
A.  
CTSU IRB Certification Form. 
 
Or 
B.  
Signed HHS OMB No. 0990-0263. 
 
Or 
 
C.  
IRB Approval Letter 
NOTE: 
The above submissions must include the following details: 
· 
Indicate all sites approved for the protocol under an assurance 
number. 
· 
OHRP assurance number of reviewing IRB 
· 
Full protocol title and number 
· 
Version Date 
· 
Type of review (full board vs. expedited) 

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· 
Date of review. 
· 
Signature of IRB official 
Checking Your Site’s Registration Status: 
Check the status of your site’s registration packets by querying the RSS site registration 
status page of the members’ section of the CTSU website.  (Note: Sites will not receive 
formal notification of regulatory approval from the CTSU Regulatory Office.) 
· 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
· 
Click on the Regulatory tab at the top of your screen 
· 
Click on the Site Registration tab 
· 
Enter your 5-character CTEP Institution Code and click on Go 
Patient Enrollment 
Patients must not start protocol treatment prior to registration. 
Treatment should start within seven working days after registration. 
Patient registration can occur only after pre-treatment evaluation is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS. 
Patients must have signed and dated all applicable consents and authorization forms. 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis. To access 
OPEN, the site user must have an active CTEP-IAM account (check at <https://eapps-
ctep.nci.nih.gov/iam/index.jsp>) and a 'Registrar' role on either the LPO or participating 
organization roster. 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the website 
at https://www.ctsu.org. 
Prior to accessing OPEN site staff should verify the following: 
· 
All eligibility criteria have been met within the protocol stated timeframes.  
· 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable).  
NOTE:  
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records.  
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
4.1 
Pre-Registration 
NOTE: 
Patients who are only pre-registered must not begin treatment.  
The following information will be requested at time of randomization: 
4.1.1 
Protocol Number  
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4.1.2 
Investigator Identification  
4.1.2.1 
Institution and affiliate name (Institution CTEP ID) 
4.1.2.2 
Investigator’s name (NCI number) 
4.1.2.3 
Cooperative Group Credit 
4.1.2.4 
Credit Investigator 
4.1.2.5 
Protocol specific contact information 
4.1.3 
Patient Identification  
4.1.3.1 
Patient’s initials (first and last) 
4.1.3.2 
Patient’s Hospital ID and/or Social Security number 
4.1.3.3 
Patient demographics 
4.1.3.3.1 
Gender 
4.1.3.3.2 
Birth date 
4.1.3.3.3 
Race 
4.1.3.3.4 
Ethnicity 
4.1.3.3.5 
Nine-digit ZIP code 
4.1.3.3.6 
Method of payment 
4.1.3.3.7 
Country of residence 
4.1.3.4 
Additional Requirements 
4.1.3.4.1 
Patients must provide a signed and dated 
written informed consent form.  
4.1.3.4.2 
Bone marrow and peripheral blood 
specimens are to be submitted at pre-
registration for defined laboratory research 
studies and future undefined research 
studies as outlined in Section 10 per patient 
consent.  
4.2 
Registration 
The following information will be requested at the time of registration.  
4.2.1 
Protocol Number  
4.2.2 
Investigator Identification  
4.2.2.1 
Institution and affiliate name (Institution CTEP ID) 
4.2.2.2 
Investigator’s name (NCI number) 
4.2.2.3 
Cooperative Group Credit 
4.2.2.4 
Credit Investigator 
4.2.2.5 
Protocol specific contact information 
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4.2.3 
Patient Identification  
4.2.3.1 
Patient’s initials (first and last) 
4.2.3.2 
Patient’s  Hospital ID and/or Social Security number 
4.2.3.3 
Patient demographics 
4.2.3.3.1 
Gender 
4.2.3.3.2 
Birth date 
4.2.3.3.3 
Race 
4.2.3.3.4 
Ethnicity 
4.2.3.3.5 
Nine-digit ZIP code 
4.2.3.3.6 
Method of payment 
4.2.3.3.7 
Country of residence 
4.3 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 3.0.  A 
registration worksheet has been appended to the protocol.  A confirmation of 
registration and patient labels will be forwarded by the ECOG-ACRIN Operations 
Office - Boston. 
4.4 
Additional Requirements  
4.4.1 
Patients must provide a signed and dated, written informed consent 
form. 
4.4.2 
Peripheral blood and bone marrow should be submitted for correlative 
studies and/or banking as indicated in Section 10 per patient consent. 
NOTE:  
ECOG-ACRIN requires that biological samples submitted 
from patients participating in E3A06 be entered and 
tracked via the online ECOG-ACRIN Sample Tracking 
System (STS). See Section 10.5. 
NOTE: 
Institutions outside of the United States and Canada must 
confer with the receiving laboratory and the ECOG-ACRIN 
Operations Office - Boston regarding logistics for 
submission of fresh samples. 
4.5 
Stratification Factors 
4.5.1 
Time Since Smoldering Multiple Myeloma Diagnosis:   1 year vs. > 1 
year. 
4.6 
Instructions for Patients who Do Not Start Assigned Protocol Treatment  
If a patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted according to the 
instructions in the E3A06 Forms Packet. Document the reason for not starting 
protocol treatment on the off treatment form. Also report the date and type of the 
first non-protocol treatment that the patient receives. 
Rev. 2/12 
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5. 
Treatment Plan 
5.1 
Administration Schedule 
5.1.1 
Arm A Lenalidomide* 
Lenalidomide 25 mg by mouth days 1-21 every 4 weeks (28 days). 
Aspirin (or alternative prophylaxis) days 1-28 for each treatment cycle. 
Suggested dose is 325 mg/day, however the dose is at the discretion 
of the treating physician. Alternative dosing of 75mg/day or higher is 
acceptable provided the patient is at low risk of thrombosis. 
All patients on Arm A are required to receive prophylaxis against 
thrombosis. For patients in Arm A, physicians should consider 
prophylaxis with aspirin alone as studies with single agent 
lenalidomide in the setting of relapsed disease show a relatively low 
incidence of thrombosis (< 5%). See Section 5.5.2.1 for acceptable 
alternative prophylaxis. 
Treatment continues until progression to symptomatic myeloma or 
discontinuation due to toxicity. 
For patients with CrCl 30-60 mL per minute, lenalidomide dose is 10 
mg per day for days 1-21 every 28 days. Creatinine clearance (CLcr) 
can either be measured CLcr or estimated by the Cockcroft-Gault 
method: {[140 – age (yrs)] × [lesser of IBW (kg) or actual weight (kg)]} 
/ [72 × serum creatinine (mg/dL)]; multiply by another factor of 0.85 if 
female. 
* NOTE: 
The first 44 patients to accrue will be placed on Arm A 
without randomization (Phase II). 
5.1.2 
Arm B Observation  
Observation continues until progression to symptomatic myeloma. 
5.2 
Adverse Event Reporting Requirements 
NOTE: 
Effective April 1, 2018 all expedited adverse event reporting done 
via CTEP-AERS will use CTCAE version 5.0 terminology and 
grading. Routine adverse event reporting and dose modifications 
guidelines for this study will continue to be based on CTCAE 
version 4.0 terminology and grading. 
5.2.1 
Purpose 
Adverse event data collection and reporting, which are required as 
part of every clinical trial, are done to ensure the safety of patients 
enrolled in the studies as well as those who will enroll in future studies 
using similar agents. Adverse events are reported in a routine manner 
at scheduled times during a trial (please refer to the E3A06 Forms 
Packet for the list of forms with directions for routine adverse event 
reporting).  Additionally, certain adverse events must be reported in 
an expedited manner for more timely monitoring of patient safety and 
care. The following sections provide information about expedited 
reporting. 
Rev. 2/12, 
7/13 
Rev. 7/13 
Rev. 7/14 
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5.2.2 
Determination of reporting requirements 
Reporting requirements may include the following considerations: 1) 
whether the patient has received an investigational or commercial 
agent; 2) the characteristics of the adverse event including the grade 
(severity), the relationship to the study therapy (attribution), and the 
prior experience (expectedness) of the adverse event; 3) the phase 
(1, 2, or 3) of the trial; and 4) whether or not hospitalization or 
prolongation of hospitalization was associated with the event. 
An investigational agent is a protocol drug administered under an 
Investigational New Drug Application (IND). In some instances, the 
investigational agent may be available commercially, but is actually 
being tested for indications not included in the approved package 
label. 
Steps to determine if an adverse event is to be reported in an 
expedited manner: 
Step 1: Identify the type of event: The descriptions and grading 
scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized until March 31, 2018 for AE reporting. Effective April 
1, 2018 all expedited adverse event reporting done via 
CTEP-AERS will use CTCAE version 5.0 terminology and 
grading. All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0. A copy of the CTCAE 
version 5.0 can be downloaded from the CTEP website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_appli
cations/ctc.htm). 
Step 2: Grade the event using the NCI CTCAE version 5.0. 
Step 3: Determine whether the adverse event is related to the 
protocol therapy (investigational or commercial). Attribution 
categories are as follows: Unrelated, Unlikely, Possible, 
Probable, and Definite. 
Step 4: Determine the prior experience of the adverse event. 
Expected events are those that have been previously 
identified as resulting from administration of the agent. An 
adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the 
severity of the event is NOT listed in:  
· 
Arm A – the current NCI Specific Protocol Exceptions to 
Expedited Reporting (SPEER) for Lenalidomide  
NOTE: 
The NCI SPEER for Lenalidomide is included in 
Section 5.3 of the protocol.  
· 
FOR THIS PROTOCOL, events listed in the 
SPEER for Lenalidomide should be 
considered EXPECTED if the grade being 
reported is the same or lower than the grade 
noted in the parentheses next to the AE in the 
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SPEER.  Events listed in the SPEER column 
should be considered UNEXPECTED if the 
grade being reported exceeds the grade 
noted in parentheses next to the AE in the 
SPEER. 
· 
The SPEER is presented in the last column of 
the CAEPR and identified with bold and 
italicized text. 
Step 5: Review the ”Additional instructions, requirements, and 
exceptions for protocol E3A06” table in Section 5.2.6 for 
protocol and/or ECOG-ACRIN specific requirements for 
expedited reporting of specific adverse events that require 
special monitoring.   
NOTE: 
For general questions regarding expedited 
reporting requirements, please contact the AEMD 
Help Desk at aemd@tech-res.com or 301-897-
7497. 
5.2.3 
Reporting procedure 
This study requires that expedited adverse event reporting use 
CTEP’s Adverse Event Reporting System (CTEP-AERS). CTEP’s 
guidelines for CTEP-AERS can be found at http://ctep.cancer.gov. A 
CTEP-AERS report must be submitted electronically to ECOG-ACRIN 
and the appropriate regulatory agencies via the CTEP-AERS Web-
based application located at http://ctep.cancer.gov. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
· 
the AE Team at ECOG-ACRIN (857-504-2900) and 
· 
the NCI (301-897-7497)  
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data:  Any supporting or follow up 
documentation must be faxed to ECOG-ACRIN (617-632-2990), 
Attention: AE within 48-72 hours.  In addition, supporting or follow up 
documentation must be faxed to the NCI (301- 897-7404) in the same 
timeframe.  
NCI Technical Help Desk:  For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
5.2.4 
When to Report an Event in an Expedited Manner 
Some adverse events require 24-hour notification (refer to Section 
5.2.6). Please complete a 24-Hour Notification Report via the CTEP-
AERS website (http://ctep.cancer.gov) within 24 hours of learning of 
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the event. The full CTEP-AERS report must be completed and 
submitted via CTEP-AERS within 5 calendar days. 
If the CTEP-AERS system is down, a 24-hour notification call must be 
made to ECOG-ACRIN (857-504-2900) and to NCI (301-897-7497).  
Once the system is restored, a 24-hour Notification Report must be 
entered into the CTEP-AERS system by the original submitter of the 
report at the site. 
When an adverse event requires expedited reporting, submit a full 
CTEP-AERS report within the timeframes outlined in Section 5.2.6. 
NOTE: 
Adverse events that meet the reporting requirements in 
Section 5.2.6 and occur within 30 days of the last dose of 
protocol treatment must be reported on an expedited 
adverse event report form (using CTEP-AERS). For any 
adverse events that occur more than 30 days after the last 
dose of treatment, only those that have an attribution of 
possibly, probably, or definitely AND meet the reporting 
requirements in Section 5.2.6 must be reported on an 
expedited adverse event report form (using CTEP-AERS). 
5.2.5 
Other Recipients of Adverse Event Reports 
DCTD/NCI will notify ECOG-ACRIN/pharmaceutical collaborator(s) of 
all AEs reported to FDA. Any additional written AE information 
requested by ECOG-ACRIN MUST be submitted to BOTH the NCI 
and ECOG-ACRIN. 
Adverse events determined to be reportable must also be reported by 
the institution, according to the local policy and procedures, to the 
Institutional Review Board responsible for oversight of the patient. 
5.2.6 
Expedited reporting for investigational agents 
Phase 2 and 3 Trials Utilizing an Agent under a CTEP IND:  CTEP-
AERS Expedited Reporting Requirements for Adverse Events 
That Occur Within 30 Days1 of the Last Dose of Investigational 
Agent (CC-5013/Lenalidomide) in this Study (Arm A) OR Within 
30 Days of the Last Dose of Any Protocol Treatment. 
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Attribution 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected 
and 
Expected 
 
 
Unexpected 
 
 
Expected 
Unexpected 
Expected 
Un-
expected Expected
with  
Hospitali-
zation 
without 
Hospitali- 
zation 
with  
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 
Calendar 
Days 
10 
Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the 
last dose of treatment with an agent under a CTEP IND require reporting as follows: 
CTEP-AERS 24-hour notification followed by complete report within 5 calendar days for: 
· Grade 4 and Grade 5 unexpected events  
 
CTEP-AERS 10 calendar day report: 
· Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
· Grade 5 expected events 
2 Although a CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, a full 
report is required as outlined in the table. See NOTE below regarding how to report a death due to progressive 
disease. 
Please see additional information below under section entitled “Additional instructions, requirements, and 
exceptions for protocol E3A06” 
 
March 2005 
NOTE: 
All deaths on study or within 30 days of the last dose of treatment require both 
routine and expedited reporting regardless of causality. Attribution to treatment or 
other cause should be provided. 
NOTE: 
A death due to progressive disease should be reported as a Grade 5 “Disease 
progression” under the System Organ Class (SOC) “General disorder and 
administration site conditions”.  Evidence that the death was a manifestation of 
underlying disease (e.g. radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) should be 
submitted. 
NOTE: 
A death that occurs > 30 days after the last dose of treatment and is attributed 
possibly, probably, or definitely to the treatment must be reported within 10 calendar 
days of learning of the event. 
· 
Expedited AE reporting timelines: 
➢ 24 Hours; 5 calendar days – The investigator must initially report the AE via 
CTEP-AERS within 24 hours of learning of the event followed by a complete 
CTEP-AERS report within 5 calendar days of the initial 24-hour report. 
➢ 10 calendar days – A complete CTEP-AERS report on the AE must be 
submitted within 10 calendar days of the investigator learning of the event. 
· 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates 
hospitalization* (or prolongation of existing hospitalization) must be 
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with the exception of any events identified as protocol-specific expedited adverse 
event reporting exclusions. 
· 
Any event that results in persistent or significant disability/incapacity, 
congenital anomaly, or birth defect must be reported via CTEP-AERS if the 
event occurs following treatment with an agent under a CTEP IND. 
· 
Use the NCI protocol number and the protocol-specific patient ID provided during 
trial registration on all reports. 
* Hospitalizations are defined as lasting 24 hours or longer and these events must be reported 
via CTEP-AERS. 
Additional instructions, requirements and exceptions for protocol E3A06 
1. 
Additional Instructions: 
➢ With respect to determining the specific day by which the event must be reported, 
the day the reporter learns of the adverse event constitutes “Day 0” 
➢ For instructions on how to specifically report events that result in persistent or 
significant disability/incapacity, congenital anomaly, or birth defect events via 
CTEP-AERS, please contact the AEMD Help Desk at aemd@tech-res.com or 
301-897-7497. This will need to be discussed on a case-by-case basis. 
2. 
ECOG-ACRIN and Protocol Specific expedited reporting requirements: 
The adverse events listed below also require expedited reporting for this trial: 
ECOG-ACRIN specific expedited reporting requirements: 
➢ 
Hospitalizations:  Any grade 1 or 2 adverse event with precipitates a 
hospitalization lasting > 24 hours (or prolongs hospitalization) must be reported 
via CTEP-AERS within 10 calendar days of learning of the event regardless of 
the attribution and designation as expected or unexpected.   
➢ 
Grade 3 expected events:  Any grade 3 expected non-hematologic event, with 
an attribution of possible, probable of definite, must be reported via CTEP-AERS 
within 10 calendar days of learning of the event, regardless of whether 
hospitalization is required. 
➢ 
Pregnancies 
Pregnancies and suspected pregnancies (including a positive or inconclusive 
pregnancy test, regardless of age or disease state) occurring while the subject is 
on Lenalidomide , or within 28 days of the subject’s last dose of Lenalidomide, 
are considered immediately reportable events. The pregnancy, suspected 
pregnancy, or positive/ inconclusive pregnancy test must be reported via CTEP-
AERS within 24 hours of the Investigator’s knowledge.  Please refer to Appendix 
XIII for detailed instructions on how to report the occurrence of a pregnancy as 
well as the outcome of all pregnancies. 
3. 
Protocol specific expedited reporting exceptions: 
For study arm A, the adverse events listed below do not require expedited reporting 
via CTEP-AERS: 
➢ Grade 4 expected myelosuppresion (unless it results in a hospitalization, in which 
case, a CTEP-AERS report is required). 
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5.2.7 
Reporting Secondary AML/MDS/ALL 
All cases of second and secondary malignancies [including acute 
myeloid leukemia (AML) and myelodysplastic syndrome (MDS)], 
regardless of attribution, that occur following treatment on NCI-
sponsred trials must be reported as follows: 
1. Submit a completed Second Primary Form within 30 days to 
ECOG-ACRIN at: 
ECOG-ACRIN Operations Office - Boston 
FSTRF 
900 Commonwealth Avenue 
Boston, MA 02215 
2. Report the diagnosis via CTEP-AERS, regardless of attribution, at 
http://ctep.cancer.gov 
Report under a.) leukemia secondary to oncology chemotherapy, 
b.) myelodysplastic syndrome, c.) treatment related secondary 
malignancy, or d.) Neoplasm Other, malignant (grade 3 or 4) 
3. Submit a copy of the pathology report to ECOG-ACRIN and 
NCI/CTEP confirming the diagnosis. 
4. If the patient has been diagnosed with AML/MDS, submit a copy 
of the cytogenetics report (if available) to ECOG-ACRIN and 
NCI/CTEP. 
NOTE: 
All new malignant tumors must be reported through 
CTEP-AERS whether or not they are thought to be 
related to either previous or current treatment.  All new 
malignancies should be reported including solid 
tumors (including non-melanoma skin malignancies), 
hematologic malignancies, Myelodysplastic Syndrome 
(MDS)/Acute Myelogenous Leukemia (AML), and in situ 
tumors. 
Whenever possible, the CTEP-AERS report should include the 
following: 
· 
tumor pathology  
· 
history of prior tumors 
· 
prior treatment/current treatment including duration 
· 
any associated risk factors or evidence regarding how long the 
tumor may have been present 
· 
when and how the tumor was detected 
· 
molecular characterization or cytogenetics or the original tumor (if 
available) and of any new tumor 
· 
tumor treatment and outcome (if available).  ng non-melanoma 
skin malignancies), hematologic malignancies, Myelodysplastic 
Syndrome (MDS)/Acute Myelogenous Leukemia (AML), and in 
situ tumors. 
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· 
Whenever possible, the CTEP-AERS report should include the 
following: 
NOTE: 
The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even 
if ECOG-ACRIN was not the patient's most recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the Second Primary 
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5.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Lenalidomide 
(CC-5013, NSC 703813) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold 
and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted 
below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for further clarification. Frequency is provided based on 4081 patients. 
Below is the CAEPR for lenalidomide (CC-5013). 
NOTE: 
FOR THIS PROTOCOL, events listed in the SPEER column should 
be considered EXPECTED if the grade being reported is the same or 
lower than the grade noted in the parentheses next to the AE in the 
SPEER. Events listed in the SPEER column should be considered 
UNEXPECTED if the grade being reported exceeds the grade noted 
in parentheses next to the AE in the SPEER. 
Version 2.8, June 27, 20191 
 
Adverse Events with Possible 
Relationship to Lenalidomide (CC-5013) 
(CTCAE 5.0 Term) 
[n= 4081] 
 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 3) 
 
Blood and lymphatic 
system disorders - 
Other (pancytopenia) 
 
  
 
Febrile neutropenia 
 
  
 
Hemolysis 
 
  
CARDIAC DISORDERS 
  
 
 
Atrial fibrillation 
  
 
 
Heart failure 
  
 
 
Myocardial infarction2 
  
EAR AND LABYRINTH DISORDERS 
  
 
Vertigo 
 
  
ENDOCRINE DISORDERS 
  
 
 
Hyperthyroidism 
  
 
Hypothyroidism 
 
 Hypothyroidism (Gr 3) 
EYE DISORDERS 
  
 
Blurred vision 
 
  
 
Cataract 
 
  
Rev. 10/11, 7/14. 
10/14, 7/16 
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Adverse Events with Possible 
Relationship to Lenalidomide (CC-5013) 
(CTCAE 5.0 Term) 
[n= 4081] 
 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) Rare but Serious (<3%)  
 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
Constipation 
 
 
 Constipation (Gr 3) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
  
 
Dyspepsia 
 
  
 
Nausea 
 
 Nausea (Gr 3) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
 
Edema limbs 
 
 Edema limbs (Gr 3) 
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 3) 
 
Generalized edema 
 
  
 
Non-cardiac chest pain  
  
 
Pain 
 
  
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
 
 
Hepatobiliary disorders - 
Other (cholestasis) 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction 
  
 
 
Anaphylaxis 
  
 
 
Immune system 
disorders - Other 
(angioedema) 
  
 
 
Immune system 
disorders - Other (graft 
vs. host disease)3 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection4 
 
 Infection4 (Gr 3) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Bruising 
 
  
 
Fall 
 
  
INVESTIGATIONS 
  
 
Alanine 
aminotransferase 
increased 
 
  
 
Alkaline phosphatase 
increased 
 
  
 
Aspartate 
aminotransferase 
increased 
 
  
 
Blood bilirubin 
increased 
 
  

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Adverse Events with Possible 
Relationship to Lenalidomide (CC-5013) 
(CTCAE 5.0 Term) 
[n= 4081] 
 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) Rare but Serious (<3%)  
 
 
GGT increased 
 
  
 
Investigations - Other 
(C-Reactive protein 
increased) 
 
  
 
 
Lipase increased 
  
 
Lymphocyte count 
decreased 
 
 Lymphocyte count 
decreased (Gr 4) 
Neutrophil count 
decreased 
 
 
 Neutrophil count decreased 
(Gr 4) 
Platelet count 
decreased 
 
 
 Platelet count decreased (Gr 
4) 
 
