Intergroup Randomized Phase 2 Four Arm Study In Patients ≥ 60 With Previously Untreated Mantle Cell Lymphoma Of Therapy With: Arm A = Rituximab+ Bendamustine Followed By Rituximab Consolidation (RB → R); Arm B = Rituximab + Bendamustine + Bortezomib Followed By Rituximab Consolidation (RBV→ R), Arm C = Rituximab + Bendamustine Followed By Lenalidomide + Rituximab Consolidation (RB → LR) or Arm D = Rituximab + Bendamustine + Bortezomib Followed By Lenalidomide + Rituximab Consolidation (RBV → LR)
Phase: PHASE2
Conditions: Lymphoma, Mantle Cell Lymphoma
Sponsor: Eastern Cooperative Oncology Group

E1411 
 
1 
Intergroup Randomized Phase II Four Arm Study In Patients With 
Previously Untreated Mantle Cell Lymphoma Of Therapy With: Arm A = 
Rituximab+ Bendamustine Followed By Rituximab Consolidation (RB → R); 
Arm B = Rituximab + Bendamustine + Bortezomib Followed By Rituximab 
Consolidation (RBV→ R), Arm C = Rituximab + Bendamustine Followed By 
Lenalidomide + Rituximab Consolidation (RB → LR) or Arm D = Rituximab 
+ Bendamustine + Bortezomib Followed By Lenalidomide + Rituximab 
Consolidation (RBV → LR) 
STUDY CHAIR: Mitchell R. Smith, M.D., Ph.D. 
ECOG-ACRIN CO-CHAIR: 
SWOG CO-CHAIR: 
CALGB CO-CHAIR: 
NCIC CTG CO-CHAIR: 
Samir Parekh, M.D. 
Brian Till, M.D. 
Peter Martin, M.D.  
Michael Crump, M.D. 
PATHOLOGY CO-CHAIR: David T. Yang, M.D. 
LABORATORY CO-CHAIRS: Eric Hsi, M.D. 
Thomas Witzig, M.D. 
Sandeep Dave, M.D. 
Randy Gascoyne, M.D. 
Curtis Hanson, M.D. 
RADIOLOGY CO-CHAIR: Lale Kostakoglu, M.D. 
STUDY STATISTICIANS: Opeyemi Jegede, M.P.H 
LYMPHOMA COMMITTEE CHAIR: Brad Kahl, M.D. 
PATIENT OUTCOMES AND SURVIVORSHIP 
CHAIR: 
 
Lynne Wagner, Ph.D. 
Version Date:  May 31, 2018 
NCI Update Date:  June 13, 2012 
STUDY PARTICIPANTS 
ACTIVATION DATE 
US Sites Only  
May 22, 2012 
Addendum #1 – Incorporated Prior to Activation 
ALLIANCE / Alliance for Clinical Trials in Oncology 
US Sites Only  
Addendum #2 – Incorporated Prior to Activation 
SWOG / SWOG US Sites Only  
Update #1 – 6/12 
NCIC-CTG / NCIC Clinical Trials Group - Entire Group 
Addendum #3 – 1/13  
NRG / NRG Oncology Foundation, Inc 
Addendum #4 – 12/13 
 
Addendum #5 – 2/14 
 
Addendum #6 – 4/14 
Addendum #7 – 9/14 
Addendum #8 – 10/14 
 
Addendum #9 – 8/15 
 
Addendum #10 – 5/16 
 
Addendum #11 – 7/16 
 
Addendum #12 – 1/17 
 
Addendum #13 
 
Addendum #14 
Bortezomib (NSC# 681239) Supplied by Millennium 
Lenalidomide (NSC# 703813) Supplied by Celgene 
Rev. 12/13 
Rev. 2/14 
Rev. 4/14 
Rev. 9/14 
Rev. 10/14 
Rev. 8/15 

ECOG-ACRIN 
E1411 
Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
2 
Table of Contents 
Schema ...................................................................................................................... 7 
1. Introduction ........................................................................................................ 8 
1.1 
Overview of Mantle Cell Lymphoma (MCL) .............................................. 8 
1.2 
Treatment of MCL ..................................................................................... 8 
1.3 
FDG PET Imaging in MCL ......................................................................... 14 
1.4 
Summary ................................................................................................. 17 
2. Objectives ......................................................................................................... 18 
2.1 
Primary Objectives .................................................................................. 18 
2.2 
Secondary Objectives .............................................................................. 18 
2.3 
Laboratory Correlative Studies ............................................................... 18 
2.4 
Quality of Life Objectives ........................................................................ 18 
2.5 
Imaging Correlative Studies .................................................................... 19 
2.6 
Residual Disease Assessment by Molecular and Flow Cytometric 
Techniques .............................................................................................. 19 
3. Selection of Patients ......................................................................................... 20 
3.1 
Step 1 Registration .................................................................................. 20 
3.2 
Step 2 Registration .................................................................................. 23 
4. Randomization Procedures ............................................................................... 26 
4.1 
Randomization (Step 1) ........................................................................... 29 
4.2 
Step 2 Registration .................................................................................. 31 
4.3 
Investigator’s Drug Brochure and Safety Alerts ...................................... 33 
4.4 
IND Status ................................................................................................ 33 
5. Treatment Plan ................................................................................................. 34 
5.1 
Administration Schedule ......................................................................... 34 
5.2 
Adverse Event Reporting Requirements ................................................. 49 
5.3 
Comprehensive Adverse Events and Potential Risks Lists ...................... 56 
5.4 
Dose Modifications ................................................................................. 71 
5.5 
Supportive Care ....................................................................................... 79 
5.6 
Duration of Therapy ................................................................................ 80 
5.7 
Duration of Follow-up ............................................................................. 81 
6. Measurement of Effect ..................................................................................... 82 
6.1 
Complete Response (CR) ......................................................................... 82 
6.2 
Partial Response (PR) .............................................................................. 83 
6.3 
Stable Disease (SD) .................................................................................. 84 
6.4 
Progression (PD) and Relapse ................................................................. 84 
6.5 
Duration of Response .............................................................................. 85 
6.6 
Survival .................................................................................................... 85 
6.7 
Progression-Free Survival ........................................................................ 85 
6.8 
PRO Assessment: Symptom Burden and HRQL ....................................... 85 
6.9 
Quality of Life Administration Schedule ................................................. 86 

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Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
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7. Study Parameters .............................................................................................. 88 
7.1 
Therapeutic Parameters .......................................................................... 88 
7.2 
Biological Sample Submissions ............................................................... 91 
8. Drug Formulation and Procurement ................................................................. 93 
8.1 
Bendamustine ......................................................................................... 93 
8.2 
Rituximab ................................................................................................ 99 
8.3 
Bortezomib (Velcade) PS-341, NSC 681239 .......................................... 103 
8.4 
Lenalidomide (NSC 703813) .................................................................. 108 
8.5 
Rituxan Hycela ....................................................................................... 115 
9. Statistical Considerations ................................................................................ 117 
9.1 
Primary Endpoints ................................................................................. 117 
9.2 
Secondary Endpoints ............................................................................. 118 
9.3 
Subset Analysis for Patients Aged 60 Years and Older ......................... 119 
9.4 
Toxicity .................................................................................................. 119 
9.5 
Study Monitoring .................................................................................. 119 
9.6 
Quality of Life ........................................................................................ 120 
9.7 
Selection of Optimal Regimen(s) ........................................................... 122 
9.8 
Imaging Correlative Studies .................................................................. 122 
9.9 
Lab Correlative Studies (FFPE tissues) ................................................... 123 
9.10 Minimal Residual Disease (MRD) Correlative Studies ........................... 123 
9.11 Gender and Ethnicity ............................................................................ 126 
10. Centralized Review ......................................................................................... 127 
10.1 FDG-PET/CT Scan Imaging ..................................................................... 127 
10.2 Pathology Review .................................................................................. 129 
10.3 ECOG-ACRIN Sample Tracking System .................................................. 131 
10.4 Banking .................................................................................................. 132 
11. Correlative Studies .......................................................................................... 133 
11.1 Submission of Blood to Mayo Clinic ...................................................... 133 
11.2 Submission of Blood and Bone Marrow to Sequenta, Inc. ................... 135 
11.3 Ki67 Proliferation Index and SOX11 Expression .................................... 136 
11.4 miRNA Profiling ..................................................................................... 137 
11.5 6-Color Flow Cytometry for Minimal Residual Disease ........................ 138 
11.6 Molecular Minimal Residual Disease .................................................... 138 
11.7 Banking .................................................................................................. 138 
11.8 Sample Inventory Submission Guidelines ............................................. 139 
11.9 Lab Data Transfer Guidelines ................................................................ 139 

ECOG-ACRIN 
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Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
4 
12. Electronic Data Capture .................................................................................. 140 
13. Patient Consent and Peer Judgment .............................................................. 140 
14. References ...................................................................................................... 140 
Appendix I  Informed Consent Template for Cancer Treatment Trials (English 
Language) [Deleted in Addendum #3] ............................................................ 146 
Appendix II  Pathology Submission Guidelines ..................................................... 147 
Appendix III  Patient Thank You Letter .................................................................. 152 
Appendix IV  Patient Pill Calendar ......................................................................... 153 
Appendix V  ECOG Performance Status................................................................. 155 
Appendix VI  Risks of Fetal Exposure, Pregnancy Testing Guidelines  and 
Acceptable Birth Control Methods ................................................................. 156 
Appendix VII  Mantle Cell Lymphoma International Prognostic Index (MIPI) ....... 160 
Appendix VIII  Modified Ann Arbor Staging System .............................................. 161 
Appendix IX  FDG-PET Imaging, Interpretation, PET and CT Data Submission, and 
Semi-quantitative Analysis .............................................................................. 162 
Appendix X  Deauville Criteria ............................................................................... 167 
Appendix XI  [Deleted in Addendum #2] ............................................................... 168 
Appendix XII  E1411 Imaging Site Personnel Form ................................................ 169 
Appendix XIII  RevAssist for Study Participants Clinical Trial Prescription Form ... 170 
Appendix XIV  E1411 Lenalidomide Information Sheet ........................................ 173 
Appendix XV  E1411 Bortezomib Drug Request Form........................................... 175 
Appendix XVI  E1411 PET/CT Adjunctive Data Sheet ............................................ 177 
Appendix XVII  Blood Collection Kit Mayo Clinic Lymphoma Laboratory Specimen 
Checklist and Shipping Instructions ................................................................ 179 
Appendix XVIII  Instructions for Reporting Pregnancies on a Clinical Trial ........... 182 
 
 

ECOG-ACRIN 
E1411 
Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
5 
 
STUDY CHAIR 
Mitchell R. Smith, M.D., Ph.D. 
Taussig Cancer Institute 
Cleveland Clinic 
9500 Euclid Avenue Cleveland, OH 44195 
Phone: (216) 444-4366 
Fax: (216) 444-9464 
Email: smithm14@ccf.org 
ECOG-ACRIN CO-CHAIR 
Samir Parekh, M.D. 
Icahn School of Medicine at Mount Sinai 
Hess Center for Science and Medicine 
1470 Madison Avenue, Rm 5-114 
New Yok, NY 10029 
Phone: (212) 824-8428 
Fax: (646) 537-9578 
Email: samir.parekh@mssm.edu 
CALGB CO-CHAIR 
Peter Martin, M.D. 
Weill Cornell Medical College 
525 East 68th Street, Box 403 
New York, NY 10065 
Phone: (646) 962-2068 
Fax: (646) 962-1605 
Email: pem9019@med.cornell.edu 
SWOG CO-CHAIR 
Brian G. Till, M.D. 
Fred Hutchinson Cancer Research Center 
1100 Fairview Avenue North 
Mailstop D3-100 
Seattle, WA 98109 
Phone: (206) 667-7269 
Fax: (206) 667-1874 
Email: tillb@fhcrc.org 
 
STUDY CHAIR LIAISON (SCL) 
NCIC CTG CO-CHAIR 
Linda Thibodeau 
Fox Chase Cancer Center 
333 Cottman Avenue 
Philadelphia, PA 19111 
Phone: (215) 728-2207 
Fax: (215) 728-2687 
Email: Linda.Thibodeau@fccc.edu 
Michael Crump, M.D. 
University Health Network-OCI 
Princess Margaret Hospital  
610 University Ave 
Toronto, ON M5G2M9 
Phone: (416) 946-4501 ext. 4567 
Fax: (416) 946-6546 
Email: michael.crump@uhn.on.ca 
Rev. 12/13 
Rev. 12/13 
Rev. 12/13 
Rev. 2/14 

ECOG-ACRIN 
E1411 
Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
6 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory 
requirements: 
For patient enrollments:  
Submit study data 
Regulatory documentation 
must be submitted to the 
CTSU via the Regulatory 
Submission Portal. 
Regulatory Submission 
Portal: (Sign in at 
www.ctsu.org, and select the 
Regulatory Submission sub-
tab under the Regulatory tab.) 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 1-866-651-
2878 to receive further 
instruction and support. 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 
for regulatory assistance. 
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_SYSTEM/ 
or https://OPEN.ctsu.org. 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this study 
will be done exclusively 
through Medidata Rave. 
Please see the data 
submission section of the 
protocol for further 
instructions.  
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’ website is 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 electronic 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.  
The CTSU Web site is located at   https://www.ctsu.org 
 
 
Rev. 12/13, 
4/14, Add13 

ECOG-ACRIN 
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Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
7 
Schema 
rituximab 375 mg/m2 IV day 1
bendamustine 90 mg/m2/d IV days 1, 2 
Repeat every 28 days x 6 cycles
rituximab 375 mg/m2 IV day 1
bendamustine 90 mg/m2/d IV days 1, 2 
Repeat every 28 days x 6 cycles
rituximab 375 mg/m2 IV day 1
bendamustine 90 mg/m2/d IV days 1, 2
bortezomib  1.6 mg/m2/day SC or IV days 1 and 8
Repeat every 28 days x 6 cycles
Step 1
Step 2
Arm A
Arm B
Arm C
R
A
N
D
O
M
I
Z
E
Stratify:
MIPI risk score1
· low
· intermediate
· high
Age
· < 60
· > 60
Accrual = 372
Cycle = 28 days
R
E
G
I
S
T
E
R
rituximab 375 mg/m2 IV day 1
bendamustine 90 mg/m2/d IV days 1, 2
bortezomib  1.6 mg/m2/day SC or IV days 1 and 8 
Repeat every 28 days x 6 cycles
Arm D
rituximab* 375 mg/m2 IV day 1 (odd 
numbered cycles 1, 3, 5 ) Total= 12 doses 
of rituximab over 24 months.
lenalidomide 15 mg po daily days 1-21 every 
28 days x 24 cycles
 +
rituximab* 375 mg/m2 IV day 1 (odd 
numbered cycles 1, 3, 5 ) Total= 12 doses 
of rituximab over 24 months.
rituximab* 375 mg/m2 IV day 1 (odd 
numbered cycles 1, 3, 5 ) Total= 12 doses 
of rituximab over 24 months.
Arm E
Arm F
Arm G
lenalidomide 15 mg po daily days 1-21 every 
28 days x 24 cycles
 +
rituximab* 375 mg/m2 IV day 1 (odd 
numbered cycles 1, 3, 5 ) Total= 12 doses 
of rituximab over 24 months.
Arm H
1. See Section 4.1.5.1 for MIPI calculator link
*
Rituximab 375 mg/m2 IV can be replaced by Rituxan Hycela (rituximab and hyaluronidase human) 1400 mg/23,400 Units SC after at least one dose of rituximab 
IV has been administered. 
 
Rev. 12/13, 2/14 
Rev. Add13 

ECOG-ACRIN 
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Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
8 
1. 
Introduction 
1.1 
Overview of Mantle Cell Lymphoma (MCL) 
Mantle cell lymphoma is a difficult disease to treat as it is incurable, like indolent 
lymphoma, but has a shorter median survival. The usual estimate for overall 
survival in MCL has been 3-5 years in the pre-rituximab era1. Recent analysis of 
survival in sequential eras demonstrated survival ~2.5 years in 1975-1986, but 
almost 5 years in 1996-2004 for patients treated with MCP, CHOP or R-CHOP2.  
Retrospective analysis of all MCL patients seen from 1997-2007 at one center 
reported median survival > 7 years3. Thus, while MCL is clearly a difficult disease 
to treat, its prognosis may not be as dismal as generally thought.  
Median age at diagnosis of MCL is in the 7th decade, while median age in two 
recent ECOG trials has been 60-62. Age is an important variable in MCL, having 
prognostic importance in the IPI and MIPI. Age and co-morbidities also factor into 
treatment decisions regarding treatment intensity, e.g. risk-benefit balance for R-
HyperCVAD-M/A4 or high dose chemotherapy with stem cell support (HDC/SCT) 
5-7. Clinical trials that use more intensive therapeutic options generally have lower 
median age, as well as upper age limits5-7. Thus, treatment strategies vary with 
age. 
Many previous studies in MCL are relatively small Phase II trials, often either with 
age restrictions or analyzed retrospectively for effects of age. In order to meet the 
challenges in MCL of completing clinical trials of adequate size in timely fashion 
utilizing strategies suitable for patients stratified by age and co-morbidities, an 
intergroup strategy has emerged. Initial treatment of patients with MCL will be 
divided by age and comorbidities. Older patients ( 60) will be treated with novel 
combinations. Younger (< 65) patients who are fit will be offered treatment with a 
more aggressive, generally HDC/SCT based, regimen when such a study is 
available. They may be treated on this less intensive treatment study based on 
physician or patient preference, when HDC/SCT is not planned, or when a more 
intensive trial is not available. Here we present the proposed trial for the older 
age group, also open to younger patients as described above. 
1.2 
Treatment of MCL 
The current benchmark for comparison of treatment outcomes in lymphoma, 
including MCL, is often R-CHOP.  Data, however, for benefit of anthracyclines in 
MCL is not strong, with an older relatively small trial showing no clear benefit8. 
Nonetheless, initial therapy for untreated MCL with R-CHOP yields high 
response rates (RR), although remissions are not durable. Howard et al9 reported 
a 96% response rate and median progression free survival (PFS) of 16 months. 
Lenz et al reported 92% RR and with consolidation treatment a 28 month PFS10.  
Treatment Approaches Applicable to Young, Fit Patients 
One approach to improving these results is to achieve better cytoreduction with 
more intensive induction therapy. R-Hyper-CVAD alternating with R-high dose 
methotrexate/cytarabine (M/A)4 was reported to have longer failure-free survival, 
5 years for those 65 or under, but only 3 years for those over 65.  A multicenter 
SWOG trial of this regimen 11 had slow accrual, perhaps indicating selection bias, 
and a median age of 57 with upper limit of 70. This trial confirmed a high rate of 
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NCI Update Date: June 13, 2012 
9 
CR/CRu of 58%, however, many patients could not complete therapy and PFS 
with short follow-up appears shorter than the single center data. An Italian 
study12 similarly found that many patients could not complete this regimen. Thus, 
while it remains to be seen whether the prolonged PFS will be reproduced in 
younger patients, it is generally accepted that this therapy cannot be safely 
administered in patients over 60 or in poor performance status patients. 
An alternative approach to improving on results with R-CHOP is to build on the 
high response rate with R-CHOP by consolidating the remission. In a randomized 
trial, 4-6 cycles of a CHOP- like regimen were followed by interferon or 
HDC/SCT. HDC/SCT significantly prolonged PFS (median 3.5 years), but not 
overall survival, perhaps because crossover, i.e. HDC/SCT at relapse, was 
permitted 5, and HDC/SCT is not curative5, 6.  
A logical extension of the above approaches, combining intensified induction 
followed by consolidation, has encouraging results. Initial treatment of patients 
age  65 with MCL (median age = 56) with addition of rituximab and high dose 
cytarabine (HDAC) cycles toR-CHOP to intensify induction, and then 
consolidating with HDC/SCT, led to prolonged PFS and a suggestion of a 
plateau, although late relapses continue to occur7. Again, this intensity of 
treatment is not generally applicable to most MCL patients, in whom median age 
at diagnosis is > 60. 
Treatment Approaches Applicable to Older Patients or Those with Comorbidities 
Approaches more generally applicable to the majority of patients with MCL will 
need to be less intensive. Since remissions, but not cure, can be obtained in a 
high percentage of MCL patients, an attractive concept is remission induction 
followed by remission consolidation to try to eradicate residual lymphoma cells. 
Several new biologically targeted agents have demonstrated activity in MCL and 
present opportunities for novel combination approaches, both for induction and 
consolidation. The previous two ECOG trials of initial therapy of MCL tested 
novel consolidation (E1499) and induction (E1405) approaches. E1499 tested 
consolidation with RIT (90Y-ibritumomab tiuxetan) after initial therapy of MCL with 
4 cycles of R-CHOP. In this study, RIT improved quality of response and led to a 
median PFS of 27 months overall, and 25 months for those > 65. This is 
encouraging for a brief, well-tolerated regimen, however, no plateau in PFS is 
apparent13. In E1405, bortezomib, approved in the U.S. as a single agent in 
relapsed MCL, was incorporated into a modified R-HyperCVAD regimen and 
response rates are > 95% with > 70% complete responses14.  
Many agents are currently under investigation in MCL with documented activity. 
Bortezomib15-19 is being studied alone and in combination regimens, as in E1405. 
Single agent, and in some cases combination, activity has been reported for a 
range of drugs including the mTOR inhibitors temsirolimus20 and everolimus21, 
nucleoside analogs fludarabine22 and cladribine23, immune modulating agents 
thalidomide24 and lenalidomide 25, 26, as well as bendamustine 27. 
Bendamustine in MCL: 
Bendamustine is an alkylating agent that structurally also contains a purine-like 
benzimidazole ring. It is approved in the U.S. for treatment of CLL and for 
indolent B cell lymphoma progressing during or within 6 months of rituximab or a 
rituximab containing regimen. Based on in vitro data suggesting synergy between 
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rituximab and bendamustine (RB), much of the data on efficacy of bendamustine 
in MCL comes from combination studies of RB. Rummel et al27 reported a Phase 
II trial RB (90 mg/m2) in relapsed/refractory NHL. This study included 16 patients 
with MCL, 7 resistant to their last therapy, with responses in 12/16 (75%), 
including 8 (50%) CR. Robinson et al 28 reported a confirmatory US study of this 
RB regimen that included 12 patients with MCL, with 11 of 12 (92%) RR including 
5 (42%) CR and 2 (17%) CRu.  Median duration of response was 19 months.  As 
initial therapy, a randomized trial in Europe comparing R-CHOP with R-
bendamustine (RB)29 has included about 100 patients with MCL among its 500 
patients. Overall, RB appears non-inferior to R-CHOP with less 
myelosuppression and without the risk of cardiac toxicity. Based on these data, 
as well as activity of bendamustine (with or without rituximab) in indolent 
lymphoma, there is interest in exploring RB as initial therapy in MCL, perhaps as 
a platform to achieve high response rates with less toxicity allowing additional 
agents to be added.  
Bortezomib in MCL: 
Bortezomib is a potent, selective and reversible inhibitor of the proteasome.  
Bortezomib 15-19 is approved in the U.S. as a single agent in relapsed MCL, with a 
RR of 47% (8% CR) and PFS in responders of almost 8 months30. Bortezomib 
has been studied in combination with rituximab with no unexpected toxicities. It is 
also feasible to combine this agent with chemotherapy regimens such as 
modified R-hyperCVAD31 and R-CHOP32. ECOG has recently completed accrual 
to a trial in mantle cell lymphoma (E1405) based on modified hyper-CVAD + 
bortezomib (VcR-CVAD), with dose modifications for neuropathy due to 
concomitant vincristine, demonstrating feasibility in the cooperative group 
setting14. Outcome results require further follow-up.  Given the single agent 
activity in relapsed MCL, and ability to administer with largely non-overlapping 
toxicity profiles with standard chemotherapy and rituximab, bortezomib warrants 
further investigation in initial combination therapy of MCL. 
A randomized Phase 1 pilot study in 24 subjects with multiple myeloma 
demonstrated that both the IV and subcutaneous (SC) routes of bortezomib 
administration have similar systemic drug exposure and proteasome inhibition71. 
Importantly, SC and IV administration of bortezomib appeared to result in similar 
efficacy profiles (ie, response rate) and similar safety profiles. The pilot study 
also provided preliminary evidence of good local tolerance for SC injection of 
bortezomib, when administered at 1 mg/mL concentration. The data from the 
Phase 1 pilot study formed the basis of the design of a randomized, Phase 3 
study that compared the efficacy and safety of subcutaneous versus intravenous 
bortezomib at the approved 1.3 mg/m(2) dose and twice per week schedule in 
patients with relapsed multiple myeloma72. 222 patients were randomly assigned 
in a 2:1 ratio to receive either subcutaneous (n=148) or intravenous (n=74) 
bortezomib. The response-evaluable population consisted of 145 patients in the 
subcutaneous group and 73 in the intravenous group. Patients received a 
median of eight cycles (range one to ten) in both groups. Overall, similar efficacy 
results were observed in the SC and IV treatment groups, and the study 
demonstrated that bortezomib SC administration is not inferior to bortezomib IV 
administration. 