Weight loss 
 
 Weight loss (Gr 2) 
 
White blood cell 
decreased 
 
 White blood cell decreased 
(Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
  
 
Hyperglycemia 
 
  
 
Hyperuricemia 
 
  
 
Hypocalcemia 
 
  
 
Hypokalemia 
 
  
 
Hypomagnesemia 
 
  
 
Hyponatremia 
 
  
 
Hypophosphatemia 
 
  
 
Iron overload 
 
  
 
 
Tumor lysis syndrome 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
  
 
Bone pain 
 
  
 
Generalized muscle 
weakness 
 
  
 
Muscle cramp 
 
 Muscle cramp (Gr 2) 
 
Myalgia 
 
 Myalgia (Gr 2) 
 
Pain in extremity 
 
  
 
 
Rhabdomyolysis5 
  

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Adverse Events with Possible 
Relationship to Lenalidomide (CC-5013) 
(CTCAE 5.0 Term) 
[n= 4081] 
 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) Rare but Serious (<3%)  
 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS 
AND POLYPS) 
  
 
 
Leukemia secondary to 
oncology chemotherapy6   
 
 
Myelodysplastic 
syndrome6 
  
 
 
Neoplasms benign, 
malignant and 
unspecified (incl cysts 
and polyps) - Other 
(tumor flare)7 
  
 
 
Neoplasms benign, 
malignant and 
unspecified (incl cysts 
and polyps) - Other 
(second primary 
malignancies) 
  
 
 
Treatment related 
secondary malignancy6 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
 
Depressed level of 
consciousness 
 
  
 
Dysesthesia 
 
  
 
Dysgeusia 
 
  
 
Headache 
 
  
 
Paresthesia 
 
  
 
Peripheral motor 
neuropathy 
 
  
 
Peripheral sensory 
neuropathy 
 
  
 
 
Stroke2 
  
 
Syncope 
 
  
 
Tremor 
 
  
PSYCHIATRIC DISORDERS 
  
 
Depression 
 
  
 
Insomnia 
 
 Insomnia (Gr 2) 
 
Psychiatric disorders - 
Other (mood altered) 
 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Epistaxis 
 
  
 
 
Pneumonitis 
  

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Adverse Events with Possible 
Relationship to Lenalidomide (CC-5013) 
(CTCAE 5.0 Term) 
[n= 4081] 
 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) Rare but Serious (<3%)  
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Dry skin 
 
  
 
 
Erythema multiforme 
  
 
Hyperhidrosis 
 
 Hyperhidrosis (Gr 2) 
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash maculo-papular  
 Rash maculo-papular (Gr 3) 
 
 
Skin and subcutaneous 
tissue disorders - Other 
(drug reaction with 
eosinophilia and 
systemic symptoms 
[DRESS]) 
  
 
Skin and subcutaneous 
tissue disorders - Other 
(pyoderma 
gangrenosum) 
 
  
 
 
Stevens-Johnson 
syndrome 
  
 
 
Toxic epidermal 
necrolysis 
  
SURGICAL AND MEDICAL PROCEDURES 
  
 
 
Surgical and medical 
procedures - Other 
(impaired stem cell 
mobilization)8 
  
VASCULAR DISORDERS 
  
 
Hematoma 
 
  
 
Hypertension 
 
  
 
Hypotension 
 
  
 
Peripheral ischemia 
 
  
 
Thromboembolic 
event9 
 
 Thromboembolic event9 (Gr 
3) 
 
Vasculitis 
 
  
1 This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision. The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
2 Myocardial infarction and cerebrovascular accident (stroke) have been observed in multiple myeloma 
patients treated with lenalidomde and dexamethasone. 
3 Graft vs. host disease has been observed in subjects who have received lenalidomide in the setting of 
allo-transplantation. 
4 Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
5 The rare adverse event of rhabdomyolysis has been observed with lenalidomide. The reports of 
rhabdomyolysis were confounded by concurrent use of statins and dexamethasone, concurrent viral 
and bacterial infections, trauma, and serotonin syndrome. Statins, infections, trauma, and serotonin 
syndrome are known risk factors for rhabdomyolysis. 

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6 There has been an increased frequency of secondary malignancies (SPM) including ALL, AML, and 
MDS, and certain other types of cancers of the skin and other organs in multiple myeloma (MM) 
patients being treated with melphalan, prednisone,  and lenalidomide post bone marrow transplant.  
The use of lenalidomide in cancers other than MM, shows that invasive SPMs occurred in a small 
number of patients.  Patients treated with lenalidomide should be closely followed for the occurance of 
SPMs. 
7 Serious tumor flare reactions have been observed in patients with chronic lymphocytic leukemia (CLL) 
and lymphoma. 
8 A decrease in the number of stem cells (CD34+ cells) collected from patients treated with >4 cycles of 
lenalidomide has been reported. 
9 Significantly increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), and arterial 
thrombosis has been observed in patients with multiple myeloma receiving lenalidomide with 
dexamethasone. 
10 Gastrointestinal hemorrhage includes: Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric 
hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal 
hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal 
hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the 
GASTROINTESTINAL DISORDERS SOC. 
11 Gastrointestinal obstruction includes:  Colonic obstruction, Duodenal obstruction, Esophageal 
obstruction, Ileal obstruction, Jejunal obstruction, Obstruction gastric, Rectal obstruction, and Small 
intestinal obstruction under the GASTROINTESTINAL DISORDERS SOC. 
12 Osteonecrosis of the jaw has been seen with increased frequency when lenalidomide is used in 
combination with bevacizumab, docetaxel (Taxotere®), prednisone, and zolendronic acid (Zometa®). 
NOTE: 
While not observed in human subjects, lenalidomide, a thalidomide analogue, 
caused limb abnormalities in a developmental monkey study similar to birth defects 
caused by thalidomide in humans. If lenalidomide is used during pregnancy, it may 
cause birth defects or embryo-fetal death. Pregnancy must be excluded before start 
of treatment. Prevent pregnancy during treatment by the use of two reliable methods 
of contraception. 
NOTE: 
In a trial of first line treatment of patients with chronic lymphocytic leukemia (CLL), 
single agent lenalidomide (CC-5013) increased the risk of death as compared to 
control arm (chlorambucil). 
NOTE: 
In two randomized trials of patients with multiple myeloma (MM), the addition of MK-
3475 (pembrolizumab) to a thalidomide analog plus dexamethasone, resulted in 
increased mortality. Treatment of patients with MM with a PD-1 or PD-L1 blocking 
antibody, such as MK-3475 (pembrolizumab), in combination with a thalidomide 
analog, such as lenalidomide, is not recommended outside of controlled clinical 
trials. 
NOTE: 
In a clinical trial in patients with Mantle cell lymphoma (MCL), there was an increase 
in early deaths (within 20 weeks); 12.9% in the lenalidomide (CC-5013) arm vs. 7.1% 
in the control arm. 
Adverse events reported on lenalidomide (CC-5013) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that lenalidomide 
(CC-5013) caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - 
Other (monocytosis); Disseminated intravascular coagulation; Eosinophilia 
CARDIAC DISORDERS - Atrial flutter; Atrioventricular block first degree; Cardiac arrest; 
Cardiac disorders - Other (cardiovascular edema); Cardiac disorders - Other (ECG 

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abnormalities); Chest pain - cardiac; Left ventricular systolic dysfunction; Palpitations; 
Pericarditis; Sinus bradycardia; Sinus tachycardia; Supraventricular tachycardia; Ventricular 
tachycardia 
EAR AND LABYRINTH DISORDERS - Tinnitus 
ENDOCRINE DISORDERS - Cushingoid 
EYE DISORDERS - Dry eye; Flashing lights; Retinopathy 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal mucositis; Ascites; Colonic 
perforation; Dysphagia; Flatulence; Gastroesophageal reflux disease; Gastrointestinal disorders 
- Other (Crohn's disease aggravated); Gastrointestinal disorders - Other (diverticulitis); 
Gastrointestinal disorders - Other (pale feces); Gastrointestinal hemorrhage10; Gastrointestinal 
obstruction11; Ileus; Mucositis oral; Pancreatitis; Rectal mucositis; Small intestinal mucositis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Malaise; Multi-organ 
failure 
HEPATOBILIARY DISORDERS - Cholecystitis 
INFECTIONS AND INFESTATIONS - Conjunctivitis; Infections and infestations - Other 
(opportunistic infection associated with >=Grade 2 Lymphopenia); Myelitis 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fracture; Hip fracture; 
Vascular access complication 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Cholesterol high; 
Creatinine increased; Electrocardiogram QT corrected interval prolonged; INR increased; 
Investigations - Other (hemochromatosis) 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperkalemia; 
Hypoglycemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Chest wall pain; 
Joint effusion; Muscle weakness lower limb; Neck pain; Osteonecrosis of jaw12 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Dysphasia; Edema cerebral; 
Encephalopathy; Intracranial hemorrhage; Ischemia cerebrovascular; Leukoencephalopathy; 
Memory impairment; Nervous system disorders - Other (hyporeflexia); Spinal cord compression; 
Seizure; Somnolence; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Psychosis 
RENAL AND URINARY DISORDERS - Urinary frequency; Urinary incontinence; Urinary tract 
pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Reproductive system and breast 
disorders - Other (hypogonadism); Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress 
syndrome; Allergic rhinitis; Atelectasis; Bronchopulmonary hemorrhage; Hypoxia; Laryngeal 
mucositis; Pharyngeal mucositis; Pleural effusion; Pulmonary hypertension; Respiratory failure; 
Tracheal mucositis; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Nail loss; Photosensitivity; 
Rash acneiform; Skin and subcutaneous tissue disorders - Other (Sweet’s Syndrome); Urticaria 
VASCULAR DISORDERS - Hot flashes; Phlebitis; Vascular disorders - Other (hemorrhage 
NOS) 
NOTE: 
Lenalidomide (CC-5013) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, 

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or the combination may result in events never previously associated with either 
agent. 
 

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5.4 
Dose Modifications 
Dose modifications are based on adverse events which are possibly, probably or 
definitely related to drug.   
All toxicity grades below are described using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. 
All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP website (http://ctep.cancer.gov). 
Lenalidomide Treatment Adjustment 
See Table below for Lenalidomide Treatment Adjustment Steps  
Lenalidomide (CC-5013) Treatment Adjustment Steps 
Starting Dose 
25 mg daily for 21 days every 28 days 
Dose Level -1 
15 mg daily for 21 days every 28 days 
Dose Level -2 
10 mg daily for 21 days every 28 days 
Dose Level -3 
5 mg daily for 21 days every 28 days 
Subjects experiencing  grade 3 adverse events will have their study drug held 
until resolution of the AE. Subjects experiencing grade 3/4 AEs prior to Day 15 of 
a cycle will need to hold lenalidomide. If AE improves to grade 1 or less prior to 
Day 21, lenalidomide should be restarted with a one dose level reduction for the 
remainder of the cycle. The next cycle will then continue with this reduced dose 
level. For grade 3 or 4 AEs which occur on or after Day 15 of a cycle, the 
subject’s study drug is to be held for the remainder of the cycle and will be 
reduced by one dose level beginning with the next cycle. Once a subject’s dose 
has been reduced, no dose-re-escalation is permitted. 

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Lenalidomide (CC-5013) Dose modifications based on adverse events (Arm A) 
NCI CTC AE Grade  
At retreatment* and Day 2-14 of Cycle 
≥ Day 15 of Cycle  
Sustained (≥ 7 days) 
Grade 3 neutropenia or 
≥ Grade 3 neutropenia 
associated with fever 
(temperature ≥ 38.5º C) 
or Grade 4 neutropenia 
Hold (interrupt dose) and follow CBC weekly. If 
the toxicity resolves to baseline or   g rade 1 prior 
to Day 21 restart at next lower dose level and 
continue the cycle until Day 21. 
Omit lenalidomide for remainder 
of cycle. If toxicity resolves, restart 
lenalidomide next cycle with a 
decrease in dose by one dose 
level. 
Thrombocytopenia 
≥ Grade 3 (platelet count 
< 50,000/mm³) 
 
Hold (interrupt dose) and follow CBC weekly. If 
the toxicity resolves to baseline or   g rade 1 prior 
to Day 21 restart at next lower dose level and 
continue the cycle until Day 21. 
Omit lenalidomide for remainder 
of cycle. If toxicity resolves, restart 
lenalidomide next cycle with a 
decrease in dose by one dose 
level. 
Non-blistering rash 
Grade 2-3 
Hold (interrupt) dose and follow. If the toxicity 
resolves to   grade 1 prior to Day 21 restart at next 
lower dose level and continue the cycle until Day 
21. 
Omit lenalidomide for remainder 
of cycle. If toxicity resolves, restart 
lenalidomide next cycle with a 
decrease in dose by one dose 
level. 
Grade 4 
Discontinue lenalidomide and do not resume. 
Discontinue lenalidomide and do 
not resume. 
Desquamating 
(blistering) rash - any 
Grade 
Discontinue lenalidomide. 
Discontinue lenalidomide and do 
not resume. 
Erythema multiforme ≥ 
Grade 3 
Discontinue lenalidomide. 
Discontinue lenalidomide and do 
not resume. 
Sinus bradycardia/ other 
cardiac Arrhythmia 
Grade 2 
Hold (interrupt) dose and follow. If the toxicity 
resolves to   grade 1 prior to Day 21 restart at next 
lower dose level and continue the cycle until Day 
21. 
Omit lenalidomide for the 
reminder of the cycle. If toxicity 
resolves, restart lenalidomide next 
cycle with a decrease in dose by 
one dose level. 
Grade 3-4 
Discontinue lenalidomide. 
Discontinue lenalidomide and do 
not resume. 
Allergic reaction or 
Hypersensitivity 
Grade 2-3 
 
 
 
Hold (interrupt) dose and follow. If the toxicity 
resolves to   grade 1 prior to Day 21 restart at next 
lower dose level and continue the cycle until Day 
21. 
 
 
Omit lenalidomide for the 
remainder of the cycle. If toxicity 
resolves, restart lenalidomide next 
cycle with a decrease in dose by 
one dose level. 
Grade 4 
Discontinue lenalidomide. 
Discontinue lenalidomide and do 
not resume. 
Constipation  
Grade 1-2 
 
 
Initiate bowel regimen and maintain dose level. 
 
Initiate bowel regimen and 
maintain dose level. 
≥ Grade 3 
Hold (interrupt) dose and follow. If the toxicity 
resolves to   grade 1 prior to Day 21 restart at 
next lower dose level and continue the cycle until 
Day 21. 
Omit lenalidomide for the 
remainder of the cycle. If toxicity 
resolves, restart lenalidomide next 
cycle with a decrease in dose by 
one dose level. 

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Renal Function 
CrCl 30-60 mL/min 
 
 
Hold (interrupt) dose and follow. If the toxicity 
resolves to < grade 1 prior to Day 21 restart at 
next lower dose level and continue the cycle until 
Day 21. 
 
Omit lenalidomide for remainder 
of cycle. Reduce dose of 
lenalidomide by one dose level for 
next cycle. 
 
CrCl <30 mL/min 
Discontinue lenalidomide. 
Discontinue lenalidomide. 
Venous 
Thrombosis/embolism 
≥ Grade 3 
Hold (interrupt) dose and start anticoagulation; 
restart at investigator’s discretion after adequate 
anticoagulation (maintain dose level). 
Omit lenalidomide for remainder 
of cycle and start anticoagulation. 
Restart at investigator’s discretion 
after adequate anticoagulation 
(maintain dose level). 
Hepatic or other 
Non-hematologic toxicity 
Assessed as 
lenalidomide- 
Related ≥ Grade 3 
Hold (interrupt) dose and follow. If the toxicity 
resolves to   grade 1 prior to Day 21 restart at 
next lower dose level and continue the cycle until 
Day 21. 
Omit lenalidomide for remainder 
of cycle. 
Hyperthyroidism or 
Hypothyroidism 
Omit lenalidomide for remainder of cycle, 
evaluate etiology, and initiate appropriate 
therapy. Restart lenalidomide next cycle 
(decrease dose by one dose level). 
Omit lenalidomide for remainder 
of cycle, evaluate etiology, and 
initiate appropriate therapy. 
Restart lenalidomide next cycle 
(decrease dose by one dose 
level). 
As noted in the table above, lenalidomide can be introduced after resolution of 
certain toxicities, midway through the cycle, provided the toxicity resolves prior to 
day 21. If drug needs to be held at the time of retreatment for adverse events, 
then the date of when treatment is resumed is considered day 1 of new treatment 
cycle. Patients requiring a treatment delay beyond 6 weeks will end protocol 
treatment. 
If lenalidomide is held for an entire cycle and toxicity resolution does not occur 
within this time, lenalidomide dosing should be permanently stopped. 
5.5 
Supportive Care 
5.5.1 
All supportive measures consistent with optimal patient care will be 
given throughout the study.  
5.5.2 
Thrombosis Prophylaxis 
5.5.2.1 
Arm A  
All patients on Arm A are to receive prophylaxis against 
thrombosis. For patients in Arm A, physicians should 
consider prophylaxis with aspirin alone as studies with 
single agent lenalidomide in the setting of relapsed 
disease show a relatively low incidence of thrombosis 
(<5%). 
If the participant is on full-dose anticoagulation and it is 
anticipated that the course of therapy with full-dose 
anticoagulation is to be completed during participation in 
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this trial, the participant must then be placed on some form 
of anti-coagulation as prophylaxis. 
Arm 
DVT prophylaxis 
Acceptable alternative prophylaxis** 
A 
Aspirin each day 
of treatment 
cycle* 
Lovenox 40 mg once a day 
subcutaneously or equivalent OR full dose 
coumadin targeting a therapeutic INR 2-3. 
For patients unable to tolerate 325 mg 
aspirin, 0 to 81 mg may be given. 
* Suggested dose of Aspirin is 325 mg/day, however the dose is at the 
discretion of the treating physician. Alternative dosing of 75mg/day or 
higher is acceptable provided the patient is at low risk of thrombosis. 
** Aspirin should not be given if patients are treated with alternative 
prophylaxis. 
5.5.2.2 
Prior or concurrent use of erythropoietin is disallowed. 
5.5.2.3 
Each site must have two trained counselors available for 
counseling all patients receiving lenalidomide supplied by 
the Division of Cancer Treatment and Diagnosis.  Trained 
counselors must complete training using the online 
program provided free by Celgene, the Celgene 
Pregnancy Prevention Counseling Program (CPPCP) 
Registration for CPPCP is done by completing the form 
found in Appendix XII and following the directions provided 
in the email notification. After the training is complete, the 
counselors must generate a training certificate and provide 
it to the CTSU for documentation. Sites may not order 
lenalidomide until documentation for two trained 
counselors is provided to the appropriate office. The 
CPPCP forms can be faxed to the CTSU at 1-888-691-
8039. 
5.6 
Duration of Therapy 
· 
Patients who progress to symptomatic myeloma at any time are discontinued 
from participation.   
· 
Patients on Arm A of therapy are strongly encouraged to undergo growth 
factor based stem cell collection following 4-6 cycles of therapy.  
· 
Patients are not permitted to undergo cyclophosphamide or other 
chemotherapy administration while on study for any reason, and specifically 
not for stem cell mobilization.  
5.6.1 
Extraordinary Medical Circumstances 
Patients will receive protocol therapy unless: 
If at any time the constraints of this protocol are detrimental to the 
patient’s health, protocol treatment should be discontinued. 
5.6.2 
Patient withdraws consent. 
5.6.3 
Patient experiences progression of disease. 
Rev. 8/11, 1/16 
Rev. 7/13 
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5.6.4 
Patient experiences unacceptable toxicity. 
5.6.5 
Non-Protocol therapies are administered. 
5.7 
Duration of Follow Up 
For this protocol, all patients, including those who discontinue protocol therapy 
early, will be followed for response until progression and for survival for 10 years 
from the date of randomization. All patients must also be followed through 
completion of all protocol therapy, and until PD, even if they initiate non-protocol 
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6. 
Measurement of Effect 
Definitions of Stringent Complete Response, Complete Response, Very Good Partial 
Response, Partial Response, and Stable Disease are based on International Uniform 
Response Criteria for Multiple Myeloma and the American Society of Hematology/Food 
and Drug Administration consensus panel recommendations for the assessment of 
disease progression.(64)   
6.1 
Response Considerations 
6.1.1 
Terms and Definitions 
6.1.1.1 
M-Protein 
Synonyms include M-spike, monoclonal protein and 
myeloma protein, monoclonal paraprotein, M-component. 
6.1.1.2 
Response Terms 
The following response terms will be used: stringent 
complete response (sCR), complete response (CR), very 
good partial response (VGPR), partial response (PR), 
stable disease (SD), and progression (PD). 
See Sections 6.2.1-6.2.6 for definitions. 
6.1.1.3 
Measurable Disease 
Defined by at least one of the following three 
measurements 
· 
Serum M protein ≥ 1 g/dL (≥ 10gm/L)(10 g/L) 
· 
Urine M protein  ≥ 200 mg/24 hours 
· 
Serum free light chain (FLC) assay: Involved free light 
chain level  ≥ 10 mg/dL (≥ 100 mg/L) provided serum 
FLC ratio is abnormal 
6.1.1.4 
Evaluable Disease 
Patients who do not have a “measurable” serum or urine 
M-spike. 
6.1.1.5 
Oligosecretory Myeloma 
Patient with Multiple Myeloma who has NEVER had 
“measurable” disease, but has had a detectable 
monoclonal protein in his/her serum and/or urine. 
6.1.1.6 
Non-Secretory Myeloma 
Patient with Multiple Myeloma who has NEVER had a 
detectable monoclonal protein in his/her serum and/or 
urine. 
6.1.1.7 
Response Evaluation and Confirmation 
Except for assessment of sCR, CR, or VGPR patients with 
measurable disease restricted to the SPEP will need to be 

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followed only by SPEP; correspondingly, patients with 
measurable disease restricted to the UPEP will need to be 
followed only by UPEP.  
Patients with measurable disease in either SPEP or UPEP 
or both will be assessed for response only based on these 
two tests and not by the FLC assay. FLC response criteria 
are only applicable to patients without measurable disease 
in the serum or urine.  
To be considered CR, both serum and urine 
immunofixation must be carried out and be negative 
regardless of the size of baseline M-protein in the serum or 
urine. 
In order to be classified as a sCR, CR, PR, or VGPR, 
confirmation of serum and urine monoclonal protein results 
is required and must be made at anytime before the 
institution of any new therapy.  Confirmation is mandatory 
for sCR, CR, PR and VGPR documentation.  
Bone marrow biopsy is required for CR; however, a repeat 
bone marrow biopsy is not needed for confirmation. 
Bone radiographs are not required to document response. 
If bone radiographs are obtained, their findings must be 
consistent with the bone response criteria. 
6.1.1.8 
Oligosecretory and Non-secretory Myeloma 
Patients with oligosecretory myeloma who have 
measurable levels on the serum FLC assay, are assessed 
for response using the FLC assay instead of serum and 
urine M-protein levels. All other requirements as outlined in 
each response category must be met. Patients with 
oligosecretory myeloma   who do not have measurable 
levels on the serum FLC assay and patients with non-
secretory myeloma may be assessed for response using 
bone marrow plasma cell involvement provided baseline 
bone marrow plasma cell percentage was ≥30%.  
6.1.1.9 
Bone Progression 
Caution must be exercised to avoid rating progression or 
relapse on the basis of variation of radiologic technique 
alone. Compression fracture does not exclude continued 
response and may not indicate progression.  
When progression is based on skeletal disease alone, it 
should be discussed with the study chair before removing 
the patient from the study. 
6.1.2 
Monoclonal Protein Considerations 
Serum M-protein level is quantitated using densitometry on serum 
protein electrophoresis (SPEP) except in cases where the SPEP is 