ECOG-ACRIN 
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Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
11 
Rituximab-bendamustine-bortezomib: 
Based on the above discussion, RB may be a base upon which to build improved 
treatment regimens in MCL.  Bortezomib has activity in lymphoma and is 
approved for relapsed MCL. It has a largely non-overlapping toxicity profile with 
RB. RBV has been investigated in a phase I/II trial in lymphoma, including a few 
patients with MCL (Friedberg JW, Vose JM, Kelly JL, Young F, Bernstein SH, 
Peterson D, Rich L, Blumel S, Proia NK, Liesveld J, Fisher RI, Armitage JO, 
Grant S, Leonard JP. The combination of bendamustine, bortezomib, and 
rituximab for patients with relapsed/refractory indolent and mantle cell non-
Hodgkin lymphoma. Blood, 117: 2807-2812 2011). R was given day 1, 
bendamustine at 90 mg/m2/d on days 1 and 4 along with bortezomib at standard 
dose and schedule of 1.3 mg/m2 days 1, 4, 8 and 11 of a 28 day cycle for a 
planned 6 cycles. This dose and schedule was tolerable with main toxicity being 
thrombocytopenia in about ½ of patients, and neuropathy. The VERTICAL trial 
used rituximab day 1, the usual bendamustine schedule days 1 and 2 and 
bortezomib weekly x 4 every 35 days33. No data using a day 1 and 4 schedule of 
single agent bendamustine exists.  
Lenalidomide in MCL: 
Lenalidomide is an immunomodulatory agent whose precise mechanism of anti-
lymphoma activity remains unclear. It has activity in a range of lymphoma 
histologies, including indolent and aggressive lymphoma and CLL. Specifically 
looking at MCL, two trials of lenalidomide in relapsed/refractory aggressive 
lymphoma included some patients with MCL. In one study, of 15 patients with 
relapsed MCL25 8 (53%) responded, including 3 (20%) CR. The other trial26 had 
39 MCL patients with 41% RR (13% CR). Lenalidomide was approved in the U.S. 
in 2013 for patients with relapsed MCL based on data showing a 28% response 
rate in heavily pre-treated patients (ref Goy A et al, JCO 2013).  Recent data 
combining lenalidomide and rituximab in indolent lymphoma and CLL, based in 
part on potential for synergy through mechanisms such as enhanced ADCC, are 
encouraging and do not indicate any unexpected toxicities. 
Rationale for choice of induction regimens: 
This trial will accrue mostly patients who are  60. Thus, the regimen needs to be 
tolerable in this group. While R-CHOP is one possible standard in such patients, 
based on the RB vs R-CHOP data the RB regimen is non-inferior and less toxic, 
making it an attractive option upon which to build. Bortezomib is active in MCL 
and can be added to this regimen, but its effect on efficacy and toxicity in this 
patient population requires study. Thus, this randomized Phase II trial will 
compare the results of each induction regimen in previously untreated patients 
with MCL.  
To ensure optimal drug therapy, and minimize other variables, we have selected 
a standard RB dose and schedule of rituximab 375 mg/m2 day 1 and 
bendamustine 90 mg/m2/day days 1 and 2 every 4 weeks. The RBV regimen will 
use the same RB dose and schedule. Originally, the standard bortezomib 
schedule of 1.3 mg/m2/d on days 1, 4, 8 and 11, also every 28 days, was 
selected to maximize the possibility of demonstrating benefit of this agent. The 
study is amended to use the weekly schedule of 1.6 mg/m2/d on days 1 and 8 of 
each 28 day cycle as it appears to be equivalent, less toxic and requires fewer 
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patient visits. As bortezomib has been approved for SC administration, either IV 
or SC route of bortezomib is permitted. 
Rituximab  Lenalidomide Consolidation Therapy: 
It is reasonable to investigate use of additional therapy following initial therapy of 
MCL, which has a high response rate but disappointing duration of response. 
Such additional therapy has included HDC/SCT in younger patients, interferon, 
rituximab or radioimmunotherapy (E1499). While the benefit of rituximab in MCL 
has been modest, recently randomized trial data has become available 
demonstrating significant prolongation of response duration following R-CHOP 
induction in MCL when rituximab was compared with interferon maintenance 
(Kluin-Nelemans, H. C., E. Hoster, et al. (2012). "Treatment of older patients with 
mantle-cell lymphoma." N Engl J Med 367(6): 520-531.), In addition, attention 
has been given to use of lenalidomide consolidation in lymphoma and myeloma. 
Lenalidomide is an immunomodulatory agent whose precise mechanism of anti-
lymphoma activity remains unclear. Nonetheless, it is active in indolent and 
aggressive lymphoma including MCL, as well as in CLL.  In CLL tumor lysis has 
been observed, suggesting that use with lower tumor burden, as in the 
maintenance setting, may be safer. Lenalidomide consolidation of remission in 
follicular lymphoma is currently being studied in an ECOG trial. Rituximab 
maintenance is part of the treatment in the previous ECOG trial E1405. 
Lenalidomide may enhance rituximab killing through ADCC. This study will use 
rituximab every 2 months for 2 years, based on this schedule being used in the 
PRIMA trial of indolent lymphoma to demonstrate prolongation of PFS, 
prolongation of duration of response following R-CHOP induction in MCL in the 
European Mantle cell Lymphoma network trial (Kluin-Nelemans, H. C., E. Hoster, 
et al. (2012). "Treatment of older patients with mantle-cell lymphoma." N Engl J 
Med 367(6): 520-531.), and ECOG 4402 in which a significant percentage of 
patients treated every 3 months had sub-therapeutic trough levels. Lenalidomide 
will be administered at 15 mg orally daily for 21 days of a 28 day cycle for the 
same 2 year period. 
Quality of Life 
Quality of Life in Mantle Cell Lymphoma: Background and Significance 
Quality of life among patients with mantle cell lymphoma has not commonly been 
assessed. Because MCL is not curable, the goal of treatment is to induce 
remission. Mantle cell lymphoma is a difficult disease to treat given the lack of 
curative treatment options, the shorter overall median survival compared to 
indolent lymphoma 59-61, and the older median age at diagnosis which requires 
consideration of comorbidities and age-related health risks in evaluating the risk-
benefit balance with regard to treatment 62-64. Patient-reported outcomes data on 
improvement of initial symptoms from treatment, treatment-emergent symptoms, 
and overall health-related quality of life (HRQL) is needed to accurately evaluate 
the trade-off between treatment-induced impairments to HRQL versus disease-
related symptom control and survival benefits. In the absence of curative therapy, 
the balance of treatment-related symptom improvement versus treatment-related 
toxicity will be an important parameter in deciding which treatment is “optimal.”  
This protocol provides the unique opportunity to assess symptom burden 
introduced by the addition of bortezomib and lenalidomide to standard therapy for 
MCL among a cohort of older adults with MCL. Neurotoxicity is anticipated to be 
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the most commonly experienced side effect from bortezomib. Lenalidomide is 
associated with hematologic adverse events and fatigue. Accordingly, treatment-
emergent symptom assessment will include targeted assessment of neuropathy 
and fatigue. The severity of fatigue associated with lenalidomide and associated 
impairments in HRQL are important to measure because the duration of 
treatment is 24 months. If observed, improvements in progression-free survival 
must be considered in light of potential long-term effects on HRQL, particularly 
given median survival for this population. This protocol will also provide the 
opportunity to assess improvements in disease-related symptoms associated 
with treatment. Last, this protocol provides the opportunity to collect longitudinal 
data among MCL patients during treatment and once treatment has been 
completed, which will provide data from the patient perspective on HRQL during 
survivorship. Given the paucity of patient-reported outcomes data among 
patients with MCL, we anticipate these findings will provide a major contribution 
to our understanding of patient well-being throughout and subsequent to 
treatment. 
Our quality of life hypotheses are: (1) Patients receiving bortezomib during 
induction therapy (Arms B and D) will report more neuropathy symptoms at the 
conclusion of induction therapy than patients who do not receive bortezomib 
(Arms A and C). (2) Patients receiving lenalidomide + rituximab during 
consolidation therapy (Arms G and H) will report more fatigue during and at the 
conclusion of consolidation therapy than patients receiving rituximab only (Arms 
E and F). (3) Patients receiving bortezomib during induction therapy and 
lenalidomide during consolidation therapy (Arm B or D followed by Arm G or H) 
will report greater reduction in overall HRQL compared to pre-treatment than 
patients on other treatment arms. Additional descriptive analyses will provide 
information on reduction in lymphoma-specific symptoms during treatment, the 
longitudinal trajectory of neuropathy, the longitudinal trajectory of fatigue, and 
overall HRQL during and following treatment. 
Quality of Life Design 
Quality of life is an important secondary endpoint for this trial. The QOL study 
design has been developed based on prior ECOG trials with QOL endpoints 
which have established a precedent, and the QOL design will allow us to address 
the QOL objectives outlined in the next section. The ECOG protocol E2408 is a 
3-arm randomized phase II trial to evaluate response among adults with follicular 
lymphoma receiving induction bendamustine-rituximab +/- bortezomib followed 
by rituximab +/- lenalidomide. The QOL design for E2408 is designed to answer 
the same questions we have set forth in this protocol, specifically the response of 
disease-related symptoms to treatment, treatment-emergent symptoms 
associated with bortezomib and lenalidomide, and the trajectory of HRQL on a 
longitudinal basis. 
Trial participants will complete a patient-reported outcomes (PRO) assessment to 
measure lymphoma-specific symptoms, treatment-emergent symptoms, and 
overall health-related quality of life. The Functional Assessment of Cancer 
Therapy – Lymphoma, FACT-Lym subscale will be administered to assess 
disease-related symptoms, specifically this scale will be used to evaluate 
improvement of disease-related symptoms in response to treatment 59, 61, 63. The 
FACT-Lym includes 15 items that assess the most common concerns among 
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Lymphoma protocols (E4402, E2408). Treatment-emergent neurotoxicity will be 
assessed using the 11-item FACT/GOG-Neurotoxicity scale (FACT/GOG-Ntx). 
The FACT/GOG-Ntx has been used to assess bortezomib-related neuropathy 
among myeloma patients 62 and is being administered to participants on ECOG 
trial E2408 to assess bortezomib-related neuropathy. Fatigue will be assessed 
using the 13-item FACT-Fatigue scale 64. The FACT-Fatigue scale has been 
administered to participants on ECOG trials for various types of cancer and is 
being administered to E2408 participants to assess fatigue associated with 
disease and associated with lenalidomide. Overall health-related quality of life 
will be assessed using the FACT-General, FACT-G 60, a 27-item scale which 
measures physical, functional, social and emotional well-being. 
Trial participants will complete PRO assessment at the time of randomization, at 
the conclusion of induction therapy, after 6 cycles of consolidation therapy, at the 
conclusion of consolidation therapy, and annually for 5 years. The assessment at 
the conclusion of induction therapy will allow us to measure bortezomib-induced 
neuropathy, HRQL, and any changes in lymphoma symptoms since baseline. 
PRO assessment after 6 cycles of consolidation therapy will allow us to examine 
the extent of fatigue and associated impairments in HRQL associated with 
lenalidomide and to evaluate additive toxicities and HRQL among participants 
who have received bortezomib and lenalidomide in addition to standard therapy. 
PRO assessment at the conclusion of consolidation therapy will allow us to 
quantify the cumulative effects of 24 months of treatment with lenalidomide on 
fatigue and HRQL, in comparison to participants receiving rituximab alone. 
Rituximab has not been associated with significant symptom burden, therefore 
we anticipate the PRO assessments during and post-consolidation therapy will 
allow us to better understand lenalidomide-associated fatigue and HRQL 
impairments. In addition PRO assessments will allow us to examine changes in 
lymphoma-specific concerns throughout the course of treatment and during 
follow-up. PRO assessments annually at follow-up (months 36, 48, 60) will 
provide the unique opportunity to prospectively assess HRQL in this rare 
population. Participants who go off protocol for progression will complete PRO 
assessment at the time of progression to allow us to quantify differences in PRO 
domains between participants who progress and those who continue on protocol. 
This data will help to inform statistical analyses to manage missing data due to 
attrition. 
1.3 
FDG PET Imaging in MCL 
The clinical course of MCL is heterogeneous and encompasses a clinical 
spectrum of indolent forms and rapidly progressive malignancy, with a poor 
prognosis. Although median survival of MCL has historically been in the range of 
3-4 years, the emergence of dose-intensified regimens, and salvage treatments 
using novel therapies has recently led to a gain of 2-3 years in overall survival2,3. 
Notwithstanding the new developments in management there is still a need to 
further understand prognostic factors, determinants of therapy efficacy to develop 
better predictive markers for response. Because of the considerable variability in 
disease course, it is essential to identify patient subsets that are most likely to 
respond to distinct therapeutic approaches. Computed tomography (CT) has 
been the mainstay of initial evaluation and response assessment which is the 
recognized modality of choice by standardized International Workgroup Criteria 
(IWG) (Cheson et al 1999). More recently, the introduction of [18F]-Fluorine-
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Deoxyglucose Positron Emission Tomography (FDG-PET),and its proven 
superior predictive value in curable subtypes of lymphoma, mainly, in Hodgkin 
lymphoma (HL), has led to the development of Revised IWC criteria incorporating 
PET into the response scheme which significantly altered response assessment 
in HL and DLBCL (Cheson et al 2007). However, the role of FDG PET remains 
under-investigated in MCL. 
There are only a limited number of studies utilizing PET in the management of 
MCL, and the available literature mostly consists of subset analyses within a 
mixed group of NHL patients (Tsukamoto et al 2007, Elstrom et al 2003, Karam 
et al 2009, Brepoels et al 2008). Only two retrospective FDG-PET series reported 
results exclusively in MCL (Karam et al 2009, Brepoels et al 2008). MCL 
presents with a broad histological spectrum, and the prognosis of various 
morphological subtypes is still under investigation. Most authors agree that the 
blastoid-variant of MCL has an even more aggressive clinical behavior with a 
very poor prognosis (Weigert et al 2007, Bosch et al 1997, Watanabe et al 
2010.). The published results of PET studies show significant variability in FDG-
uptake, with higher FDG uptake obtained in more aggressive subtypes 
suggesting that pre-treatment FDG PET may identify patients with an 
unfavorable prognosis. Brepoels et al reported a high sensitivity for FDG PET for 
the detection of MCL (100%) but 20 % of these patients had very low grade FDG 
uptake (Brepoels et al 2008). A higher FDG-uptake was shown in patients with 
the more aggressive blastoid and large-cellular variants of MCL variant of MCL, 
which are known to have a more aggressive disease course compared to 
common MCL. This finding confirms the results of Karam et al, who have shown 
a more aggressive disease course in patients with high FDG uptake compared to 
those with low FDG uptake (Karam et al 2009). In support of these findings, in a 
mixed group of 36 untreated NHL patients (26 aggressive, 2 mantle, 8 indolent), 
a positive correlation was observed between the SUVmax at the biopsy site and 
the MIB-1 labeling index (r = 0.69, p < 0.001) (Watanabi et al 2010). 
Consequently, there is some evidence that SUVmax may stratify patients with 
more aggressive disease course, although it is unproven whether or not FDG-
PET may be useful to diagnose high-grade MCL. 
Although assessment of response is important in lymphoma, it is not yet clear 
how response evaluation should be effectively performed in MCL. In a 
retrospective study of 37 MCL patients, after either front line (CHOP or RCHOP) 
or 2nd or 3rd line therapy, the investigators found no difference between CT-
based or PET-based evaluations with respect to response; similar outcomes 
were reported for PR and CR determined by revised IWC employing FDG-PET 
(Brepoels 2008). In a more recent prospective study, in 49 patients with relapsed 
or refractory follicular lymphoma (FL) or MCL (n=10), the percent reduction in 
SUVmax (70% vs 29%) and maximum perpendicular diameter (78% vs 48%) 
after completion of therapy were significantly greater in patients with complete 
response than in patients with non-CR (P<0.0001). The positive and negative 
predictive value of SUVmax at a threshold of 61% was 77% and 78%, 
respectively (Tateishi et al 2011). Bodet-Milin et al, retrospectively reported a 
positive and negative predictive value of 62.5 and 100%, respectively, for revised 
IWC with PET for identifying relapse at one year in a multicenter study involving 
seven centers and 44 MCL patients (Bodet-Milin et al 2010). With a median 
follow-up of 21 months, only the revised IWC criteria were accurate to identify 
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criteria modified both event-free survival (EFS) (p = .02 and .0001, respectively) 
and overall survival duration (p = .03 and .05, respectively). Combining mantle 
cell prognostic index (MIPI) (Hoster et al 2008) and SUVs may provide a better 
means as a predictive measure of outcome but this hypothesis should be proven 
by further prospective investigations (Bodet-Milin et al 2010). Consequently, 
there are limited data in patients with MCL using FDG-PET and the existing 
studies have reported mixed results and mixed patient populations, currently 
making it very difficult to extract useful and uniform information.  
Measuring chemosensitivity early during therapy as a predictor of response has 
been reported in a two-center retrospective cohort study although the results of 
this study have not been formally published (Mato et al 2010). In this study of 82 
advanced stage MCL patients undergoing HDT/SCT, FDG-PET post-2 cycles 
and post-3 cycles were positive in 34% and 18% of patients, respectively. With a 
median follow-up of 23 months, interim PET status was not found to be 
associated with PFS or OS (p=0.8). In corroboration with prior studies, post 
treatment PET status was statistically significantly associated with PFS (p=.001) 
and trended towards significance for OS (p=0.1). Post treatment PET status 
remained an independent predictor of PFS in a multivariate analysis that included 
MIPI score, blastoid variant and Ki-67. (Mato et al 2010). Although these data do 
not support the prognostic utility of an interim, a prospective multicenter trial 
using a standardized approach towards PET protocol and interpretation is still 
warranted to prove or refute its role. Due to the inherent nature of the frequent 
relapses, early detection of persistent disease may lead to more aggressive 
management. However, it is also conceivable that MCL patients will always have 
some residual disease early during therapy that it may not be useful segregating 
patients into different response categories. It is an unknown whether or not there 
is a significant difference between PET-CR and PET-PR patients with respect to 
survival. In this regard, the persistence or resolution of the metabolic activity at 
completion of therapy may be more valuable for stratifying different response 
groups with respect to chemo-resistance. It is also possible that PET may 
complement the predictive value of serum molecular markers since eradication of 
all remaining viable lymphoma cells in the blood may not parallel responses at 
the nodal or extranodal sites. For example, in a prior study, at the completion of 
rituximab and CHOP therapy, 36% of patients had no evidence of PCR-
detectable disease, however, only 44% of these patients who were in molecular 
remission had clinical, radiologic, or pathologic CR/CRu therapy; the remaining 
56% of molecular responders achieved only a PR at completion of induction 
therapy (Howard et al 2002).  
Consequently, prospective investigations are necessary in further evaluating 
disease biology as well as the relevance of assessment of metabolic response 
both in the interim and post therapy setting, particularly in those patients 
undergoing front-line therapy. 
 