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felt to be unreliable such as in patients with IgA monoclonal proteins 
migrating in the beta region. IF SPEP is not available or felt to be 
unreliable for routine M-protein quantitation during therapy, then 
quantitative immunoglobulin levels on nephelometry or turbidometry 
can be accepted. However, this must be explicitly reported; and only 
nephelometry can be used for that patient to assess response and 
SPEP and nephelometric values cannot be used interchangeably. 
Urine M-protein measurement is estimated using 24-hour urine 
protein electrophoresis (UPEP) only. Random or 24 hour urine tests 
measuring kappa and lambda light chain levels are not reliable and 
are not allowed. 
6.2 
Response Categories 
NOTE: 
For this protocol, patients will only have measurable serum and/or 
urine M-protein. 
6.2.1 
Stringent Complete Response (sCR) 
CR as defined below plus all of the following: 
· 
Normal serum FLC ratio at two consecutive times and 
· 
Absence of clonal cells in bone marrow by immunohistochemistry, 
immunofluorescence, flow cytometry, or any other clonality 
determination method.a 
a Presence/absence of clonal cells is based upon the k/  ratio. An 
abnormal k/  ratio by immunohistochemistry and/or 
immunofluorescence requires a minimum of 100 plasma cells for 
analysis. An abnormal ratio reflecting presence of an abnormal 
clone is k/  of > 4:1 or < 1:2. 
6.2.2 
Complete Response (CR) 
Patients who have complete disappearance of an M-protein and no 
evidence of myeloma in the bone marrow are considered to have 
complete response. To be considered CR, patients must meet all of 
the following criteria: 
· 
Negative immunofixation on the serum and urine at two 
consecutive times, and 
· 
Disappearance of any soft tissue plasmacytomas and 
· 
< 5% plasma cells in bone marrow 
6.2.3 
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 < 100 mg per 24 hours (by SPEP and UPEP) 
· 
If the serum and urine M protein are unmeasurable and the 
immunoglobulin free light chain parameter is being used to 
measure response, a ≥ 90% decrease in the difference between 

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involved and uninvolved free light chain (FLC) levels is required in 
place of the M protein criteria. 
6.2.4 
Partial Response (PR)  
· 
Patients who have measurable disease in the serum at baseline 
require ≥ 50% reduction in the level of serum M-protein (by 
SPEP). 
· 
Patients who have measurable disease in the urine at baseline 
require ≥ 90% reduction in the level of urine M-protein or the urine 
M-protein must be < 200mg/24hr (by 24 hr UPEP). 
· 
If the serum and urine M-protein are unmeasurable and the 
immunoglobin free light chain parameter is being used to measure 
response, a ≥ 50% decrease in the difference between involved 
and uninvolved free light chain (FLC) levels is required in place of 
the M-protein criteria. 
· 
If serum and urine M-protein are unmeasurable, and serum free 
light assay is also unmeasurable, ≥ 50% reduction in plasma cells 
is required in place of M-protein, provided baseline bone marrow 
plasma cell percentage was ≥ 30%. 
· 
In addition to above listed criteria, if present at baseline, a ≥ 50% 
reduction in size of soft tissue plasmacytomas is also required. 
6.2.5 
Stable Disease (SD) 
Failure to meet response criteria outlined above.  
6.2.6 
Progression (PD) 
The investigation that qualified as progression should be repeated 
and verified on a subsequent occasion only if treating physician 
deems it clinically necessary. Patients will be considered to have 
progression if both of the following criteria are met.(64)   
1.  Any one or more of the following: 
· 
Increase in serum M-protein to ≥ 25% above the lowest 
response level, which must also be an absolute increase of at 
least 0.5g/dl to qualify as “progression.” 
· 
Increase in urine M-protein to ≥ 25% above the lowest 
response level for 24-hour excretion, which also must be an 
absolute increase of at least 200mg/24 hours of urine M-
protein to qualify as “progression.” 
· 
Increase in bone marrow plasma cell percentage to ≥ 25% 
from lowest response value (the absolute % increase must be 
≥ 10%). 
AND 
2.  Any one or more of the following felt related to the underlying 
clonal plasma cell proliferative disorder: 
· 
Hypercalcemia (> 11 mg/dL)  
· 
Decrease in hemoglobin of ≥ 2 gms/dL 

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· 
Serum creatinine level ≥ 2mg/dL   
· 
Development of myeloma bone lesions or soft tissue 
plasmacytoma. 
If subsequent verification is done, progression should be recorded as 
the date when the abnormality was first detected, not the date when it 
was confirmed. 
6.3 
Quality of Life Measurement 
6.3.1 
QOL Instruments 
For the primary quality of life endpoint we will use a combined scale 
comprised of the well established and validated functional well-being 
(FWB) and physical wellbeing (PWB) components of FACT-G version 
4 (14 questions), which will address the physical and functional well-
being of SMM patients.  
In addition, a new MM specific subscale (MMS) (14 questions) will be 
evaluated as a secondary endpoint. The MM subscale was developed 
in a three-step process using both expert and patient input. First, a 
pool of potential items was generated from the literature to create an 
item rating survey. These items were reviewed by thirteen health care 
providers with expertise in the diagnosis and treatment of Multiple 
Myeloma recruited through ECOG-ACRIN Myeloma Committee as 
well as from Mayo Clinic in Scottsdale, AZ, Mayo Clinic in Rochester, 
MN, and Marshfield Clinic in Marshfield, WI. Items were rated 
according to how common and how important they are when 
occurring in patients with this condition. Finally, experts were asked to 
circle up to 20 of the most important items (including self-nominated 
items) affecting patients with Multiple Myeloma. Expert input was 
compiled and ten additional items nominated during the surveys were 
added to the item rating survey. This survey was then formatted to be 
a semi-structured, self-administered, web-based interview that was 
conducted with a sample of forty-one MM patients. Identification and 
enrollment of eligible patients was performed using the International 
Myeloma Foundation website. Further candidate items were then 
generated by these patients using this semistructured interview 
designed to elicit personal experiences about how Multiple Myeloma 
and its treatment may affect physical status, emotional well-being, 
functional well-being, family/social issues, sexuality/intimacy, work 
status, and future orientation. Patients were also asked to complete 
the same item rating survey administered to the experts (with the 
additional ten questions) as well as answer basic disease and 
treatment questions. Patients were also given the opportunity to 
provide comments on items as well as additional feedback. Second, a 
team of CORE staff with extensive experience in QOL research, 
assessment and scale construction followed a standard process of 
item review and reduction as well as scale construction creating a 
final list of 14 items. Third, this final list of items was then reviewed by 
the Multi-Lingual Translation Team to screen for potential translation 
issues and to correct item wording in problematic instances. 

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6.3.2 
Timing of QOL Assessments 
The QOL assessment utilizing the FACT PWB+FWB and the MMS 
instruments will first be administered at registration (+ 7days) prior to 
initiation of treatment or observation. During the treatment or 
observation period, QOL will be measured every 6 cycles (day end + 
7 days) up to cycle 48 and at the end of treatment (+ 14 days).  For 
patients who discontinue protocol therapy or go off observation early 
not due to disease progression, QOL will also be assessed at the next 
quarterly Long Term follow-up visit (+ 14 days). After this, these 
patients will not be followed further for QOL. 

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7. 
Study Parameters for Arm A and Arm B 
7.1 
Therapeutic Parameters (for both arms of the study) 
1. Prestudy scans and x-rays used to assess all measurable or non-measurable sites of disease must be done 
within 4 weeks (28 days) prior to randomization/registration. 
2. Prestudy CBC (with differential and platelet count) should be done   4 weeks (28 days) before randomization/ 
registration.  
3. All required prestudy chemistries, as outlined in Section 3, should be done   4 weeks (28 days) before 
randomization/registration unless specifically required on Day 1 as per protocol. 
Rev. 8/11 
Procedure 
Prior to 
registration  
( 28 days) 1 
10-14 days 
prior to 
starting 
Treatment 
or 
Observation 
< 24 hours 
prior to 
starting 
Treatment 
or 
Observation 
Induction- At the 
end of each 
Treatment or 
Observation 
cycle 
Day 1 
of 
each 
cycle 
Studies 
needed 
to 
confirm 
sCR or 
CR  
Periodically 
during 
Treatment or 
Observation 
At study 
discontinuation 
or progression 
(whichever 
comes first) 
28 Days 
after 
discontinue-
ation of 
treatment 
Post 
treatment 
to 10 
years from 
study 
entry11 
 
History and 
exam6 
X 
 
 
X 
 
 
 
X 
 
X 
 
Bone Marrow 
Aspirate and 
Biopsy9 
X 
 
 
 
 
X 
 
 
 
 
 
ECOG 
Performance 
Status 
X 
 
 
X 
 
 
 
X 
 
X 
 
NYHA 
Classification 
X 
 
 
 
 
 
 
 
 
 
 
Chemistry 
labs3 
X 
 
 
X 
 
 
 
X 
 
X 
 
CBC with 
differential4 
X 
 
 
X 
 
 
 
X 
 
X 
 
Serum light 
chain assay 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Serum 
immunoglobin 
G, A, M 
X 
 
 
X 
 
 
 
X 
 
X 
 
QOL7 
X 
 
 
X 
 
 
 
X 
 
X 

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SPEP  
X 
 
 
X 
 
 
 
X 
 
X 
 
Serum M-
protein 
immunofixation 
X 
 
 
 
 
X 
 
 
 
 
 
24 hr UPEP 
X 
 
 
X2,10 
 
 
 
X2,10 
 
X2,10 
 
Urine M-
protein  
immunofixation 
X 
 
 
 
 
X 
 
 
 
 
 
Metastatic 
bone survey  
X 
 
 
 
 
 
X12 
X 
 
X12 
 
ECG (12-lead) 
X 
 
 
 
 
 
 
 
 
 
 
Serum 
Pregnancy test 
for FCBP5 
X 
X5 
X5 
X5 
 
 
 
X5 
X5 
 
Rev. 8/11 
Patient 
Education and 
Counseling14 
X 
 
X 
X 
X 
 
 
X 
X 
 
 
Serum Beta-2 
microglobulin 
X 
 
 
 
 
 
 
X 
 
 
 
C-reactive 
protein 
X 
 
 
 
 
 
 
 
 
 
 
LDH 
X 
 
 
 
 
 
 
 
 
 
Rev. 8/11 
Dispense  
lenalidomide15 
 
 
X 
 
X 
 
 
 
 
 
Rev. 7/14 
TSH (ARM A 
ONLY)16 
X 
 
 
 
 
 
 
 
 
X13 
 
Ultrasound8 
 
 
 
X 
 
 
 
 
 
 
 
Documentation 
of oral drug 
 
 
 
X 
 
 
 
 
 
 
 
MRI (spine and 
pelvis) 
X 
 
 
 
 
 
 
 
 
 
Rev. 12/13 
 
Biological 
Sample 
Submissions 
See Section 7.2 
 
1. Registration test results can be used for cycle 1 if less than 7 days before starting cycle 1. 

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2. If serum and urine M-components are measurable, both must be followed in order to evaluate response. Measurable levels of monoclonal 
protein (M-protein) are defined as ≥ 1.0 g/dL on serum protein electrophoresis or ≥ 200 mg 24hr of monoclonal light chain on a 24-hour urine 
protein electrophoresis; results must be obtained with 4 weeks prior to randomization. 
3. Chemistry includes sodium, potassium, calcium, magnesium, phosphorus, blood urea nitrogen (BUN), creatinine, creatinine clearance, 
glucose, alkaline phosphatase, total bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Magnesium and 
phosphorus is not required but should be tested as clinically indicated. 
4. Hematology (CBC with differential) includes WBC, ANC, Platelets, Hgb, and Hct required for protocol therapy must be done < 24 hours prior 
to the treatment cycle. 
5. Pregnancy tests for females of childbearing potential for patients on Arm A only. A female of childbearing potential (FCBP) is a sexually mature 
female, regardless of sexual orientation or whether they have undergone tubal ligation, who: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the 
preceding 24 consecutive months). Pregnancy tests (sensitivity of 25 mIu/mL) must occur within 10 – 14 days and again within 24 hours prior to 
initiation of lenalidomide. FCBP with regular or no menstruation must have a pregnancy test weekly for the first 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 VI. 
6. Clinical exam should look for plasmacytoma. 
7. QOL timepoints: At registration (+ 7 days) prior to initiation of treatment or observation; the last day (+ 7) of cycles 6, 12, 18, 24, 30, 36, 42, 
and 48; and at the end of treatment or observation (+14 days). For patients that discontinue protocol therapy or go off observation early not 
due to disease progression, QOL will also be assessed at the next quarterly Long Term follow-up visit (+ 14 days). After this, patients will not 
be followed further for QOL. 
8. If leg swelling or pain is present in legs, an ultrasound of the legs will be done for deep vein thrombosis. 
9. Bone marrow biopsy or aspirate performed to evaluate plasma cells %, presence of sheets of plasma cells and presence of plasma cell 
clonality. Absence of plasma cell clonality required for sCR.  
10. Needed if urine M-spike at study entry was ≥ 200 mg/24 hr or if VGPR needs to be documented. 
11. Patients will be followed for progression every 3 months if patient is < 2 years from study entry, every 6 months if patient is 2-5 years from 
study entry, every 12 months if patient is 6-10 years from study entry. No specific requirements if patient is more than 10 years from study 
entry. Patients will be followed for survival only once progression occurs and study treatment ends. 
12. To be repeated every year or if clinically indicated for progression or symptoms.  
13. To be assessed every 4 months. 
14. All patients must be counseled about pregnancy precautions, risks of fetal exposure and other risks.  The counseling must be done on Day 1 of 
each cycle (or at a minimum of every 28 days) and at drug discontinuation. The Lenalidomide Education and Counseling Guidance Document 
(Appendix VII) must be completed and signed by a trained counselor at the participating site prior to each dispensing of lenalidomide 
treatment. A copy of this document must be maintained in the patient records. A Lenalidomide Information Sheet (Appendix VIII) will be 
supplied to each patient receiving lenalidomide treatment. The patient must read this document prior to starting lenalidomide study treatment and 
each time they receive new supply of study drug. 
15. Only enough lenalidomide for 28 days or one cycle of study treatment may be provided to the patient each cycle. 
16. TSH should be tested for Arm A ONLY and then only when clinically indicated by the Principal Investigator. 
Rev. 8/11 
Rev. 8/11 
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7.2 
Biological Sample Submissions  
1. Bone marrow and peripheral blood samples should be submitted as outlined 
in Section 10 of E3A06 for correlative studies and/or banking per patient 
consent. Kits are being provided for the collection and shipment of the 
samples, please refer to Section 10 and Appendices III and IV for 
instructions. 
NOTE: 
Institutions outside of the United States and Canada must confer with 
the receiving laboratory and the ECOG-ACRIN Operations Office - 
Boston regarding logistics for submission of fresh samples. 
NOTE: 
It is required that biological sample submissions be logged into the 
ECOG-ACRIN Sample Tracking System (STS) (see Section 10.5) for 
purposes of monitoring compliance. 
NOTE:  
An informed consent must be signed prior to the submission of any 
samples for laboratory studies and/or banking. Samples for the 
optional laboratory studies and/or banking should be submitted only 
from patients who have given written consent for the use of their 
samples for these purposes. 
Rev. 7/14 
 
Biological 
Materials3,4 
 
Pre-
Registration1 
At Study 
Discontinuation 
or Progression2 
Ship To: 
 
From Patients Who Answer “YES” to “I agree to participate in the laboratory research studies that are being 
done as part of this clinical trial.” 
 
Peripheral Blood  
Two (2) ACD tubes 
(yellow top), 14mL 
X 
X 
Mayo Clinic Myeloma 
Reference Laboratory 
Rev. 2/12 
Four (4) 10mL Green Top 
tubes (sodium heparin) 
X 
X 
Yale University 
 
Bone Marrow Core 
Biopsy 
Five (5) Unstained Slides 
X 
X 
Mayo Clinic Myeloma  
Reference Laboratory 
Rev. 2/12 
Snap Frozen 
X 
X 
University of Arkansas 
Rev. 7/13 
Bone Marrow 
Aspirate 
[Deleted in Addendum #7] 
Mayo Clinic Myeloma  
Reference Laboratory 
Rev. 7/13 
One (1) ACD tube (yellow 
top), 7mL 
X 
X 
Rev. 2/12 
5-10mL Sodium Heparin 
(green top tube) 
X 
X 
Yale University 
Rev. 2/12 
EDTA tube (purple top), 
10-20mL 
X 
X 
University of Arkansas 
 
From Patients Who Answer “YES” to “I agree to provide additional blood for research.” 
Rev. 2/12 
Peripheral Blood 
One (1) SST tube (red 
top), 5-7mL 
X 
X 
Mayo Clinic Myeloma  
Reference Laboratory 
1. Prior to treatment. 
2. Whichever comes first. Biopsies performed at time of suspected progression are requested. 
3. Submissions are optional based on patient consent to the correlative studies and/or banking 
as outlined in Section 10. 
4. Kits are available for the collection and shipment of the samples. See Section 10.3. 
 
Rev. 2/12 
Rev. 2/12 
7/14 
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8. 
Drug Formulation and Procurement 
8.1 
Lenalidomide (NSC 703813), (IND) 
NOTE: 
Before lenalidomide is dispensed, patients must 1) have a negative 
pregnancy test (if applicable) and 2) be counseled by a trained 
counselor. Pharmacists may be trained counselors (see Lenalidomide 
Counselor Program Site Counselor Identification Form in the 
protocol). The counseling requirements for investigational-use 
lenalidomide are separate from the RevAssist program. Only a 28-day 
supply may be dispensed to a patient at one time. 
8.1.1 
Other names 
Revlimid® (formerly Revimid® ), CDC-501, CC-5013 
8.1.2 
Classification 
Immunomodulatory drug. 
8.1.3 
Mode of Action 
Lenalidomide, a thalidomide analog, is an immunomodulatory agent 
with a spectrum of activity that is still under investigation.  Some of its 
effects include inhibition of inflammation, inhibition of angiogenesis, 
inhibition of hematopoetic tumor cell proliferation, modulation of stem 
cell differentiation and upregulating responses of T cells and NK cells. 
8.1.4 
How Supplied 
Celgene supplies and CTEP, NCI, DCTD distributes lenalidomide 5 
mg (size 2) and 25 mg (size 0) hard gelatin capsules in tamper-
evident, child-resistant, opaque, high density polyethylene (HDPE) 
bottles with HDPE caps. Bottles contain 100 capsules per container. 
The capsules also contain anhydrous lactose, microcrystalline 
cellulose, croscarmellose sodium, and magnesium stearate. 
8.1.5 
Storage and Stability 
Storage: The capsules should be stored at room temperature (15-
30°C) away from moisture and direct sunlight. 
Stability: Refer to the package labeling for expiration date. 
Lenalidomide stability is adequate for at least 28 days after 
transferring to a pharmacy vial. 
NOTE: 
Per FDA guidelines for prevention of pregnancy that only 
one month supply of lenalidomide may be dispensed to the 
patient at one time. 
Dispensing 
Only a 28-day supply may be dispensed at one time. Sites may not 
mail lenalidomide to patients. 
Rev. 8/11 
Rev. 8/11 
Rev. 8/11 
Rev. 8/11, 12/13 
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8.1.6 
Dose Specifics 
For Arm A patients, lenalidomide is initiated on Day 1 of Cycle 1 at a 
dose of 25 mg orally and will be taken days 1-21 for each 28 day 
cycle. 
Only enough lenalidomide for one cycle of therapy will be supplied to 
the patient each cycle.  
Lenalidomide capsules should be swallowed whole, and should not be 
broken, chewed, or opened. 
If a dose of lenalidomide is missed, it should be taken as soon as 
possible on the same day.  If it is missed for the entire day, it should 
not be made up. 
Patients who take more than the prescribed dose of lenalidomide 
should be instructed to seek emergency medical care if needed and 
contact study staff immediately. 
8.1.7 
Route of Administration 
Take lenalidomide by mouth with or without food. Do not crush, chew 
or open capsules. 
8.1.8 
Patient Care Implications and Counseling 
Risks Associated with Pregnancy 
Lenalidomide is structurally related to thalidomide. Thalidomide is a 
known human teratogenic active substance that causes severe life-
threatening birth defects. An embryofetal development study in 
animals indicates that lenalidomide produced malformations in the 
offspring of female monkeys who received the drug during pregnancy. 
The teratogenic effect of lenalidomide in humans cannot be ruled out. 
Therefore, a risk minimization plan to prevent pregnancy must be 
observed. 
Definition of female of childbearing potential (FCBP) 
This protocol defines a female of childbearing potential as a sexually 
mature woman who: 1) has not undergone a hysterectomy or bilateral 
oophorectomy or 2) has not been naturally postmenopausal 
(amenorrhea following cancer therapy does not rule out childbearing 
potential) for at least 24 consecutive months (i.e., has had menses at 
any time in the preceding 24 consecutive months). 
Before starting study drug:   
Female Subjects:   
· 
FCBP must have two negative pregnancy tests (minimum 
sensitivity of 25 mIU/mL) prior to starting study drug.  The first 
pregnancy test must be performed within 10-14 days prior to the 
start of study drug and the second pregnancy test must be 
performed within 24 hours prior to the start of study drug.  The 
subject may not receive study drug until the Investigator has 
verified that the results of these pregnancy tests are negative. 
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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. 
All Subjects: 
· 
Only enough lenalidomide for one cycle of therapy may be 
dispensed with each cycle of therapy.  
· 
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. 
Counseling 
· 
In investigational studies where lenalidomide is supplied by the 
NCI, patients will be counseled by a qualified healthcare 
professional (including but not limited to, nurses, pharmacists and 
physicians). Two healthcare professionals at each site will be 
trained by Celgene in requirements specific to counseling of 
subjects (investigators cannot counsel patients as part of this 
requirement). Refer to specific protocol sections for more 
information about training requirements. 
· 
Once trained, these healthcare staff will counsel subjects prior to 
medication being dispensed to ensure that the subject has 
complied with all requirements including use of birth control and 
pregnancy testing (FCBP) and that the subject understands the 
risks associated with lenalidomide. This step will be documented 
with a completed Lenalidomide Education and Counseling 
Guidance Document (Appendix VII) and no drug will be dispensed 
until this step occurs. Counseling includes verification with the 
patient that required pregnancy testing was performed and results 
were negative. A Lenalidomide Information Sheet (Appendix VIII) 
will be supplied with each medication dispense. 
8.1.9 
Potential Drug Interactions 
Periodic monitoring of digoxin levels is recommended during 
coadministration with lenalidomide. Digoxin levels were slightly higher 
when digoxin was administered with lenalidomide in a clinical study.  
There was no effect on lenalidomide pharmacokinetics.  
Warfarin and lenalidomide may be co-administered without additional 
monitoring.  No pharmacokinetic or pharmacodynamic interactions 
were observed between lenalidomide and warfarin.  
Nonclinical in vitro metabolism studies suggest that lenalidomide is 
not likely to result in metabolic drug interactions in humans. In vitro, 
lenalidomide did not significantly inhibit marker enzyme activities for 
CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4.  In 
rats, no induction of any CYP450 enzymes was observed. 