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1.4 
Summary 
Our hypotheses are that: (1) a novel combination of RB or RBV as initial therapy 
for MCL will be generally applicable MCL, particularly in older patients not 
considered candidates for more aggressive HyperCVAD and SCT based 
regimens, achieve a higher rate of CR and be as tolerable as R-CHOP; and (2) 
consolidation with lenalidomide-rituximab in these patients will be tolerable, 
increase overall and complete response rates, as well as prolong PFS compared 
with rituximab consolidation alone. 
At this point, given the range of questions that need to be answered and current 
resources, in particular the number of MCL patients available, as well as the lack 
of an accepted standard initial therapy, we believe that a series of smaller Phase 
II trials will be more informative than large randomized phase 3 trials.  This 
randomized Phase II induction plus consolidation approach is designed to select 
the optimal regimen(s), on the basis of efficacy (primary endpoint of PFS), safety, 
and impact on patient-reported quality of life to take forward in subsequent trials.  
Secondary endpoints of overall and complete response rates at the end of 
induction therapy, conversion to complete response during consolidation and 
toxicity will be factored into this decision. Concurrent European trials of RB 
followed by scheduled rituximab will help inform these decisions as well. 
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2. 
Objectives 
2.1 
Primary Objectives 
2.1.1 
To determine whether the addition of bortezomib (RBV) to an 
induction regimen of rituximab-bendamustine (RB) improves 
progression-free survival (PFS) compared to RB alone in patients with 
previously untreated mantle cell lymphoma. 
2.1.2 
To determine whether the addition of lenalidomide to a consolidation 
regimen of rituximab following an induction regimen of RB or RBV 
improves PFS compared to consolidation rituximab alone in this 
patient population. 
2.2 
Secondary Objectives 
2.2.1 
To determine whether the addition of bortezomib to induction therapy 
improves the PET-documented complete response rate compared to 
RB alone. 
2.2.2 
To determine the objective response rate (ORR) for RB and RBV. 
2.2.3 
Among patients who do not have PET-documented CR at the end of 
induction, to determine whether the addition of lenalidomide to 
consolidation therapy improves CR and ORR compared with rituximab 
alone. 
2.2.4 
To determine overall survival (OS) in the treatment arms. 
2.2.5 
To determine safety, with attention to the addition of bortezomib in the 
induction regimen and lenalidomide-rituximab as consolidation 
therapy. 
2.3 
Laboratory Correlative Studies 
2.3.1 
To collect paraffin embedded tissue for creation of tissue microarray. 
2.3.2 
To collect and bank serum and blood mononuclear cells for future 
studies. 
2.3.3 
To collect formalin fixed paraffin embedded (FFPE) tissue to analyze 
potential prognostic factors: 
2.3.3.1 
Ki-67 proliferation index by immunohistochemistry and 
correlation with proposed 5 gene set of proliferation 
markers analyzed by RNA PCR. 
2.3.3.2 
SOX 11 expression by immunohistochemistry. 
2.3.3.3 
Micro-RNA levels by microarray. 
2.4 
Quality of Life Objectives 
2.4.1 
Using patient-reported outcomes data, to determine the extent and 
severity of neuropathy associated with the addition of bortezomib to 
induction treatment. 
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2.4.2 
Using patient-reported outcomes data, to determine the extent and 
severity of fatigue associated with the addition of lenalidomide to 
consolidation treatment. 
2.4.3 
To evaluate the effects of the addition of bortezomib and lenalidomide 
on patient-reported health-related quality of life. 
2.4.4 
To evaluate the effects of bortezomib-related neuropathy on patient-
reported health-related quality of life.  
2.4.5 
To evaluate the response of lymphoma-specific symptoms to 
treatment. 
2.4.6 
Using longitudinal patient-reported outcomes data, to describe the 
trajectory of lymphoma symptoms, neuropathy, fatigue and overall 
health-related quality of life prior to, during and following treatment 
among older adults with MCL. 
2.5 
Imaging Correlative Studies 
2.5.1 
To assess the proportion of patients up and down staging when FDG-
PET/CT is added to standard Ann Arbor staging.  
2.5.2 
To assess the ability of pre-treatment FDG-PET/CT semi quantitative 
parameters including SUVmax and metabolic measurements to 
predict response rate and PFS. 
2.5.3 
Among patients with interim FDG-PET/CT imaging, to assess the 
correlation of interim FDG-PET/CT imaging with response rate and 
PFS both during induction and consolidation therapy.  
2.5.4 
To assess standard FDG-PET/CT metrics including SUVmax, tumor 
metabolic burden, total tumor burden, and association with pathology 
features (blastoid variant vs. other, and Ki67) in the setting of MCL.  
2.5.5 
To assess differences in overall and complete response rates when 
using Deauville vs. International Harmonization Project FDG-PET/CT 
interpretation criteria. 
2.5.6 
To determine whether there is a correlation between FDG-PET/CT 
response and residual disease assessment by molecular and/or flow 
cytometric techniques. 
2.6 
Residual Disease Assessment by Molecular and Flow Cytometric Techniques 
2.6.1 
To determine whether the number of malignant cells in circulation 
predict the number of cells in marrow 
2.6.2 
To determine whether the number of malignant cells in circulation/in 
marrow at the end of induction correlate with CR and 2 year PFS. 
2.6.3 
To determine whether there is a higher rate of minimal residual 
disease (MRD) negativity among patients randomized to RBV as 
compared with RB, and among patients treated with LR maintenance 
compared with R. 
2.6.4 
To compare the two methods of MRD detection - molecular 
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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: 
There is no provision for stem cell collection in this study, but there is 
also no prohibition of stem cell collection. If the treating physician feels 
collection is warranted, the following guidelines must be followed:  
· 
Stem cell collection may only be performed after cycle 6 of step 1 
· 
Mobilization should begin around Day 21 of cycle 6, or coming off 
cycle 6  
· 
Only growth factors may be used; no chemotherapy, for mobilization 
· 
There must be 14 days from last growth factor to start of step 2 
therapy. 
3.1 
Step 1 Registration 
3.1.1 
MIPI score must be calculated and entered in OPEN (see Section 
4.1.5.1). 
NOTE: 
For this calculation WBC 7,500/mm3 = 7,500/uL = 7.5 x 
109/L should be entered as 7500. 
3.1.2 
Age ≥ 18 years. 
3.1.3 
Females of childbearing potential must not be pregnant or breast-
feeding due to risk of fetal harm by the chemotherapeutic agents 
prescribed in this protocol. 
All females of childbearing potential must have a blood test or urine 
study within 2 weeks prior to registration to rule out pregnancy. 
Female? ______  (Yes or No) 
Date of blood test or urine study: ____________ 
A female of childbearing potential (FCBP) is any woman, regardless 
of sexual orientation or whether they have undergone tubal ligation, 
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who meets the following criteria: 1) has not undergone a hysterectomy 
or bilateral oophorectomy; or 2) has not been naturally 
postmenopausal for at least 24 consecutive months (i.e., has had 
menses at any time in the preceding 24 consecutive months). 
3.1.4 
Women of childbearing potential and sexually active males must be 
strongly advised to use an accepted and effective method of 
contraception.  
3.1.5 
Patients must have measurable disease as defined in Section 6. 
3.1.6 
Histologically confirmed untreated mantle cell lymphoma, with 
documented cyclin D1 (BCL1) by immunohistochemical stains and/or 
t(11;14) by cytogenetics or FISH. 
3.1.7 
 Patients must have at least one objective measurable disease 
parameter. Baseline measurements and evaluations must be obtained 
within 4 weeks of registration to the study. Abnormal PET scans will 
not constitute evaluable disease, unless verified by CT scan or other 
appropriate imaging. Measurable disease in the liver is required if the 
liver is the only site of lymphoma. If the only radiographically 
assessable disease is splenomegaly (without discrete measurable 
nodules), the patient can be enrolled, but for such patients CR cannot 
be differentiated from PR (per Section 6.1.3), while the spleen will be 
considered nodal with respect to criteria for PD (see Section 6.4.5). 
3.1.8 
ECOG performance status between 0-2. 
3.1.9 
Hematologic parameters (unless due to marrow involvement) 
obtained within 4 weeks prior to registration. 
3.1.9.1 
ANC  1500/ mm3 (1.5 x 109/L) 
3.1.9.2 
 Platelets  100,000/ mm3 (100 x 109/L) 
3.1.10 
Liver/Renal function, obtained within 4 weeks prior to registration 
3.1.10.1 
AST/ALT  2 x upper limit of normal (ULN) 
3.1.10.2 
 Total bilirubin  2 x upper limit of normal (ULN) or, if total 
elevated, direct bilirubin  2 x upper limit of normal (ULN) 
3.1.10.3 
Calculated creatinine clearance by Cockroft-Gault formula 
 30 ml/min 
3.1.11 
No evidence of prior malignancy except: adequately treated non-
melanoma skin cancer, adequately treated in situ carcinoma,  low 
grade prostate carcinoma (Gleason grade ≤ 6) managed with 
observation that has been stable for at least 6 months, or any 
malignancy treated with curative intent continuously disease free for  
 3 years so as not to interfere with interpretation of radiographic 
response. 
3.1.12 
No prior therapy for MCL, except: < 2 weeks of steroid therapy for 
symptom control or local radiation therapy for symptom control if there 
is measurable disease outside the radiation portal. Patients may be 
on chronic steroids for non-malignant disease if on a stable dose 
equivalent to ≤ 20 mg prednisone per day. 
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3.1.13 
Patient must have no known CNS involvement. 
3.1.14 
Patient agrees that if randomized to Arms C or D, and proceeding 
onto Arms G or H, they must register into the mandatory RevAssist 
program, and be willing and able to comply with the requirements of 
RevAssist. 
Patients must have no medical contra-indications to, and be willing to 
take, DVT prophylaxis as all patients registering to the 
lenalidomide/rituximab Arms G and H will be required to have deep 
vein thrombosis (DVT) prophylaxis. Patients randomized to Arms G or 
H who have a history of a thrombotic vascular event will be required to 
have full anticoagulation, therapeutic doses of low molecular weight 
heparin or warfarin to maintain an INR between 2.0 – 3.0, or any other 
accepted full anticoagulation regimen (e.g. direct thrombin inhibitors 
or Factor Xa inhibitors) with appropriate monitoring for that agent. 
Patients on Arms G and H without a history of a thromboembolic 
event are required to take a daily aspirin (81 mg or 325 mg) for DVT 
prophylaxis. Patients who are unable to tolerate aspirin should receive 
low molecular weight heparin therapy or warfarin treatment or another 
accepted full anticoagulation regimen. 
Ways to minimize risk of DVT should be discussed with patients, 
including, but not limited to, avoiding smoking, minimizing pro-
thrombotic hormone replacement, avoiding prolonged periods of 
inactivity (e.g. uninterrupted long car or plane trips). 
3.1.15 
HIV positive patients are not excluded, but to enroll, must meet all of 
the below criteria: 
3.1.15.1 
HIV is sensitive to antiretroviral therapy. 
3.1.15.2 
Must be willing to take effective antiretroviral therapy if 
indicated. 
3.1.15.3 
CD4 count at screening ≥ 300 cells/mm3. 
3.1.15.4 
No history of AIDS-defining conditions. 
3.1.15.5 
If on antiretroviral therapy, must not be taking zidovudine 
or stavudine. 
Must be willing to take prophylaxis for Pneumocystis jiroveci 
pneumonia (PCP) during therapy and until at least 2 months following 
the completion of therapy or until the CD4 cells recover to over 250 
cells/mm3, whichever occurs later. 
3.1.16 
Patients must not have grade 2 or greater peripheral neuropathy. 
3.1.17 
Patients must not have NYHA Class III or IV heart failure, uncontrolled 
angina severe uncontrolled ventricular arrhythmias, or 
electrocardiographic evidence of acute ischemia. 
3.1.18 
Patients must not have hypersensitivity to bortezomib, boron or 
mannitol. 
3.1.19 
Patients must not have a serious medical or psychiatric illness likely to 
interfere with study participation. 
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3.1.20 
Patients must not be participating in any other therapeutic clinical trial 
or taking any other experimental medications within 14 days prior to 
registration. 
3.2 
Step 2 Registration 
3.2.1 
ECOG performance status between 0-2 
3.2.2 
CR, PR or SD after Step 1. 
3.2.3 
Prior to beginning consolidation, patients must meet the following 
criteria: 
Hematologic parameters: 
3.2.3.1 
ANC  1000 cells/mm3 (1.0 x 109/L) 
3.2.3.2 
Platelets  75,000 cells/mm3 (75 x 109/L) 
3.2.3.3 
AST/ALT  2 x upper limit of normal (ULN) 
3.2.3.4 
Total bilirubin  2 x upper limit of normal (ULN) or, if total 
elevated, direct bilirubin  2 x upper limit of normal (ULN) 
3.2.3.5 
Calculated creatinine clearance by Cockroft-Gault formula 
 30 ml/min 
3.2.4 
Patient agrees that if randomized to Arms C or D, and proceeding 
onto Arms G or H, they must register into the mandatory REMS 
program, and be willing and able to comply with the requirements of 
REMS. 
3.2.4.1 
Pregnancy tests must occur within 10 - 14 days and again 
within 24 hours prior to initiation of Cycle 1 of lenalidomide. 
*Females of childbearing potential (FCBP)* with regular or 
no menstruation must have a pregnancy test weekly for the 
first 28 days and then every 28 days while on lenalidomide 
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 lenalidomide 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: Risks of Fetal Exposure, Pregnancy 
Testing Guidelines and Acceptable Birth Control Methods). 
*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 and again within 24 
hours prior to 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 
______
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use a latex condom during sexual contact with a FCBP 
even if they have had a successful vasectomy. All patients 
must be counseled at a minimum of every 28 days about 
pregnancy precautions and risks of fetal exposure. See 
Appendix VI: Risks of Fetal Exposure, Pregnancy Testing 
Guidelines and Acceptable Birth Control Methods, AND 
also Appendix XIV: Lenalidomide Information Sheet. 
*A female of childbearing potential is any sexually mature 
female, regardless of sexual orientation of whether they 
have undergone tubal ligation, who meets the following 
criteria: 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). 
Female of childbearing Potential? ________ (Yes or No) 
Date of blood or urine study? ___________ 
3.2.4.2 
Females of childbearing potential (FCBP) must agree to 
use two reliable forms of contraception simultaneously or 
to practice complete abstinence from heterosexual 
intercourse during the following time periods related to this 
study/lenaliomide: 1) for at least 28 days before starting 
lenalidomide; 2) while participating in the study including 
interruptions in therapy; and 3) for at least 28 days after 
discontinuation/stopping lenalidomide. The two methods of 
reliable contraception must include one highly effective 
method (i.e. intrauterine device (IUD), hormonal [birth 
control pills, injections, or implants], tubal ligation, partner’s 
vasectomy) and one additional effective (barrier) method 
(i.e. latex condom, diaphragm, cervical cap). FCBP must 
be referred to a qualified provider of contraceptive methods 
if needed.  
3.2.4.3 
Women must agree to abstain from donating blood during 
study participation and for at least 28 days after 
discontinuation from protocol treatment. 
3.2.4.4 
Males must agree to abstain from donating blood, semen, 
or sperm during study participation and for at least 28 days 
after discontinuation from protocol treatment. 
All males, regardless of whether they have undergone a 
successful vasectomy, must agree to use a latex condom 
during sexual contact with a female of childbearing 
potential, or to practice complete abstinence from 
heterosexual intercourse with any female of childbearing 
potential during all cycles of study treatment and for at 
least 28 days following discontinuation of protocol 
treatment 
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3.2.4.5 
Patients must have no medical contra-indications to, and 
be willing to take, DVT prophylaxis as all patients 
registering to the lenalidomide/rituximab Arms G and H will 
be required to have deep vein thrombosis (DVT) 
prophylaxis. Patients randomized to Arms G or H who 
have full anticoagulation, a history of a thrombotic vascular 
event will be required to have therapeutic doses of low 
molecular weight heparin or warfarin to maintain an INR 
between 2.0 – 3.0, or any other accepted full 
anticoagulation regimen (e.g. direct thrombin inhibitors or 
Factor Xa inhibitors) with appropriate monitoring for that 
agent. Patients on Arms G and H without a history of a 
thromboembolic event are required to take a daily aspirin 
(81 mg or 325 mg) for DVT prophylaxis. Patients who are 
unable to tolerate aspirin should receive low molecular 
weight heparin therapy or warfarin treatment or another 
accepted full anticoagulation regimen. 
Ways to minimize risk of DVT should be discussed with 
patients, including, but not limited to, avoiding smoking, 
minimizing pro-thrombotic hormone replacement, avoiding 
prolonged periods of inactivity (e.g. uninterrupted long car 
or plane trips). 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: This signature line is provided for use by institutions 
wishing to use the eligibility checklist as source 
documentation. 
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4. 
Randomization Procedures 
CTEP Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually. To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam). In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 
clinical site staff requiring write access to OPEN, RAVE, or TRIAD or acting as a primary 
site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). 
Documentation requirements per registration type are outlined in the table below 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
 
HSP/GCP training 
 
 
 
 
Agent Shipment Form (if applicable) 
 
 
 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and CTSU (Cancer Trials Support Unit) websites and applications. In 
addition, IVRs and NPIVRs must list all clinical practice sites and IRBs covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
· 
Added to a site roster 
· 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
· 
Act as the site-protocol PI on the IRB approval 
Additional information can be found on the CTEP website at 
<https://ctep.cancer.gov/investigatorResources/default.htm>. For questions, please 
contact the RCR Help Desk by email at <RCRHelpDesk@nih.gov>. 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
IRB Approval: 
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.  Assignment of site 
registration status in the CTSU Regulatory Support System (RSS) uses extensive data 
to make a determination of whether a site has fulfilled all regulatory criteria including but 
not limited to the following: 
· 
An active Federal Wide Assurance (FWA) number 
· 
An active roster affiliation with the Lead Network or a participating organization 
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· 
A valid IRB approval 
· 
Compliance with all protocol specific requirements. 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
· 
Active registration status 
· 
The IRB number of the site IRB of record listed on their Form FDA 1572 
· 
An active status on a participating roster at the registering site. 
Downloading Site Registration Documents: 
Site registration forms may be downloaded from the E1411 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 
· 
Either enter the protocol # in the search field at the top of the protocol tree, or 
· 
Click on the By Lead Organization folder to expand 
· 
Click on the ECOG-ACRIN link to expand, then select trial protocol E1411 
· 
Click on LPO Documents, select the Site Registration Documents link, and download 
and complete the forms provided. 
Requirements for E1411 site registration: 
· 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, 
an IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted) 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS. 
Regulatory Submission Portal: www.ctsu.org (members’ area) → Regulatory Tab 
→Regulatory Submission 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
Required Protocol Specific Regulatory Documents 
1.  
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. 
2.  
A.  
CTSU IRB Certification Form. 
Or 
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B.  
Signed HHS OMB No. 0990-0263 (replaces Form 310) 
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) 
· 
Date of review. 
· 
Signature of IRB official 
Checking Your Site’s Registration Status: 
You can verify your site registration status on the members’ section of the CTSU 
website. 
· 
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 
· 
Click on the Site Registration tab 
· 
Enter your 5-character CTEP Institution Code and click on Go 
NOTE: 
The status given only reflects compliance with IRB documentation and 
institutional compliance with protocol-specific requirements outlined by the 
Lead Network. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status 
with the NCI or their affiliated networks. 
Patient Enrollment 
Patients must not start protocol treatment prior to randomization. 
Treatment should start within ten 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://ctepcore.nci.nih.gov/iam>) and a 'Registrar' role on either the 
LPO or participating organization roster. Registrars must hold a minimum of an 
AP registration type. 
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 and, upon enrollment, 
initializes the patient in the Rave database. 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. To assign an IVR or NPIVR as the treating, 
crediting, consenting, drug shipment (IVR only), or investigator receiving a 
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transfer in OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR the 
IRB number used on the site’s IRB approval. 
Prior to accessing OPEN site staff should verify the following: 
· 
All eligibility criteria has 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 
Randomization (Step 1)  
Patients must not start protocol treatment prior to randomization. 
Treatment should start within ten working days after registration. 
The following information will be requested at time of randomization: 
4.1.1 
Protocol Number  
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 
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4.1.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.1. An eligibility checklist has been appended to the protocol. 
4.1.5 
Classification/Stratification Factors 
4.1.5.1 
Mantle cell lymphoma IPI (MIPI) score: low, intermediate, 
or high (65). 
MIPI score = 0.03 535 × age (y) + 0.6978 (if ECOG-ACRIN 
> 1) + 1.367 × log10(LDH/ULN) + 0.9393 × log10(WBCs per 
mm3). 
NOTE: MIPI calculator can be accessed using the 
European MCL Network website.  
http://www.european-mcl.net/en/clinical_mipi.php  
4.1.5.2 
Age (< 60 years vs ≥ 60 years) 
4.1.6 
Additional Requirements  
4.1.6.1 
Patients must provide a signed and dated, written informed 
consent form. 
4.1.6.2 
PET/CT scans must be submitted for central review as 
outlined in Section 10.1. 
4.1.6.3 
Pathology materials must be submitted for central review 
per Section 10.2.  
4.1.6.4 
Additional specimens are to be submitted for laboratory 
research studies and/or banking as indicated in Sections 
10 and 11 per patient consent. 
4.1.6.5 
Data collection for this study will be done exclusively in 
Medidata Rave. Access to the trial in Rave is granted 
through the iMedidata application to all persons with the 
appropriate roles assigned in Regulatory Support System 
(RSS). To access Rave via iMedidata, the site user must 
have an active CTEP-IAM account (check at 
<https://ctepcore.nci.nih.gov/iam>) and the appropriate 
Rave role (Rave CRA, Read-Only, CRA (Lab Admin, SLA 
or Site Investigator)) on either the LPO or participating 
organization roster at the enrolling site. To the hold Rave 
CRA role or CRA Lab Admin role, the user must hold a 
minimum of an AP registration type. To hold the Rave Site 
Investigator role, the individual must be registered as an 
NPIVR or IVR.  Associates can hold read-only roles in 
Rave. 
Upon initial site registration approval for the study in RSS, 
all persons with Rave roles assigned on the appropriate 
roster will be sent a study invitation e-mail from iMedidata. 
To accept the invitation, site users must log into the Select 
Login (https://login.imedidata.com/selectlogin) using their 
CTEP-IAM user name and password, and click on the 
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“accept” link in the upper right-corner of the iMedidata 
page. Please note, site users will not be able to access the 
study in Rave until all required Medidata and study specific 
trainings are completed. Trainings will be in the form of 
electronic learnings (eLearnings), and can be accessed by 
clicking on the link in the upper right pane of the iMedidata 
screen 
Users that have not previously activated their 
iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive 
a separate invitation from iMedidata to activate their 
account. Account activation instructions are located on the 
CTSU website, Rave tab under the Rave resource 
materials (Medidata Account Activation and Study 
Invitation Acceptance). Additional information on 
iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by 
e-mail at ctsucontact@westat.com 
NOTE: Submitted scans and specimens must be entered and 
tracked via the ECOG-ACRIN Sample Tracking System 
(STS). See Section 10.3.  
4.1.7 
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 E1411 Completion Guidelines. 
4.2 
Step 2 Registration 
Patients should not start protocol treatment prior to step 2 registration. 
Treatment should start per instructions in Section 4. The following information will 
be requested at 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 
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 

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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 
4.2.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.2. An eligibility checklist has been appended to the protocol. 
4.2.5 
Classification Factors 
4.2.5.1 
Induction Treatment on Step 1. 
4.2.6 
Additional Requirements  
4.2.6.1 
PET/CT scans must be submitted for central review as 
outlined in Section 10.1. 
4.2.6.2 
Additional specimens are to be submitted for laboratory 
research studies and/or banking as indicated in Sections 
10 and 11 per patient consent. 
NOTE: Submitted scans and specimens must be entered and 
tracked via the ECOG-ACRIN Sample Tracking System 
(STS). See Section 10.3. 
4.2.6.3 
REMS® Program 
Lenalidomide will be provided to patients on Arms G and H 
for the duration of their participation in this trial at no 
charge to them or their insurance providers. Lenalidomide 
will be provided in accordance with the REMS® program of 
Celgene Corporation. Per standard REMS® requirements 
all physicians who prescribe lenalidomide for research 
subjects enrolled into this trial, and all research subjects 
randomized to Arms C or D who then proceed on to Arms 
G or H of this trial, must be registered in and comply with 
all requirements of the REMS® program. Refer to Section 
8.4.8 of the protocol for complete information on the 
REMS® Program. 
4.2.6.4 
Data collection for this study will be done exclusively in 
Medidata Rave. Prior to beginning data entry in Rave, 
study staff must be registered in Medidata and complete 
the required training modules. Study staff will receive an 
invitation to join the study in Rave after evidence of IRB 
approval is submitted to RSS. 
4.2.7 
Instructions for Patients Who Do Not Start Assigned Protocol 
Treatment  
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If a patient does not receive any assigned protocol treatment, follow-
up data will still be collected and must be submitted according to the 
instructions in the E1411 Completion Guidelines. 
4.3 
Investigator’s Drug Brochure and Safety Alerts 
The Investigator Drug Brochure (IDB) for lenalidomide and bortezomib are 
available for download from the ECOG webpage. The IDB provides relevant and 
current scientific information about the investigational product. The IDB should be 
submitted to your IRB/EC according to GCP regulations. The IDB and any 
correspondence to the Institutional Review Board (IRB)/Ethics Committee (EC) 
should be kept in the E1411 regulatory files. 
Should any SAE report on this study qualify as a safety alert report requiring 
expedited reporting, the SAE report will be sent by the respective pharmaceutical 
company to regulatory authorities globally (including the FDA) and ECOG-
ACRIN. If applicable, ECOG-ACRIN will disseminate these safety alert reports to 
all ECOG-ACRIN investigators in the bimonthly group mailings. These reports 
should be forwarded to your IRB/EC within 90 days of receipt for review. 
Reporting instructions are provided with each safety alert. These safety alerts 
and any correspondence to your IRB/EC should be maintained in your E1411 
study files. 
4.4 
IND Status 
When used in this protocol lenalidomide and bortezomib are classified as an 
“unapproved use of an approved agent” and by definition considered 
investigational agents. However, while it is not an indication currently approved 
by the FDA, the use of lenalidomide and bortezomib in this protocol are exempt 
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5. 
Treatment Plan 
5.1 
Administration Schedule 
5.1.1 
ARM A/ARM E 
5.1.1.1 
Step 1 Induction (Arm A) 
Rituximab 375 mg/m2 IV day 1 
Bendamustine 90 mg/m2/day IV days 1 and 2  
Repeat cycles every 4 weeks for a total of 6 cycles  
NOTE: 
Rituximab dose may be rounded to the nearest 
50 mg 
Other agents may be rounded  5% 
NOTE: 
Cycle length may be altered to 25 days  
(-3 days) or to 31 days (+3 days), for holidays 
or other extenuating scheduling situations. 
NOTE:  
Prophylactic Neupogen or Neulasta (or an 
approved biosimilar agent) may be used 
according to ASCO guidelines. 
NOTE: 
Dose Modifications – See Section 5.4. 
Premedication 
· 
Acetaminophen (650 or 1000 mg) and 
diphenhydramine (25 or 50 mg) or equivalent is to be 
administered 30 to 60 minutes prior to starting each 
infusion of rituximab. Since transient hypotension may 
occur during rituximab infusion, consideration should 
be given to withholding anti-hypertensive medications 
12 hours prior to rituximab infusion. 
· 
Standard anti-emetic therapy may be given to patients 
prior to administration of each RB treatment: including 
5-HT3 serotonin receptor antagonists and steroids 
(e.g., dexamethasone). 
Administration Schedule 
The following are to be administered, preferably in the 
order indicated (1 cycle = 28 days). 
· 
Rituximab 375 mg/m2 IV Day 1. The rituximab dose 
may be rounded to the nearest 50 mg.  See Section 
5.4.1.1 regarding rituximab infusion rates. 
· 
See Section 5.4.1.1 for patients felt to be at risk for, or 
who have had, infusion reactions. 
· 
Bendamustine 90 mg/m2/day will be administered to 
patients by IV infusion on days 1 and 2 of each 28-day 
cycle. The infusions are given over a 60-minute period 
Rev. 12/13 
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ECOG-ACRIN 
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Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
35 
and on day 1 it is preferable that it be administered to 
patients after the administration of rituximab. 
NOTE:  
See Section 5.5 regarding supportive care 
recommendations.  
Restaging and Length of Therapy 
· 
Repeat cycles every 28 days for a total of 6 cycles. 
Patients may be evaluated in the office more 
frequently if needed at physician discretion. 
· 
Patients will be restaged after 3 cycles of therapy.  
Patients who are in at least stable disease (SD, PR, or 
CR) after 3 cycles will receive 3 subsequent cycles. 
Patients who have progressive disease (PD) at 
restaging will be discontinued from study treatment. 
5.1.1.2 
Step 2 (Arm E) 
Patients who have improved their response or have had no 
interval change in their tumor measurements with 
restaging from cycle 3 to 6 on Arm A will then proceed to 
Step 2 on Arm E.  
Rituximab 375 mg/m2 IV or Rituxan Hycela (rituximab and 
hyaluronidase human) 1400 mg/23,400 Units SC every 8 
weeks for 12 doses. 
NOTE: 
The first dose of rituximab consolidation should 
be given 8 weeks (± 3 working days if needed 
for scheduling) after the start of cycle 6 of 
induction (this will be the start of week 29). In 
the event of a treatment delay, the first dose of 
rituximab may be given up to 16 weeks after the 
start of cycle 6 of induction. 
NOTE: 
Rituximab IV dose may be rounded to the 
nearest 50 mg 
NOTE: 
There are no prescribed dose modifications for 
rituximab. If, however, a patient has grade 3 or 
4 neutropenia in the absence of other grade 3 
or 4 cytopenias, consider the possibility of “late-
onset neutropenia” associated with rituximab. 
Manage per institutional standards. Often, 
myeloid growth factor is administered and per 
investigator’s choice rituximab may be 
administered on schedule or delayed by 1 week 
intervals with repeat CBC to ensure resolution 
of neutropenia, and then start the new cycle. If 
not recovered by 4 weeks despite growth factor, 
patient will be removed from treatment.  
NOTE: 
If there have been no dose delays or reductions 
during step 2 for 4 consecutive cycles, the 
Rev. 12/13 
Rev. 12/13 
Rev. 12/13 
Rev. 8/15 
Rev. 5/16 
Rev. Add13 
Rev. Add13 