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Administration of lenalidomide in monkeys showed no effects on the 
activities of CYP1A, CYP2B, CYP2C, CYP2E, CYP3A, or CYP4A. 
8.1.10 
Availability 
Available as a 5 mg and 25 mg hard gelatin capsule. 
Drug Ordering: Maintenance of NCI drug accountability records is 
required. Lenalidomide may be requested by the Principal Investigator 
(or their authorized designees) at each participating institution. 
Pharmaceutical Management Branch (PMB) policy requires that drug 
be shipped directly to the institution where the patient is to be treated. 
PMB does not permit the transfer of agents between institutions 
(unless prior approval from PMB is obtained - see general 
information). 
NCI SUPPLIED AGENT(S) - GENERAL INFORMATION 
Active CTEP-registered investigators and investigator-designated 
shipping designees and ordering designees can submit agent 
requests through the PMB Online Agent Ordering Processing (OAOP) 
application (http://eapps-ctep.nci.nih.gove/OAOP/pages/login.jspx). 
Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account (https://eapps-
ctep.nci.nih.gov/iam/) and the maintenance of an “active” account 
status and a “current” password.  
For questions about drug orders, transfers, returns, or accountability, 
call (240) 276-6575 Monday through Friday between 8:30 am and 
4:30 pm (ET) or email PMBDAfterHours@mail.nih.gov anytime. 
Drug Accountability:  The investigator, or a responsible party 
designated by the investigator, must maintain a careful record of the 
receipt, disposition, and return of all drugs received from the PMB 
using the NCI Investigational Agent Accountability Record available 
on the NCI home page (http://ctep.cancer.gov) or by calling the PMB 
at 240-276-6575. 
8.1.11 
Side Effects 
See CAEPR (Section 5.3) 
8.1.12 
Nursing/ Patient Implications 
Please refer to Appendix VI: Risk Associated with Pregnancy and 
Appendix VII: Education and Counseling Guidance Document. 
1. Ensure women of childbearing age are not pregnant and sexually 
active women and men are abstaining or are using an effective 
form of contraception while taking lenalidomide. 
2. Caution patient not to drive or use hazardous machinery until the 
potential sedative effects of the drug are known in the patient. 
3. Caution patient to report leg swelling or shortness of breath, 
because of the risk of thrombosis/embolism 
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4. Counsel patient to report abnormal sensations in hands or feet, 
such as decreased sensation or dysesthesia.  Paresthesias are 
often noted early before neuropathy develops. 
5. Advise patient to immediately report rashes or fever. 
6. Advise patient to take dose at the same time each day. 
8.1.13 
References 
1. Richardson PG, Schlossman RL, Weller E, et al. 
Immunomodulatory drug CC-5013 overcomes drug resistance and 
is well tolerated in patients with relapsed Multiple Myeloma. Blood 
2002; 100:3063-7. 
2. Richardson P, Jagannath S, Schlossman R, et al. A Multi-center, 
Randomized, Phase 2 Study to Evaluate the Efficacy and Safety 
of 2 CDC-5013 Dose Regimens When Used Alone or in 
Combination with Dexamethasone (Dex) for the Treatment of 
Relapsed or Refractory Multiple Myeloma (MM). Blood 2003; 
102:235a. 
3. Zangari M, Tricot G, Zeldis J, Eddlemon P, Saghafifar F, Barlogie 
B. Results of Phase I Study of CC-5013 for the Treatment of 
Multiple Myeloma (MM) Patients Who Relapse after High Dose 
Chemotherapy (HDCT). Blood 2001:775a (A3226). 
4. Davies FE, Raje N, Hideshima T, et al. Thalidomide and 
immunomodulatory derivatives augment natural killer cell 
cytotoxicity in Multiple Myeloma. Blood 2001; 98:210-6. 

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9. 
Statistical Considerations 
9.1 
Introduction 
This revised statistical considerations section reflects observed accrual and 
updated results of the Spanish SMM trial at ASH 2014 (Mateos et al. Blood 
2014). 
As of the end of June 2015, 93 patients have enrolled over the 26 months since 
accrual began on the Phase III study (Feb 2013). The accrual rate over this time 
was approximately 3.5 patients per month, which approximates 50% of the 
anticipated accrual rate (7 patients per month). Accrual over the last 6 months 
has averaged 4.5 patients per month. Following the recommendation of the Data 
Safety Monitoring Committee, the anticipated accrual rate is revised in 
addendum #11 to reflect the current actual accrual. 
At the same time, the expected median PFS on observation (Obs) arm is revised 
in addendum #11 to reflect results from the Spanish SMM trial  reported at ASH 
2014 (Mateos et al. Blood 2014). In this study, 119 patients were randomized to 
receive induction lenalidomide (25 mg/day d1-21)-dexamethasone (20 mg/day 
d1-4, d12-15) (Rd) for 9 cycles and then maintenance lenalidomide (10 mg/day) 
up to 2 years total treatment versus watchful waiting. Long-term follow-up results 
showed a survival hazard ratio (watchful waiting/Rd) of 4.35 [95% CI (1.5-13.0)]. 
Time-to-progression (TTP) hazard ratio was 6.21 [95% CI (3.1-12.7)]. When 
E3A06 was originally designed, the median progression free survival (PFS) on 
observation was expected to be 31 months, and it was considered that patients 
treated with lenalidomide (Revlimid; R) would have comparatively longer PFS (60 
months). However, the recent update showed that the median time to 
progression (TTP) on the watchful waiting arm (akin to the E3A06 observation 
arm) was 21 months which suggests that the median PFS on the Obs arm might 
be shorter than we had originally expected. Thus, in this addendum, in addition to 
the anticipated accrual rate, the expected median PFS on the Obs arm is also 
revised. The total accrual, the total information time and the interim analysis plan 
are also amended, accordingly. 
Before this amendment (addendum #11), the trial was designed to have 95% 
power, at the one-sided 0.025 significance level, to reject the null hypothesis of 
no difference between Obs and R arms, given a true PFS Obs/R hazard ratio of  
2.0 or more with 336 patients (accrued over 48 months and followed an 
additional 6 months) and 124 PFS events. The design incorporated 5 interim 
analyses and one final analysis for the PFS comparison. No interim analysis has 
been performed prior to this amendment. 
9.2 
Accrual  
Accrual to E4A03, an ECOG study of newly diagnosed patients looking at 
treatment with lenalidomide and dexamethasone, reached a rate of 300 patients 
per year. For every 10 newly diagnosed myeloma patients, the study team feels 
there are 2 newly diagnosed SMM patients, equating to 60 newly diagnosed 
SMM patients per year. Of these newly diagnosed SMM patients, approximately 
90% fall into intermediate and high risk class based on Kyle’s definition which 
provides for 54 patients per year. Approximately 90% of these have abnormal 
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free light chain (< 0.26 or > 1.65), however, we will conservatively estimate 65% 
enrollment. Therefore, the ECOG-ACRIN accrual rate to this study is expected to 
be 36 patients per year, or 3 patients per month. SWOG and other collaborative 
groups' contribution to accrual is estimated at 4 patients per month or 48 patients 
per year. Given an estimated accrual rate of 7 patients per month, we will accrue 
for 48 months to obtain 336 patients (168 on each arm) for the Phase III study. 
Based on observed accrual as of June 2015, the accrual rate is revised to 3-4 
patients per month. With a new accrual target of 180 patients and approximately 
87 patients remaining to be enrolled, it is anticipated enrollment will be completed 
in 24 months. 
9.3 
Phase II Study 
A phase II group of patients will be enrolled all receiving lenalidomide at a fixed 
dose of 25 mg days 1-21 every 28 days to evaluate the early toxicity and 
tolerance of this dosing. Patients will be treated until progression or excessive 
toxicity. While all toxicities and dose modifications will be monitored, the primary 
endpoint for the phase II study will be grade 3 toxicity effecting vital organ 
function (such as cardiac, hepatic or thromboembolic) or any grade 4 or higher 
non-hematologic toxicity observed within 6 cycles of treatment. Toxicities 
evaluated will be based on CTEP-AERS expedited reporting. An acceptable 
toxicity rate is 15% and a toxicity rate of 30% or greater is considered 
unacceptable. 34 patients will be enrolled in the phase II cohort. If 9 or more 
patients experience toxicity as defined then the study will not continue. With this 
design, the probability of stopping early is 73.2% if the true but unknown toxicity 
rate is 30%, and 5.9% if the true rate is 15%. Accrual is expected to take 
approximately 5 months and the toxicity expected to be analyzed approximately 
2-3 months after the last patient has completed 6 cycles of treatment. 
Thirty-six patients enrolled in the phase II study. Due to an error in the 
registration system, 8 additional patients were directly assigned to lenalidomide 
treatment. These 8 patients will be analyzed with the phase II cohort in the final 
analysis of study results, and in particular will be included in the final adverse 
event analyses. They may also be included in some correlative analyses. The 
final phase II cohort thus includes 44 patients. 
9.4 
Primary Clinical Endpoint 
The most clinically relevant endpoint for this high-risk SMM population is 
progression free survival (PFS) as defined by the ASH FDA consensus panel, 
where failure is defined as death or the appearance of symptomatic myeloma 
indicating treatment.(64) Following the ASH/FDA consensus, symptomatic MM is 
present or imminent end-organ damage characterized by hypercalcemia, renal 
insufficiency, anemia or bone disease related to the plasma cell proliferative 
process.(64) Our primary analysis is the comparison of progression-free survival 
(PFS) of high risk SMM patients treated with lenalidomide to those given no 
treatment. Patients will be randomized in equal proportions to R or Obs. 
Treatment will be assigned using permuted blocks within strata with dynamic 
balancing within main institution and their affiliate networks. PFS in each of the 
arms will be estimated using the method of Kaplan and Meier.(65) PFS between 
the two arms will be compared using a stratified log-rank test.(66) 
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It is expected that the median PFS of patients on the Obs arm will be 24.8 
months (hazard rate of 0.0279). The study is designed to detect a 60% reduction 
in hazard rate to 0.011. If PFS follows an exponential distribution, this difference 
corresponds to a 150% improvement in PFS to a median of 62 months. These 
rates are derived from studies cited earlier (more specifically a 2-yr progression 
rate of 41.5% for the obs arm based on the Dispenzieri study)(23),an NIH funded 
phase III trial of thalidomide plus zoledronic acid versus zoledronic acid alone at 
the Mayo Clinic and the Spanish SMM study (Mateos et al. Blood 2014). The 
primary analysis will be intention-to-treat analysis.  Accrual duration is estimated 
at 45 months in order to obtain 180 patients (90 on each arm), and follow 
patients for an additional 9 months after closure to accrual. At this point, full 
information which is considered to be when 76 patients have progressed or died 
will be obtained. 
With the expected accrual and failure rates above, the trial will have 96% power, 
at the one-sided 0.025 significance level, to detect a hazard ratio of 2.5 or more 
(for Obs versus R). By starting with such high power, the study is designed to 
accommodate potential treatment non-adherence. For example, if (a random) 5% 
of the patients on each arm cross over to the opposite treatment, then the ITT 
hazard ratio would be expected to be about 2.2 (when the true Obs vs R ratio for 
the full population is 2.5), and the design would still have about 91.1% power, 
and if 10% of the patients on each arm cross over to the opposite treatment, then 
the ratio would be decreased to about 1.97, and the ITT analysis would still have 
at least 78% power.   
This design incorporates 5 interim analyses and one final analysis for the PFS 
comparison. The final analysis will occur at full information (76 patients 
progressed/died). This study incorporates a group sequential monitoring plan to 
adjust for sequential testing to stop early in favor of the alternative hypothesis. 
Once the trial reaches approximately 25% information, one analysis will be 
performed every 6 months to correspond with the scheduled Data Monitoring 
Committee (DMC) meeting. Critical values will be determined using a truncated 
version of the Lan-Demets error spending rate function corresponding to the 
O’Brien-Fleming boundary.(67) At each interim analysis, the null hypothesis of 
equal PFS rates on the two arms will be tested against the one-sided alternative 
of increased PFS on the R arm. The p-value from a one-sided stratified log-rank 
test will be compared to the critical value. At any of the interim analyses, if the 
null hypothesis is rejected, the DMC may consider closing the study. The table 
below gives the expected timing of the analyses and the critical values for 
rejecting the null hypothesis. 
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Repeated 
analysis 
Time from 
Study Start 
(Months) 
Information 
Time (%) 
Failures under 
the Alternative 
Hypothesis 
Nominal 
Significance level 
for Rejecting the 
Null Hypothesis 
1 
24 
26 
20 
0.0005 
2 
30 
39 
29 
0.0005 
3 
36 
53 
40 
0.0015 
4 
42 
69 
52 
0.0061 
5 
48 
86 
65 
0.0130 
6 
54 
100 
76 
0.0199 
In addition to monitoring the study for early stopping in favor of the alternative 
hypothesis of increased PFS on the R arm, the study will also be monitored for 
early stopping in favor of the null hypothesis of no significant increase in PFS on 
the R arm using the repeated confidence interval methodology similar to that 
described by Jennison and Turnbull.(68) At each interim analysis, a nominal one-
sided (1-alpha) confidence interval around the hazard ratio (Obs over R) 
produced by the Cox proportional hazards model will be computed.(69) The 
alpha used to compute the confidence interval is the nominal significance level of 
the use function boundary at the information fraction at the particular analysis 
time. The target hazard ratio will be adjusted for observed treatment non-
adherence. If at any of the analyses the confidence interval does not contain the 
target hazard ratio, the DMC may consider stopping the trial early for lack of 
treatment difference. 
9.5 
Secondary Clinical Endpoints 
Secondary endpoints for this study include response rate and duration of 
response among responders. Response rate (CR+PR) on the R arm will be 
calculated and a 95% confidence interval will be computed around the response 
rate. The maximum width of a 95% confidence interval around response rate 
would be 21.5%. Duration of response among responders will be estimated using 
the Kaplan-Meier method.(65) Cox proportional hazards model will be used to 
assess PFS outcome in multiple regression analyses of established prognostic 
factors.(69) Adverse events will be monitored on all patients and summarized by 
arm. The difference in rates of all Grade 3 or higher toxicities will be evaluated for 
all randomized patients using the Fisher’s Exact Test. 
Overall Survival (OS) in each of the arms will be estimated using the method of 
Kaplan and Meier.(65) OS between the two arms will be compared using 
stratified log-rank test. (66) Cox proportional hazards model will be used to 
estimate the hazard rate between arms (69). OS will be evaluated at month 90/ 
year 7.5 when there is adequate power. The estimated 3-year survival probability 
on the R arm is supposed to parallel the probability for the general population of 
persons aged over 65 years (93%). The 3-year survival probability for an 
untreated high-risk SMM population is estimated at 83%.(23) Assuming 
exponential distributions, these probabilities correspond to a median OS of 28.7 
and 11.2 years. For this analysis, we assume the R treated high-risk SMM 
population has a slightly inferior hazard of death than the general population: 3-
year survival probability of 91% (hazard rate=0.0315). This estimate is 
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unchanged although the Spanish study reported 93% survival after 
approximately 5 years of follow-up (Mateos et al. Blood 2014). In the first report 
(Mateos et al. NEJM 2013), the 3-year survival on the watchful waiting arm of the 
Spanish study was 80%. In the long-term update, 5-year survival was 67% 
corresponding to a median OS of 9.2y on the watchful waiting arm. In this 
redesign, the 3-year OS estimate for the Obs arm was thus reduced to 79%. If 
OS follows an exponential distribution, this corresponds to medians of 22 years 
(R) and 8.8 years (Obs). There is 81% power to detect this difference assuming a 
one-sided 0.025 significance level and 47 events out of n=180 patients at the 
time of analysis. 
Overall Survival (OS) in each of the arms will be estimated using the method of 
Kaplan and Meier.(65) OS between the two arms will be compared using 
stratified log-rank test. (66) Cox proportional hazards model will be used to 
estimate the hazard rate between arms (69). OS will be evaluated at month 90/ 
year 7.5 when there is adequate power. The estimated 3-year survival probability 
on the R arm is supposed to parallel the probability for the general population of 
persons aged over 65 years (93%). The 3-year survival probability for an 
untreated high-risk SMM population is estimated at 83%.(23) Assuming 
exponential distributions, these probabilities correspond to a median OS of 28.7 
and 11.2 years. For this analysis, we assume the R treated high-risk SMM 
population has a slightly inferior hazard of death than the general population: 3-
year survival probability of 91% (hazard rate=0.0314). This estimate is 
unchanged and was confirmed with results from the Spanish study [ref]. The 3-
year survival probability on the watchful waiting arm of the Spanish study, 
however, was 67%. Given the Spanish study was comprised of higher risk 
patients, a 3-year probability of 79% is assumed. If OS follows an exponential 
distribution, this corresponds to medians of 22 years (R) and 8.8 years (Obs). 
There is 81% power to detect this difference assuming a one-sided 0.025 
significance level and 47 events out of n=180 patients at the time of analysis  
9.6 
Stem Cell Mobilization 
Patients are recommended to undergo stem cell mobilization with growth factors 
following 4 to 6 cycles of therapy. Successful mobilization defined as collection of 
5x106 cd34 cells per kilogram weight is an important outcome for patients treated 
with lenalidomide treatment. A growth factor mobilization failure rate of 10% is 
considered acceptable and a rate of 25% or less is unacceptable. Assuming 60% 
of patients on the lenalidomide arm opt for stem cell growth factor mobilization 
then there will be approximately 54 evaluable patients. An early stopping rule on 
the first 13 evaluable patients will be imposed. With 13 evaluable patients, if 3 or 
more patients fail, the study team will consider stopping this trial for an 
unacceptable growth factor mobilization failure rate. With this design based on 
exact binomial distribution, the probability of stopping early is 67% if the true but 
unknown failure rate is 25%, and 13% if the true rate is 10%. 
9.7 
Quality of Life  
9.7.1 
Primary QOL Endpoints 
Quality of life assessment is performed in an identical fashion in both 
arms A and B and will be administered to both arms on the same 
schedule and frequency. The QOL assessment utilizing the FACT-
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FWB+PWB and MMS instruments will first be administered at 
registration (+ 7 days) prior to initiation of treatment or observation. 
During the treatment or observation period, QOL will be measured 
every 6 cycles (day end + 7 days) and at the end of treatment or 
observation (+ 14 days). For patients that discontinue protocol therapy 
or go off observation early not due to disease progression, QOL will 
also be assessed at the next quarterly Long Term follow-up visit (+ 14 
days). After this, these patients will not be followed further for QOL. 
Patients will be asked to complete the QOL questionnaire just prior to 
meeting with health care providers at scheduled visits. This should 
reduce the impact of health care related information upon perceived 
QOL. 
The FACT-FWB+PWB PRO instrument has 14 items and the score 
ranges from 0-56. The primary endpoint for the QOL study will be 
defined as the mean change of the FACT-FWB+PWB score from 
registration (prior to randomization) to cycle 24. The null hypothesis is 
that the FACT-FWB+PWB mean change score between the two 
groups is the same over this time period. Based on the length of this 
PRO instrument, a minimal absolute difference in means change 
scores of the two arms of 4-6 is considered clinically significant 
between two groups.(70) Nevertheless, for this analysis the difference 
in drug-related QOL must be much greater to overcome a significant 
PFS benefit. The FACT- FWB+PWB domains are reported to have a 
standard deviation (SD) of 11. (Personal Correspondence with K. Yost 
dtd 12.26.08) 
Differences in FACT-FWB+PWB mean change scores between the 
treatment arms from time of registration to cycle 24 that can be 
detected with 80% power are presented in following table. The 
expected hazard rates on each arm served to establish patients alive 
without PD at the end of the interval. Sensitivity for the % of patients 
alive without PD (n=55 patients given expected hazard rates) 
assumed to complete the questionnaire at the end of cycle 24 
(compliance rates of 55%, 70%, 85%), allowing for slightly more 
variability in the instrument (11.0, 12.0) and assuming different 
correlation (0.4, 0.6, 0.8) between repeated measures was performed. 
For example, assuming a SD of 11.0 for the FACT-FWB+PWB, a 
correlation between repeated measures of 0.6 and using a two-sided 
t-test with a 0.05 significance level, there is sufficient power to detect 
a true difference in the FACT-FWB+PWB mean change score 
between the two arms of 7.3-9.2. Given our chosen interval for the 
primary endpoint and the reduced sample size with the redesign, we 
will only be able to detect large differences in mean change score 
between arms at expected compliance rate (70%). 
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Differences detected with 80% power between Treatment Arms in Mean Change 
Score from Registration to end of Cycle 24: FACT-FWB+PWB 
 
standard 
deviation 
(SD) 
correlation 
SD of 
change 
55% 
compliance 
n=30 
70% 
compliance 
n=38 
85% 
compliance 
n=56 
11.0 
0.4 
12.05 
11.2 
9.9 
9.0 
  
0.6 
9.84 
9.2 
8.1 
7.3 
  
0.8 
6.96 
6.5 
5.7 
5.2 
12.0 
0.4 
13.15 
12.2 
10.8 
9.8 
  
0.6 
10.73 
10.0 
8.8 
8.0 
  
0.8 
7.59 
7.1 
6.2 
5.7 
9.7.2 
Secondary QOL Endpoints 
We will also explore the impact of the differential treatment survival 
(PFS) on the quality of life at certain clinically meaningful time points. 
More specifically, we will first evaluate the difference in the FACT-
FWB+PWB mean scores between patients that experience disease 
progression (PD) and patients who do not experience PD using mixed 
effects model, where the longitudinal scores were collected from the 
following eight intervals: 
· 
Interval 1: (registration prior to randomization – end cycle 6) 
· 
Interval 2: (beg cycle 7 - end cycle 12) 
· 
Interval 3: (beg cycle 13 - end cycle 18) 
· 
Interval 4: (beg cycle 19 - end cycle 24) 
· 
Interval 5: (beg cycle 25 - end cycle 30) 
· 
Interval 6: (beg cycle 31 - end cycle 36) 
· 
Interval 7: (beg cycle 37 - end cycle 42) 
· 
Interval 8: (beg cycle 43 - end cycle 48) 
Patients are included in the analysis of an interval if they have not 
failed up to the beginning of the interval. During an interval, for those 
patients that experience PD or discontinue treatment due to other 
reasons, the QOL assessment at the time of progression/ 
discontinuation will be used and for those who survive the interval, the 
QOL assessment at the end of the interval is used.  We will also 
perform sensitivity for patients that did experience PD during the 
interval with respect to change in QOL status since last QOL 
assessment. Given the expected high level of missingness in the QOL 
data, we will analyze that data according to the methods described in 
Schluchter and in Schluchter, Greene and Beck.(71, 72)   
These methods take into account the possibility of informative 
missingness by jointly modeling the longitudinal response (here, QOL 
scores) and the time to dropout. 