ECOG-ACRIN 
E1411 
Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
36 
patient may be seen every other cycle for 
subsequent cycles.The patient should be 
contacted by phone at the time of the even 
numbered cycle to assess clinical status and 
toxicities and still requires every 8 week blood 
draws. The phone contact and lab data must be 
documented. 
NOTE: 
If using Rituxan Hycela, patients must receive 
at least one full dose of a rituximab product IV 
before receiving Rituxan Hycela SC. Please 
refer to the commercial package insert. 
5.1.2 
ARM B/ARM F 
5.1.2.1 
Step 1 Induction (Arm B) 
Bortezomib 1.6 mg/m2/day SC or IV on days 1 and 8 
Rituximab 375 mg/m2 IV day 1 
Bendamustine 90 mg/m2/day IV days 1 and 2  
Repeat cycles every 4 weeks for a total of 6 cycles  
NOTE: 
Rituximab dose may be rounded to the nearest 
50 mg. 
Other agents may be rounded  5% 
NOTE: 
Cycle length may be altered to 25 days (-3 
days) or to 31 days (+3 days), for holidays or 
other extenuating scheduling situations. 
NOTE: 
Prophylactic Neupogen or Neulasta (or an 
approved biosimilar agent) may be used 
according to ASCO guidelines. 
NOTE: 
Prophylactic acyclovir 400-800 po BID or per 
institutional standard dosing, or valacyclovir 
1,000 once a day (or 500 twice a day) until at 
least one month post-treatment with 
Bortezomib. 
Premedication 
· 
Acetaminophen (650 or 1000 mg) and 
diphenhydramine (25 or 50 mg) or equivalent is to be 
administered 30 to 60 minutes prior to starting each 
infusion of rituximab. Since transient hypotension may 
occur during rituximab infusion, consideration should 
be given to withholding anti-hypertensive medications 
12 hours prior to rituximab infusion. 
· 
Standard anti-emetic therapy should be given to 
patients prior to administration of each RBV treatment: 
including 5-HT3 serotonin receptor antagonists and 
steroids (e.g., dexamethasone). 
Rev. 12/13 
Rev. 12/13 
Rev. 12/13 
Rev. 1/17 
Rev. Add13 
Rev. Add13 

ECOG-ACRIN 
E1411 
Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
37 
Administration Schedule 
The following are to be administered, preferably in the 
order indicated (1 cycle = 28 days) 
· 
Bortezomib 1.6 mg/m2 SC or IV Days 1 and 8 (two total 
doses per cycle). 
· 
Rituximab 375 mg/m2 IV Day 1. The rituximab dose 
may be rounded to the nearest 50 mg. See Section 
5.4.1.1 regarding rituximab infusion rates. 
· 
Bendamustine 90 mg/m2/day will be administered to 
patients by IV infusion on days 1 and 2 of each 28-day 
cycle. The infusions are given over a 60-minute period 
and on day 1 it is preferable that it be administered to 
patients after the administration of rituximab. 
NOTE: 
See Section 5.5 regarding supportive care 
recommendations. 
NOTE: 
Dose Modifications – See Section 5.4. 
Restaging and length of therapy 
· 
Repeat cycles every 28 days for a total of 6 cycles. 
Patients may be evaluated more frequently if needed at 
physician discretion. 
· 
Patients will be restaged after 3 cycles of therapy.  
Patients who are in at least stable disease (SD, PR, or 
CR) after 3 cycles will receive 3 subsequent cycles. 
Patients who have progressive disease (PD) at 
restaging will be discontinued from study treatment.  
5.1.2.2 
Step 2 (Arm F) 
Patients who have improved their response or have had no 
interval change in their tumor measurements with 
restaging from cycle 3 to 6 on Arm B will then proceed to 
Step 2 on Arm F. 
Rituximab 375 mg/m2 IV or Rituxan Hycela (rituximab and 
hyaluronidase human) 1400 mg /23,400 Units SC every 8 
weeks for 12 doses. 
NOTE: 
The first dose of rituximab consolidation should 
be given 8 weeks (± 3 working days if needed 
for scheduling) after the start of cycle 6 of 
induction (this will be the start of week 29). In 
the event of a treatment delay, the first dose of 
rituximab may be given up to 16 weeks after the 
start of cycle 6 of induction. 
NOTE: 
There are no prescribed dose modifications for 
rituximab. If, however, a patient has grade 3 or 
4 neutropenia in the absence of other grade 3 
or 4 cytopenias, consider the possibility of “late-
Rev. 12/13 
Rev. 12/13 
Rev. 12/13 
Rev. 12/13 
Rev. 8/15 
Rev. 8/15 
Rev. 5/16 
Rev. Add13 

ECOG-ACRIN 
E1411 
Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
38 
onset neutropenia” associated with rituximab. 
Manage per institutional standards. Often, 
myeloid growth factor is administered and per 
investigator’s choice rituximab may be 
administered on schedule or delayed by 1 week 
intervals with repeat CBC to ensure resolution 
of neutropenia, and then start the new cycle. If 
not recovered by 4 weeks despite growth factor, 
patient will be removed from treatment.  
NOTE: 
If there have been no dose delays or reductions 
during step 2 for 4 consecutive cycles, the 
patient may be seen every other cycle for 
subsequent cycles.The patient should be 
contacted by phone at the time of the even 
numbered cycle to assess clinical status and 
toxicities and still requires every 8 week blood 
draws. The phone contact and lab data must be 
documented. 
NOTE: 
If using Rituxan Hycela, patients must receive 
at least one full dose of a rituximab product IV 
before receiving Rituxan Hycela SC. Please 
refer to the commercial package insert. 
5.1.3 
ARM C/ARM G 
5.1.3.1 
Step 1: Induction (Arm C) 
Rituximab 375 mg/m2 IV day 1 
Bendamustine 90 mg/m2/day IV days 1 and 2  
Repeat cycles every 4 weeks for a total of 6 cycles  
NOTE: 
Rituximab dose may be rounded to the nearest 
50 mg. 
Other agents may be rounded ± 5% 
NOTE: 
Cycle length may be altered to 25 days (-3 
days) or to 31 days (+3 days), for holidays or 
other extenuating scheduling situations. 
NOTE: 
Prophylactic Neupogen or Neulasta (or an 
approved biosimilar agent) may be used 
according to ASCO guidelines. 
For premedication and administration schedules for Arm C 
Step 1 (Induction), follow instructions for Arm A, Step 1 
(Induction). 
5.1.3.2 
Step 2 (Arm G) 
Patients who have improved their response or have had no 
interval change in their tumor measurements with 
restaging from cycle 3 to 6 on Arm C will then proceed to 
Step 2 on Arm G. 
Rev. 12/13 
Rev. 8/15 
Rev. 1/17 
Rev. Add13 

ECOG-ACRIN 
E1411 
Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
39 
Lenalidomide 15 mg po daily days 1-21 every 28 days x 24 
cycles  
Lenalidomide may begin either the same day as, or up to 2 
days after, rituximab on cycles in which rituximab is 
administered 
Rituximab 375 mg/m2 IV or Rituxan Hycela (rituximab 
and hyaluronidase human) 1400 mg/23,400 Units SC 
once every 8 weeks for 12 doses 
NOTE: 
Dose modifications see Section 5.4. 
Administration Schedule for Step 2 (Arm G) 
· 
Lenalidomide 15 mg PO days 1 through 21 on a 28-
day cycle. 
NOTE: 
The first cycle of lenalidomide will start 8 weeks 
(± 3 working days if needed for scheduling) 
after the start of cycle 6 of induction (this will be 
the start of week 29). Patients who, due to 
unacceptable lab values or other reasons, are 
unable to start consolidation within 16 weeks 
after the start of Cycle 6 of induction will be 
withdrawn from study treatment and followed as 
per step 2 guidelines. 
NOTE: 
Rituximab IV may be rounded to the nearest 50 
mg. 
NOTE: 
Lenalidomide may begin either the same day 
as, or up to 2 days after, rituximab on cycles in 
which rituximab is administered. 
NOTE: 
Prior to initiating any lenalidomide cycle, the 
ANC must be ≥ 1000 cells/mm3 (1.0 x 109/L) 
and the platelet count must be ≥ 75,000 
cells/mm3 (75 x 109/L). See Section 5.4.4.1 for 
dose modifications. 
NOTE: 
Creatinine clearance (CrCl) should be 
calculated prior to the first dosing of 
lenalidomide. If CrCl  30 ml/min but < 50 
ml/min, lenalidomide dose should be decreased 
to 10 mg (see Section 5.4.4.2). 
If CrCl < 30 ml/min, or for patients on dialysis, 
lenalidomide should not be given. 
NOTE: 
All patients receiving lenalidomide based 
consolidation therapy must complete the 
lenalidomide pill diary for each cycle/dose of 
lenalidomide (see Appendix IV). 
NOTE: 
If there have been no dose delays or reductions 
during step 2 for 4 consecutive cycles, the 
patient may be seen every other cycle for 
Rev. 12/13 
Rev. 12/13 
Rev. 12/13 
Rev. 8/15 
Rev. 8/15 
Rev. 5/16 
Rev. 5/16 
Rev. 5/16 
Rev. 1/17 
Rev. Add13 
Rev. Add13 

ECOG-ACRIN 
E1411 
Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
40 
subsequent cycles. The patient should be 
contacted by phone at the time of the even 
numbered cycle to assess clinical status and 
toxicities and still requires every 4 week blood 
draws prior to prescribing lenalidomide. The 
phone contact and lab data must be 
documented. The pill diary must still be 
collected for each cycle. 
· 
Rituximab 375 mg/m2 IV or Rituxan Hycela (rituximab 
and hyaluronidase human) 1400 mg/23,400 Units SC 
Day 1. The rituximab IV dose may be rounded to the 
nearest 50 mg 
NOTE: 
The first dose of rituximab consolidation should 
be given 8 weeks ( 3 working days if needed 
for scheduling) after the start of cycle 6 of 
induction (this will be the start of week 29). 
NOTE: 
In the event of a treatment delay, the first dose 
of rituximab may be given up to 16 weeks after 
the start of cycle 6 induction. 
NOTE: 
Rituximab therapy will be given every 8 weeks 
(every 56 days) “on schedule” regardless of 
potential delay or withdrawal of lenalidomide 
except if a patient has grade 3 or 4 neutropenia 
in the absence of other grade 3 or 4 cytopenias, 
consider the possibility of “late-onset 
neutropenia” associated with rituximab. 
Administer myeloid growth factor. Delay 
treatment by 1 week intervals with repeat CBC 
to ensure resolution of neutropenia and then 
start the new cycle.If not recovered by 4 weeks 
despite growth factor, patient will be removed 
from treatment. 
NOTE: 
If using Rituxan Hycela, patients must receive 
at least one full dose of a rituximab product IV 
before receiving Rituxan Hycela SC. Please 
refer to the commercial package insert. 
Length of Therapy 
· 
Repeat rituximab dosing every 8 weeks for a total of 12 
doses. 
· 
Lenalidomide therapy is given every 4 weeks for a total 
of 24 cycles. 
Anticoagulation 
All subjects randomized to lenalidomide/rituximab 
consolidation therapy will be required to have deep vein 
thrombosis (DVT) prophylaxis every day during 
lenalidomide therapy. Subjects with a history of a 
Rev. 12/13 
Rev. 2/14 
Rev. 8/15 
Rev. 5/16 
Rev. 5/16 
Rev. Add13 
Rev. Add13 

ECOG-ACRIN 
E1411 
Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
41 
thrombotic vascular event are required to have full 
anticoagulation, therapeutic doses of low molecular weight 
heparin or warfarin to maintain an INR between 2.0–3.0, or 
any other accepted full anticoagulation regimen (e.g. direct 
thrombin inhibitors or Factor Xa inhibitors) with appropriate 
monitoring for that agent. All subjects without a history of a 
thromboembolic event are required to take a daily aspirin 
(81mg or 325 mg) for DVT prophylaxis. Subjects who are 
unable to tolerate aspirin should receive low molecular 
weight heparin therapy or warfarin treatment or another 
accepted full anticoagulation regimen. 
Of note, if patients’ platelets decline to < 50,000/mm3 (50 x 
109/L), prophylactic anti-coagulation should be stopped (in 
addition to holding lenalidomide as below in Section 5.4.4). 
If/when lenalidomide is restarted (with return of platelet 
toxicity to ≤ Grade 2 as in Table 7 in Section 5.4.4), then 
prophylactic anti-coagulation should also be restarted. 
5.1.3.2.1 
Lenalidomide Fertility Instructions 
NOTE:  Please also see Appendix VI 
“Risks of Fetal Exposure, 
Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods.” 
Before starting study drug: 
 All study participants must be registered 
into the mandatory REMS program, and be 
willing and able to comply with the 
requirements of REMS. 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 prescribing lenalidomide (prescriptions 
must be filled within 7 days) and must either 
commit to continued abstinence from 
heterosexual intercourse or begin TWO 
acceptable methods of birth control, one 
highly effective method and one additional 
effective method AT THE SAME TIME, at 
least 28 days before she starts taking 
lenalidomide.  FCBP must also agree to 
ongoing pregnancy testing. Men must agree 
to use a latex condom during sexual contact 
with a FCBP even if they have had a 
successful vasectomy. See Appendix VI: 
Risks of Fetal Exposure, Pregnancy Testing 
Guidelines and Acceptable Birth Control 
Methods. 
Rev. 5/16 

ECOG-ACRIN 
E1411 
Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
42 
NOTE: A female of childbearing potential 
(FCBP) is any sexually mature 
female, regardless of sexual 
orientation or whether they have 
undergone tubal ligation, who 
meets the following criteria: 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). 
5.1.4 
ARM D/ARM H 
5.1.4.1 
Step 1 Induction (Arm D) 
Bortezomib 1.6 mg/m2/day SC or IV on days 1 and 8 
Rituximab 375 mg/m2 IV day 1 
Bendamustine 90 mg/m2/day IV days 1 and 2  
Repeat cycles every 4 weeks for a total of 6 cycles  
NOTE: 
Rituximab may be rounded to the nearest 50 
mg. 
Other agents may be rounded  5% 
NOTE: 
Cycle length may be altered to 25 days (-3 
days) or to 31 days (+3 days), for holidays or 
other extenuating scheduling situations. 
NOTE: 
Prophylactic Neupogen or Neulasta (or an 
approved biosimilar agent) may be used 
according to ASCO guidelines. 
NOTE: 
Prophylactic acyclovir 400-800 po BID or per 
institutional standard dosing, or valacyclovir 
1,000 once a day (or 500 twice a day) until at 
least one month post-treatment with 
Bortezomib. 
Restaging and Length of Therapy 
· 
Repeat cycles every 28 days for a total of 6 cycles. 
Patients may be evaluated more frequently if needed at 
physician discretion. 
· 
Patients will be restaged after 3 cycles of therapy.  
Patients who are in at least stable disease (SD, PR, or 
CR) after 3 cycles will receive 3 subsequent cycles. 
Patients who have progressive disease (PD) at 
restaging will be discontinued from study treatment.  
Rev. 12/13 
Rev. 12/13 
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Rev. 8/15 

ECOG-ACRIN 
E1411 
Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
43 
For premedication and administration schedules for Step 1 
Induction (Arm D), follow instructions for Step 1 Induction 
(Arm B). 
5.1.4.2 
Step 2 (Arm H) 
Patients who have improved their response or have had no 
interval change in their tumor measurements with 
restaging from cycle 3 to 6 on Arm D will then proceed to 
Step 2 on Arm H. 
Lenalidomide 15 mg po daily days 1-21 every 28 days x 24 
cycles. 
Lenalidomide may begin either the same day as, or up to 2 
days after, rituximab on cycles in which rituximab is 
administered 
Rituximab 375 mg/m2 IV or Rituxan Hycela (rituximab 
and hyaluronidase human) 1400 mg/23,400 Units SC 
once every 8 weeks for 12 doses. 
NOTE: 
Dose modifications see Section 5.4 
Administration Schedule for Step 2 (Arm H) 
· 
Lenalidomide 15 mg PO days 1 through 21 on a 28-
day cycle. 
NOTE: 
The first cycle of lenalidomide will start 8 weeks 
(± 3 working days if needed for scheduling) 
after the start of cycle 6 of induction (this will be 
the start of week 29). Patients who, due to 
unacceptable lab values or other reasons, are 
unable to start consolidation within 16 weeks 
after the start of Cycle 6 of induction will be 
withdrawn from study treatment and followed as 
per step 2 guidelines. 
NOTE: 
Lenalidomide may begin either the same day 
as, or up to 2 days after, rituximab on cycles in 
which rituximab is administered 
NOTE: 
Prior to initiating any lenalidomide cycle, the 
ANC must be ≥ 1000 cells/mm3 (1.0 x 109/L) 
and the platelet count must be ≥ 75,000 
cells/mm3 (75 x 109/L). See Section 5.4.4.1 for 
dose modifications. 
NOTE: 
Creatinine clearance (CrCl) should be 
calculated prior to the first dosing of 
lenalidomide. If CrCl  30 ml/min but < 50 
ml/min, lenalidomide dose should be decreased 
to 10 mg (see Sec 5.4.4.2). 
If CrCl < 30 ml/min, or for patients on dialysis, 
lenalidomide should not be given. 
Rev. 12/13 
Rev. 12/13 
Rev. 5/16 
Rev. Add13 

ECOG-ACRIN 
E1411 
Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
44 
For administration schedules and 
anticoagulation for Step 2 Arm H, follow 
instructions for Step 2 Arm G. 
NOTE: 
All patients receiving lenalidomide based 
consolidation therapy must complete the 
lenalidomide pill diary for each cycle/dose of 
lenalidomide (see Appendix IV). 
NOTE: 
If there have been no dose delays or reductions 
during step 2 for 4 consecutive cycles, the 
patient may be seen every other cycle for 
subsequent cycles. The patient should be 
contacted by phone at the time of the even 
numbered cycle to assess clinical status and 
toxicities and still requires every 4 week blood 
draws prior to prescribing lenalidomide. The 
phone contact and lab data must be 
documented. The pill diary must still be 
collected for each cycle. Rituximab 375 mg/m2 
IV or Rituxan Hycela (rituximab and 
hyaluronidase human) 1400 mg/23,400 Units 
SC Day 1. The rituximab IV dose may be 
rounded to the nearest 50 mg 
NOTE: 
The first dose of rituximab consolidation should 
be given 8 weeks ( 3 working days if needed 
for scheduling) after the start of cycle 6 of 
induction (this will be the start of week 29). 
NOTE: 
In the event of a treatment delay, the first dose 
of rituximab may be given up to 16 weeks after 
the start of cycle 6 induction. 
NOTE: 
Rituximab therapy will be given every 8 weeks 
(every 56 days) “on schedule” regardless of 
potential delay or withdrawal of lenalidomide 
except if a patient has grade 3 or 4 neutropenia 
in the absence of other grade 3 or 4 cytopenias, 
consider the possibility of “late-onset 
neutropenia” associated with rituximab. 
Administer myeloid growth factor. Delay 
treatment by 1 week intervals with repeat CBC 
to ensure resolution of neutropenia and then 
start the new cycle.If not recovered by 4 weeks 
despite growth factor, patient will be removed 
from treatment. 
NOTE: 
If using Rituxan Hycela, patients must receive 
at least one full dose of a rituximab product IV 
before receiving Rituxan Hycela SC. Please 
refer to the commercial package insert. 
Rev. 8/15, 1/17 
Rev. Add13 
Rev. Add13 

ECOG-ACRIN 
E1411 
Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
45 
Length of Therapy 
· 
Repeat rituximab dosing every 8 weeks for a total of 12 
doses. 
· 
Lenalidomide therapy is given every 4 weeks for a total 
of 24 cycles. 
Anticoagulation 
All subjects randomized to lenalidomide/rituximab 
consolidation therapy will be required to have deep vein 
thrombosis (DVT) prophylaxis every day during 
lenalidomide therapy. Subjects with a history of a 
thrombotic vascular event are required to have full 
anticoagulation, therapeutic doses of low molecular weight 
heparin or warfarin to maintain an INR between 2.0–3.0, or 
any other accepted full anticoagulation regimen (e.g. direct 
thrombin inhibitors or Factor Xa inhibitors) with appropriate 
monitoring for that agent. All subjects without a history of a 
thromboembolic event are required to take a daily aspirin 
(81mg or 325 mg) for DVT prophylaxis. Subjects who are 
unable to tolerate aspirin should receive low molecular 
weight heparin therapy or warfarin treatment or another 
accepted full anticoagulation regimen. 
Of note, if patients’ platelets decline to < 50,000/mm3 (50 x 
109/L), prophylactic anti-coagulation should be stopped (in 
addition to holding lenalidomide as below in Section 5.4.4). 
If/when lenalidomide is restarted (with return of platelet 
toxicity to ≤ Grade 2 as in Table 7 in Section 5.4.4), then 
prophylactic anti-coagulation should also be restarted. 
5.1.4.2.1 
Lenalidomide Fertility Instructions 
NOTE: 
Please also see Appendix VI 
“Risks of Fetal Exposure, 
Pregnancy Testing Guidelines 
and Acceptable Birth Control 
Methods.” 
Before starting study drug: 
All study participants must be registered into 
the mandatory REMS program, and be 
willing and able to comply with the 
requirements of REMS. 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 prescribing lenalidomide (prescriptions 
must be filled within 7 days) and must either 
commit to continued abstinence from 
heterosexual intercourse or begin TWO 
acceptable methods of birth control, one 

ECOG-ACRIN 
E1411 
Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
46 
highly effective method and one additional 
effective method AT THE SAME TIME, at 
least 28 days before she starts taking 
lenalidomide.  FCBP must also agree to 
ongoing pregnancy testing. Men must agree 
to use a latex condom during sexual contact 
with a FCBP even if they have had a 
successful vasectomy. See Appendix VI: 
Risks of Fetal Exposure, Pregnancy Testing 
Guidelines and Acceptable Birth Control 
Methods. 
NOTE: A female of childbearing potential 
(FCBP) is any sexually mature 
female, regardless of sexual 
orientation or whether they have 
undergone tubal ligation, who 
meets the following criteria: 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). 

ECOG-ACRIN 
E1411 
Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
47 
5.1.5 
Study Table 
RANDOMIZATION  stratification factor: MIPI low, intermediate, or high AGE < 60 or ≥ 60 yrs 
6 cycles of Induction 
Cycle = 28 days 
Step 1, Arm A 
Rituximab/Bendamustine  
Step 1, Arm B 
Rituximab/Bendamustine/ 
Bortezomib(V)  
Step 1, Arm C 
Rituximab/Bendamustine  
Step 1, Arm D 
Rituximab/Bendamustine/ 
Bortezomib(V)  
1: wk 1-4 
#1 
#1 
#1 
#1 
2: wk 5-8 
#2 
#2 
#2 
#2 
3: wk 9-12 
#3 
#3 
#3 
#3 
RESTAGE ALL ARMS 
(CT or PET/CT) 
 
 
 
 
4: wk13-16 
#4 
#4 
#4 
#4 
5: wk17-20 
#5 
#5 
#5 
#5 
6: wk21-24 
#6 
#6 
#6 
#6 
RESTAGE ALL ARMS 
(PET/CT) 
 
 
 
 
24 months 
Cycle = 28 days 
For all arms, every 4 week 
evaluations C1-6 
STEP 2 Arm E  
Rituximab 
Odd Numbered cycles 1, 3, 
5,… 
STEP 2 Arm F 
Rituximab 
Odd Numbered cycles 1, 3, 
5,… 
 STEP 2 Arm G 
Lenalidomide/Rituximab 
Consolidation 
Step 2 Arm H 
Lenalidomide/Rituximab 
C1:wk29-32 
Rituximab 
Rituximab 
Lenalidomide and Rituximab 
Lenalidomide and Rituximab 
2: wk33-36 
 
 
Lenalidomide 
Lenalidomide 
3: wk37-40 
Rituximab 
Rituximab 
Lenalidomide and Rituximab 
Lenalidomide and Rituximab 
4: wk41-44 
 
 
Lenalidomide 
Lenalidomide 
5: wk45-48 
Rituximab 
Rituximab 
Lenalidomide and Rituximab 
Lenalidomide and Rituximab 
6: wk49-52 
 
 
Lenalidomide  
Lenalidomide  
RESTAGE ALL ARMS 
(CT or PET/CT, except 
PET/CT  if last PET+) 
 
 
 
 
If there have been no 
dose delays/reductions in 
step 2 C1-6, patient may 
be seen every other cycle 
 
 
 
 
7: wk53-56 
Rituximab 
Rituximab 
Lenalidomide and Rituximab 
Lenalidomide and Rituximab 
8: wk57-60 
 
 
Lenalidomide  
Lenalidomide  
9: wk61-64 
Rituximab 
Rituximab 
Lenalidomide and Rituximab 
Lenalidomide and Rituximab 
10: wk65-68 
 
 
Lenalidomide  
Lenalidomide  
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11: wk69-72 
Rituximab 
Rituximab 
Lenalidomide and Rituximab 
Lenalidomide and Rituximab 
12: wk73-76 
 
 
Lenalidomide  
Lenalidomide  
RESTAGE ALL ARMS 
(CT or PET/CT) 
 
 
 
 
13: wk 77-80 
Rituximab 
Rituximab 
Lenalidomide and Rituximab 
Lenalidomide and Rituximab 
14: wk 81-84 
 
 
Lenalidomide 
Lenalidomide 
15: wk85-88 
Rituximab 
Rituximab 
Lenalidomide and Rituximab 
Lenalidomide and Rituximab 
16: wk 89-92 
 
 
Lenalidomide 
Lenalidomide 
17: wk 93-96 
Rituximab 
Rituximab 
Lenalidomide and Rituximab 
Lenalidomide and Rituximab 
18: wk 97-100 
 
 
Lenalidomide 
Lenalidomide 
RESTAGE ALL ARMS 
(CT or PET/CT) 
 
 
 
 
19: wk 101-104 
Rituximab 
Rituximab 
Lenalidomide and Rituximab 
Lenalidomide and Rituximab 
20: wk105-108 
 
 
Lenalidomide 
Lenalidomide 
21: wk 109-112 
Rituximab 
Rituximab 
Lenalidomide and Rituximab 
Lenalidomide and Rituximab 
22: wk 113-116 
 
 
Lenalidomide 
Lenalidomide 
23:wk 117-120 
Rituximab 
Rituximab 
Lenalidomide and Rituximab 
Lenalidomide and Rituximab 
24: wk 121-124 
 
 
Lenalidomide 
Lenalidomide 
RESTAGE After completion of treatment, or when a patient comes off treatment. (CT or PET/CT) 
 
 

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5.1.5.1 
QOL Questionnaire 
If a patient misses an appointment on the scheduled date, 
the questionnaires may be completed by telephone on the 
appointed date or they may be completed at the time the 
appointment is rescheduled. If the missed scheduled date 
is on a treatment date, the quality of life assessment will be 
done when the patient comes for the rescheduled 
treatment. 
If a patient cannot complete the questionnaire because 
he/she is too sick, this should be documented on the 
Assessment Compliance Form. 
5.2 
Adverse Event Reporting Requirements 
5.2.1 
Purpose 
Adverse event (AE) data collection and reporting, which are required 
as part of every clinical trial, are done to ensure the safety of the 
patients enrolled, as well as those who will enroll in future studies 
using similar agents.  
· 
Routine reporting: Adverse events are reported in a routine 
manner at scheduled times during the trial using Medidata 
Rave.  
· 
Expedited reporting: In addition to routine reporting, certain 
adverse events must be reported in an expedited manner for 
timelier monitoring of patient safety and care. The following 
sections provide information and instructions regarding 
expedited adverse event reporting. 
5.2.2 
Terminology 
· 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of a drug in humans, whether or not 
considered drug related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered 
related to the medicinal product.  
· 
Attribution: An assessment of the relationship between the 
adverse event and the protocol treatment, using the following 
categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to treatment 
Unlikely 
The AE is doubtfully related to treatment 
Possible 
The AE may be related to treatment 
Probable 
The AE is likely related to treatment 
Definite 
The AE is clearly related to treatment 
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· 
CAEPR (Comprehensive Adverse Events and Potential 
Risks List):  An NCI generated list of reported and/or potential 
AEs associated with an agent currently under an NCI IND.  
Information contained in the CAEPR is compiled from the 
Investigator’s Brochure, the Package Insert, as well as 
company safety reports.   
· 
CTCAE:  The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized 
for AE reporting.  A grade (severity) is provided for each AE 
term.   
· 
Expectedness: 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, when either the type of event or 
the severity of the event is NOT listed in the protocol or drug 
package. 
5.2.3 
Reporting Procedure 
This study requires that expedited adverse event reporting use the 
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 FDA (1-800-332-1088)  
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 uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours. In addition, supporting or follow up 
documentation must be faxed to the FDA (800-332-0178) 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 
Determination of Reporting Requirements 
Many factors determine the reporting requirements of each individual 
protocol, and which events are reportable in an expeditious manner, 
including:   
· 
the phase (0, 1, 2, or 3) of the trial  
· 
whether the patient has received an investigational or commercial 
agent or both 
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· 
the Common Terminology Criteria for Adverse Events (CTCAE) 
grade 
· 
the relationship to the study treatment (attribution) 
· 
the expectedness of the adverse event 
Using these factors, the instructions and tables in the following 
sections have been customized for protocol E1411 and outline 
the specific expedited adverse event reporting requirements for 
study E1411. 
5.2.5 
Steps to Determine if an Adverse Event is to be Reported in an 
Expedited Manner 
 
Identify the type and grade of the 
event using CTCAE v5.0 
Determine if the event is related to 
the protocol treatment (attribution) 
With this information, review the 
chart in Section 5.2.6 to determine if 
event is reportable via CTEP-AERS 
Refer to footnote b in Section 
5.2.6 to determine if the event 
meets the protocol specific 
reporting requirements for this 
study. If so, report the event via 
CTEP-AERS 
Is the event 
reportable? 
No 
Yes 
Report the event via CTEP-AERS 
Determine the expectedness of the 
event. An unexpected event is 
defined as one where the type of 
severity of the event is not listed in 
the investigator’s brochure, package 
insert or protocol. 
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5.2.6 
Expedited Reporting Requirements for Arms A, B, C, D, E, F, G, and 
H on protocol E1411 
Commercial Agents:  Rituximab and Bendamustine 
IND Exempt Agents:  Lenalidomide and Bortezomib 
Expedited reporting requirements for adverse events experienced by patients on arms with using the 
commercial reporting requirements (Arms A, B, C, D, E, F, G, and H) 
Attribution 
Grade 4 
Grade 5a 
ECOG-ACRIN 
and Protocol-
Specific 
Requirements 
Unexpected 
Expected 
Unexpected 
Expected 
See footnote (b) 
for special 
requirements. 
Unrelated or 
Unlikely 
 
 
7 calendar days 
7 calendar 
days 
Possible, 
Probable, 
Definite 
7 calendar days 
 
7 calendar days 
7 calendar 
days 
7 Calendar Days: 
Indicates a full CTEP-AERS report is to be submitted within 7 calendar days of 
learning of the event. 
a 
A death occurring while on study or within 30 days of the last dose of treatment requires both 
routine and expedited reporting, regardless of causality.  Attribution to treatment or other cause 
must 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: 
Any 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 7 
calendar days of learning of the event. 
b 
Protocol-specific expedited reporting requirements: The adverse events listed below also require 
expedited reporting for this trial: 
Serious Events: 
Any event following treatment that results in persistent or significant 
disabilities/incapacities, congenital anomalies, or birth defects must be 
reported via CTEP-AERS within 7 calendar days of learning of the event.  For 
instructions on how to specifically report these 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. 
Pregnancies (Arms G and H only):  
Female Subjects of Childbearing Potential 
Pregnancies and suspected pregnancies (including a positive/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/inclusive pregnancy test must be reported via CTEP-AERS 
within 24 hours of the Investigator’s knowledge. Please refer to Appendix XVIII for detailed 
instructions on how to report the occurrence of a pregnancy as well as the outcome of all 
pregnancies. 
Rev. 12/13 
Rev. 2/14 
Rev. 8/15 
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5.2.7 
Other Recipients of Adverse Event Reports and Supplemental Data 
ECOG-ACRIN will forward CTEP-AERS reports to the appropriate 
regulatory agencies and pharmaceutical company, if applicable.    
A drug supporter representative may call a site for additional or 
supplemental information regarding a serious adverse event. Any 
additional written AE information requested by the drug supporter 
MUST be submitted to BOTH ECOG-ACRIN and the drug supporter. 
Adverse events determined to be reportable via CTEP-AERS 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. 
5.2.8 
Second Primary Cancer Reporting Requirements – Arms A, B, C, D, 
E, and F 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN using Medidata Rave. 
· 
A second malignancy is a cancer that is UNRELATED to 
any prior anti-cancer treatment (including the treatment 
on this protocol).  Second malignancies require ONLY 
routine reporting as follows: 
1. Complete a Second Primary Form in Medidata Rave 
within 14 days. 
2. Upload a copy of the pathology report to ECOG-ACRIN 
via Medidata Rave confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, upload 
a copy of the cytogenetics report (if available) to ECOG-
ACRIN via Medidata Rave. 
· 
A secondary malignancy is a cancer CAUSED BY any prior 
anti-cancer treatment (including the treatment on this 
protocol).  Secondary malignancies require both routine 
and expedited reporting as follows: 
1. Complete a Second Primary Form within 2 weeks via 
Medidata Rave. 
2. Report the diagnosis via CTEP-AERS at 
http://ctep.cancer.gov 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) 
treatment related secondary malignancy 
3. Upload a copy of the pathology report to ECOG-ACRIN 
via Medidata Rave and submit a copy to NCI/CTEP 
confirming the diagnosis. 
4. If the patient has been diagnosed with AML/MDS, upload 
a copy of the cytogenetics report (if available) to ECOG-

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ACRIN via Medidata Rave and submit a copy to 
NCI/CTEP. 
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 Form 
5.2.9 
Second Primary Cancer Reporting Requirements – Arms G and H 
(Lenalidomide arms) 
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-
sponsored trials must be reported as follows: 
1. 
Complete a Second Primary Form in Medidata Rave within 14 
days. 
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. 
Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming 
the diagnosis. 
4. 
If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave and submit a copy to 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 

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· 
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).   
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 Form. 

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5.3 
Comprehensive Adverse Events and Potential Risks Lists 
5.3.1 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Rituximab (NSC 687451) 
The Comprehensive Adverse Events and Potential Risks List 
(CAEPR) provides a thorough and detailed list of reported and/or 
potential adverse events associated with the agent below. The 
information listed in the CAEPR below, as well as the investigator’s 
brochure, package insert or protocol can be used to determine 
expectedness of an event when evaluating if the event is reportable 
via CTEP-AERS.Please refer to the package insert for more 
information. Frequency is provided based on 986 patients. Below is 
the CAEPR for Rituximab. 
Version 2.1, March 19, 20101 
 
 Adverse Events with Possible  
 Relationship to Rituximab 
 (CTCAE 4.0 Term) 
[n= 986] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
 
 
Blood and lymphatic system 
disorders - Other (Hyperviscosity: 
Waldenstrom’s) 
 
 
Febrile neutropenia 
 
CARDIAC DISORDERS  
 
Myocardial infarction 
 
 
Sinus tachycardia 
 
 
Supraventricular tachycardia 
 
GASTROINTESTINAL DISORDERS  
 
Abdominal pain 
 
 
Diarrhea 
 
 
Nausea 
 
 
Vomiting 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Chills 
 
 
 
Edema limbs 
 
 
Fatigue 
 
Fever 
 
 
Infusion related reaction 
 
 
 
Pain 
 
IMMUNE SYSTEM DISORDERS 
 
Allergic reaction 
 
 
 
Anaphylaxis 
 
Serum sickness 
 
INFECTIONS AND INFESTATIONS 
 
Infection2 
 
Rev. 4/14 
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 Adverse Events with Possible  
 Relationship to Rituximab 
 (CTCAE 4.0 Term) 
[n= 986] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
Infections and infestations - Other 
(Activation of Hepatitis B, C, CMV, 
parvovirus B19, JC virus, varicella 
zoster, herpes simplex, West Nile 
virus) 
 
 
Infections and infestations - Other 
(Infection in HIV Positive Patients) 
 
INVESTIGATIONS 
Lymphocyte count decreased 
 
 
 
Neutrophil count decreased 
 
 
Platelet count decreased 
 
 
White blood cell decreased 
 
METABOLISM AND NUTRITION DISORDERS  
 
Hyperglycemia 
 
 
Hypocalcemia 
 
 
Hypokalemia 
 
 
 
Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
 
 
Back pain 
 
 
Myalgia 
 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) 
 
Tumor pain 
 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
 
 
Headache 
 
 
Lethargy 
 
 
 
Nervous system disorders - 
Other (progressive multifocal 
leukoencephalopathy) 
 
Seizure 
 
RENAL AND URINARY DISORDERS 
 
Acute kidney injury 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
 
Adult respiratory distress 
syndrome 
 
Allergic rhinitis 
 
 
Bronchospasm 
 
 
Cough 
 
 
Dyspnea 
 
 
Hypoxia 
 
 
Pneumonitis 
 
 
Sore throat 
 

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 Adverse Events with Possible  
 Relationship to Rituximab 
 (CTCAE 4.0 Term) 
[n= 986] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Erythema multiforme 
 
Hyperhidrosis 
 
 
Pruritus 
 
 
Rash maculo-papular 
 
 
Skin and subcutaneous tissue 
disorders - Other (angioedema) 
 
 
 
Stevens-Johnson syndrome 
 
 
Toxic epidermal necrolysis 
 
Urticaria 
 
VASCULAR DISORDERS 
 
Flushing 
 
 
Hypertension 
 
 
Hypotension 
 
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 Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
3 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. 
4 Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal 
perforation under the GASTROINTESTINAL DISORDERS SOC. 
Also reported on rituximab trials but with the relationship to rituximab still undetermined: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Bone marrow hypocellular; Hemolysis 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac disorders - Other (cyanosis); 
Left ventricular systolic dysfunction; Sinus bradycardia; Ventricular fibrillation 
EYE DISORDERS - Conjunctivitis; Eye disorders - Other (ocular edema); Uveitis; Watering 
eyes 
GASTROINTESTINAL DISORDERS - Constipation; Dyspepsia; Dysphagia; Gastrointestinal 
obstruction3; Gastrointestinal perforation4; Mucositis oral 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like symptoms; 
Non-cardiac chest pain 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (Opportunistic infection 
associated with >=Grade 2 Lymphopenia) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fracture 
INVESTIGATIONS - Alkaline phosphatase increased; Aspartate aminotransferase increased; 
Blood bilirubin increased; Cardiac troponin I increased; Cardiac troponin T increased; Creatinine 
increased; Investigations - Other (hyperphosphatemia); Investigations - Other (LDH increased); 
Weight loss 

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METABOLISM AND NUTRITION DISORDERS - Anorexia; Hypercalcemia; Hyperkalemia; 
Hypermagnesemia; Hypernatremia; Hyperuricemia; Hypoglycemia; Hypomagnesemia; 
Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis 
NERVOUS SYSTEM DISORDERS - Nervous system disorders - Other (Cranial Neuropathy 
NOS); Peripheral motor neuropathy; Peripheral sensory neuropathy; Pyramidal tract syndrome; 
Reversible posterior leukoencephalopathy syndrome; Syncope 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Depression; Insomnia 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Epistaxis; 
Pharyngolaryngeal pain; Pleural effusion; Pulmonary edema; Respiratory, thoracic and 
mediastinal disorders - Other (bronchiolitis obliterans) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Skin and subcutaneous tissue 
disorders - Other (paraneoplastic pemphigus) 
VASCULAR DISORDERS - Phlebitis; Thromboembolic event; Vasculitis 
NOTE: Rituximab in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination 
may result in events never previously associated with either agent. 

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5.3.2 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Lenalidomide (CC-5013, NSC 703813) 
The Comprehensive Adverse Events 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. The information listed in the CAEPR below, as well as 
the investigator’s brochure, package insert or protocol can be used to 
determine expectendess of an event when evaluating if the event is 
reportable via CTEP-AERS.  Frequency is provided based on 4081 
patients. Below is the CAEPR for lenalidomide (CC-5013). 
Version 2.7, March 14, 20181 
 
 Adverse Events with Possible  
 Relationship to Lenalidomide (CC-5013) 
 (CTCAE 5.0 Term) 
[n= 4081] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
Anemia 
 
 
 
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 
 
EYE DISORDERS 
 
Blurred vision 
 
 
Cataract 
 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
 
Constipation 
 
 
Diarrhea 
 
 
 
Dry mouth 
 
 
Dyspepsia 
 
 
Nausea 
 
 
Vomiting 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Chills 
 
 
Edema limbs 
 
Fatigue 
 
 
 
Fever 
 
 
Generalized edema 
 
Rev. 12/13 
Rev. 10/14, 
7/16 
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 Adverse Events with Possible  
 Relationship to Lenalidomide (CC-5013) 
 (CTCAE 5.0 Term) 
[n= 4081] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
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 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
Bruising 
 
 
Fall 
 
INVESTIGATIONS 
 
Alanine aminotransferase increased  
 
Alkaline phosphatase increased 
 
 
Aspartate aminotransferase 
increased 
 
 
Blood bilirubin increased 
 
 
GGT increased 
 
 
Investigations - Other (C-Reactive 
protein increased) 
 
 
 
Lipase increased 
 
Lymphocyte count decreased 
 
Neutrophil count decreased 
 
 
Platelet count decreased 
 
 
 
Weight loss 
 
 
White blood cell decreased 
 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
 
Dehydration 
 
 
Hyperglycemia 
 
 
Hyperuricemia 
 
 
Hypocalcemia 
 
 
Hypokalemia 
 
 
Hypomagnesemia 
 
 
Hyponatremia 
 
 
Hypophosphatemia 
 
 
Iron overload 
 

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 Adverse Events with Possible  
 Relationship to Lenalidomide (CC-5013) 
 (CTCAE 5.0 Term) 
[n= 4081] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
 
 
Back pain 
 
 
Bone pain 
 
 
Generalized muscle weakness 
 
 
Muscle cramp 
 
 
Pain in extremity 
 
 
 
Rhabdomyolysis5 
 
Myalgia 
 
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 
 
 
Psychiatric disorders - Other (mood 
altered) 
 
RENAL AND URINARY DISORDERS 
 
 
Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Cough 
 
 
Dyspnea 
 

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 Adverse Events with Possible  
 Relationship to Lenalidomide (CC-5013) 
 (CTCAE 5.0 Term) 
[n= 4081] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
Epistaxis 
 
 
 
Pneumonitis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Dry skin 
 
 
 
Erythema multiforme 
 
Hyperhidrosis 
 
 
Pruritus 
 
 
Rash maculo-papular 
 
 
 
Skin and subcutaneous tissue 
disorders - Other (drug reaction 
with eosinophilia and systemic 
symptoms [DRESS]) 
 
Skin and subcutaneous tissue 
disorders - Other (pyroderma 
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 
 
 
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. 
6 There has been an increased frequency of secondary malignancies (including ALL, AML, and MDS) in 
multiple myeloma patients being treated with melphalan, prednisone, and lenalidomide post bone 
marrow transplant. 

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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. 
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 
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 

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

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5.3.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Bortezomib (PS-341, NSC 681239) 
The Comprehensive Adverse Events and Potential Risks List 
(CAEPR) provides a thorough and detailed list of reported and/or 
potential adverse events associated with the agent below. They are 
developed and continuously monitored by the CTEP Investigational 
Drug Branch (IDB). The information listed in the CAEPR below, as 
well as the investigator’s brochure, package insert or protocol can be 
used to determine expectedness of an event when evaluating if the 
event is reportable via CTEP-AERS. Frequency is provided based on 
2084 patients. Below is the CAEPR for bortezomib (PS-341). 
Version 2.6, May 25, 20171 
 
 Adverse Events with Possible  
 Relationship to Bortezomib (Velcade) 
 (CTCAE 4.0 Term) 
[n= 2084] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
Anemia 
 
 
CARDIAC DISORDERS 
 
 
Heart failure 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
 
Constipation 
 
 
Diarrhea 
 
 
 
Dyspepsia 
 
 
Gastrointestinal hemorrhage2 
 
 
 
Gastrointestinal perforation3 
 
Ileus 
 
Nausea 
 
 
Vomiting 
 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Chills 
 
 
Edema limbs 
 
Fatigue 
 
 
Fever 
 
 
HEPATOBILIARY DISORDERS 
 
 
Hepatic failure4 
 
 
Hepatobiliary 
disorders 
- 
Other 
(hepatitis)4 
INFECTIONS AND INFESTATIONS 
Infection5 
 
 
INVESTIGATIONS 
 
 
Alanine aminotransferase increased4 
 
 
Alkaline phosphatase increased4 
 
 
Aspartate 
aminotransferase 
increased4 
 
 
Blood bilirubin increased4 
 
 
GGT increased4 
 
 
INR increased4 
Rev. 9/14 
Rev. Add13 

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 Adverse Events with Possible  
 Relationship to Bortezomib (Velcade) 
 (CTCAE 4.0 Term) 
[n= 2084] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Investigations - Other (albumin)4 
 
Neutrophil count decreased 
 
Platelet count decreased 
 
 
 
Weight loss 
 
METABOLISM AND NUTRITION DISORDERS 
Anorexia 
 
 
 
Dehydration 
 
 
 
Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
 
 
Back pain 
 
 
Bone pain 
 
 
Musculoskeletal and connective tissue 
disorder - Other (muscle spasms) 
 
 
Myalgia 
 
 
Pain in extremity 
 
NERVOU S SYSTEM DISORDERS 
 
Dizziness 
 
 
Headache 
 
 
 
Leukoencephalopathy 
 
Neuralgia 
 
 
Paresthesia 
 
Peripheral motor neuropathy 
 
 
Peripheral sensory neuropathy 
 
 
 
 
Reversible 
posterior 
leukoencephalopathy syndrome 
PSYCHIATRIC DISORDERS 
 
Anxiety 
 
 
Insomnia 
 
RENAL AND URINARY DISORDERS 
 
 
Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
 
Adult respiratory distress syndrome 
 
Cough 
 
 
Dyspnea 
 
 
Pharyngeal mucositis 
 
 
 
Pulmonary hypertension 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Rash maculo-papular 
 
VASCULAR DISORDERS 
 
Hypotension 
 
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 Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 

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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. 
3 Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal 
perforation under the GASTROINTESTINAL DISORDERS SOC. 
4 Cases of acute liver failure have been reported in patients receiving multiple concomitant medications 
and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, 
increases in liver enzymes, and hyperbilirubinemia. 
5 Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
Adverse events reported on bortezomib (Velcade) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that bortezomib 
(Velcade) caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - 
Other (hematocrit low); Blood and lymphatic system disorders - Other (lymphadenopathy); 
Disseminated intravascular coagulation; Febrile neutropenia; Hemolytic uremic syndrome; 
Leukocytosis 
CARDIAC DISORDERS - Acute coronary syndrome; Asystole; Atrial fibrillation; Atrial flutter; 
Atrioventricular block complete; Cardiac arrest; Cardiac disorders - Other (cardiac amyloidosis); 
Cardiac disorders - Other (cardiomegaly); Chest pain - cardiac; Left ventricular systolic 
dysfunction; Mobitz type I; Myocardial infarction; Palpitations; Pericardial effusion; Pericardial 
tamponade; Pericarditis; Right ventricular dysfunction; Sinus bradycardia; Sinus tachycardia; 
Supraventricular tachycardia; Ventricular arrhythmia; Ventricular fibrillation; Ventricular 
tachycardia 
EAR AND LABYRINTH DISORDERS - External ear inflammation; Hearing impaired; Tinnitus 
ENDOCRINE DISORDERS - Hypothyroidism 
EYE DISORDERS - Blurred vision; Conjunctivitis; Dry eye; Extraocular muscle paresis; Eye 
disorders - Other (chalazion); Eye disorders - Other (choroidal effusion); Eye disorders - Other 
(conjunctival hemorrhage); Eye disorders - Other (retinal hemorrhage with bilateral vision 
impairment); Keratitis; Watering eyes 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Bloating; Colitis; Dry 
mouth; Duodenal ulcer; Dysphagia; Enterocolitis; Esophagitis; Flatulence; Gastritis; 
Gastroesophageal reflux disease; Gastrointestinal disorders - Other (colonic wall thickening); 
Gastrointestinal disorders - Other (early satiety); Gastrointestinal disorders - Other (eructation); 
Gastrointestinal disorders - Other (ileitis); Gastrointestinal disorders - Other (ischemic bowel); 
Gastrointestinal disorders - Other (mouth/tongue ulceration); Gastrointestinal disorders - Other 
(retching); Gastrointestinal pain; Gingival pain; Hemorrhoids; Mucositis oral; Oral pain; 
Pancreatitis; Small intestinal obstruction; Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Flu like 
symptoms; Gait disturbance; General disorders and administration site conditions - Other 
(catheter related complication); General disorders and administration site conditions - Other 
(hepato-renal syndrome); Hypothermia; Injection site reaction; Malaise; Multi-organ failure; Non-
cardiac chest pain; Pain; Sudden death NOS 
HEPATOBILIARY DISORDERS - Hepatobiliary disorders - Other (portal vein thrombosis); 
Hepatobiliary disorders - Other (VOD) 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Cytokine release syndrome 