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9.7.3 
Exploratory QOL Endpoints 
For both the PACT-FWB+PWB and MMS subscales, we will provide 
descriptive statistics and calculate Chronbach’s alpha to assess 
reliability. Further we will assess the differences in the MMS between 
the two arms at cycle 24 visit. We also are interested in the 
relationships between individual elements of the FACT-PWB+FWB 
and the MMS instrument and important clinical measures in an effort 
to discern criterion validity. We will segment patients into clinical 
groups such as ECOG performance status 0-1 vs 2 that we expect to 
have significantly different scores and analyze these relationships with 
1-way multivariate analysis of variance (MANOVA). When MANOVA 
is significant then a univariate analysis of variance is done on each 
dependent variable. 
9.8 
Correlative Studies 
Phase II correlative samples will be used for descriptive stats, assay validation, 
and for preliminary feasibility purposes. 
9.8.1 
Gene Expression Profiling 
GEP will be evaluated at baseline and post-treatment at time of 
progression (or at off-study if patients discontinue protocol therapy for 
reasons other than progression). For patients randomized to the 
lenalidomide arm, comparisons will be made of their baseline GEP 
versus their post-treatment sample drawn as described above at the 
time of progression or off-study. Data preprocessing is the first step in 
microarray data analysis. This entails background adjustment, 
normalization (e.g., scaling and quantile normalization), and 
summarization. These tasks can be accomplished using various 
software such as MAS 5.0 from Affy, or the R packages affy, 
affycomp, gcrma, and affyPLM. Exploratory analyses will then be 
performed to examine the underlying distributions using box plots, 
density plots, scatter plots, etc. Next differential expression analysis of 
the two groups (baseline vs. off-study) will be performed. Since 
statistical tests will be conducted upon tens of thousands of genes 
simultaneously, the false discovery rate (FDR) will be used to control 
the percentages of false positives among selected genes.(73) 
Relevant tools for differential expression analysis include permutation 
procedures, SAM,(74) empirical Bayes methods, q-value, etc.(75, 76) 
Once significant genes have been identified, hierarchical clustering 
analysis will be performed to investigate any relation among the 
selected genes.(77) In this context we will also evaluate the role of 
DKK1 expression. 
All of our calculations for the GEP correlative endpoints assume 
samples are obtained from all patients. To evaluate GEP as a 
prognostic marker, we will evaluate the difference in PFS outcome by 
GEP-defined risk group (high-risk vs standard-risk) within each arm (R 
and Obs) and overall. The table below presents the PFS hazard ratios 
with GEP-defined high risk being an unfavorable subtype that can be 
detected with 80% power assuming a 5% level of significance and 
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exponential distribution of events under various scenarios of high-risk 
subtype prevalence, sample size (overall vs. single arm) and PFS 
event estimates. The event count (n=123 PFS events) assumes the 
GEP analysis is done at 7.5 years from activation parallel with the 
timing of the overall survival analysis. For example, comparing 
patients with a high-risk sub-type to those with standard risk in the 
entire cohort of patients, the log rank test will have 80% power to 
detect a HR of 1.91 or greater if prevalence of high-risk subgroup is 
15%. The HR narrows to 1.67 or greater if the prevalence is as high 
as 35%. Within a single arm, the number of PFS events is estimated 
as half the expected PFS information (n=62 events), 30% less (n=43 
events) or 30% more (n=80 events). For example, comparing patients 
with a high-risk sub-type to those with standard-risk in the a single 
arm and a prevalence of 25%, there is 80% power assuming 0.05 
significance to detect a hazard ratio ranging from 2.02-2.42 depending 
on the events estimate. This improves with greater prevalence. 
Hazard Ratios: GEP Risk Group 
Scenario 
High-Risk subgroup 
prevalence 
N events 
Hazard Ratio (high-risk 
vs. standard-risk) 
alpha 0.05/0.10 
n=180 (all patients) 
 
 
  
10% 
123 
2.11/1.96 
  
15% 
123 
1.91/1.78 
  
20% 
123 
1.80/1.69 
  
25% 
123 
1.73/1.63 
  
30% 
123 
1.69/1.60 
  
35% 
220 
1.67/1.58 
n=90 (R or Obs arm) 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
25% 
43 
2.42/2.21 
 
25% 
62 
2.15/1,98 
  
25% 
80 
2.02/1.87 
  
 
 
 
 
 
 
 
  
 
 
 
We will also explore the treatment effect within each GEP-defined risk 
group but will only be able to detect large treatment effects. The table 
below outlines the hazard ratios (Obs:R) that can be detected with 
80% power assuming 5% significance and exponential distribution of 
events under different prevalence and event scenarios. For example, 
if the high-risk group has a prevalence of 15% and if 90% of patients 
in that group experience a PFS event (13% of total events) then the 
HR is 4.72. If 60% of patients in that group experience a PFS event 
(20% of total events) then the HR is 3.60. 

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Hazard Ratios: Treatment Effect 
Scenario 
High-Risk 
subgroup 
prevalence 
N 
patients 
% Total 
events 
Hazard Ratio  
(Obs vs R) 
alpha 
0.05/0.10 
High-Risk  
 
 
 
  
15% 
27 
13% 
4.72/3.83 
  
15% 
27 
20% 
3.16/2.78 
  
25% 
45 
22% 
3.13/2.72 
  
25% 
45 
33% 
2.41/2.18 
  
35% 
63 
31% 
2.57/2.30 
  
35% 
63 
46% 
2.11/1.94 
Standard-Risk 
 
 
 
  
85% 
286 
87% 
1.73/1.62 
  
85% 
286 
80% 
1.77/1.66 
  
75% 
252 
78% 
1.78/1.68 
  
75% 
252 
67% 
1.87/1.74 
  
65% 
218 
69% 
1.85/1.72 
  
65% 
218 
54% 
2.03/1.87 
9.8.2 
Immune Function 
In a recent SWOG study, immune function as measured by SOX-2 
has been studied. In that patient population, a large difference in 
progression-free survival for SOX-2 positive versus SOX-2 negative 
patients was found. SOX-2 positive patients experience much longer 
progression-free survival (HR=0.15, p=0.01). In this study, we will 
evaluate whether this observation can be generalized. At baseline, 
approximately 2/3 of patients will be SOX-2 negative versus 1/3 of 
patients being SOX-2 positive. Given 33% prevalence of SOX-2 
positive, analysis at 7.5y, and full sample yield, this study has 80% 
power to detect HR of 0.33, 0.43, and 0.50 or lower if the number of 
events in the R-treated arm are n=43 events, n=62 events, and n=80 
events, respectively given 5% significance (0.38, 0.48 and 0.54 with 
10% significance). Changes in immune expression with R therapy will 
be evaluated only by descriptive statistics for hypothesis generation. 
9.8.3 
Radiologic Studies (MRI) 
The presence of focal lesions on MRI has emerged as an important 
predictor of outcome in MM. (11) All consenting patients will undergo 
an MRI scan at baseline in order to evaluate the number of focal 
lesions. The data about the presence of focal lesions on baseline MRI 
studies will be analyzed and correlated with clinical outcome. We will 
analyze the difference in response rates (CR/PR) between R only 
patients with abnormal versus normal MRI using the Fisher’s exact 
test assuming a target overall response rate of 30% and 5% level of 
significance. The Fisher’s exact test will have approximately 89% 
power to detect a difference in response of at least 31% between 
those with abnormal MRI and those without abnormal MRI if the 
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9.8.4 
Cytogenetic Abnormalities 
Based on Dr. Fonseca’s research, patients with t(4;14) or t(14;16) or 
17p13 deletion will be classified as High Risk (“HR-SMM”). In 
symptomatic MM, the prevalence of these cytogenetic abnormalities is 
approximately 25%. Since these abnormalities are believed to occur 
at the onset of disease course, the prevalence in a SMM population 
should also be 25%.  The remainder of the population is classified as 
Standard Risk (“SR-SMM”), with a prevalence of 75%. The primary 
analysis will center on the comparison of HR-SMM to SR-SMM.  Full 
event information for the primary PFS endpoint is n=76 events given 
45 months of accrual and 6 months of follow up.  Assuming overall lab 
sample submission yield of 55% to full event information, we will have 
approximately n=42 events. There will be 80% power with the logrank 
test to detect a hazard ratio (HR) comparing High-Risk vs. Standard-
Risk cytogenetic groups of 2.43 and 2.21 with significance of 5% and 
10%, respectively. The increased risk conferred on the HR-SMM 
population is within expectations. Additionally, distributions by High- 
and Standard-Risk cytogenetic groups will be estimated using the 
method of Kaplan and Meier. Post-treatment samples are collected 
since unlike t4;14 and t14;16, the deletion of 17p- can be late event 
and may be captured only at the time of disease progression. We will 
provide descriptive statistics on data from post-treatment samples. 
9.9 
Gender and Ethnicity  
Based on previous data from E4A03 the anticipated accrual in subgroups defined 
by gender and race is (phase III only): 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
1 
4 
5 
Not Hispanic or Latino 
84 
91 
175 
Ethnic Category: Total of all subjects 
85 
95 
180 
Racial Category 
American Indian or Alaskan Native 
1 
0 
1 
Asian 
2 
0 
2 
Black or African American 
12 
9 
21 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
70 
86 
156 
Racial Category: Total of all subjects 
85 
95 
180 
9.10 
Study Monitoring 
This study will be monitored by the ECOG-ACRIN Data Monitoring Committee 
(DMC). The DMC meets twice each year. For each meeting, all monitored 
studies are reviewed for safety and progress toward completion. When 
appropriate, the DMC will also review interim analyses of outcome data. Copies 
of the toxicity reports prepared for the DMC meetings are included in the study 
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reports prepared for the ECOG-ACRIN group meeting. These group meeting 
reports are made available to the local investigators, who may provide them to 
their IRBs. Only the study statistician and the DMC members will have access to 
interim analyses of outcome data. Prior to completion of this study, any use of 
outcome data will require approval of the DMC. Any DMC recommendations for 
changes to this study will be circulated to the local investigators in the form of 
addenda to this protocol document. A complete copy of the ECOG-ACRIN DMC 
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10. 
Correlative Studies 
NOTE: 
An informed consent must be signed prior to the submission of any samples 
for any laboratory studies and/or banking.  Samples for the optional 
laboratory studies and/or banking should be submitted only from patients who 
have given written consent for the use of their samples for these purposes.  
NOTE:  
Institutions outside of the United States and Canada must confer with the 
receiving laboratory and the ECOG-ACRIN Operations Office - Boston 
regarding logistics for submission of fresh samples. 
NOTE:  
ECOG-ACRIN requires that all biological samples submitted be entered and 
tracked via the online ECOG-ACRIN Sample Tracking System.  An STS 
shipping manifest form must be generated and shipped with the sample 
submissions. See Section 10.5.  
10.1 
Bone Marrow and Peripheral Blood for Laboratory Studies at Mayo Clinic 
The goal of the planned laboratory correlative studies is to better understand the 
impact of certain cytogenetic characteristics with differential risk of progression 
given respective treatments. Specifically, we will evaluate the impact of the high-
risk cytogenetics which includes patients with t(4;14)(p16;q32), t(14;16) 
(q32;q23), and those having 17p deletions, all of which we hypothesize will 
adversely affect the risk of progression.   
Biologic features of patients will be performed by assessing the molecular 
cytogenetic category by FISH.  This analysis will be performed at the Mayo Clinic 
– Arizona, under the direction of Dr. Rafael Fonseca. 
The slide based bone marrow plasma cell labeling index (PCLI) is now being 
determined by a cytometric flow procedure (PCPRO). This technique provides 
identification of clonal plasma cells and cells in S-phase of the cell cycle. 
Circulating plasma cells will be assessed by a CD38/CD45 immunofluorescence 
flow cytometry assay. 
The Beta-2-Microglobulin levels are ascertained using an automated system 
based on nephelometry. 
These studies will be performed at the ECOG-ACRIN Myeloma Reference Core 
Laboratory at Mayo Clinic. 
10.1.1 
Sample Submission Schedule   
Collect samples of peripheral blood, bone marrow aspirates and bone 
marrow core biopsy slides at: 
· 
Preregistration  
· 
At study discontinuation or progression, whichever comes first 
NOTE:  
Pre-study samples for research should be collected at the 
same time as the diagnostic blood and bone marrow 
studies that are required to establish the diagnosis of 
myeloma and determine eligibility. Additional procedures to 
collect the research specimens should not be required. 
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10.1.2 
Sample Preparation Guidelines  
Myeloma Tumor Biology Kits are available to order, and will include 
materials necessary for the preparation and shipment of samples. 
Three separate kits will be provided per time point for the samples 
being sent to Mayo Clinic, University of Arkansas, and Yale 
University. 
Kits should be ordered at least 24 hours in advance of each sample 
time point. To order kits call Kim Henderson - Mayo Myeloma Clinic 
Reference Laboratory at (507) 284-3805 or e-mail 
henderson.kimberly@mayo.edu. 
Any questions concerning sample collection and shipments can be 
directed to Kim Henderson - Mayo Reference Laboratory at (507) 
284-3805. 
10.1.2.1 
Peripheral Blood 
Draw 14 mL of peripheral blood into two (2) ACD 
Vacutainer tubes (yellow top). Provided in the kit. Ship day 
of collection. 
Collect 5-7 mL of peripheral blood into red top serum 
separator tube (e.g., SST®; Becton-Dickinson). Tubes 
must be centrifuged at 1000g for 10 minutes.  
10.1.2.2 
Bone Marrow Aspirate 
This redirect bone marrow aspirate should be drawn at the 
same time that a bone marrow aspiration/ biopsy is being 
done for clinical and diagnostic purposes and should be 
done through the same skin puncture site that the clinical 
sample was obtained. 
Draw one (1) 7mL of redirect bone marrow aspirate into an 
ACD vacutainer tube (yellow top). 
10.1.2.3 
[Deleted in Add#7] 
10.1.2.4 
Bone Marrow Core Biopsy Slides 
5 air-dried, unstained “charged” slides from the paraffin 
block of the bone marrow core biopsy. EXCEPTION: Core 
biopsy slides can be mailed later if they are not available at 
the time of shipping. 
10.1.3 
Shipping Guidelines 
Log the samples into the ECOG-ACRIN Sample Tracking System 
(STS) the day of shipment. If the STS is unavailable, an Generic 
Specimen Submission Form (#2981) must be submitted with the 
samples, along with the Patient Information Form (Appendix III). Once 
STS is available, retroactively log the shipment into STS using the 
actual collection and shipping dates. 
If your shipment was not logged into the ECOG-ACRIN STS please 
call Kim Henderson at (507) 284-3805 or e-mail 
Henderson.Kimberly@mayo.edu to notify the laboratory when 
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samples are being shipped. Indicate the ECOG-ACRIN protocol 
number, the FedEx tracking number, and name and phone number of 
the contact person. 
Samples are to be shipped day of collection. The specimens from 
multiple patients may be shipped together, but must be placed in 
separately labeled tubes and bags. All specimens must be clearly 
labeled with the protocol number E3A06, the patient’s initials (last 
name, first name), ECOG-ACRIN patient ID number, date of 
collection, and type of sample (PB or BM). A current white blood 
count and differential should be included with each submission, 
entered via the Sample Tracking System. 
Specimens should be mailed the day they are obtained and shipped 
overnight to arrive during normal working hours. Follow packing 
guidelines listed in the kits. If samples are sent late in the week and 
will arrive on the weekend, please note “Saturday Delivery” on the 
Federal Express form.  
FRIDAY AND PRE-HOLIDAY SHIPMENTS SHOULD BE AVOIDED. 
It is requested that the bone marrow core biopsy slides be sent with 
the other samples in the Myeloma Tumor Biology Kit. However, they 
may be shipped separately, within one month of the collection, if they 
cannot be prepared on the same day as the other samples are 
collected. 
Complete the specimen ID label on each tube. Each tube must be 
clearly labeled. Each sample should be labeled with the protocol 
number E3A06, the patient’s initials (last name, first name), ECOG-
ACRIN patient ID number and sample type (peripheral blood (PB) or 
bone marrow (BM)). 
· 
Place the slightly thawed Kool-PAK in bottom of Styrofoam 
container (Kool-PAK should be frozen at least 24 hours in 
advance. Allow the frozen ice pack to thaw at room temperature 
for 2-3 hours before preparing the specimen for shipment). 
· 
Place absorbent toweling on top of the Kool-PAK. 
· 
Place specimens in their individual plastic bags provided, wrap in 
paper toweling and place them in the Styrofoam container and 
close the lid. Do not place the specimen(s) directly on the ice 
pack. 
· 
Place the Styrofoam container and the Sample Tracking System 
Shipping Manifest Form within the cardboard mailing sleeve. 
· 
Prepare the package for shipping, applying packing tape as 
needed. Complete the sender portion of the return FedEx Air bill 
and adhere to the exterior lid of the box. Ship specimens priority 
overnight delivery the same day collected. 
· 
Notify Federal Express for pick-up and/or leave package at the 
designated FedEx drop-off location. 
Please call Kim Henderson at (507) 284-3805 or email 
henderson.kimberly@mayo.edu to notify the Mayo Clinic Myeloma 
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Reference Laboratory when specimen(s) are being shipped. The 
samples in the Myeloma Tumor Biology kit should be shipped to the 
following: 
Kim Henderson 
Mayo Clinic Myeloma Reference Laboratory 
613 Stabile 
200 First Street Southwest 
Rochester, MN 55905 
An STS shipping manifest form must be generated and shipped with 
all sample submissions. 
Samples shipped to the Mayo Clinic Myeloma Reference Laboratory 
will be used for studies done at the Tumor Biology Laboratory. 
10.2 
Bone Marrow for Gene Expression Profiling (GEP) – University of Arkansas 
Molecular testing is important in a variety of ways for patients with myeloma.  (1-
6) Gene expression profiling (GEP) has revealed important underlying biology 
such as DKK-1 expression.  (1)  In addition, GEP patterns have allowed the 
identification of 7 molecular subgroups of disease (Zhan et al., 2006) and 
identified both high and low risk disease in these subgroups as well as localizing 
critical genes to particular segments of chromosome 1q and 1p  (2-6)   
GEP analysis of CD138 purified plasma cells will be performed to determine the 
disease subtype and risk category patients fall into using the molecular 
classification model as well as the 70-gene risk model developed by Dr. 
Shaughnessy. Multivariate Cox-regression will then be used to determine 
whether the risk-category as determined by the 70-gene model can be validated 
in the cooperative-group setting. 
New unpublished data from Dr. Epstein’s laboratory have now also identified 
genes expression patterns in whole bone biopsies that are predictive of outcome 
that is capable of detecting more high risk than identified with the 70-gene model 
on purified plasma cells. This is a potentially important advance in the use of 
GEP in the clinical management of the disease as biopsies do not require 
extensive processing as bone marrow biopsies do not require the extensive 
processing required for isolating tumor cells from bone marrow aspirates and can 
be flash frozen at the time of procurement and shipped to the core facility. Thus, 
GEP of tumor cells and whole bone biopsies in the intergroup setting will be 
performed with the following sub-aims: 
1) To determine whether GEP signatures, i.e. 7-group model, DKK1, high-risk 
as defined by a validated 70-gene GEP model, of tumor cells isolated from 
bone marrow aspirates taken at enrollment exhibit significant associations 
with EFS/OS in the lenalidomide arm and/or rate progression in the 
observational arm.  
2) To determine whether GEP signatures of the bone microenvironment derived 
from whole bone biopsies can be related to EFS/OS on the lenalidomide arm 
and/or progression in the observational arm. 
3) Determine whether a 20-gene risk signature derived from whole biopsies 
from patients on TT3 can be predictive of outcome following lenalidomide 
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treatment and if the same score is related to risk of progression in the 
observational arm 
4) Once in CR or n-CR, use GEP of whole bone biopsies to determine whether 
the “normalization” of GEP signatures can be used as an indication of 
profound tumor cytoreduction with durable EFS. 
Gene expression profiling has emerged as a powerful means of disease 
classification and risk stratification in multiple myeloma.  Dr. Shaughnessy and 
the University of Arkansas Medical Sciences have previously identified and 
validated the existence of 7 distinct subtypes of myeloma each exhibiting distinct 
clinical features and survival times.  They have also recently defined and 
validated in numerous trial settings, the existence of a high risk entity present in 
approximately 15-20% of newly diagnosed disease, that is not benefiting from 
any of the current treatment strategies employed. In a comparison of the 
outcomes of these various molecular entities in newly diagnosed disease treated 
on the clinical trials Total Therapy 2 versus Total Therapy 3, they have shown 
that while high risk disease within each of the 8 molecular entities does not 
benefit from the changes in protocol design in Total Therapy 3, e.g. addition of 
Velcade upfront and throughout therapy and shorted induction and consolidation 
time frames, the low risk form of the MS or t(4;14)-positive disease is 
experiencing a dramatic benefit in both EFS and OS (Pineda et al., 2007 or 8).  
Moreover, exciting new data is emerging that suggests that GEP signatures of 
the tumor and its microenvironment, as seen in the analyses of whole biopsies, 
can be a strong prognostic variable in TT3 trials at UAMS. Thus this study is 
interested in whether the combination of lenalidomide with other new agents will 
have an effect on molecularly defined subgroups and risk groups defined by GEP 
of the tumor cell alone and tumor-host microenvironment, with the hope that its 
inclusion will benefit high-risk disease.  Finally, unpublished data emerging from 
the S0120 trial suggests that elevated expression of the gene coding for DKK1 is 
significantly correlated with the risk of progression of MGUS/SMM to 
symptomatic MM.  Expression of DKK1 mRNA in tumor cells and DKK1 protein in 
BM serum isolated from E3A06 will be correlated with bone disease and 
outcome. 
This analysis will be performed at the University of Arkansas, under the direction 
of Dr. Joshua Epstein. 
10.2.1 
Sample Submission Schedule 
Collect samples of bone marrow aspirate and bone marrow biopsy 
core at: 
· 
Preregistration 
· 
At study discontinuation or progression, whichever comes first 
NOTE: 
Pre-study samples for research should be collected at the 
same time as the diagnostic blood and bone marrow 
studies that are required to establish the diagnosis of 
myeloma and determine eligibility. Additional procedures to 
collect the research specimens should not be required. 
To obtain a high quality sample not affected by dilution 
effects from PBL contamination, the gene array sample 
should be taken as part of diagnostic marrow. Making sure 
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that the sample is taken with diagnostic sample will 
increase the likelihood that sufficient number of malignant 
CD138-positive tumor cells will be isolated and therefore 
preclude a request for another sample.  If there are 
insufficient plasma cells in the sample to perform gene 
array, an additional bone marrow pull may be requested. 
10.2.2 
Sample Preparation Guidelines 
All submitted specimens must be labeled with the ECOG-ACRIN 
protocol number (E3A06), ECOG-ACRIN patient ID number, patient’s 
initials (last name, first name), and date of specimen collection, also 
note on label “for separation for GEP.” 
Kits are available to order for the collection and shipment of the 
samples, please refer to Section 10.1.2 for guidelines and Appendix 
IV “Bone Marrow Aspirate Kit University of Arkansas” and Appendix XI 
“Bone Marrow Core Biopsy Kit University of Arkansas” for specimen 
checklist and shipping instructions. 
10.2.2.1 
Bone Marrow Aspirate 
Bone Marrow (BM) should be drawn from iliac crest so that 
it is immediately diluted in EDTA anticoagulant.  BM, 10-
20mL, should be drawn at a ratio of 4:1 - BM to EDTA.  
Sample should be gently mixed and immediately stored on 
ice.  BM should be tightly packed with wet ice in Styrofoam 
cooler.  The samples should be in the center of cooler 
volume so that ice is on all sides. Sample should be 
shipped priority overnight.  Because of shipping and 
receiving requirements, bone marrow aspirates should 
not be taken on Fridays, Saturdays or Sundays.  All 
specimens should be drawn and shipped Monday - 
Thursday. 
 