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INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Fall; Fracture; 
Vascular access complication 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; CD4 lymphocytes 
decreased; CPK increased; Carbon monoxide diffusing capacity decreased; Cardiac troponin I 
increased; Cardiac troponin T increased; Cholesterol high; Creatinine increased; Ejection 
fraction decreased; Investigations - Other (BUN); Investigations - Other (low chloride); 
Investigations - Other (pancytopenia); Lipase increased; Lymphocyte count decreased; Serum 
amylase increased; Weight gain; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hyperuricemia; Hypoalbuminemia; Hypocalcemia; Hypoglycemia; Hypokalemia; 
Hypomagnesemia; Hyponatremia; Hypophosphatemia; Metabolism and nutrition disorders - 
Other (failure to thrive); Metabolism and nutrition disorders - Other (hypoproteinemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Avascular 
necrosis; Buttock pain; Chest wall pain; Generalized muscle weakness; Joint range of motion 
decreased; Muscle weakness lower limb; Musculoskeletal and connective tissue disorder - 
Other (cramping); Osteonecrosis of jaw 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Tumor pain 
NERVOUS SYSTEM DISORDERS - Acoustic nerve disorder NOS; Akathisia; Ataxia; Cognitive 
disturbance; Depressed level of consciousness; Dysesthesia; Dysgeusia; Dysphasia; Edema 
cerebral; Encephalopathy; Facial muscle weakness; Facial nerve disorder; Hypersomnia; 
Intracranial hemorrhage; Ischemia cerebrovascular; Lethargy; Memory impairment; Nervous 
system disorders - Other (autonomic neuropathy); Nervous system disorders - Other (Bell's 
palsy); Nervous system disorders - Other (cranial palsy); Nervous system disorders - Other 
(dysautonomia); Nervous system disorders - Other (L sided facial droop); Nervous system 
disorders - Other (paralysis); Nervous system disorders - Other (polyneuropathy); Nervous 
system disorders - Other (spinal cord compression); Nervous system disorders - Other (tongue 
paralysis); Presyncope; Seizure; Somnolence; Stroke; Syncope; Tremor; Vasovagal reaction 
PSYCHIATRIC DISORDERS - Agitation; Confusion; Delirium; Depression; Personality change; 
Psychosis 
RENAL AND URINARY DISORDERS - Bladder spasm; Chronic kidney disease; Cystitis 
noninfective; Hematuria; Proteinuria; Renal and urinary disorders - Other (bilateral 
hydronephrosis); Renal and urinary disorders - Other (calculus renal); Renal and urinary 
disorders - Other (glomerular nephritis proliferative); Urinary frequency; Urinary incontinence; 
Urinary retention; Urinary tract pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; Aspiration; 
Atelectasis; Bronchopulmonary hemorrhage; Bronchospasm; Epistaxis; Hiccups; Hypoxia; 
Laryngeal edema; Mediastinal hemorrhage; Pharyngolaryngeal pain; Pleural effusion; Pleuritic 
pain; Pneumonitis; Postnasal drip; Pulmonary edema; Respiratory failure; Respiratory, thoracic 
and mediastinal disorders - Other (obstructive airways disease); Respiratory, thoracic and 
mediastinal disorders - Other (pleurisy); Respiratory, thoracic and mediastinal disorders - Other 
(respiratory distress); Respiratory, thoracic and mediastinal disorders - Other (tachypnea); 
Tracheal mucositis; Tracheal stenosis; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Bullous dermatitis; Dry skin; 
Erythema multiforme; Erythroderma; Hyperhidrosis; Pain of skin; Palmar-plantar 
erythrodysesthesia syndrome; Pruritus; Purpura; Rash acneiform; Skin and subcutaneous 
tissue disorders - Other (angioedema); Skin and subcutaneous tissue disorders - Other 

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(leukoclastic vasculitis); Skin and subcutaneous tissue disorders - Other (skin lesion NOS); 
Urticaria 
VASCULAR DISORDERS - Capillary leak syndrome; Flushing; Hematoma; Hypertension; 
Thromboembolic event; Vascular disorders - Other (trach site); Vasculitis 
NOTE: 
Bortezomib (Velcade) in combination with other agents could cause an exacerbation 
of any adverse event currently known to be caused by the other agent, or the 
combination may result in events never previously associated with either agent 
 

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5.4 
Dose Modifications 
All toxicity grades below are described using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting 
beginning April 1, 2018. 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 web site (http://ctep.cancer.gov). 
5.4.1 
Dose Modifications – Rituximab 
5.4.1.1 
Hypersensitivity and Infusion Reactions and Rituximab 
Infusion Rates 
Available at the bedside prior to rituximab administration 
will be epinephrine for subcutaneous injection, 
diphenhydramine hydrochloride for IV injection, and 
resuscitation equipment for the emergency management of 
anaphylactoid reactions. 
Rituximab should be administered intravenously through a 
dedicated line at an initial rate of 50 mg/hr, or slower if 
clinically indicated. Rituximab administration schedules 
should be followed as per the standard of care at each 
institution. In general, if hypersensitivity or infusion-related 
events do not occur, escalate the infusion rate in 50 mg/hr 
increments every 30 minutes, to a maximum of 300 mg/hr.  
If hypersensitivity or infusion-related events develop, the 
infusion should be temporarily slowed or interrupted.  The 
patient should be treated according to the appropriate 
standard of care.  The infusion can be continued at one-
half the previous rate when symptoms abate.  Subsequent 
rituximab infusions can be administered at an initial rate of 
100 mg/hr, and increased at 30-minute intervals by 100 
mg/hr increments to a maximum of 400 mg/hr. 
NOTE: In addition, alternative rituximab infusion rates 
(i.e., “rapid rituximab infusion”) can be used per 
institutional guidelines as long as the total number 
of milligrams of rituximab is the same and that 
“rapid infusion” is not administered with the 
patients first rituximab cycle. Further, a rituximab 
infusion time should never be given over less than 
90 minutes (common infusion time for “rapid 
infusion” is 20% of the bag volume over 30 
minutes, and then 80% of the remaining bag 
volume over 60 mintues). 
NOTE: If in the clinical judgement of the treating 
physician it may be safer for the patient, or if 
required by persistent infusion reactions to 
rituximab, rituximab infusion may be divided over 
days 1 and 2. In such cases, bendamustine 
should be administered at the end of each daily 
rituximab infusion if possible. 
Rev. 12/13 
Rev. 8/15 
Rev. Add13 

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Table 3 Rituximab Infusion Rate Adjustments 
Infusion 
Rate 
Fever 
 
 
Rigors 
 
 
Mucosal 
Congestion/ 
Edema 
 
 
Hypotension 
 
(or) 
→ 
(or) 
→ 
 
→ 
 
Decrease ½ >38ºC  
Mild 
 
Mild 
 
Mild 
Interrupt 
>39ºC 
 
Moderat
e 
 
Moderate 
 
Mild to Moderate 
During the rituximab infusion, the patient's vital signs 
(blood pressure, pulse, respiration, temperature) should be 
monitored per institutional standards, generally at least 
every 15 minutes x 4 and then hourly until the infusion is 
discontinued.   
5.4.1.2 
Cardiovascular 
Infusions should be discontinued in the event of serious or 
life-threatening cardiac arrhythmias. Patients who develop 
clinically significant arrhythmias should undergo cardiac 
monitoring during and after subsequent infusions of 
rituximab. Patients with preexisting cardiac conditions 
including arrhythmias and angina have had recurrences of 
these events during rituximab therapy and should be 
monitored throughout the infusion and immediate post-
infusion period. 
5.4.1.3 
Tumor Lysis Syndrome  
Rituximab rapidly decreases benign and malignant CD20 
positive cells.  Tumor lysis syndrome has been reported to 
occur within 12 to 24 hours after the first rituximab infusion 
in patients with high numbers of circulating malignant 
lymphocytes. Patients with high tumor burden (bulky 
lesions) may also be at risk.  Patients at risk of developing 
tumor lysis syndrome should be followed closely and 
appropriate laboratory monitoring performed.  Appropriate 
medical therapy should be provided for patients who 
develop tumor lysis syndrome.   
5.4.2 
Dose Modifications – Bendamustine 
5.4.2.1 
 Bendamustine treatment modifications, ie, dose delays 
and dose reductions, are permitted for patients who are 
unable to tolerate the protocol-specified dosing schedule. 
Dose modifications will be made according to the 
guidelines described below. All toxicity (both hematologic 
and nonhematologic, excluding hemoglobin and ALC) 
must resolve to grade 0 or 1 (except ANC ≥ 1 x 109/L) or 
the grade at baseline before beginning the next treatment 
cycle. Toxicity is measured using the National Cancer 
Rev. 8/15 
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Institute Common Terminology Criteria for Adverse Events, 
version 5.0 (NCI CTCAE v5.0). 
See Section 8.1.11. 
5.4.2.2 
Hematologic 
5.4.2.2.1 
At the start of each cycle, ANC must be at 
least 1000/mm3 (ANC ≥ 1 x 109/L) and 
platelet count must be at least 75000/mm3  
(≥ 75 x 109/L) to proceed with treatment 
(unless the patient has documented marrow 
involvement with lymphoma). Routine 
granulocyte-colony stimulating factor (G-
CSF) support is not required but in the case 
of grade 3 or 4 neutropenia, G-CSF is 
recommended. It is recommended that 
cycles be delayed in 1-week increments for 
a maximum of 4 weeks until hematologic 
parameters allow the next cycle of RB to be 
administered (eg, ANC ≥ 1 x 109/L, platelets 
≥ 75 x109/L). 
5.4.2.3 
Dose Reductions 
5.4.2.3.1 
If thrombocytopenia or neutropenia of grade 
3 or higher requiring a dose delay of 2 
weeks, a reduction in the dose of 
bendamustine will be required (as described 
below) and will be implemented for all 
subsequent cycles once the neutrophil and 
platelet counts return to an acceptable level.  
NOTE: If there is a delay of more than 28 
days due to bendamustine-related 
toxicity, treatment with 
bendamustine should be 
discontinued. 
5.4.2.3.2 
Patients who experience bendamustine-
related grade 4 hematologic (neutropenia or 
thrombocytopenia only) or grade 3 or 4 non-
hematologic toxicity at a dose of 90 mg/m2 
(except for alopecia or grade 3 nausea or 
vomiting) will have their dose of 
bendamustine decreased to 75 mg/m2/day. 
Similarly, patients who experience grade 2 
or greater thrombocytopenia or grade 3 or 
greater neutropenia who require a dose 
delay of 2 weeks at 90 mg/m2/day will have 
their dose of bendamustine decreased to 75 
mg/m2/day in the subsequent cycle (Table 
4).  
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NOTE: In the case of neutropenia only, G-
CSF support should be used 
before considering a dose 
reduction. G-CSF should be 
administered to the patient 
according to local and ASCO 
guidelines (see 
http://www.asco.org). If 
neutropenia occurs despite G-CSF 
support, then a dose reduction of 
bendamustine should be 
implemented. The patient should 
receive further G-CSF support for 
all subsequent treatment cycles.  
5.4.2.3.3 
If a patient again experiences 
bendamustine–related grade 4 hematologic 
toxicity, grade 3 or 4 nonhematologic 
toxicity, or grade 2 or greater 
thrombocytopenia or grade 3 or greater 
neutropenia (with G-CSF support) requiring 
another dose delay of 2 weeks of 
bendamustine at 75 mg/m2/day, the dose 
will be further reduced to 60 mg/m2 (Table 
4). 
Table 4. Bendamustine Dose Reduction Schedule 
Dose 
Toxicity 
Action 
90 mg/m2 
Grade 4 hematologic toxicity 
Reduce dose to 75 mg/m2 
Grade 2 or greater thrombocytopenia or grade  
3 or higher neutropenia* that requires a dose 
delay of 2 weeks 
Reduce dose to 75 mg/m2 
 
75 mg/m2 
Grade 4 hematologic toxicity 
Reduce dose to 60 mg/m2 
Grade 2 or greater thrombocytopenia or grade  
3 or higher neutropenia that requires a dose 
delay of 2 weeks 
Reduce dose to 60 mg/m2 
 
60 mg/m2 
Grade 4 hematologic toxicity 
Reduce dose to 45 mg/m2 
Grade 2 or greater thrombocytopenia or grade  
3 or higher neutropenia that requires a dose 
delay of 2 weeks 
Reduce dose to 45 mg/m2 
 
45 mg/m2 
Grade 4 hematologic toxicity 
Stop bendamustine 
Grade 2 or greater thrombocytopenia or grade  
3 or higher neutropenia that requires a dose 
delay of 2 weeks 
Stop bendamustine 
* In the case of neutropenia only, G-CSF support should occur before considering dose reduction. 

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5.4.3 
Dose Modifications – Bortezomib 
5.4.3.1 
RB Component 
5.4.3.1.1 
Hematologic and non-hematologic (besides 
neurotoxicity):  see Section 5.4.1 and 5.4.2.   
5.4.3.2 
Bortezomib (Velcade) 
5.4.3.2.1 
 For hematologic toxicities, there is no 
planned adjustment of bortezomib dose; 
see Table 4 above regarding adjustments of 
bendamustine. If a day 8 CBC is obtained 
and platelets are < 30,000/mm3 (< 30 x 
109/L), document if the dose is not given 
based on treating physician clinical 
judgement and patient safety. It would be 
skipped, not to be “made up” later. 
5.4.3.2.2 
For grade 3 or grade 4 non-hematologic 
toxicitiy (besides neurotoxicity) that is 
considered by the investigator to be likely or 
definitely related to bortezomib, then drug is 
to be held. For non-hematologic toxicities, 
bortezomib may be held for up to 3 weeks 
until the toxicity returns to Grade 1 or better.  
If, after bortezomib has been held, the 
toxicity does not resolve as defined above, 
then the drug must be discontinued.  If the 
toxicity returns to Grade 1 or better, and 
bortezomib is to be restarted, the dose must 
be reduced by as follows (for all days): 
· 
If the patient was receiving 1.6 mg/m2, 
reduce dose to 1.3 mg/m2. 
· 
If the patient was receiving 1.3 mg/m2, 
reduce dose to 1 mg/m2. 
· 
If the patient was receiving 1 mg/m2, 
reduce dose to 0.7 mg/m2. 
· 
If the patient was receiving 0.7 mg/m2, 
the case should be discussed with the 
Principal Investigator. 
5.4.3.2.3 
Local Reactions to SC Administration 
Sites for each injection (thigh or abdomen) 
should be rotated. New injections should be 
given at least one inch from an old site and 
never into areas where the site is tender, 
bruised, erythematous, or indurated. If local 
injection site reactions occur following 
bortezomib administration subcutaneously, 
a less concentrated bortezomib solution (1 
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mg/mL instead of 2.5 mg/mL) may be 
administered subcutaneously.  Alternatively, 
the IV route of administration should be 
considered. 
5.4.3.2.4 
Neurotoxicity 
Follow the table immediately below when 
assessing neurotoxicity. Bortezomib dose 
reductions apply to doses on both days 1 
and 8 of each cycle. All dose modification 
will be permanent and no dose re-
escalations will be attempted. Please 
contact the study chair if uncertainties arise 
regarding the application of Tables 5 and 6 
below. Please also see the neurotoxicity-
directed quality of life form (FACT-GOG 
neurotoxicity). This is an important tool for 
determining the presence and intensity of 
neuropathic pain and/or peripheral 
neuropathy from the patient’s perspective. 
Neuropathic symptoms are more prominent 
than abnormalities on the clinical 
examination. After the patient completes the 
neurotoxicity-directed questionnaire, the 
questionnaire should be reviewed to assist 
with the evaluation of the onset and 
intensity of peripheral neuropathy and other 
neurotoxicities that may possibly require 
intervention or dose modification. 
Table 5. Dose modification for bortezomib-related neuropathic pain and/or 
peripheral sensory neuropathy. 
Severity of Peripheral Neuropathy 
Signs and Symptoms 
Modification of Dose and Regimen 
Grade 1 (paresthesias) without pain or 
loss of function 
No action 
Grade 1 with pain or Grade 2 (limiting 
instrumental ADL) 
Reduce by one dose level (see 
Table 6) 
Grade 2 with pain or Grade 3 (limiting 
self care ADL) 
Hold* bortezomib therapy until 
toxicity improves/resolves. When 
toxicity improves /resolves, re-initiate 
with a reduction by two dose levels 
(see Table 6) 
Grade 4 (life-threatening consequences; 
urgent intervention indicated) 
Discontinue bortezomib 
(permanently) 
ADLs = activities of daily living 
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*Hold:  Interrupt bortezomib for up to 2 weeks until the toxicity returns to 
Grade 1 or resolves. 
Table 6. Dose level reductions of bortezomib. 
One dose level 
1.6 to 1.3, or 1.3 to 1.0, or 1.0 to 0.7 mg/m2/dose* 
Two dose levels 
1.6 to 1.0, or from either 1.3 or 1 reduce to 0.7 
mg/m2/dose* 
* If the patient is receiving 0.7 mg/m2/dose and experiences repeat grade 1 with 
pain or grade 2 (or worse), discontinue bortezomib. 
5.4.4 
Dose Modifications- Lenalidomide 
NOTE: 
See Section 5.4.4.2 for dosing in renal insufficiency. 
Subjects will be evaluated for adverse events at each visit with the 
NCI CTCAE v.5.0 used as a guide for the grading of severity. The 
dose of lenalidomide for each subject will be interrupted and modified 
following toxicity as described below. Refer to the table below for 
instructions on dose modifications and Section 5.4.4.1 for dose 
reduction instructions for lenalidomide. 
Table 7. Dose Modifications for Lenalidomide. 
 
Toxicity Grade 
Action Required 
 
Grade ≥ 3 neutropenia at the 
beginning of a cycle. 
Or if any of the following occur 
during a cycle: 
Sustained (≥ 7 days) 
Grade 3 neutropenia or > any 
Grade 3 neutropenia 
associated with fever 
(temperature > 38.5o C) or any 
Grade 4 neutropenia 
Hold (interrupt dosing) 
Follow CBC every seven days 
If neutropenia has resolved to ≤ Grade 2 restart at next lower dose 
level 
Use of growth factors (Neupogen, Neulasta) is permitted at the 
discretion of the investigator 
 
Thrombocytopenia ≥ Grade 2 
at the beginning of a cycle 
(<75,000 cells/mm3) or Grade 
≥ 3 on a CBC done during a 
cycle (platelet count < 50,000 
cells/mm3 [50 X 109/L]) 
Hold (interrupt dosing) lenalidomide. 
Hold prophylactic anti-coagulation. 
Follow CBC weekly every seven days 
If thrombocytopenia resolves to ≤ Grade 1 restart at next lower dose 
level (and restart prophylactic anti-coagulation) 
 
Allergic reaction or 
hypersensitivity* 
 
 
Grade 2 
Hold (interrupt) dose. Follow at least every seven days 
Rash should resolve to ≤ grade 1 prior to starting the next cycle of 
therapy. When the toxicity resolves to ≤ Grade 1, restart at next lower 
dose level. 
 
Grade 3-4 
Discontinue lenalidomide study drug 
 
Desquamating (blistering) 
rash- any Grade  
Discontinue lenalidomide. 
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Toxicity Grade 
Action Required 
 
Venous thrombosis/embolism 
 
 
≥ Grade 3 
Hold (interrupt) lenalidomide and start anticoagulation; restart 
lenalidomide at investigator’s discretion (maintain dose level). 
Omit lenalidomide for remainder of cycle. See Anticoagulation 
Consideration (Section 5.5.4) 
 
Other non-hematologic toxicity  
≥ Grade 3** 
Hold (interrupt) lenalidomide dose.  Follow at least weekly. 
If the toxicity resolves to ≤ grade 2 prior to Day 21, restart 
lenalidomide and continue through the scheduled end of the cycle.  
Otherwise, omit for remainder of cycle.  Omitted doses are not made 
up.  For toxicity attributed to lenalidomide, reduce the lenalidomide 
dose by 1 dose level when restarting lenalidomide. 
*  These measures should be taken only for those reactions attributed to lenalidomide. 
**  See Section 5.4.4.2 regarding modifications for renal insufficiency. 
The next cycle of treatment may begin on the scheduled Day 1 if: 
· 
The ANC is ≥ 1,000 cells/mm3 (1 X 109/L); 
· 
The platelet count is ≥ 75,000 cells/mm3 (75 X 109/L); 
· 
Lenalidomide-related allergic reaction or hypersensitivity not requiring 
discontinuation have resolved to ≤ Grade 1 severity; 
· 
Any other lenalidomide-related AE not requiring discontinuation has 
resolved to ≤ Grade 2 severity. 
If these conditions are not met on Day 1 of a new cycle, the subject will 
be evaluated once every seven days and a new cycle of lenalidomide will 
not be initiated until the toxicity has resolved as described above. If a new 
cycle is delayed for more than 28 days, the Principal Investigator must be 
notified. 
If lenalidomide is held on day 1 or during a cycle, dosing will restart when 
toxicity has resolved as per Table 7, but missed doses will not be “made 
up”. This will maintain cycle length. Rituximab will be administered as 
scheduled every 8 weeks. 
If lenalidomide dosing was halted during the previous cycle and was 
restarted with a one-level dose reduction without requiring an interruption 
for the remainder of the cycle, then that reduced dose level will be 
initiated on Day 1 of the new cycle. There will be no more than one dose 
reduction from one cycle to the next. 
5.4.4.1 
Lenalidomide Dose Reduction 
The daily oral dose of lenalidomide may be reduced 
successively by one level from the starting dose of 15 mg 
daily on Days 1-21 every 28 days. 
Table 8. Dose Reduction Steps for Adverse Events 
Related to Lenalidomide. 
Starting Dose 
15 mg daily on Days 1-21, every 28 days 
Level –1 Dose  
10 mg daily on Days 1-21, every 28 days 
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Level –2 Dose  
5 mg daily on Days 1-21, every 28 days 
Level –3 Dose*  
5 mg on alternate days from Days 1-21, every 28 days 
NOTE: 
Once a subject’s dose has been reduced, no dose re-
escalation is permitted. 
* Subjects who cannot tolerate Dose Level –3 are to have lenalidomide 
discontinued permanently. 
5.4.4.2 
Renal Insufficiency:  Lenalidomide dosing 
Patients with creatinine clearance of ≥ 50 mL/min should 
be started at lenalidomide 15 mg daily on Days 1-21 of 
each 28-day cycle as above. No dose adjustments are 
required for patients with CrCl  50 mL/min. Patients with 
creatinine clearance of ≥ 30 mL/min but < 50 mL/min 
should be started at lenalidomide 10 mg daily on Days 1-
21 of each 28-day cycle (these patients could be escalated 
once to 15 mg daily on Days 1-21 of each 28-day cycle if 
they are tolerating lenalidomide well – the escalation 
should occur at the start of a cycle). For these patients who 
start on 10 mg daily, de-escalation will be allowed to 5 mg 
(dose level -2), and then 5 mg every other day (dose level -
3). Once a subject’s dose has been reduced, no dose re-
escalation is permitted. 
Patients with a CrCl < 30 mL/min and those on dialysis will 
be excluded.  
5.5 
Supportive Care 
5.5.1 
All supportive measures consistent with optimal patient care will be 
given throughout the study. 
5.5.2 
Filgrastim (Neupogen) or Pegfilgrastim (Neulasta) granulocyte colony 
stimulating factors (G-CSFs), or approved biosimilar agents, are not 
recommended for routine use in this study. It is recommended that 
investigators follow the most recent ASCO guidelines (101). In the 
event of neutropenic fever, infection, and/or dose delay or reduction, 
please see Sections 5.4.2 or 5.4.3 regarding further instructions. 
Prophylactic antibiotic therapy (e.g. levofloxacin) during induction 
chemotherapy to prevent febrile neutropenia is at the discretion of the 
treating physician as discussed above (Sections 5.4.2 and 5.4.3). 
Anti-viral prophylactic therapy (e.g., acyclovir, famciclovir) should be 
administered for patients on Arm B or Arm D; for Arms A and C, anti-
viral prophylactic therapy should be administered at the discretion of 
the treating physician, but it is recommended for patients with recent 
history of zoster or other HSV infection. 
5.5.3 
 For patients on lenalidomide/rituximab consolidation (step 2), 
pregnancy testing should be repeated within 2 weeks of the start of 
treatment. See Section 3.1.3 for definition of female of childbearing 
potential (FCBP). Before starting lenalidomide: FCBP must have two 
negative pregnancy tests (sensitivity of at least 25 mIU/mL). The first 
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pregnancy test must be performed within 10-14 days prior to the start 
of lenalidomide and the second pregnancy test must be performed 
within 24 hours prior to the start of lenalidomide. The subject may not 
receive lenalidomide until the Investigator has verified that the results 
of these pregnancy tests are negative. Female subjects will be 
warned that sharing study drug is prohibited and will be counseled 
about pregnancy precautions and potential risks of fetal exposure. 
During study participation and for 28 days following discontinuation 
from the study: FCBP with regular cycles must agree to have 
pregnancy tests weekly for the first 28 days of study participation and 
then every 28 days while on study, at study discontinuation, and at 
day 28 following discontinuation from the study. If menstrual cycles 
are irregular, the pregnancy testing must occur weekly for the first 28 
days and then every 14 days while on study, at study discontinuation, 
and at days 14 and 28 following discontinuation from the study. In 
addition to the required pregnancy testing, the Investigator must 
confirm with FCBP at each visit 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. During counseling, 
subjects must be reminded to not share study drug and to not donate 
blood. Pregnancy testing and counseling must be performed if a 
subject misses her period or if her pregnancy test or her menstrual 
bleeding is abnormal. Lenalidomide treatment must be discontinued 
during this evaluation. 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. 
5.5.4 
Patients must have no medical contra-indications to, and be willing to 
take, DVT prophylaxis as all patients registering to the 
lenalidomide/rituximab Arms G and H will be required to have deep 
vein thrombosis (DVT) prophylaxis. Patients randomized to Arms G or 
H who have a history of a thrombotic vascular event will be required to 
have full anticoagulation, therapeutic doses of low molecular weight 
heparin or warfarin to maintain an INR between 2.0 – 3.0, or any other 
accepted full anticoagulation regimen (e.g. direct thrombin inhibitors 
or Factor Xa inhibitors) with appropriate monitoring for that agent. 
Patients on Arms G and H without a history of a thromboembolic 
event are required to take a daily aspirin (81 mg or 325 mg) for DVT 
prophylaxis. Patients who are unable to tolerate aspirin should receive 
low molecular weight heparin therapy or warfarin treatment or another 
accepted full anticoagulation regimen. 
Ways to minimize risk of DVT should be discussed with patients, 
including, but not limited to, avoiding smoking, minimizing pro-
thrombotic hormone replacement, avoiding prolonged periods of 
inactivity (e.g. uninterrupted long car or plane trips). 
5.6 
Duration of Therapy 
Patients will receive protocol therapy unless: 
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5.6.1 
Extraordinary medical circumstances: If at any time the constraints of 
this protocol are detrimental to the patient's health, protocol treatment 
should be discontinued. In this event submit forms according to the 
schedule in the E1411 Forms Completion Guidelines. 
5.6.2 
Patient withdraws consent. 
5.6.3 
Patient has progressive disease 
5.6.4 
Patient experiences unacceptable toxicity. 
5.6.5 
Non-protocol therapies are administered.  
5.6.6 
Suspected or documented pregnancy occurs 
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, even if non-protocol therapy 
is initiated, and for survival for 15 years from the date of registration. All patients 
must also be followed through completion of all protocol therapy.  
 

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6. 
Measurement of Effect 
Non-Hodgkin Lymphoma Response Criteria 
NOTE: These criteria are based on the Revised Response Criteria for Malignant 
Lymphoma, (Cheson et al.), Journal of Clinical Oncology, 2007, Vol. 25:579-
586. 
The criteria use the following categories of response: Complete Response (CR), Partial 
Response (PR), Stable Disease (SD), Relapse and Progression (PD). In the case of 
stable disease, follow-up assessments must have met the SD criteria at least once after 
study entry at a minimum interval of six weeks.  
The following guidelines are to be used for establishing tumor measurements at baseline 
and for subsequent comparison: 
· 
The six largest dominant nodes or extranodal masses must be identified at baseline.  
· 
If there are 6 or fewer nodes and extranodal masses, all must be listed as dominant 
· 
If there are more than 6 involved nodes or extranodal masses, the 6 largest 
dominant nodes or extranodal masses should be selected according to the following 
features: a) they should be clearly measurable in at least two perpendicular 
measurements; b) they should be from as disparate regions of the body as possible; 
and c) they should include mediastinal and retroperitoneal areas of disease 
whenever these sites are involved.  
· 
Measurements on non-dominant nodes are not required. They will be assessed 
subsequently as “resolved” or “not-resolved.” 
· 
The lymph nodes or extranodal masses selected for measurement should be 
measured in two perpendicular diameters, one of which is the longest perpendicular 
diameter. The lymph nodes should be measured in centimeters to the nearest one 
tenth of a centimeter (e.g. 2.0 cm, 2.1 cm, 2.2 cm, etc.) 
· 
The two measured diameters of each lymph node site or extranodal mass should be 
multiplied giving a product for each nodal site or extranodal mass. The product of 
each nodal site should be added, yielding the sum of products of the diameters 
(SPD). The SPD will be used in determining the definition of response for those who 
have less than a complete response. 
6.1 
Complete Response (CR) 
Complete disappearance of all detectable clinical evidence of disease, and 
disease-related symptoms if present prior to therapy. 
6.1.1 
In patients with no pre-treatment PET scan, or if the PET scan was 
positive prior to therapy: a post-treatment residual mass of any size is 
permitted as long as it is PET-negative. 
6.1.2 
In a pretreatment PET scan was negative:  all lymph nodes and 
extranodal masses must have regressed on CT to normal size (≤ 1.5 
cm in their greatest transverse diameter for nodes > 1.5 cm prior to 
therapy).  Previously involved nodes that were 1.1-1.5 cm in their long 
axis and > 1.0 cm in their short axis prior to treatment must have 
decreased to ≤ 1 cm in their short axis after treatment. 
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6.1.3 
The spleen and/or liver, if considered enlarged prior to therapy on the 
basis of a physical examination or CT scan, should not be palpable on 
physical examination, and nodules related to lymphoma should 
disappear. However, no normal size can be specified because of the 
difficulties in accurately evaluating splenic and hepatic size and 
involvement.  For instance, a spleen considered normal size may 
contain lymphoma, whereas an enlarged spleen may not necessarily 
reflect the presence of lymphoma, but variations in anatomy, blood 
volume, the use of hematopoietic growth factors, or other causes. 
6.1.4 
If the bone marrow was involved by lymphoma prior to treatment, the 
infiltrate must have cleared on repeat bone marrow biopsy.  The 
biopsy sample on which this determination is made must be adequate 
(with a goal of > 20 mm unilateral core).  If the sample is 
indeterminate by morphology, it should be negative by 
immunohistochemistry. A sample that is negative by 
immunohistochemistry but demonstrating a small population of clonal 
lymphocytes by flow cytometry will be considered a CR until data 
become available demonstrating a clear difference in patient outcome. 
NOTE: Complete Remission/unconfirmed (CRu): Using the above 
definition for CR and that below for PR eliminates the 
category of CRu. 
6.2 
Partial Response (PR) 
The designation of PR requires all of the following: 
6.2.1 
A ≥ 50% decrease in sum of the product of the diameters (SPD) of up 
to 6 of the largest dominant nodes or extranodal masses. These 
nodes or masses should be selected according to the following: (a) 
they should be clearly measurable in at least 2 perpendicular 
dimensions; if possible, they should be from disparate regions of the 
body; (b) they should include mediastinal and retroperitoneal areas of 
disease whenever these sites are involved. 
6.2.2 
No increase in the size of other nodes, liver or spleen. 
6.2.3 
Bone marrow assessment is irrelevant for determination of a PR if the 
sample was positive prior to treatment. However, if positive, the cell 
type should be specified, e.g. large-cell lymphoma or small cleaved 
cell lymphoma. 
6.2.4 
No new sites of disease. 
6.2.5 
If there was was PET-positive prior to therapy, the post-treatment PET 
should be positive at any previously involved sites. 
6.2.6 
If a pretreatment PET scan was negative, CT scan criteria should be 
used. 
6.2.7 
Patients who achieve a CR by the above criteria, but who have 
persistent morphologic bone marrow involvement will be considered 
partial responders. 
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6.2.8 
When the bone marrow was involved before therapy and a clinical CR 
was achieved, but with no bone marrow assessment after treatment, 
patients should be considered partial responders. 
6.3 
Stable Disease (SD) 
6.3.1 
Failing to attain the criteria needed for a PR or CR, but not fulfilling 
those for progressive disease (see below). 
6.3.2 
The PET should be positive at prior sites of disease with no new 
areas of involvement on the post-treatment CT or PET. 
6.3.3 
For patients without a pretreatment PET scan or if the pre-treatment 
PET was negative, there must be no change in the size of the 
previous lesions on the post-treatment CT scan. 
6.4 
Progression (PD) and Relapse 
For determination of relapsed and progressive disease, lymph nodes should be 
considered abnormal if the long axis is more than 1.5 cm, regardless of the short 
axis.  If a lymph node has a long axis of 1.1 to 1.5 cm, it should only be 
considered abnormal if the short axis is more than 1 cm.  Lymph nodes < 1 x < 1 
cm will not be considered as abnormal for relapse or progressive disease. 
Treatment decisions in patients with presumed refractory, relapsed or 
progressive disease should not be made solely on the basis of a single PET scan 
without histologic confirmation. 
6.4.1 
Appearance of any new lesion more than 1.5 cm in any axis during or 
at the end of therapy, even if other lesions are decreasing in size. 
Increased FDG uptake in a previously unaffected site should only be 
considered relapsed or progressive disease after confirmation with 
other modalities.  In patients with no prior history of pulmonary 
lymphoma, new lung nodules identified by CT are mostly benign. 
Thus, a therapeutic decision should not be made solely on the basis 
of the PET without histologic confirmation. 
6.4.2 
At least a 50% increase from nadir in the SPD of any previously 
involved nodes or extranodal masses, or in a single involved node or 
extranodal mass, or the size of other lesions (e.g. splenic or hepatic 
nodules).  To be considered progressive disease, a lymph node or 
extranodal mass with a diameter of the short axis of less than 1.0 cm 
must increase by > 50% and to a size of 1.5 cm x 1.5 cm or more than 
1.5 cm in the long axis. 
6.4.3 
At least a 50% increase in the longest diameter of any single 
previously identified node or extranodal mass more than 1 cm in its 
short axis. 
6.4.4 
Lesions should be PET positive if observed in a typical FDG-avid 
lymphoma or the lesion was PET positive before therapy unless the 
lesion is too small to be detected with current PET systems (< 1.5 cm 
in its long axis by CT). 
6.4.5 
Measurable extranodal disease should be assessed in a manner 
similar to that for nodal disease.  For these response criteria, the 
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spleen is considered nodal disease.  Disease that is only assessable 
(e.g., pleural effusions, bone lesions) will be recorded as present or 
absent only, unless, while an abnormality is still noted by imaging 
studies or physical examination, it is found to be histologically 
negative. 
6.5 
Duration of Response 
This is measured from the documented beginning of response (CR or PR) to the 
time of relapse. This is measured in responders.  
6.6 
Survival 
Overall survival is defined as the date of study entry to the date of death. 
6.7 
Progression-Free Survival 
Progression-free Survival (PFS) is defined as the time from entry onto study until 
lymphoma progression or death from any cause. PFS is often considered the 
preferable endpoint in lymphoma clinical trials, especially those involving 
incurable histologic subtypes (e.g., follicular and low grade, mantle cell 
lymphoma).  PFS reflects tumor growth and, therefore, occurs prior to the 
endpoint of overall survival. In addition, PFS is not confounded by the 
administration of subsequent therapy.  Whether a prolongation of PFS represents 
direct clinical benefit or a surrogate for clinical benefit depends on the magnitude 
of the effect and the risk-benefit ratio of the therapy under investigation.  Unlike 
survival, the precise date of progression is generally unknown.  It may be defined 
as the first date of documentation of a new lesion or enlargement of a previous 
lesion, or the date of the scheduled clinic visit immediately after radiologic 
assessment has been completed.  Where there is missing information, censoring 
of the data may be defined as the last date at which progression status was 
adequately assessed. 
6.8 
PRO Assessment: Symptom Burden and HRQL 
6.8.1 
Neurotoxicity 
Neurotoxicity associated with bortezomib will be assessed using the 
11-item FACT/GOG-Ntx subscale. Administration of the FACT/GOG-
Ntx prior to, during and following treatment will yield valuable 
information on the longitudinal trajectory of this symptom. The 
FACT/GOG-Ntx includes items that assess severity of neurotoxicity 
and associated functional impairments. 
6.8.2 
Fatigue 
Fatigue associated with disease, induction therapy, and the addition 
of lenalidomide to consolidation therapy will be assessed using the 
13-item FACT-Fatigue subscale. The FACT-Fatigue includes items 
that assess severity of fatigue and functional interference. 
6.8.3 
Lymphoma-specific Concerns 
The 15-item FACT-Lymphoma subscale will be used to assess 
lymphoma-specific concerns, including symptoms and uncertainty 
about the future due to disease. Longitudinal administration of the 

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FACT-Lymphoma subscale will provide the opportunity to assess 
symptom response to treatment and the trajectory of lymphoma 
symptoms among older adults with this rare disease. Administration of 
the FACT-Lymphoma at the time of progression for participants who 
progress before protocol completion will allow us to examine 
symptoms associated with progression as a secondary question. 
6.8.4 
Overall Health-Related Quality of Life (HRQL) 
The 27-item FACT-General will be administered to assess overall 
health-related quality of life. The FACT-G includes four subscales: 
physical, functional, emotional and social well-being. The FACT-G will 
provide data from the patient perspective on quality of life and 
functional status throughout treatment and post-treatment during 
survivorship. 
6.9 
Quality of Life Administration Schedule 
6.9.1 
Assessment Schedule 
Participants will complete a patient-reported outcomes assessment to 
measure the following: 
Symptom/Domain 
Measure 
Number of 
items 
Neurotoxicity 
FACT/GOG-Ntx subscale 
11 
Fatigue 
FACT-Fatigue subscale 
13 
Lymphoma-specific concerns 
FACT-Lymphoma subscale 
15 
Overall health-related quality of life 
FACT-General 
27 
Please complete QOLs at the following time points from initial 
registration to the study 
· 
Baseline Step 1 
· 
6 Months 
( 28 days) 
· 
12 Months 
( 28 days) 
· 
30 Months 
( 28 days) 
· 
36 Months 
( 28 days) 
· 
48 Months 
( 28 days) 
· 
60 Months 
( 28 days) 
If the patient ends step 1 treatment early, for any reason (including 
progression), complete an end of induction QOL then continue with 
the above schedule (if the next scheduled QOL is within 90 days of 
the end of induction QOL, the next scheduled QOL is not required). 
If the patient ends step 2 treatment early complete an end of 
consolidation QOL then continue with the above schedule (if the next 
scheduled QOL is within 90 days of the 12-month QOL or within 180 
days of the end of consolidation QOL, the next scheduled QOL is not 
required). 
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6.9.2 
PRO Administration Instructions 
6.9.2.1 
The questionnaires must be administered at the timepoints 
listed above. The patient should be instructed to respond 
to the questionnaires in terms of his/her experience during 
the time frame specified on each questionnaire. 
6.9.2.2 
The patient should be asked to read the instructions at the 
beginning of each questionnaire and complete all the 
items. It is permissible to assist the patient with the 
completion of the questionnaires as long as the staff 
person does not influence the patient’s responses. 
6.9.2.3 
The questionnaires must be reviewed by the protocol 
nurse or research coordinator as soon as the patient 
completes them to ensure all items were marked 
appropriately. If more than one answer was marked, the 
patient should be asked to choose the answer which best 
reflects how he/she is feeling. If a question was not 
answered, the patient should be asked if he/she would like 
to answer it. The patient should always have the option to 
refuse. If the patient refuses, it should be indicated on the 
questionnaire that he/she declined to answer the item. 
6.9.2.4 
If the patient cannot complete a questionnaire, or if the 
patient refuses to complete the questionnaire, the reason 
should be noted on the Assessment Compliance Form. 
 

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7. 
Study Parameters 
7.1 
Therapeutic Parameters  
1. Prestudy scans and x-rays used to assess all measurable or non-measurable sites of disease must be done ≤ 4 
weeks prior to randomization. 
2.  Patients must have a staging bone marrow biopsy and aspirate prior to randomization. The bone marrow biopsy 
and aspirate should be completed ≤ 8 weeks prior to registration. 
3. History and Physical Exam and PS should be done ≤ 4 weeks before randomization. 
4. All required prestudy blood tests, should be done ≤ 4 weeks before randomization – unless specifically required 
on Day 1 as per protocol, or pregnancy test as per footnote 7. 
5. See Section 7.2 below regarding biological sample submissions. 
 
 
 
Induction (RB or RBV) 
Consolidation (rituximab or 
lenalidomide/rituximab) 
Post-Therapy 
Follow-up 
Rev. 12/13, 
2/14, 1/17 
Parameter 
Pre-study 
Cycles1 
(± 3 days) 
Restaging 
Cycles2 
(± 3 days) 
Restaging  
Every 24 weeks and 
at completion of 
consolodation 
 
 
Assignment of MIPI scores3 
X 
 
 
 
 
 
 
History and Physical examination 
X 
Every cycle 
X 
X 
 
 
 
Performance Status 
X 
Every cycle 
X 
X 
 
  X15 
 
Tumor Measurements by Physical Exam (if applicable) 
X 
 
X 
 
X 
  X15 
Rev. Add13 CBC and Differential4 
X4 
Every cycle 
X 
X20 
 
  X15 
 
Serum Chemistries (electrolytes, SGOT, SGPT,  total 
bilirubin, direct bilirubin,5 LDH, creatinine, glucose, 
alkaline phos, and calcium) 
X 
Every cycle 
X 
 X20 
 
X15 
 
Beta-2-microglobulin 
X 
 
After cycle 6 
 
 
  X15 
 
Uric acid 
X 
 
X 
 
 
 
 
Bone marrow aspirate biopsy 
  X16 
 
After cycle 66 
 
 
 
 
Pregnancy test (for women of child-bearing potential)7,8 
X 
 
 
 X8 
 
 
 
Hepatitis B surface antigen and core antibody testing9 
 X9 
 
 
 
 
 
 
TSH 
X 
 
X 
 
X 
 
 
CD4 count and HIV viral load (HIV + patients only) 
X 
 
  X18 
 
  X18 
 
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Creatinine clearance (calculated by Cockcroft-Gault) 
  X10 
 
After cycle 6 
  X10 
 
 
 
CT Neck, Chest, Abdomen, and Pelvis 
  X11 
 
After cycle 311 
 
          X11, 12 
  X15 
 
FDG-PET/CT Scan 
  X11 
 
After cycle 611 
 
1st restaging, if positive 
end of induction 
 
 
Quality of life studies13 
X 
  X14 
 
  X14 
 
  X14 
 
Registration to REMS17 
  X17 
 
 
  X17 
 
 
 
Research Blood Samples (see Section 7.2) 
  X19 
 
  X19 
After cycles 3 
and 6 
 
  X19 
After step 2 cycles 4, 
8, 12, 18 and 24 
 
1. Cycles are every 28 days. Patients may be evaluated in the office more frequently, if needed, at physician discretion. 
2. Refer to treatment schedule Section 5 If a delay occurs in lenalidomide, rituximab treatment should still be continued “on time.” 
3. Value should be entered for MIPI score. See Section 4.1.5.1 for the MIPI Calculator link. 
4. At baseline: please record the absolute lymphocyte count.  
5. Direct bilirubin is required only if total bilirubin is elevated. 
6. Repeat biopsy/core and aspirate only if positive at baseline and otherwise is in CR. Bone marrow biopsy and aspirate should also be 
obtained at time of relapse. If baseline marrow is positive only by flow cytometry, the aspirate and flow cytometry should be repeated 
7. Within 10-14 days prior to start of induction treatment. See Section 3 for definition of female of childbearing potential. 
8. For patients randomized to Arms C and D, who proceed to Arms G and H, pregnancy tests are needed for females of childbearing potential.  
A female of childbearing potential (FCBP) is a sexually mature female regardless of sexual orientation or whether she has undergone a 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 must occur within 10 – 14 
days and again within 24 hours prior to prescribing lenalidomide (prescriptions must be filled within 7 days).  FCBP with regular or no 
menstruation must have a pregnancy test weekly for the first 28 days and then every 28 days while on therapy (including breaks in therapy); 
at discontinuation of lenalidomide and at Day 28 post the last dose of lenalidomide.  Females with irregular menstruation must have a 
pregnancy test weekly for the first 28 days and then every 14 days while on therapy (including breaks in therapy), at discontinuation of 
lenalidomide and at Day 14 and Day 28 post the last dose of lenalidomide.  
9. Patients must be tested for hepatitis B surface antigen within 6 weeks of randomization. Liver function tests and quantitative PCR assay for 
HBV levels in serum to be performed monthly until 6 months following last rituximab dose, for HBcAb positive patients who receive rituximab.  
Further, consideration should be given to treat patients with anti-viral prophylaxis  prior to, during, and for 6 months after completion of the 
last dose of rituximab. Patients who are positive for HBsAg (surface antigen) are not allowed to enroll on study. 
10. Calculate at baseline before induction, and then calculate again at baseline before consolidation therapy starts for patients continuing to 
lenalidomide therapy, and then repeated thereafter as clinically indicated. 
11. PET/CT scan is preferred at baseline.  Diagnostic CT scans of the neck/chest/abdomen/pelvis must be performed if PET/CT scan cannot be 
obtained at baseline due to timing constraints, insurance or reimbursement issues, or other reasons, and must be documented in the 
patient’s chart.  Either PET/CT or diagnostic CT scans are required after cycle three (3) of induction therapy to document response, PET/CT 
scan is required upon completion of induction therapy.  Staging scans will be done during consolidation after cycle 6 (week 52 ± 1 week), 
Rev. 12/13 
Rev. 12/13 
Rev. 2/14 
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cycle 12 (week 76 ± 1 week), cycle 18 (week 100 ± 1 week) and at completion of consolidation.  If the end of induction PET scan is not 
negative, the first restaging scan at consolidation week 24 should be a repeat of the PET scan. Otherwise, these scans during and at the end 
of consolidation can be either PET or diagnostic CT, though it is highly recommended the same modality be used in an individual patient. If 
PET negative at the end of induction, no further PET imaging is required.  PET/CTs and CTs will be reviewed centrally for quality assurance 
purposes. If the baseline PET/CT study is performed combined with the intravenous and oral contrast, then all subsequent PET/CT studies 
should be performed following the same methodology to avoid variability in SUV max among the PET/CT studies with the same patient.  
PET/CT scans are to be sent to the CALGB imaging core laboratory as outlined in Section 10.1 and Appendix IX. 
12. Refer to Section 5.1.5 for restaging schedule. 
13. See Section 6.8 
14. See Section 6.9 for administration schedule. 
15. Patients in follow-up will follow this schedule until disease progression: 
For history, physical and blood tests 
· Every 3 months if the patient is less than 2.5 years from end of consolidation. 
· Every 6 months if the patient is between 5 and 10 years from the study entry. 
For imaging 
· CT chest/abdomen/pelvis annually (± 1 month) until 5 years from end of consolidation, then as clinically indicated 
For disease progression and survival 
· Every 12 months if the patient is between 10 and 15 years from the study entry. 
· Once patients have documented disease progression (Sec 5.6; 5.7) they are followed only for survival every 6 months for the first 5 years 
and then every 12 months until study completion. 
16. Patients must have a staging bone marrow biopsy and aspirate ≤ 8 weeks prior to randomization 
17. After registration to Arm C and D, and prior to registration to Arms G and H. See Section 8.4.8 for information on the REMS program. 
18. At the time of restaging for Induction (after cycles 3 and 6). At the time of restaging during consolidation treatment. Please refer to the 
treatment table 5.1.5 for the restaging schedule. 
19. For patients who have consented to research sample collection, see Sec 7.2 for schedule of blood and marrow submissions. 
20 Patients on Arms E and F only, these labs may be completed every 8 weeks. 
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Rev. 12/13 
Rev. 12/13 
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7.2 
Biological Sample Submissions  
NOTE:  Submitted scans and specimens must be entered and tracked via the ECOG-ACRIN Sample Tracking 
System (STS). See Section 10.3.  
NOTE:  An informed consent must be signed prior to the submission of any samples including mandatory diagnostic 
reviews, laboratory studies and/or banking. Samples for 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. 12/13, 
8/15 
 
Baseline 
Post 
Cycle 
Three 
Post 
Cycle Six 
(End of 
Induction) 
Every Four (4) 
Months During 
First Year of 
Maintenance 
Every Six (6) 
Months During 
Second Year of 
Maintenance 
Twelve (12) 
Months After 
Completion of 
Maintenance 
Ship to: 
 
MANDATORY for Central Review  
 
Diagnostic Tumor Biopsy 
X 
 
 
Any on study 
biopsy5 
 
 
ALLIANCE Biorepositiry 
at Ohio State 
(Section 10.2/ 
Appendix II) 
 
Submissions Based on Additional Patient Consent   
 
Peripheral Blood, ACD (yellow top tubes)3,6 
 X1 
X 
X 
 
 
 
Mayo Clinic Lymphoma 
Laboratory 
(Section 11.1) 
 
Peripheral Blood, EDTA (purple top tube)3,5 
 X1 
X 
X 
 
 
 
 
Peripheral Blood, red top tube3,5 
 X1 
X 
X 
 
 
 
 
Peripheral Blood, EDTA (purple top tube)3,6 
 X1 
X 
X 
X 
X 
X 
Sequenta, Inc. 
(Section 11.2) 
 
Bone Marrow Aspirate, EDTA (purple top tube)3,6 
 X7 
  
 X4 
 
 
 
1. Baseline blood should be collected after randomization, prior to treatment.  
2. [Deleted in Addendum #2] 
3. Kits are available for the collection and shipment of the blood and bone marrow samples. See Section 11.1.2 for instructions.  
4. Patients in CR only. 
5. Submit from patients who answer “Yes” to “I agree to provide additional specimens/blood for research.” 
6. Submit 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.” 
7. Patient must sign consent before submission of optional bone marrow aspirate (this should be from the bone marrow biopsy done prior to 
enrollment, do not have repeat bone marrow biopsy collected for research only). If submitting initial bone marrow aspirate to Sequenta prior to 
patient enrollment to the trial, please call Kim Henderson at Mayo Clinic (507) 284-3805 to obtain an interim patient number. Do not label the 
Rev. 12/13 
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tube with any patient identifiers aside from the number given by Kim.  Please use the ECOG-ACRIN Generic Specimen Submission Form 
(#2981) when sending the bone marrow to Sequenta. Once the patient has been randomized please call Kim with the ECOG-ACRIN patient 
sequence number and enter the information into the ECOG-ACRIN Sample Tracking System. If patient has had marrow done prior to signing 
consent, submit the blood samples, but do not repeat the marrow simply for research purposes. 