10.2.2.2 
Bone Marrow Biopsy Core 
A portion of the bone marrow biopsy core should be 
submitted for research genomic evaluation studies.  Bone 
marrow biopsy core of sufficient length (1-2cm) should be 
taken prior to the aspirate.  PBL is removed by touching 
to sterile swab and placed in 1.5 ml chilled eppendorf 
cyrotube. Bone marrow biopsy cores must be snap-frozen 
immediately after resection by dropping into liquid nitrogen 
(if possible) or placed in dry ice.  The frozen cores should 
then be transferred into a tube that has been kept on dry 
ice to prevent thawing of the core, and either immediately 
shipped on dry ice or stored at -70°C and batch shipped at 
a later date on dry ice via Federal Express. 
10.2.3 
Shipping Guidelines 
Log the samples into the ECOG-ACRIN Sample Tracking System 
(STS) the day of shipment. If the STS is unavailable, an Generic 
Specimen Submission Form (#2981) must be submitted with the 

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samples.  Once STS is available, retroactively log the shipment into 
STS using the actual collection and shipping dates. 
Samples are to be shipped day of collection. The specimens from 
multiple patients may be shipped together, but must be placed in 
separately labeled tubes and bags.  
Specimens should be mailed the day they are obtained and shipped 
overnight to arrive during normal working hours. Specimens must be 
mailed Sunday through Wednesday using Federal Express or other 
overnight priority delivery to arrive on Monday through Thursday (no 
later than 12:00 p.m. on Thursday) Follow packing guidelines listed in 
the kits.  
Aspirate sample should be shipped overnight courier on wet ice 
ensuring that enough ice or cold packs are present so that the 
sample will never go to room temperature. 
Biopsies must be shipped by overnight courier with sample 
buried in dry ice. 
FRIDAY AND PRE-HOLIDAY SHIPMENTS SHOULD BE AVOIDED. 
1. The specimen must be wrapped in an absorbable material. 
2. The specimen must be placed in an AIRTIGHT container (like a 
re-sealable bag). 
3. Pack the re-sealable bag and specimen in a Styrofoam shipping 
container. 
4. Pack the Styrofoam shipping container in a cardboard box. 
5. The cardboard box must be marked as "BIOHAZARD". 
Please contact Shayu Deshpande at sdeshpande@uams.edu or (501) 
526-6990 ext. 8941 to notify them when specimen(s) are being 
shipped. 
Bone marrow specimens for GEP should be shipped to the following 
address: 
University of Arkansas for Medical Sciences 
Attn: Shayu Deshpande 
Rockefeller Cancer Institute, Room 940 
4301 W Markham, Slot 724 
Little Rock, AR 72205-7199 
Phone: (501) 526-6990 ext. 8941 
An STS shipping manifest form must be generated and shipped with 
all sample submissions. 
10.3 
Specimens for Immunology Testing – Yale University 
Studies from the Dhodapkar lab and others have extensively characterized the 
changes in immune effector cells in MM. Immune system is currently thought to 
be a major target of these “immune modulatory drugs”, although the precise 
mechanism of the effects and their correlation with clinical outcome remains 
unclear. Most studies with revlimid in MM now utilize combination therapies. 
Therefore the effects of the drug are difficult to ascertain. As discussed 
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previously, this trial therefore provides an unprecedented opportunity to 
prospectively evaluate this issue in the context of a controlled study with single 
agent revlimid. Two aspects are of particular interest in this trial. 
· 
Changes in antigen specific T cell function, particularly those against stem 
cell associated antigens such as SOX2, and selected cancer-testis antigens 
(7-9). T cell immunity will be analyzed using overlapping peptide libraries 
using methods as described previously.  
· 
Changes in number and activation status of natural killer and natural killer T 
(NKT) cells, analyzed using flow cytometry, using methods as described 
previously by the Dhodapkar lab. (10,11)  
The presence of spontaneous T cell immunity to SOX2, an embryonal stem cell 
antigen that marks putative stem cells in MM, correlates with risk of progression.  
We hypothesize that these features will correlate with response to Revlimid and 
risk of disease progression. Finally, this trial also provides an unprecedented 
opportunity to evaluate the changes in immune effector cells as well as changes 
in gene expression in response to single agent Revlimid in patients with early 
MM.   
This analysis will be performed at Yale University, under the direction of Dr. 
Madhav Dhodapkar. 
10.3.1 
Sample Submission Schedule 
Collect samples of peripheral blood and bone marrow aspirate at: 
· 
Preregistration 
· 
At study discontinuation or progression (whichever comes first) 
NOTE:  
Pre-study samples for research should be collected at the 
same time as the diagnostic blood and bone marrow 
studies that are required to establish the diagnosis of 
myeloma and determine eligibility. Additional procedures to 
collect the research specimens should not be required. 
10.3.2 
Sample Preparation Guidelines 
All submitted specimens must be labeled with the ECOG-ACRIN 
protocol number (E3A06), ECOG-ACRIN patient ID number, patient’s 
initials, and date of specimen collection. 
Kits are available to order for the collection and shipment of the 
samples, please refer to Section 10.1.2 for guidelines and Appendix X 
“Bone Marrow Aspirate and Peripheral Blood Kit-Yale University” for 
specimen checklist and shipping instructions. 
· 
Peripheral blood: Collect four (4) 10mL green top tubes (sodium 
heparin anti-coagulant). 
· 
Bone marrow aspirate: Collect 5-10mL of bone marrow aspirate in 
one (1) sodium heparin coagulant (green top tube). 
Questions regarding immunology specimens/shipment should be 
directed to Lin Zhang at (203) 737-5176 or lin.zhang@yale.edu. 
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10.3.3 
Shipping Guidelines 
Log the samples into the ECOG-ACRIN Sample Tracking System 
(STS) the day of shipment. If the STS is unavailable, an Generic 
Specimen Submission Form (#2981) must be submitted with the 
samples.  Once STS is available, retroactively log the shipment into 
STS using the actual collection and shipping dates. 
The specimens should be shipped the same day as collection.  The 
specimens from multiple patients may be shipped together, but must 
be placed in separately labeled tubes and bags.  Follow packing 
guidelines listed in the kits.  
Specimens must be mailed on Sunday through Wednesday using 
EshipGlobal to arrive on Monday through Thursday (no later than 
12:00 p.m. on Thursday). Avoid Friday or preholiday shipments. 
Tubes should be sent at room temperature (NOT frozen). 
Please contact Lin Zhang at the Dhodapkar lab at (203) 737-5176 or 
lin.zhang@yale.edu prior to sending the shipment as she will need to 
print the shipping label and either fax or e-mail to the person sending 
the samples to the lab. 
Specimens should be submitted to: 
Madhav Dhodapkar, M.D. – Yale University 
Dhodapkar Lab 
Nathan Smith Bldg, Room NSB-287B 
Yale School of Medicine 
333 Cedar Street 
New Haven, CT 06510 
An STS shipping manifest form must be generated and shipped with 
all sample submissions. 
10.4 
Banking 
The residuals and/or derivatives of samples collected for this study will be 
retained at the Mayo Tumor Biology Laboratory for possible use in future ECOG-
ACRIN approved studies. If future use is denied or withdrawn by the patient, the 
samples will be removed for consideration for use in any future study. 
10.5 
ECOG-ACRIN Sample Tracking System 
It is required (barring special circumstances) that all samples submitted on this 
trial be entered and tracked using the ECOG-ACRIN Sample Tracking System 
(STS). The software will allow the use of either 1) an ECOG-ACRIN user-name 
and password previously assigned (for those already using STS), or 2) a CTSU 
username and password. 
When you are ready to log the collection and/or shipment of the samples 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst 
Important: Please note that the STS software creates pop-up windows, so you 
will need to enable pop-ups within your web browser while using the software. A 
user manual and interactive demo are available by clicking this link: 
Rev. 7/13, 12/13 
Rev. 12/13, 
7/14 
Rev. 12/13 

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http://www.ecog.org/general/stsinfo.html. Please take a moment to familiarize 
yourself with the software prior to using the system. 
A shipping manifest form must be generated and shipped with all sample 
submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu. 
10.5.1 
Study Specific Notes 
10.5.1.1 
An Generic Specimen Submission Form (#2981) will be 
required only if STS is unavailable at time of sample 
submission. Indicate the appropriate Lab ID # on the 
submission form: 
· 
0005 = ECOG-ACRIN Myeloma Core Laboratory 
· 
159 = University of Arkansas 
· 
158 = Yale University 
Retroactively enter all collection and shipping information 
when STS is available. 
10.6 
Sample Inventory Submission Guidelines  
Inventories of all samples collected, aliquoted, and used on the above mentioned 
laboratory correlative studies will be submitted electronically by secure web 
application to the ECOG-ACRIN Operations Office - Boston on a monthly basis, 
or upon request by any laboratory holding and/or using any specimens 
associated with this study. 
10.7 
Lab Data Transfer Guidelines  
The data collected or generated on the above mentioned laboratory correlative 
studies will be submitted electronically via secure data portal to the ECOG-
ACRIN Operations Office - Boston by the central laboratories on a quarterly 
basis. The quarterly cut-off dates are March 31, June 30, September 30 and 
December 31. 
Rev. 2/12 
Rev. 2/12 
Rev. 2/12 
Rev. 2/12 
Rev. 12/13 

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11. 
Records to Be Kept 
Please refer to the E3A06 Forms Packet for the forms submission schedule and copies 
of all forms. The E3A06 Forms Packet may be downloaded by accessing the ECOG 
World Wide Web Home Page (http://www.ecog.org). Forms must be submitted to the 
ECOG-ACRIN Operations Office - Boston, FSTRF, 900 Commonwealth Avenue, 
Boston, MA 02215 (ATTN: DATA). 
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office - Boston to CTEP by electronic means. 
11.1 
Records Retention  
FDA regulations (21 CFR 312.62) require clinical investigators to retain all trial-
related documentation, including source documents, long enough to allow the 
sponsor to use the data to support marketing applications. 
This study will be used in support of a US marketing application (New Drug 
Application), all records pertaining to the trial (including source documents) must 
be maintained for: 
· 
two years after the FDA approves the marketing application, or 
· 
two years after the FDA disapproves the application for the indication being 
studied, or 
· 
two years after the FDA is notified by the sponsor of the discontinuation of 
trials and that an application will not be submitted.  
Please contact the ECOG-ACRIN Operations Office - Boston prior to destroying 
any source documents. 
12. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
13. 
References 
1. 
Kyle RA, Rajkumar SV. Multiple Myeloma. Blood 2008; 111:2962-72. 
2. 
Kyle RA, Rajkumar SV. Multiple Myeloma. N Engl J Med 2004; 351:1860-73. 
3. 
Rajkumar SV, Kyle RA. Plasma Cell Disorders. In: Goldman L, Ausiello D, editors. 
Cecil Textbook of Medicine, 23rd Edition. Philadephia: Saunders; 2007. p. 1426-37. 
4. 
Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory 
multiple myeloma [see comments]. New England Journal of Medicine 1999; 
341:1565-71. 
5. 
Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in 
relapsed, refractory myeloma. N Engl J Med 2003; 348:2609-17. 
6. 
Richardson PG, Schlossman RL, Weller E, et al. Immunomodulatory drug CC-5013 
overcomes drug resistance and is well tolerated in patients with relapsed multiple 
myeloma. Blood 2002; 100:3063-7. 

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Version Date: September 26, 2019 
 
NCI Update Date: February 3, 2016 
86 
7. 
Hideshima T, Anderson KC. Molecular mechanisms of novel therapeutic 
approaches for multiple myeloma. Nature Reviews Cancer 2002; 2:927-37. 
8. 
Rajkumar SV, Mesa RA, Fonseca R, et al. Bone marrow angiogenesis in 400 
patients with monoclonal gammopathy of undetermined significance, multiple 
myeloma, and primary amyloidosis. Clin Cancer Res 2002; 8:2210-6. 
9. 
Dimopoulos MA, Moulopoulos LA, Maniatis A, Alexanian R. Solitary plasmacytoma 
of bone and asymptomatic multiple myeloma. Blood 2000; 96:2037-44. 
10. Kyle RA, Rajkumar SV. Plasma Cell Disorders. In: Goldman L, Ausiello D, editors. 
Cecil Textbook of Medicine, 22nd Ed. Philadelphia: W. B. Saunders; 2004. p. 1184-
95. 
11. Kyle RA, Greipp PR. Smoldering multiple myeloma. N Engl J Med 1980; 302:1347-
49. 
12. Kyle RA, Remstein ED, Therneau TM, et al. Clinical Course and Prognosis of 
Smoldering (Asymptomatic) Multiple Myeloma. N Engl J Med 2007; 356:2582-90. 
13. Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of Monoclonal 
Gammopathy of Undetermined Significance. N Engl J Med 2006; 354:1362-9. 
14. Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis of 
monoclonal gammopathy of undetermined significance. N Engl J Med 2002; 
346:564-69. 
15. The International Myeloma Working Group. Criteria for the classification of 
monoclonal gammopathies, multiple myeloma and related disorders: a report of the 
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16. Rajkumar SV, Dispenzieri A, Fonseca R, et al. Thalidomide for previously untreated 
indolent or smoldering multiple myeloma. Leukemia 2001; 15:1274-76. 
17. Rajkumar SV, Dispenzieri A, Kyle RA. Monoclonal gammopathy of undetermined 
significance, Waldenstrom macroglobulinemia, AL amyloidosis, and related plasma 
cell disorders: diagnosis and treatment. Mayo Clinic Proceedings 2006; 81:693-703. 
18. Wang M, Alexanian R, Delasalle K, Weber D. Abnormal MRI of spine is the 
dominant risk factor for early progression of asymptomatic multiple myeloma. Blood 
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19. Witzig TE, Kyle RA, WM OF, Greipp PR. Detection of peripheral blood plasma cells 
as a predictor of disease course in patients with smoldering multiple myeloma. 
British Journal of Haematology 1994; 87:266-72. 
20. Weber DM, Dimopoulos MA, Moulopoulos LA, Delasalle KB, Smith T, Alexanian R. 
Prognostic features of asymptomatic multiple myeloma. Br J Haematol 1997; 
97:810-4. 
21. Dimopoulos MA, Moulopoulos A, Smith T, Delasalle KB, Alexanian R. Risk of 
disease progression in asymptomatic multiple myeloma. Am-J-Med 1993; 94:57-61. 
22. Mariette X, Zagdanski AM, Guermazi A, et al. Prognostic value of vertebral lesions 
detected by magnetic resonance imaging in patients with stage I multiple myeloma. 
Br J Haematol 1999; 104:723-9. 

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Version Date: September 26, 2019 
 
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87 
23. Dispenzieri A, Kyle RA, Katzmann JA, et al. Immunoglobulin free light chain ratio is 
an independent risk factor for progression of smoldering (asymptomatic) multiple 
myeloma. Blood 2008; 111:785-9. 
24. Rajkumar SV, Mesa R, Fonseca R, et al. Bone marrow angiogenesis in 400 patients 
with monoclonal gammopathy of undetermined significance (MGUS), smoldering 
myeloma (SMM), active myeloma (MM), relapsed myeloma (RMM) and primary 
amyloidosis (AL). Blood 2000; 96:836a (A3612). 
25. Rajkumar SV, Gertz MA, Lacy MQ, et al. Thalidomide as initial therapy for early-
stage myeloma. Leukemia 2003; 17:775-9. 
26. Hideshima T, Chauhan D, Shima Y, et al. Thalidomide and its analogs overcome 
drug resistance of multiple myeloma cells to conventional therapy. Blood 2000; 
96:2943-50. 
27. Zangari M, Tricot G, Zeldis J, Eddlemon P, Saghafifar F, Barlogie B. Results of 
Phase I Study of CC-5013 for the Treatment of Multiple Myeloma (MM) Patients 
Who Relapse after High Dose Chemotherapy (HDCT). Blood 2001:775a (A3226). 
28. Richardson P, Jagannath S, Schlossman R, et al. A Multi-center, Randomized, 
Phase 2 Study to Evaluate the Efficacy and Safety of 2 CDC-5013 Dose Regimens 
When Used Alone or in Combination with Dexamethasone (Dex) for the Treatment 
of Relapsed or Refractory Multiple Myeloma (MM). Blood 2003; 102:235a. 
29. Dimopoulos M, Weber D, Chen C, et al. Evaluating oral lenalidomide (Revlimid-) 
and dexamethasone versus placebo and dexamethasone in patients with relapsed 
or refractory multiple myeloma. Haematologica 2005; 90 (s2):160 (Abstract 0402). 
30. Rajkumar SV, Hayman SR, Lacy MQ, et al. Combination therapy with lenalidomide 
plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 2005; 
106:4050-3. 
31. Lacy MQ, Gertz MA, Dispenzieri AA, et al. Long-term Results of Response to 
Therapy, Time to Progression, and Survival With Lenalidomide Plus 
Dexamethasone in Newly Diagnosed Myeloma. Mayo Clin Proc 2007; 82:1179-84. 
32. Rajkumar SV, Jacobus S, Callander N, et al. A Randomized Trial of Lenalidomide 
Plus High-Dose Dexamethasone (RD) Versus Lenalidomide Plus Low-Dose 
Dexamethasone (Rd) in Newly Diagnosed Multiple Myeloma (E4A03): A Trial 
Coordinated by the Eastern Cooperative Oncology Group. ASH Annual Meeting 
Abstracts 2007; 110:74. 
33. Kumar S, Dispenzieri A, Lacy MQ, et al. Impact of lenalidomide therapy on stem cell 
mobilization and engraftment post-peripheral blood stem cell transplantation in 
patients with newly diagnosed myeloma. Leukemia 2007; 21:2035-42. 
34. Niesvizky R, Jayabalan DS, Christos PJ, et al. BiRD 
(Biaxin(R)[clarithromycin]/Revlimid(R)[lenalidomide]/dexamethasone) combination 
therapy results in high complete- and overall-response rates in treatment-naive 
symptomatic multiple myeloma. Blood 2007; 111:1101-9. 
35. Richardson P, Jagannath S, Raje N, et al. Lenalidomide, Bortezomib, and 
Dexamethasone (Rev/Vel/Dex) as Front-Line Therapy for Patients with Multiple 
Myeloma (MM): Preliminary Results of a Phase 1/2 Study. ASH Annual Meeting 
Abstracts 2007; 110:187-. 

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Version Date: September 26, 2019 
 
NCI Update Date: February 3, 2016 
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36. Richardson PG, Blood E, Mitsiades CS, et al. A randomized phase 2 study of 
lenalidomide therapy for patients with relapsed or relapsed and refractory multiple 
myeloma 10.1182/blood-2006-04-015909. Blood 2006; 108:3458-64. 
37. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus Dexamethasone for 
Relapsed Multiple Myeloma in North America. N Engl J Med 2007; 357:2133-42. 
38. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus Dexamethasone for 
Relapsed or Refractory Multiple Myeloma. N Engl J Med 2007; 357:2123-32. 
39. Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with 
dexamethasone for previously untreated multiple myeloma. Journal of Clinical 
Oncology 2003; 21:16-9. 
40. Richardson P, Jagannath S, Hussein M, et al. Safety and efficacy of single-agent 
lenalidomide in patients with relapsed and refractory multiple myeloma. Blood 2009; 
114:772-8. 
41. Rajkumar SV, Blood E. Lenalidomide and Venous Thrombosis in Multiple Myeloma. 
N Engl J Med 2006; 354:2080. 
42. List A, Kurtin S, Roe DJ, et al. Efficacy of lenalidomide in myelodysplastic 
syndromes.[see comment]. New England Journal of Medicine 2005; 352:549-57. 
43. Bartlett JB, Tozer A, Stirling D, Zeldis JB. Recent clinical studies of the 
immunomodulatory drug (IMiD) lenalidomide. British Journal of Cancer 2005; 
93:613-9. 
44. Vacca A, Ribatti D, Roncali L, et al. Bone marrow angiogenesis and progression in 
multiple myeloma. British Journal of Haematology 1994; 87:503-8. 
45. Rajkumar SV, Fonseca R, Witzig TE, Gertz MA, Greipp PR. Bone marrow 
angiogenesis in patients achieving complete response after stem cell 
transplantation for multiple myeloma. Leukemia 1999; 13:469-72. 
46. Rajkumar SV, Leong T, Roche PC, et al. Prognostic value of bone marrow 
angiogenesis in multiple myeloma. Clin Cancer Res 2000; 6:3111-16. 
47. Munshi N, Wilson CS, Penn J, et al. Angiogenesis in newly diagnosed multiple 
myeloma: Poor prognosis with increased microvessel density (MVD) in bone 
marrow biopsies. Blood 1998; 92:98a (A400). 
48. Cella DF, Tulsky DS, Gray G, et al. The Functional Assessment of Cancer Therapy 
scale: development and validation of the general measure. Journal of Clinical 
Oncology 1993; 11:570-9. 
49. Kumar S, Witzig TE, Wellik L, Greipp PR, Rajkumar SV. Effect of Thalidomide 
Therapy on Bone marrow Angiogenesis in Multiple Myeloma. Leukemia 2004; 
18:624-7. 
50. Kumar S, Witzig TE, Timm M, et al. Expression of VEGF and its receptors by 
myeloma cells. Leukemia 2003; 17:2025-31. 
51. Kumar S, Witzig TE, Timm M, et al. Bone marrow angiogenic ability and expression 
of angiogenic cytokines in myeloma: Evidence favoring loss of marrow 
angiogenesis inhibitory activity with disease progression. Blood 2004; 104:1159-65. 

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Version Date: September 26, 2019 
 
NCI Update Date: February 3, 2016 
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52. Kumar S, Greipp PR, Haug J, et al. Gene Expression Profiling of Myeloma Cells at 
Diagnosis Can Predict Response to Therapy with Thalidomide and Dexamethasone 
Combination. Blood 2005; 106:152a (A508). 
53. Fonseca R, Harrington D, Oken MM, et al. Biological and prognostic significance of 
interphase Fluorescence is situ hybridization detection of chromosome 13 
abnormalities in multiple myeloma: an Eastern Cooperative Oncology Group Study. 
Cancer Res 2002; 62:715-20. 
54. Fonseca R, Blood E, Rue M, et al. Clinical and biologic implications of recurrent 
genomic aberrations in myeloma. Blood 2003; 101:4569-75. 
55. Nowakowski GS, Witzig TE, Dingli D, Tracz MJ, Greipp PR, Rajkumar SV. 
Circulating plasma cells detected by flow cytometry as a predictor of survival in 
patients with newly diagnosed multiple myeloma. J Clin Oncol (Meeting Abstracts) 
2005; 23:580s (A6580). 
56. Shaughnessy Jr J, Zhan F, Barlogie B, Stewart AK. Gene expression profiling and 
multiple myeloma. Best Practice & Research Clinical Haematology 2005; 18:537-
52. 
57. Shaughnessy JD, Jr, Zhan F, Burington BE, et al. A validated gene expression 
model of high-risk multiple myeloma is defined by deregulated expression of genes 
mapping to chromosome 110.1182/blood-2006-07-038430. Blood 2007; 109:2276-
84. 
58. Zhan F, Barlogie B, Arzoumanian V, et al. Gene-expression signature of benign 
monoclonal gammopathy evident in multiple myeloma is linked to good prognosis 
10.1182/blood-2006-07-037077. Blood 2007; 109:1692-700. 
59. Dhodapkar MV, Krasovsky J, Osman K, Geller MD. Vigorous premalignancy-
specific effector T cell response in the bone marrow of patients with monoclonal 
gammopathy.[see comment]. Journal of Experimental Medicine 2003; 198:1753-7. 
60. Zhan F, Huang Y, Colla S, et al. The molecular classification of multiple myeloma 
10.1182/blood-2005-11-013458. Blood 2006; 108:2020-8. 
61. Spisek R, Kukreja A, Chen LC, et al. Frequent and specific immunity to the 
embryonal stem cell-associated antigen SOX2 in patients with monoclonal 
gammopathy. Journal of Experimental Medicine 2007; 204:831-40. 
62. Dhodapkar MV, Osman K, Teruya-Feldstein J, et al. Expression of cancer/testis 
(CT) antigens MAGE-A1, MAGE-A3, MAGE-A4, CT-7, and NY-ESO-1 in malignant 
gammopathies is heterogeneous and correlates with site, stage and risk status of 
disease. Cancer Immunity 2003; 3:9. 
63. Chang DH, Osman K, Connolly J, et al. Sustained expansion of NKT cells and 
antigen-specific T cells after injection of alpha-galactosyl-ceramide loaded mature 
dendritic cells in cancer patients.[see comment][erratum appears in J Exp Med. 
2007 Oct;204(10):2487]. Journal of Experimental Medicine 2005; 201:1503-17. 
64. Anderson KC, Kyle RA, Rajkumar SV, Stewart AK, Weber D, Richardson P. 
Clinically relevant end points and new drug approvals for myeloma. Leukemia 2007; 
22:231-9. 
65. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am 
Stat Assoc 1958; 53:457-81. 

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Version Date: September 26, 2019 
 
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66. Mantel N. Evaluation of survival data and two new rank order statistics arising in its 
consideration. 1966: Cancer Chemotherapy Reports; 50:163-170. 
67. O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 
1979; 35:549-56. 
68. Jennison C, Turnbull BW. Repeated confidence intervals for group sequential 
clinical trials. Controlled Clinical Trials 1984; 5:33-45. 
69. Cox DR. Regression models and life tables. J R Stat Soc (B) 1972; 34:187-202. 
70. Yost KJ, Eton DT. Combining distribution- and anchor-based approaches to 
determine minimally important differences: The FACT experience. . Evaluation of 
the Health Professions: 2005; 28:172-91. 
71. Schluchter MD. Methods for the analysis of informatively censored longitudinal data. 
Statistics in Medicine 1992; 11:1861-70. 
72. Schluchter MD, Greene T, Beck GJ. Analysis of change in the presence of 
informative censoring: application to a longitudinal clinical trial of progressive renal 
disease. Statistics in Medicine 2001; 20:989-1007. 
73. Hochberg Y, Benjamini Y. More powerful procedures for multiple significance 
testing. Statistics in Medicine 1990; 9:811-8. 
74. Tusher VG, Tibshirani R, Chu G. Significance analysis of microarrays applied to the 
ionizing radiation response.[erratum appears in Proc Natl Acad Sci U S A 2001 Aug 
28;98(18):10515]. Proceedings of the National Academy of Sciences of the United 
States of America 2001; 98:5116-21. 
75. Storey JD, Tibshirani R. Statistical significance for genomewide studies. 
Proceedings of the National Academy of Sciences of the United States of America 
2003; 100:9440-5. 
76. Storey JD, Tibshirani R. Statistical methods for identifying differentially expressed 
genes in DNA microarrays. Methods in Molecular Biology 2003; 224:149-57. 
77. Alon U, Barkai N, Notterman DA, et al. Broad patterns of gene expression revealed 
by clustering analysis of tumor and normal colon tissues probed by oligonucleotide 
arrays. Proceedings of the National Academy of Sciences of the United States of 
America 1999; 96:6745-50. 

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Randomized Phase III Trial of Lenalidomide Versus Observation Alone in Patients with 
Asymptomatic High-Risk Smoldering Multiple Myeloma 
Appendix I 
 
Informed Consent Template for Cancer Treatment Trials (English Language) 
[Deleted in Addendum #7] 
 
INFORMED CONSENT INTENTIONALLY REMOVED FROM 
PROTOCOL DOCUMENT 
Appendix I was removed from the protocol document in Addendum #7 and is posted as a 
separate document on the ECOG website. This was removed from the protocol to comply 
with NCI formatting guidelines. 

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Randomized Phase III Trial of Lenalidomide Versus Observation Alone in Patients with 
Asymptomatic High-Risk Smoldering Multiple Myeloma 
 
Appendix II 
 
Patient Thank You Letter 
[PATIENT NAME] 
 
 
 
 
 
 
 
 
 
[DATE] 
[PATIENT ADDRESS] 
 
 
 
Dear [PATIENT SALUTATION], 
 
 
Thank you for agreeing to take part in this important clinical trial. Trials like this offer a chance to 
get the best care while helping us make better care available for all patients. Many questions 
remain unanswered in myeloma. With the participation of people like you in clinical trials, we will 
improve treatment and quality of life for those with your type of cancer. 
 
We believe this program will provide you with high quality, thorough care.  Your physician and 
research staff will maintain very close contact with you. This is important to allow your physician 
to provide you with the best care while learning as much as possible to help you and other 
patients. 
 
On behalf of [INSTITUTION] and the ECOG-ACRIN Cancer Research Group, we thank you 
again and look forward to helping you. 
 
Sincerely, 
 
 
[PHYSICIAN NAME] 
 
 
Rev. 7/14 

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NCI Update Date: February 3, 2016 
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Randomized Phase III Trial of Lenalidomide Versus Observation Alone in Patients with 
Asymptomatic High-Risk Smoldering Multiple Myeloma 
 
Appendix III 
 
Myeloma Tumor Biology Kit 
Specimen Checklist and Shipping Instructions 
 
** PLEASE AVOID DRAWING OR SENDING SPECIMENS ON FRIDAYS AND HOLIDAYS ** 
Kit Contents: 
· 
5 lb Styrofoam box and cardboard mailing sleeve 
· 
Patient Information Form 
· 
FedEx Airbill with pre-printed return address 
· 
7mL ACD (yellow top) collection tubes 
· 
SST (serum separator tube) collection tube  
· 
[Deleted in Addendum #7] 
· 
Four (4) zip lock specimen bags labeled for bone marrow and peripheral blood 
· 
(1) Ice pack. Place the ice pack in the freezer for at least 24 hours prior to specimen 
shipment. Allow the frozen ice pack to thaw at room temperature for 2-3 hours before 
preparing the specimens for shipment. 
Packing and Shipping Instructions: 
1. Collect the following specimens: 
· 
Peripheral blood – Draw two (2) 7mL ACD tubes (yellow top). 
· 
Peripheral blood – Draw one (1) 7mL SST tube. Centrifuge tube at 1000g for 10 
minutes.  
· 
Bone Marrow aspirate - Draw 7mLs of a ‘redirect’ bone marrow aspirate in one (1) ACD 
tube (yellow top). 
· 
[Deleted in Addendum #7] 
· 
Bone marrow core biopsy slides– 5 air-dried, unstained biopsy slides. Exception:  
Unstained core biopsy slides can be mailed later if they are not available at the time of 
shipping the bone marrow aspirate and peripheral blood. 
2. Place the slightly thawed Kool-PAK in bottom of Styrofoam container. 
3. Place absorbent toweling on top of Kool-PAK. 
4. Place specimens in their individual plastic bags provided, wrap in paper toweling and place 
them in the Styrofoam container and close the lid. Do not place the specimen(s) directly on 
the ice pack. 
5. Place the Styrofoam container and the Sample Tracking System Shipping Manifest Form 
within the cardboard mailing sleeve. 
6. Prepare the package for shipping, applying packing tape as needed.  Complete the sender 
portion of the return FedEx Airbill and adhere to the exterior lid of the box.  Ship specimens 
via overnight delivery the same day collected. 
7. Notify Federal Express for pick-up and/or leave package at the designated FedEx drop-off 
location. 
Rev. 2/12 
Rev. 2/12 
Rev. 2/12, 7/13 
Rev. 2/12 
Rev. 2/12 
Rev. 2/12 
Rev. 7/13 
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The ECOG-ACRIN Sample Tracking System will automatically contact the Myeloma 
Reference Laboratory. If you did not use the ECOG-ACRIN Sample Tracking System 
please call Kim Henderson at (507) 284-3805 or e-mail Henderson.Kimberly@mayo.edu to 
notify the laboratory when samples are being shipped. Indicate the ECOG-ACRIN protocol 
number, the FedEx tracking number, and name and phone number of the contact person. The 
blood samples in prepared kits should be shipped to the following: 
The samples in this prepared kit should be shipped to the following: 
Kim Henderson 
Mayo Clinic Myeloma Reference Laboratory 
613 Stabile 
200 First Street Southwest 
Rochester, MN  55905 
Patient Information Form 
It is required that samples submitted from patients participating in E3A06 be entered and 
tracked via the online ECOG-ACRIN Sample Tracking System (see Section 10.2). This form is 
used only in the event that the STS is inaccessible and then the shipments are to be logged in 
retroactively, indicating the actual dates of collection and shipment. 
Specimen Date:  
  
 
/ 
/ 
 
 
 
 
 
 
Institution/Affiliate:  
 
 
 
 
 
 
 
 
 
 
Physician:   
 
 
 
 
 
 
 
 
 
 
Patient Initials (last name, first name):  
 
 
 
 
 
 
 
ECOG-ACRIN Parent Protocol #:   
 
E3A06  
 
 
 
 
 
ECOG-ACRIN Patient Sequence #:    
 
 
 
 
 
 
 
Contact Person:   
 
 
 
 
 
 
 
 
 
 
Institution:  
 
  
 
 
 
 
 
 
 
 
Address:   
 
 
 
 
 
 
 
 
 
 
 
 
City 
 
 
 
State  
Zip 
 
 
Phone #: 
 
 
 
 
 
 
 
 
 
 
Fax #: 
 
 
 
 
 
 
 
 
 
 
PLEASE INCLUDE A CURRENT WHITE BLOOD COUNT AND DIFFERENTIAL 
WBC:   
 
 
 
 
 
 
 
 
% of Lymphocytes:  
 
 
 
 
 
 
 
 
% of Monocytes:   
 
 
 
 
 
 
 
 
Please indicate which samples are being shipped at this time: 
1. Preregistration  
2. At study discontinuation or progression; whichever comes first 
Any questions concerning these samples, or to obtain a Myeloma Tumor Biology kit, please 
contact:
Rev. 7/14 
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Version Date: September 26, 2019 
 
NCI Update Date: February 3, 2016 
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Kim Henderson 
Mayo Clinic Myeloma Reference Laboratory 
(507) 284-3805 
henderson.kimberly@mayo.edu 
Affiliates who anticipate participating in this study should please call in advance for kits. 
 

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Version Date: September 26, 2019 
 
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Randomized Phase III Trial of Lenalidomide Versus Observation Alone in Patients with 
Asymptomatic High-Risk Smoldering Multiple Myeloma 
 
Appendix IV 
 
Bone Marrow Aspirate Kit – University of Arkansas 
Specimen Checklist and Shipping Instructions 
 
** PLEASE AVOID DRAWING OR SENDING SPECIMENS ON FRIDAYS AND HOLIDAYS ** 
Kit Contents: 
· 
Styrofoam box and cardboard mailing sleeve 
· 
FedEx Airbill with pre-printed return address 
· 
10mL EDTA (purple top) collection tubes 
· 
Zip lock specimen bags  
Packing and Shipping Instructions: 
1. Collect the following specimens: 
· 
Bone Marrow Aspirate - Draw 10-20 ml of a ‘re-direct’ bone marrow aspirate and place in 
EDTA (purple top) tubes.  Samples should be gently mixed and immediately stored 
on ice. 
2. Specimens should be labeled with ECOG-ACRIN protocol number (E3A06), ECOG-ACRIN 
patient ID number, patient’s initials (last name, first name), and date of specimen collection. 
3. Place specimens in their individual plastic bags and place in the Styrofoam cooler tightly 
packed with wet ice OR with cold packs.  Samples should be in the center of the cooler 
so ice is on all sides.  
4. Place the Styrofoam container and the Sample Tracking System Shipping Manifest Form 
within the cardboard mailing sleeve. 
5. Prepare the package for shipping, applying packing tape as needed.  Complete the sender 
portion of the return FedEx Airbill and adhere to the exterior lid of the box.  Ship specimens 
via overnight delivery the same day collected. 
6. Notify Federal Express for pick-up and/or leave package at the designated FedEx drop-off 
location. 
Please contact Shayu Deshpande at sdeshpande@uams.edu or (501) 526-6990 ext. 8941 
to notify them when specimen(s) are being shipped. 
The samples in this prepared kit should be shipped to the following: 
University of Arkansas for Medical Sciences 
Rockefeller Cancer Institute, Room 940 
Attn: Shayu Deshpande 
4301 West Markham, Slot 724 
Little Rock, AR  72205-7199 
 
Rev. 2/12, 
2/16 
Rev. 2/16 

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Randomized Phase III Trial of Lenalidomide Versus Observation Alone in Patients with 
Asymptomatic High-Risk Smoldering Multiple Myeloma 
Appendix V 
 
Patient Pill Diary 
Please use this diary to record your daily protocol medication.  Use the space below marked 
“Comments” to make notes about things you would like to tell the doctor (including unusual 
symptoms you experience, other medicine you have taken, and anything else you think would 
be of interest.) 
Day 
Date 
# of 5 mg 
Lenalidomide 
capsules taken 
# of 25 mg 
Lenalidomide 
capsules taken 
Aspirin daily or 
other 
recommended 
prophylaxis 
Comments 
1  
 
 
 
 
2  
 
 
 
 
3  
 
 
 
 
4  
 
 
 
 
5  
 
 
 
 
6  
 
 
 
 
7  
 
 
 
 
8  
 
 
 
 
9  
 
 
 
 
10  
 
 
 
 
11  
 
 
 
 
12  
 
 
 
 
13  
 
 
 
 
14  
 
 
 
 
15  
 
 
 
 
16  
 
 
 
 
17  
 
 
 
 
18  
 
 
 
 
19  
 
 
 
 
20  
 
 
 
 
21  
 
 
 
 
22  
 
 
 
 
23  
 
 
 
 
24  
 
 
 
 
25  
 
 
 
 
26  
 
 
 
 
27  
 
 
 
 
28  
 
 
 
 
Patient/Administrator Signature:_______________________________ Date: ____________ 
Rev.7/13 

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Version Date: September 26, 2019 
 
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Randomized Phase III Trial of Lenalidomide Versus Observation Alone in Patients with 
Asymptomatic High-Risk Smoldering Multiple Myeloma 
Appendix VI 
 
Risks Associated with Pregnancy 
Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic 
active substance that causes severe life-threatening birth defects.  An embryofetal development 
study in animals indicates that lenalidomide produced malformations in the offspring of female 
monkeys who received the drug during pregnancy. The teratogenic effect of lenalidomide in 
humans cannot be ruled out.  Therefore, a risk minimization plan to prevent pregnancy must be 
observed. 
Criteria for females of childbearing potential (FCBP) 
This protocol defines a female of childbearing potential as a woman who: 1) has achieved 
menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) 
has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out 
childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in 
the preceding 24 consecutive months). 
Counseling 
For a female of childbearing potential, lenalidomide is contraindicated unless all of the following 
are met (i.e., all females of childbearing potential must be counseled concerning the following 
risks and requirements prior to the start of lenalidomide):  
· 
She understands the potential teratogenic risk to the unborn child 
· 
She understands the need for effective contraception, without interruption, 4 weeks before 
starting study treatment, throughout the entire duration of study treatment, dose interruption 
and 28 days after the end of study treatment 
· 
She should be capable of complying with effective contraceptive measures 
· 
She is informed and understands the potential consequences of pregnancy and the need to 
notify her study doctor immediately if there is a risk of pregnancy 
· 
She understands the need to commence the study treatment as soon as study drug is 
dispensed following a negative pregnancy test 
· 
She understands the need and accepts to undergo pregnancy testing based on the 
frequency outlined in this protocol 
· 
She acknowledges that she understands the hazards and necessary precautions associated 
with the use of lenalidomide 
The investigator must ensure that for females of childbearing potential: 
· 
Complies with the conditions for pregnancy risk minimization, including confirmation that she 
has an adequate level of understanding 
· 
Acknowledge the aforementioned requirements 
For a female NOT of childbearing potential, lenalidomide is contraindicated unless all of the 
following are met (i.e., all females NOT of childbearing potential must be counseled concerning 
the following risks and requirements prior to the start of lenalidomide):  
· 
She acknowledges that she understands the hazards and necessary precautions associated 
with the use of lenalidomide 
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Traces of lenalidomide have been found in semen.  Male patients taking lenalidomide must 
meet the following conditions (i.e., all males must be counseled concerning the following risks 
and requirements prior to the start of lenalidomide): 
· Understand the potential teratogenic risk if engaged in sexual activity with a pregnant female 
or a female of childbearing potential 
· Understand the need for the use of a condom even if he has had a vasectomy, if engaged in 
sexual activity with a pregnant female or a female of childbearing potential.   
· Understand the potential teratogenic risk if the subject donates semen or sperm. 
Contraception 
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two reliable 
forms of contraception simultaneously or to practice complete abstinence (true abstinence is 
acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic 
abstinence [eg calendar, ovulation, symptothermal or post-ovulation methods] and withdrawal 
are not acceptable methods of contraception) from heterosexual contact during the following 
time periods related to this study: 1) for at least 28 days before starting study drug; 2) while 
participating in the study; 3) during dose interruptions; and 4) for at least 28 days after study 
treatment discontinuation.  
The two methods of reliable contraception must include one highly effective method and one 
additional effective (barrier) method. FCBP must be referred to a qualified provider of 
contraceptive methods if needed. The following are examples of highly effective and additional 
effective methods of contraception:   
· 
Highly effective methods: 
− Intrauterine device (IUD) 
− Hormonal (birth control pills, injections, implants, levonorgestrel-releasing intrauterine 
system [IUS], medroxyprogesterone acetate depot injections, ovulation inhibitory 
progesterone-only pills [e.g. desogestrel]) 
− Tubal ligation 
− Partner’s vasectomy 
· 
Additional effective methods: 
− Male condom 
− Diaphragm 
− Cervical Cap 
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased 
risk of infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics 
should be considered particularly in patients with neutropenia.  
Pregnancy testing 
Medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be 
performed for females of childbearing potential, including females of childbearing potential who 
commit to complete abstinence (true abstinence is acceptable when this is in line with the 
preferred and usual lifestyle of the subject. Periodic abstinence [eg calendar, ovulation, 
symptothermal or post-ovulation methods] and withdrawal are not acceptable methods of 
contraception), as outlined below. 

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Before starting study drug 
Female Patients: 
FCBP must have two negative pregnancy tests (minimum sensitivity of 25 mIU/mL) prior to 
starting study drug.  The first pregnancy test must be performed within 10 to 14 days prior to the 
start of study drug and the second pregnancy test must be performed within 24 hours prior to 
the start of study drug.  The patient may not receive study drug until the study doctor has 
verified that the results of these pregnancy tests are negative. 
Male Patients: 
Must practice complete abstinence (true abstinence is acceptable when this is in line with the 
preferred and usual lifestyle of the subject. Periodic abstinence [eg calendar, ovulation, 
symptothermal or post-ovulation methods] and withdrawal are not acceptable methods of 
contraception) or agree to use a condom during sexual contact with a pregnant female or a 
female of childbearing potential while participating in the study, during dose interruptions and for 
at least 28 days following study drug discontinuation, even if he has undergone a successful 
vasectomy.    
During study participation and for 28 days following study drug discontinuation  
Female Patients: 
· 
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 study drug discontinuation. 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 study drug 
discontinuation.   
· 
At each visit, the Investigator must confirm with the FCBP that she is continuing to use two 
reliable methods of birth control.   
· 
Counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted at a minimum of every 28 days.  
· 
If pregnancy or a positive pregnancy test does occur in a study patient, study drug must be 
immediately discontinued. 
· 
Pregnancy testing and counseling must be performed if a patient misses her period or if her 
pregnancy test or her menstrual bleeding is abnormal.  Study treatment must be 
discontinued during this evaluation. 
· 
Females must agree to abstain from breastfeeding during study participation and for at least 
28 days after study drug discontinuation. 
Male Patients: 
· 
Counseling about the requirement for complete abstinence (true abstinence is acceptable 
when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence 
[eg calendar, ovulation, symptothermal or post-ovulation methods] and withdrawal are not 
acceptable methods of contraception)  or condom use during sexual contact with a pregnant 
female or a female of childbearing potential and the potential risks of fetal exposure to 
lenalidomide must be conducted at a minimum of every 28 days. 
· 
If pregnancy or a positive pregnancy test does occur in the partner of a male study patient 
during study participation, the investigator must be notified immediately. 
Additional precautions 

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· 
Patients should be instructed never to give this medicinal product to another person and to 
return any unused capsules to the study doctor at the end of treatment. 
· 
Female patients should not donate blood during treatment, during dose interruptions, and for 
at least 28 days the last dose of lenalidomide. 
· 
Male patients should not donate blood, semen or sperm during treatment, during dose 
interruptions, and  for at least 28 days after stopping lenalidomide. 
Only enough study drug for 28 days or one cycle of therapy (whichever is shorter) may be 
dispensed with each cycle of therapy. 

ECOG-ACRIN 
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Version Date: September 26, 2019 
 
NCI Update Date: February 3, 2016 
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Randomized Phase III Trial of Lenalidomide Versus Observation Alone in Patients with 
Asymptomatic High-Risk Smoldering Multiple Myeloma 
Appendix VII 
 
Lenalidomide Education and Counseling Guidance Document 
To be completed prior to each dispensing of study drug. 
Protocol Number: ____________________________________________ 
Patient Name (Print): __________________ DOB: _____/_____/_____ (mm/dd/yyyy) 
(Check the appropriate box to indicate risk category) 
Female:  □ 
If female, check one: 
□ FCBP (Female of childbearing potential): a female who: 1) has achieved 
menarche at some point 2) has not undergone a hysterectomy (the surgical 
removal of the uterus) or bilateral oophorectomy (the surgical removal of both 
ovaries) or 3) has not been naturally postmenopausal (amenorrhea following 
cancer therapy does not rule out childbearing potential) for at least 24 consecutive 
months (i.e., has had menses at any time during the preceding 24 consecutive 
months) 
□ NOT FCBP 
Male: 
□ 
 
Do Not Dispense study drug if: 
· 
The patient is pregnant. 
· 
No pregnancy tests were conducted for a FCBP. 
· 
The patient states she did not use TWO reliable methods of birth control (unless 
practicing complete abstinence of heterosexual contact) [at least 28 days prior to 
treatment, during treatment and during dose interruption]. 
· 
The subject stated that he or she has or does not want to adhere to pregnancy 
precautions outlined within this Pregnancy Prevention Plan (PPP). 
FCBP: 
1. I verified that the required pregnancy tests performed are negative. 
2. I counseled FCBP regarding the following: 
− Potential risk of fetal exposure to lenalidomide:  If lenalidomide is taken during 
pregnancy, it may cause birth defects or death to any unborn baby.  Females are 
advised to avoid pregnancy while taking lenalidomide. The teratogenic potential of 
lenalidomide in humans cannot be ruled out.  FCBP must agree not to become pregnant 
while taking lenalidomide.  
− Using TWO reliable methods of birth control at the same time or complete abstinence 
(True abstinence is acceptable when this is in line with the preferred and usual lifestyle 
Rev. 8/11, 1/16 
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of the subject. Periodic abstinence [eg calendar, ovulation, symptothermal or 
post-ovulation methods] and withdrawal are not acceptable methods of 
contraception.)from heterosexual contact [at least 28 days prior to treatment, during 
treatment, during dose interruption and 28 days after discontinuation of lenalidomide]. 
That even if she has amenorrhea she must comply with advice on contraception 
− Use of one highly effective method and one additional method of birth control AT THE 
SAME TIME. The following are examples of highly effective and additional effective methods 
of contraception:   
− Highly effective methods: 
o Intrauterine device (IUD) 
o Hormonal (birth control pills, injections, implants, levonorgestrel-releasing 
intrauterine system [IUS], medroxyprogesterone acetate depot injections, ovulation 
inhibitory progesterone-only pills [e.g. desogestrel]) 
o Tubal ligation 
o Partner’s vasectomy 
− Additional effective methods: 
o Male condom 
o Diaphragm 
o Cervical Cap 
· Pregnancy tests before, during, and after treatment, even if the patient agrees not to have 
reproductive heterosexual contact.  Two pregnancy tests will be performed prior to receiving 
study drug, one within 10 to 14 days and the second within 24 hours of the start of study 
drug. 
· Frequency of pregnancy tests to be done: 
− Every week during the first 28 days of this study and a pregnancy test every 28 days 
during the patient’s participation in this study if menstrual cycles are regular or every 14 
days if cycles are irregular.   
− If the patient missed a period or has unusual menstrual bleeding.   
− When the patient is discontinued from the study and at day 28 after study drug 
discontinuation if menstrual cycles are regular.  If menstrual cycles are irregular, 
pregnancy tests will be done at discontinuation from the study and at days 14 and 28 
after study drug discontinuation. 
− Stop taking study drug immediately in the event of becoming pregnant and to call their 
study doctor as soon as possible.  
− NEVER share study drug with anyone else. 
− Do not donate blood while taking study drug, during breaks (dose interruptions), and for 
at least 28 days after stopping the last dose of the study drug. 
− Do not breastfeed while taking lenalidomide and for at least 28 days after the last dose 
of lenalidomide. 
− Do not break, chew, or open study drug capsules. 
− Return unused study drug to the study doctor. 

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Provide Lenalidomide Information Sheet to the patient. 
FEMALE NOT OF CHILDBEARING POTENTIAL (NATURAL MENOPAUSE FOR AT LEAST 
24 CONSECUTIVE MONTHS, A HYSTERECTOMY, OR BILATERAL OOPHORECTOMY): 
I counseled the female NOT of child bearing potential regarding the following: 
− Potential risks of fetal exposure to lenalidomide (Refer to item #2 in FCBP) 
− NEVER share study drug with anyone else. 
− Do not donate blood while taking study drug, during breaks (dose interruptions), and for at 
least 28 days after the last dose of the study drug. 
− Do not break, chew, or open study drug capsules 
− Return unused study drug capsules to the study doctor. 
3. Provide Lenalidomide Information Sheet to the patient. 
MALE: 
4. I counseled the Male patient regarding the following: 
− Do not donate blood, semen or sperm 
− Potential risks of fetal exposure to lenalidomide (Refer to item #2 in FCBP). 
− To engage in complete abstinence (True abstinence is acceptable when this is in line 
with the preferred and usual lifestyle of the subject. Periodic abstinence [eg calendar, 
ovulation, symptothermal or post-ovulation methods] and withdrawal are not acceptable 
methods of contraception.) or use a condom when engaging in sexual contact (including 
those who have had a vasectomy) with a pregnant female or a female of childbearing 
potential,  while taking study drug, during dose interruptions and for 28 days after 
stopping study drug. 
− Should not impregnate his female partner while in the study. 
− Males should notify their study doctor when their female partner becomes pregnant and 
female partners of males taking study drug should be advised to call their healthcare 
provider immediately if they get pregnant. 
− NEVER share study drug with anyone else. 
− Do not donate blood while you take lenalidomide, during breaks (dose interruptions), and 
for at least 28 days after stopping study drug the last dose of lenalidomide. 
− Do not break, chew, or open study drug capsules. 
− Return unused study drug capsules to the study doctor. 
5. Provide Lenalidomide Information Sheet to the patient. 
 
Counselor Name (Print): ____________________  
 
Counselor Signature: _______________________  Date: _____/_____/_____ 
 
**Maintain a copy of the Lenalidomide Education and Counseling Guidance Document in the 
patient records.** 
Rev. Add14 

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Version Date: September 26, 2019 
 
NCI Update Date: February 3, 2016 
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Randomized Phase III Trial of Lenalidomide Versus Observation Alone in Patients with 
Asymptomatic High-Risk Smoldering Multiple Myeloma 
Appendix VIII 
 
Lenalidomide Information Sheet 
FOR PATIENTS ENROLLED IN CLINICAL RESEARCH STUDIES 
Please read this Lenalidomide Information Sheet before you start taking lenalidomide and each 
time you get a new supply, since there may be new information. This Lenalidomide Information 
Sheet does not take the place of an informed consent to participate in clinical research or talking 
to your study doctor or healthcare provider about your medical condition or your treatment. 
What is the most important information I should know about lenalidomide? 
Lenalidomide may cause birth defects (deformed babies) or death of an unborn baby. 
Lenalidomide is similar to the medicine thalidomide. It is known that thalidomide causes life-
threatening birth defects. Lenalidomide has not been tested in pregnant women but may also 
cause birth defects. Findings from a monkey study indicate that lenalidomide caused birth 
defects in the babies of female monkeys who received the drug during pregnancy. 
If you are a woman who is able to become pregnant: 
Do not take study drug if you are pregnant or plan to become pregnant 
Either do not have sexual intercourse at all or use two reliable, separate forms of 
effective birth control at the same time:  
− for 28 days before starting lenalidomide 
− while taking lenalidomide 
− during dose interruptions of lenalidomide 
− for 28 days after stopping lenalidomide 
You must have pregnancy testing done at the following times: 
− within 10 to 14 days and again 24 hours prior to the first dose of lenalidomide 
− weekly for the first 28 days 
− every 28 days after the first month or every 14 days if you have irregular menstrual periods 
− if you miss your period or have unusual menstrual bleeding 
− 28 days after the last dose of lenalidomide (14 and 28 days after the last dose if menstrual 
periods are irregular) 
Stop taking study drug if you become pregnant during treatment 
− If you suspect you are pregnant at any time during the study, you must stop lenalidomide 
immediately and immediately inform your study doctor. Your study doctor will report all 
cases of pregnancy to the National Cancer Institute and the pharmaceutical collaborator, 
Celgene Corporation.  
Do not breastfeed while taking lenalidomide and for at least 28 days after the last dose of 
lenalidomide. 
The study doctor will be able to advise you where to get additional advice on contraception. 
Rev. 8/11, 1/16 

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NCI Update Date: February 3, 2016 
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If you are a female not of childbearing potential: 
In order to ensure that an unborn baby is not exposed to lenalidomide, your study doctor will 
confirm that you are not able to become pregnant. 
If you are a man: 
Lenalidomide is detected in trace quantities in human semen. The risk to the fetus in females of 
child bearing potential whose male partner is receiving lenalidomide is unknown at this time.   
Men (including those who have had a vasectomy) must either abstain from sexual intercourse or 
use a condom during sexual contact with a pregnant female or a female that can become 
pregnant: 
− While you are taking lenalidomide 
− During dose interruptions of lenalidomide 
− For 28 days after you stop taking lenalidomide 
Men should not donate sperm or semen while taking lenalidomide, during breaks (dose 
interruptions), and for at least 28 days after stopping lenalidomide. 
If you suspect that your partner is pregnant any time during the study, you must 
immediately inform your study doctor. The study doctor will report all cases of 
pregnancy to the National Cancer Institute who will report the cases to the 
pharmaceutical collaborator, Celgene Corporation. Your partner should call their 
healthcare provider immediately if she gets pregnant. 
Restrictions in sharing lenalidomide and donating blood: 
Do not share lenalidomide with other people. It must be kept out of the reach of children 
and should never be given to any other person. 
Do not donate blood while you take lenalidomide, during breaks (dose interruptions), and for at 
least 28 days after stopping the last dose of lenalidomide.  
Do not break, chew, or open study drug capsules. 
You will get no more than a 28-day supply of lenalidomide at one time. 
Return unused study drug capsules to your study doctor. 
Additional information is provided in the informed consent form and you can ask your study 
doctor for more information. 

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Version Date: September 26, 2019 
 
NCI Update Date: February 3, 2016 
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Randomized Phase III Trial of Lenalidomide Versus Observation Alone in Patients with 
Asymptomatic High-Risk Smoldering Multiple Myeloma 
 
Appendix IX 
 
Cooperative Research and Development Agreement (CRADA/CTA) 
The agent lenalidomide supplied by CTEP, DCTD, NCI used in this protocol is provided to the 
NCI under a Collaborative Agreement (CRADA, Agent-CRADA, CTA, CSA) between Celgene 
(hereinafter referred to as a “Collaborator(s)”) and the NCI Division of Cancer Treatment and 
Diagnosis. Therefore, the following obligations/guidelines, in addition to the provisions in the 
“Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/default.htm) contained within the terms of award, 
apply to the use of the Agent(s) in this study: 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
investigational Agents contain confidential information and should not be shared or 
distributed without the permission of the NCI.  If a copy of this protocol is requested by a 
patient or patient’s family member participating on the study, the individual should sign a 
confidentiality agreement.  A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different collaborative agreements, 
the access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as “Multi-Party Data”): 
a NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NIH, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own investigational Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
investigational Agent. 
3 Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate 
and unless additional disclosure is required by law or court order.  Additionally, all Clinical 
Data and Results and Raw Data will be collected, used, and disclosed consistent with all 
applicable federal statutes and regulations for the protection of human subjects including, if 
applicable, the Standards for Privacy of Individually Identifiable Health Information set forth 
in 45 C.F.R. Part 164. 

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4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the date 
of receipt for review.  Collaborator shall have the right to request that publication be delayed 
for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent 
to: 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
Executive Plaza North, Suite 7111 
Bethesda, Maryland 20892 
FAX 301-402-1584 
Email: ncicteppubs@mail.nih.gov 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 

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Version Date: September 26, 2019 
 
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Asymptomatic High-Risk Smoldering Multiple Myeloma 
 
Appendix X 
 
Bone Marrow Aspirate and Peripheral Blood Kit — Yale University 
Specimen Checklist and Shipping Instructions 
 
** PLEASE AVOID DRAWING OR SENDING SPECIMENS ON FRIDAYS AND HOLIDAYS** 
 
Kit Contents: 
· 
Styrofoam box and cardboard mailing sleeve 
· 
10ml Sodium Heparin (green top) collection tubes 
· 
Zip lock specimen bag 
Packing and Shipping Instructions: 
1. Collect the following specimens: 
· 
Peripheral blood – Draw four (4) 10ml Sodium Heparin tubes (green top). 
· 
Bone Marrow Aspirate - Draw 5-10ml of a ‘re-direct’ bone marrow aspirate in one (1) 
Sodium Heparin tube (green top). 
2. Specimens should be labeled with ECOG-ACRIN protocol number (E3A06), ECOG-ACRIN 
patient ID number, patient’s initials (last name, first name), and date of specimen collection. 
3. Place specimens in zip lock plastic bag, wrap with absorbent material and place in the 
Styrofoam cooler.  Tubes should be sent at room temperature. 
4. Place the Styrofoam container and the Sample Tracking System Shipping Manifest within 
the cardboard mailing sleeve. 
5. Prepare the package for shipping, applying packing tape as needed. Ship specimens via 
overnight delivery the same day collected. 
6. Please contact Lin Zhang at (203) 737-5176 or lin.zhang@yale.edu prior to sending the 
shipment as she will need to print the shipping label and either fax or e-mail to the person 
sending the samples to the lab. 
The samples in this prepared kit should be shipped using EshipGlobal to the following: 
Dhodapkar Laboratory 
Nathan Smith Building 
Room NSB-287B 
Yale School of Medicine 
333 Cedar Street 
New Haven, CT  06510 
Tel: (203) 737-5176 
 
Rev. 12/13 
Rev. 12/13 
Rev. 12/13 
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Asymptomatic High-Risk Smoldering Multiple Myeloma 
 
Appendix XI 
 
Bone Marrow Core Biopsy Kit—University of Arkansas 
Specimen Checklist and Shipping Instructions 
 
** PLEASE AVOID DRAWING OR SENDING SPECIMENS ON FRIDAYS AND HOLIDAYS** 
 
Kit Contents: 
· 
Styrofoam box and cardboard mailing sleeve 
· 
FedEx Airbill with pre-printed return address 
· 
Zip lock specimen bag 
Packing and Shipping Instructions: 
8. Collect the following specimen: 
· 
Bone Marrow Core Biopsy – Snap-freeze immediately after resection by dropping into 
liquid nitrogen or dry ice. 
9. Transfer the frozen core into a tube that has been kept on dry ice to prevent thawing of the 
core. 
10. Immediately ship on dry ice OR store at 70oC and batch ship at a later date. 
11. Specimens should be labeled with ECOG-ACRIN protocol number (E3A06), ECOG-ACRIN 
patient ID number, patient’s initials (last name, first name), and date of specimen collection. 
12. Place specimens in their individual plastic bags and place in the Styrofoam cooler tightly 
packed with dry ice. 
13. Place the Styrofoam container and the Sample Tracking System Shipping Manifest Form 
within the cardboard mailing sleeve. 
14. Prepare the package for shipping, applying packing tape as needed.  Complete the sender 
portion of the return FedEx Airbill and adhere to the exterior lid of the box.  Ship specimens 
via overnight delivery. 
15. Notify Federal Express for pick-up and/or leave package at the designated FedEx drop-off 
location. 
Please contact Shayu Deshpande at sdeshpande@uams.edu or (501) 526-6990 ext. 8941 
to notify them when specimen(s) are being shipped. 
The samples in this prepared kit should be shipped to the following: 
University of Arkansas for Medical Sciences 
Rockefeller Cancer Institute, Room 940 
Attn:  Shayu Deshpande 
4301 West Markham, Slot 724 
Little Rock, AR  72205-7199 
Rev. 2/12, 
2/16 
Rev. 2/16 

ECOG-ACRIN 
E3A06 
Cancer Research Group 
Version Date: September 26, 2019 
 
NCI Update Date: February 3, 2016 
111 
Randomized Phase III Trial of Lenalidomide Versus Observation Alone in Patients with 
Asymptomatic High-Risk Smoldering Multiple Myeloma 
Appendix XII 
 
Celgene Pregnancy Prevention & Counseling Program Site Counselor Identification Form 
Celgene 
Corporation 
Celgene Pregnancy Prevention & Counseling Program Site Counselor Identification Form 
NCI Protocol #: 
 
· Please identify at least two (2) counselors and fax back to 888-314-2392 
· Use one form per counselor. 
· Identified counselors must be licensed healthcare professionals (e.g. RN, PA, RPh, PhD, 
LPN, CNP, or MD) and must not be the principal investigator.  
· If you have any questions, please email (coop_ma@celgene.com) 
General Information 
Principal Investigator: 
 
Institution Name: 
 
Counselor Information 
CTEP person ID: 
 
CTEP site ID: 
 
First Name: 
 
Middle Initial: 
 
Last Name: 
 
License Type: (circle one) MD   PhD   PA   CNP   RN   LPN   RPh   Other:  
 
Email Address: 
 
Phone: 
 
Fax: 
 
Institution Street Address: 
 
City: 
 
State/Region: 
 
Zip/Post Code: 
 
Country: 
 
Which training will you require?   □Adult □Pediatric 
Were you previously approved as a Counselor?   □No □Yes (Previous training)   □Adult □Pediatric 
If no, please list all the protocols #(s), corresponding CTEPsiteID(s) and institution names(s) that you plan to 
provide counseling for: 
 
If yes, please list the protocols #(s), corresponding CTEPsiteID(s) and institution names(s) for protocols 
Celgene has already associated you with: 
 
Protocol#: 
CTEPsiteID 
Institution 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rev. 8/11, 1/16 

ECOG-ACRIN 
E3A06 
Cancer Research Group 
Version Date: September 26, 2019 
 
NCI Update Date: February 3, 2016 
112 
Randomized Phase III Trial of Lenalidomide Versus Observation Alone in Patients with 
Asymptomatic High-Risk Smoldering Multiple Myeloma 
 
Appendix XIII 
 
Instructions for Reporting Pregnancies on a Clinical Trial 
 
What needs to be reported? 
All pregnancies and suspected pregnancies (including a positive or inconclusive pregnancy test 
regardless of age or disease state) of a female patient while she is on Lenalidomide, or within 
28 days of the female patient’s last dose of Lenalidomide must be reported in an expeditious 
manner.  The outcome of the pregnancy and neonatal status must also be reported. 
How should the pregnancy be reported? 
The pregnancy, suspected pregnancy, or positive/inconclusive pregnancy test must be reported 
via CTEP’s Adverse Event Reporting System (CTEP-AERS)   
(http://ctep.cancer.gov) 
When does a pregnancy, suspected pregnancy or positive/inconclusive pregnancy test 
need to be reported? 
An initial report must be done within 24 hours of the Investigator’s learning of the event, followed 
by a complete expedited CTEP-AERS report within 5 calendar days of the initial 24-hour report. 
What other information do I need in order to complete the CTEP-AERS report for a 
pregnancy? 
· 
The pregnancy (fetal exposure) must be reported as a Grade 3 “Pregnancy, puerperium and 
perinatal conditions – Other (pregnancy)” under the System Organ Class (SOC) “Pregnancy, 
puerperium and perinatal conditions” 
· 
The pregnancy must be reported within the timeframe specified in the Adverse Event 
Reporting section of the protocol for a grade 3 event.   
· 
The start date of the pregnancy should be reported as the calculated date of conception.   
· 
The potential risk of exposure of the fetus to the investigational agent(s) or chemotherapy 
agent(s) should be documented in the “Description of Event” section of the CTEP-AERS 
report.  
What else do I need to know when a pregnancy occurs to a patient? 
· 
The Investigator must follow the female patient until completion of the pregnancy and must 
report the outcome of the pregnancy and neonatal status via CTEP-AERS.  
· 
The decision on whether an individual female patient can continue protocol treatment will be 
made by the site physician in collaboration with the study chair and ECOG Operations Office 
- Boston.  Please contact the ECOG Operations Office - Boston to ask for a conference call 
to be set up with the appropriate individuals.   
· 
It is recommended the female subject be referred to an obstetrician-gynecologist, preferably 
one experienced in reproductive toxicity for further evaluation and counseling.  
How should the outcome of a pregnancy be reported? 
Rev. 7/14 
Rev. Add13 
Rev. Add14 

ECOG-ACRIN 
E3A06 
Cancer Research Group 
Version Date: September 26, 2019 
 
NCI Update Date: February 3, 2016 
113 
The outcome of a pregnancy should be reported as an amendment to the initial CTEP-AERS 
report if the outcome occurs on the same cycle of treatment as the pregnancy itself.  However, if 
the outcome of the pregnancy occurred on a subsequent cycle, a new CTEP-AERS report 
should be initiated reporting the outcome of the pregnancy. 
What constitutes an abnormal outcome? 
An abnormal outcome is defined as any pregnancy that results in the birth of a child with 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions (formerly referred to as disabilities), congenital anomalies, or birth defects.  For 
assistance in recording the grade or category of these events, please contact the CTEP AEMD 
Help Desk at 301-897-7497 or aemd@tech-res.com, for it will need to be discussed on a case 
by case basis.   
Reporting a Pregnancy Loss 
A pregnancy loss is defined in CTCAE as “A death in utero.” 
It must be reported via CTEP-AERS as Grade 4 “Pregnancy loss” under the System Organ 
Class (SOC) “Pregnancy, puerperium and perinatal conditions”. 
A fetal death should NOT be reported as a Grade 5 event as currently CTEP-AERS recognizes 
this event as a patient’s death. 
Reporting a Neonatal Death 
A neonatal death is defined in CTCAE as “A death occurring during the first 28 days after birth” 
that is felt by the investigator to be at least possibly due to the investigational agent/intervention.  
However, for this protocol, any neonatal death that occurs within 28 days of birth, without regard 
to causality, must be reported via CTEP-AERS AND any infant death after 28 days that is 
suspected of being related to the in utero exposure to Lenalidomide must also be reported via 
CTEP-AERS. 
It must be reported via CTEP-AERS as Grade 4 “Death Neonatal” under the System Organ 
Class (SOC) “General disorder and administration site conditions”. 
A neonatal death should NOT be reported as a Grade 5 event as currently CTEP-AERS 
recognizes this event as a patient’s death. 
Additional Required Forms: 
When submitting CTEP-AERS reports for pregnancy, pregnancy loss, or neonatal loss, the 
CTEP 'Pregnancy Information Form' must be completed and faxed along with any additional 
medical information to CTEP (301-897-7404). This form is available on CTEP's website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/PregnancyReportFor
m.pdf)