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8. 
Drug Formulation and Procurement 
IND Status 
When used in this protocol lenalidomide and bortezomib are classified as an 
“unapproved use of an approved agent” and by definition considered investigational 
agents. However, while it is not an indication currently approved by the FDA, the use of 
lenalidomide and bortezomib in this protocol are exempt from the requirements of an 
IND and described under Title 21 CFR 312.2(b). 
8.1 
Bendamustine 
CAUTION: There are currently two different preparations of bendamustine 
commercially available; the lyophilized preparation of bendamustine under 
the trade name of Treanda® requiring reconstitution and described under 
Section 8.1 and a new preparation of a ready-to-dilute solution under the 
trade name of Bendeka™. Both preparations are given at the same dose 
and schedule and have the same expected toxicity and dose modifications 
as described in the protocol. However, the preparation, rate of infusion and 
stability between the two products are significantly different. Either 
commercially available agent may be used for E1411. However, please 
exercise caution and indicate which preparation was used to alert 
personnel administering the infusion whether a 10 minute or a 60 minute 
infusion time is to be used. 
8.1.1 
Other Names 
Bendamustine hydrochloride, CEP-18083), TREANDA, BENDEKA. 
8.1.2 
Classification 
Bendamustine hydrochloride (herein bendamustine) is an alkylating 
agent, which contains a bifunctional mechlorethamine derivative, a 
benzimidazole heterocyclic ring, and a butyric acid substituent. 
8.1.3 
Mode of Action 
Mechlorethamine and its derivatives develop electrophilic alkyl groups 
and form covalent bonds with electron-rich nucleophilic moieties, 
which result in interstrand deoxyribonucleic acid (DNA) crosslinks. 
The bifunctional covalent linkage leads to cell death via several 
pathways; however, the exact mechanism of action of bendamustine 
remains unknown. 
8.1.4 
Storage and Stability 
8.1.4.1 
TREANDA 
Reconstituted parenteral solutions are stable for 3 hours at 
room temperature, and for 24 hours if refrigerated. 
8.1.4.2 
BENDEKA 
BENDEKA (bendamustine hydrochloride) Injection 
contains no antimicrobial preservative. The admixture 
should be prepared as close as possible to the time of 
patient administration. 
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If diluted with 0.9% Sodium Chloride Injection, USP, or 
2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the 
final admixture is stable for 24 hours when stored 
refrigerated (2-8°C or 36-46°F) or for 6 hours when stored 
at room temperature (15-30°C or 59-86°F) and room light. 
Administration of diluted BENDEKA (bendamustine 
hydrochloride) Injection must be completed within this 
period of time. 
In the event that 5% Dextrose Injection, USP is utilized, the 
final admixture is stable for 24 hours when stored 
refrigerated (2-8°C or 36-46°F) or for only 3 hours when 
stored at room temperature (15-30°C or 59-86°F) and 
room light. Administration of diluted BENDEKA must be 
completed within this period of time. 
Retain the partially used vial in original package to protect 
from light and store refrigerated (28°C or 36-46°F) if 
additional dose withdraw from the same vial is intended. 
Stability of Partially Used Vials (Needle Punched Vials) 
BENDEKATM (bendamustine hydrochloride) Injection is 
supplied in a multiple-dose vial. Although it does not 
contain any antimicrobial preservative, BENDEKA is 
bacteriostatic. The partially used vials are stable for up to 
28 days when stored in its original carton under 
refrigeration (2-8°C or 36-46°F). Each vial is not 
recommended for more than a total of six (6) dose 
withdrawals. 
After first use, the partially used vial should be stored in the 
refrigerator in the original carton at 2°C to 8°C or 36-46°F 
and then discarded after 28 days. 
8.1.5 
Dose Specifics 
8.1.5.1 
TREANDA 
TREANDA will be administered as a 60-minute iv infusion 
at a dose of 90 mg/m2 on days 1 and 2 of each 28-day 
cycle. 
8.1.5.2 
BENDEKA 
BENDEKA will be admistered as a 10-minute iv infusion at 
a dose of 90 mg/m2 on days 1 and 2 of each 28-day cycle. 
8.1.6 
Dosage in Renal or Hepatic Failure 
In a population pharmacokinetic analysis of bendamustine in patients 
receiving 120 mg/m2 there was no meaningful effect of renal 
impairment (CrCL 40 - 80 mL/min, N=31) on the pharmacokinetics of 
bendamustineThese results are, however, limited, and therefore 
bendamustine should be used with caution in patients with mild or 
moderate renal impairment. Bendamustine has not been studied in 
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patients with CrCL < 40 mL/min, so the package insert states that 
bendamustine should not be used in patients with CrCL < 40 mL/min. 
Bendamustine is not renally excreted to a significant degree, however, 
and clinical experience does not suggest any excess toxicity when 
bendamustine is administered with CrCL 30-40. Thus, the lower limit 
for CrCL in eligibility criteria for this study, as well as for ongoing 
cycles durig step 1, is 30 mL/min. 
In a population pharmacokinetic analysis of bendamustine in patients 
receiving 120 mg/m2 there was no meaningful effect of mild (total 
bilirubin ≤ ULN, AST ≥ ULN to 2.5 x ULN, and/or ALP ≥ ULN to 5.0 x 
ULN, N=26) hepatic impairment on the pharmacokinetics of 
bendamustine. Bendamustine has not been studied in patients with 
moderate or severe hepatic impairment. These results are however 
limited, and therefore bendamustine should be used with caution in 
patients with mild hepatic impairment. Bendamustine should not be 
used in patients with moderate (AST or ALT 2.5 - 10 x ULN and total 
bilirubin 1.5 - 3 x ULN) or severe (total bilirubin > 3 x ULN) hepatic 
impairment. 
8.1.7 
Preparation 
8.1.7.1 
TREANDA 
It will be reconstituted with 20 mL of only Sterile Water for 
Injection, USP. The volume needed of the reconstituted 
bendamustine should be aseptically withdrawn for the 
required dose (based on 5-mg/mL concentration) and 
immediately transferred to an infusion bag of 0.9% Sodium 
Chloride Injection, USP (normal saline). As an alternative 
to 0.9% Sodium Chloride Injection, USP (normal saline), 
an infusion bag of 2.5% Dextrose/0.45% Sodium Chloride 
Injection, USP, may be considered. The resulting final 
concentration of bendamustine in the infusion bag should 
be within 0.2 and 0.6 mg/mL. For a dose of bendamustine 
in the 50- to 180-mg range, a 250-ml infusion bag may be 
used. For a dose of bendamustine in the 100- to 360-mg 
range, a 500-ml infusion bag should be used. The 
reconstituted solution must be transferred to the infusion 
bag within 30 minutes of reconstitution. After transferring, 
thoroughly mix the contents of the infusion bag. The 
admixture should be a clear and colorless to slightly yellow 
solution. 
8.1.7.2 
BENDEKA 
BENDEKATM (bendamustine hydrochloride) Injection, for 
intravenous use is a clear, and colorless to yellow ready-
to-dilute solution supplied as 100 mg/4 ml multiple-dose 
vials. Allow vial to reach room temperature.  If particulate 
matter is observed, the product should not be used. 
Aseptically withdraw the volume needed for the required 
dose from the 25 mg/mL solution and immediately transfer 

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the solution to a 50 mL infusion bag of one of the following 
diluents: 
− 0.9% Sodium Chloride Injection, USP; or 
− 2.5% Dextrose/0.45% Sodium Chloride Injection, USP;  
OR 
− 5% Dextrose Injection, USP. 
The resulting final concentration of bendamustine 
hydrochloride in the infusion bag should be within 1.85 
mg/mL – 5.6 mg/mL.  After transferring, thoroughly mix the 
contents of the infusion bag. The admixture should be a 
clear, and colorless to yellow solution. 
No other diluents have been shown to be compatible. The 
5% Dextrose Injection, USP, offers a sodium-free method 
of administration for patients with certain medical 
conditions requiring restricted sodium intake. 
8.1.8 
Administration 
8.1.8.1 
TREANDA 
Drug should be administered as an IV infusion over 60 
minutes. If medical conditions necessitate, e.g., fluid 
management issues or infusion reactions, the infusion may 
be given over a longer period of time. However, the entire 
infusion time should be < 120 minutes.  In–line filters are 
not required for administration. Prime the infusion line with 
drug solution and accurately record infusion start and stop 
times as part of your source documentation.  Unless there 
are extenuating circumstances, all of the drug should be 
administered to the patient with the exception of what 
remains in the line.  Be sure to document any problems 
you may encounter with the infusion.  If for any reason the 
drug cannot be entirely administered, please measure the 
remaining volume in the infusion bad and record on your 
source documentation.  
8.1.8.2 
BENDEKA 
The prepared infusion is administered intravenously 
over 10-minutes at the dose and schedule described by 
the protocol. 
8.1.9 
Compatibilities 
For specific details refer to handbook on injectable drugs by Lawrence 
A. Trissel. 
8.1.10 
Availability 
Bendamustine is commercially available. See Package Insert for 
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8.1.11 
Side Effects 
The adverse events specified below are also likely to be of clinical 
importance and may result in bendamustine dose delays or dose 
reductions, as outlined in Section 5.4.2. 
· 
Infection and pneumonia: Infection, including pneumonia and 
sepsis, has been reported and, in rare cases, infection has been 
associated with hospitalization, septic shock, and death. Patients 
with myelosuppression following bendamustine treatment are 
susceptible to infections and should be advised to contact a 
physician if they have symptoms or signs of infection, including 
fever or respiratory symptoms. 
· 
Infusion reactions and anaphylaxis: Infusion reactions with 
bendamustine have occurred commonly in clinical studies with 
symptoms that are generally mild and include fever, chills, 
pruritus, and rash. In rare instances, severe infusion reactions, 
described as anaphylactic and anaphylactoid reactions, have 
occurred, particularly in the second and subsequent cycles of 
therapy. Patients should be asked about symptoms suggestive of 
infusion reactions after their first cycle of therapy. Measures to 
prevent severe reactions, including antihistamines, antipyretics, 
and corticosteroids should be considered in subsequent cycles in 
patients who have previously experienced infusion reactions. 
· 
Tumor lysis syndrome: Tumor lysis syndrome has been reported 
with bendamustine, with onset typically within the first treatment 
cycle. Tumor lysis syndrome may lead to acute renal failure and 
death without appropriate medical intervention. Preventive 
measures include maintaining adequate volume status, close 
monitoring of blood chemistry (particularly potassium and uric acid 
levels), and the use of allopurinol during the first 1 to 2 weeks of 
bendamustine treatment. 
· 
Skin reactions: Skin reactions have been reported with the use of 
bendamustine, including non-specific rash, toxic skin reactions, 
and bullous exanthema. The relationship of skin reactions to 
bendamustine administration is often unclear as bendamustine is 
frequently administered with other anti-cancer therapies. A case of 
fatal TEN has been reported in 1 patient treated with a 
combination of bendamustine and rituximab. The TEN was 
considered possibly related to either agent. The relationship of this 
adverse event to bendamustine remains uncertain as TEN has 
also been reported with single-agent rituximab. When skin 
reactions occur, they may be progressive and increase in severity 
with further treatment. If skin reactions are severe or progressive, 
bendamustine should be withheld or discontinued. 
· 
Other malignancies: Development of premalignant and malignant 
disorders following treatment with bendamustine has been 
reported. The reports are limited and included development of 
myelodysplastic syndromes, myeloproliferative disorders, acute 
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confounding effects of other previous chemotherapy in these 
patients, the relationship to bendamustine could not be 
determined. 
8.1.12 
Drug Interactions 
Bendamustine is a substrate for the cytochrome P450(CYP) 1A2 
isoenzyme. 
8.1.12.1 
Bendamustine is metabolized to minimally active 
metabolites by CYP1A2. Concurrent administration of a 
CYP1A2 inhibitor such as atazanavir, cimetidine, 
ciprofloxacin, fluvoxamine, mexiletine, tacrine, 
thiabendazole, zileuton, norfloxacin, and/or ethinyl 
estradiol may increase bendamustine concentrations in 
plasma. Caution should be exercised, or alternative 
treatments considered, when coadministering 
bendamustine with a CYP1A2 inhibitor. 
8.1.12.2 
Bendamustine is metabolized to minimally active 
metabolites by CYP1A2. Concurrent administration of a 
CYP1A2 inducer such as barbiturates, carbamazepine, 
and/or rifampin may cause a decrease in bendamustine 
plasma concentrations and a potential decrease in 
cytotoxicity. The parent compounds are believed to be 
primarily responsible for the cytotoxicity of this agent. 
Caution should be exercised, or alternative treatments 
considered, when coadministering bendamustine with a 
CYP1A2 inducer. 
8.1.12.3 
Bendamustine is metabolized to minimally active 
metabolites by CYP1A2. Smoking tobacco has been 
shown to induce CYP1A2, and may cause a decrease in 
bendamustine plasma concentrations and a potential 
decrease in cytotoxicity. The parent compound is believed 
to be primarily responsible for the cytotoxicity of this agent. 
Caution should be exercised, or smoking cessation 
considered, when coadministering bendamustine with a 
CYP1A2 inducer. 
8.1.13 
Nursing /Patient Implications 
1.  Monitor CBC, platelet count. Advise patients of increased risk of 
infection with absolute neutrophil count less than 500 cells/mm³ 
and increased risk of bleeding with platelet counts less than 
20,000 cells/mm³. Advise patients to call the clinic if they develop 
a fever above 101ºF or notice any easy bruising, petechiae 
(pinpoint red spots on skin), or prolonged bleeding. 
2.  Advise patient of possible alopecia, although this is very 
uncommon with bendamustine therapy. 
3.  Assess hydration and fluid balance. Patients should be 
encouraged to have at least 1 liter of fluids per day for 72 hours 
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4.  Consider premedication with antiemetics. 
5.  Observe for possible phlebitis at injection site. 
6.  Administer antiemetics as indicated. 
8.1.14 
References 
Bertoni F, Zucca E. Bendamustine in lymphomas: More to combine? 
Leukemia & Lymphoma 2007;48(7):1264-6. 
Chow KU, Sommerlad WD, Boehrer S, Schneider B, Seipelt G, 
Rummel MJ, et al. Anti- CD20 antibody (IDEC-C2B8, rituximab) 
enhances efficacy of cytotoxic drugs on neoplastic lymphocytes in 
vitro: role of cytokines, complement, and caspases. Haematologica 
2002;87(1):33-43. 
Friedberg J, Cohen P, Chen L, Robinson K, Forero-Torres A, La 
Casce A, et al. Bendamustine in patients with rituximab-refractory 
indolent and transformed non- Hodgkin’s lymphoma: Results form a 
Phase II multicenter, single-agent study. J Clin Oncol 2008;26(2):204-
10. 
Robinson K, Williams M, Cohen P, Tulpule A, van der Jagt R, Herst J, 
et al. Phase II multicenter study of bendamustine plus rituximab in 
patients with relapsed indolent Bcell and mantle cell non-Hodgkin's 
lymphoma. J CLin Oncol [serial online] 2008;17.001v1:[Epub]. 
Rummel MJ, Al-Batran SE, Kim SZ, Welslau M, Hecker R, Kofahl-
Krause D, et al. Bendamustine plus rituximab is effective and has a 
favorable toxicity profile in the treatment of mantle cell and low-grade 
non-Hodgkin's lymphoma. J Clin Oncol 2005;23(15):3383-9. 
8.2 
Rituximab  
8.2.1 
Other Names 
IDEC-C2B8, Chimeric anti-CD20 monoclonal antibody, Rituxan. 
8.2.2 
Classification 
Antibody. 
8.2.3 
Mode of Action 
Rituximab is a chimeric murine/human gamma 1 kappa monoclonal 
antibody (Chinese hamster ovary [CHO] transfectoma). It recognizes 
the CD20 antigen expressed on normal B cells and most malignant B-
cell lymphomas. It binds with high affinity to CD20-positive cells, 
performs human effector functions in vitro, and depletes B cells in 
vivo. The Fab domain of rituximab binds to the CD20 antigen on B-
lymphocytes and the Fc domain recruits immune effector functions to 
mediate Bcell lysis in vitro. The biological effect is manifested by B-
cell depletion in peripheral blood, lymph nodes, and bone marrow. 
8.2.4 
Storage and Stability 
Intact vials of rituximab are stored at refrigerated temperatures of 2 
degrees to 8 degrees Celsius (36 degrees to 46 degrees Fahrenheit). 

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Protect vials from direct sunlight. Once diluted to a concentration of 1 
to 4 mg/mL in polyvinylchloride or polyolefin IV bags containing 
normal saline or 5% dextrose, the product is stable for up to 24 hours 
at 2 degrees to 8 degrees Celsius, and at room temperature for an 
additional 12 hours after refrigeration (for a maximum period of 36 
hours) if protected from light. 
8.2.5 
Dose Specifics 
Rituxumab will be administered at 375 mg/m² intravenously 
throughout each aspect of this trial (induction and consolidation). 
8.2.6 
Preparation 
Withdraw the necessary amount of rituximab and dilute to a final 
concentration of 1 to 4 mg/mL into an infusion bag containing either 
0.9% Sodium Chloride or 5% Dextrose in Water. Gently invert the bag 
to mix the solution. Caution should be taken during the preparation of 
the drug, as shaking can cause aggregation and precipitation of the 
antibody. 
8.2.7 
Administration 
Rituximab is administered intravenously. An in-line filter is not 
required. The initial rate is 50 mg/hr for the first hour, or slower if 
clinically indicated. If no toxicity is seen, the rate may be escalated 
gradually in 50 mg/hour increments at 30-minute intervals to a 
maximum of 300mg/hr. If the first dose is well tolerated, the initial rate 
for subsequent dose is 100mg/hr, increased gradually in 100 mg/hr 
increments at 30-minute intervals, not to exceed 400 mg/hr. If the 
patient experiences fever and rigors, the antibody infusion is 
discontinued. The severity of the side effects should be evaluated. If 
the symptoms improve, the infusion is continued initially at one-half 
the previous rate. Following the antibody infusion, the intravenous line 
should be maintained for medications as needed. Oral pre-medication 
(650 to 1000 mg of acetaminophen and 25 to 50 mg 
diphenhydramine) or equivalent will be administered 30 to 60 minutes 
prior to starting each infusion of rituximab. The patient should be 
treated according to the best available local practices and procedures. 
In patients with detectable circulating lymphoma cells, it is often 
recommended that the initial infusion rate be reduced to 25 mg/hr; 
these patients may experience more frequent and severe transient 
fever and rigors, shortness of breath, and hypotension. 
NOTE:  In addition, alternative rituximab infusion rates (i.e., “rapid 
rituximab infusion”) can be used per institutional guidelines 
as long as the total number of milligrams of rituximab is the 
same and that “rapid infusion” is not administered with the 
patient’s first rituximab cycle. Further, a rituximab infusion 
should never be given over less than 90 minutes (common 
infusion time for “rapid infusion” is 20% of the bag volume 
over 30 minutes, and then 80% of the remaining bag volume 
over 60 mintues). 
Rev. 12/13 
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8.2.7.1 
Hypersensitivity and Infusion Reactions  
Available at the bedside prior to rituximab administration 
will be epinephrine for subcutaneous injection, 
diphenhydramine hydrochloride for IV injection, and 
resuscitation equipment for the emergency management of 
anaphylactoid reactions. 
Rituximab should be administered intravenously through a 
dedicated line at an initial rate of 50 mg/hr.  If 
hypersensitivity or infusion-related events do not occur, 
escalate the infusion rate in 50 mg/hr increments every 30 
minutes, to a maximum of 300 mg/hr. If hypersensitivity or 
infusion-related events develop, the infusion should be 
temporarily slowed or interrupted.  The patient should be 
treated according to the appropriate standard of care. The 
infusion can be continued at one-half the previous rate 
when symptoms abate. Subsequent rituximab infusions 
can be administered at an initial rate of 100 mg/hr, and 
increased at 30-minute intervals by 100 mg/hr increments 
to a maximum of 400 mg/hr. 
Rituximab Infusion Rate Adjustments 
Infusion  
Rate 
Fever 
 
 
Rigors 
 
 
Mucosal 
Congestion/ 
Edema 
 
 
Hypotension 
 
(or) 
→ 
(or) 
→ 
 
→ 
 
Decrease ½ >38.0ºC 
 
Mild 
 
Mild 
 
Mild 
Interrupt 
>39.0ºC 
 
Moderate 
 
Moderate 
 
Mild to 
Moderate 
During the rituximab infusion, the patient's vital signs 
(blood pressure, pulse, respiration, temperature) should be 
monitored at least every 15 minutes x 4 and then hourly 
until the infusion is discontinued.  Following the antibody 
infusion, the intravenous line should be maintained for 
medications as needed.  
8.2.7.2 
Cardiovascular 
Infusions should be discontinued in the event of serious or 
life threatening cardiac arrhythmias. Patients who develop 
clinically significant arrhythmias should undergo cardiac 
monitoring during and after subsequent infusions of 
rituximab.  Patients with preexisting cardiac conditions 
including arrhythmias and angina have had recurrences of 
these events during rituximab therapy and should be 
monitored throughout the infusion and immediate post-
infusion period. 
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8.2.7.3 
Tumor Lysis Syndrome   
Rituximab rapidly decreases benign and malignant CD20 
positive cells.  Tumor lysis syndrome has been reported to 
occur within 12 to 24 hours after the first rituximab infusion 
in patients with high numbers of circulating malignant 
lymphocytes. Patients with high tumor burden (bulky 
lesions) may also be at risk.  Patients at risk of developing 
tumor lysis syndrome should be followed closely and 
appropriate laboratory monitoring performed. Appropriate 
medical therapy should be provided for patients who are at 
risk for, or who develop, tumor lysis syndrome. 
8.2.8 
Compatibility/Incompatibilities 
Do not mix or dilute rituximab with other drugs. No incompatibilities 
between rituximab and polyvinylchloride or polyethylene bags have 
been observed. 
8.2.9 
Availability 
Commercially available: 
Preservative-free injection 10mg/mL, in 10 and 50 mL single-unit 
vials. 
Please see Package Insert for further information. 
8.2.10 
Side Effects 
Please refer to CAEPR in Section 5.3.1. 
8.2.11 
Nursing /Patient Implications 
1.  Monitor blood pressure, pulse, respiration, and temperature every 
15 minutes x 4 or until stable and then hourly until the infusion is 
discontinued. 
2.  Have epinephrine for subcutaneous injections, diphenhydramine 
for intravenous injection, and resuscitation equipment for 
emergency management of anaphylactoid reactions available. 
3.  Monitor and alter infusion rates in the presence of toxicities. 
4. 
Carriers of hepatitis B virus should be closely monitored for 
clinical and laboratory signs of active HBV infection and for signs 
of hepatitis throughout study participation. 
5. 
Due to the risks of bowel obstruction and bowel perforation, 
patients should be monitored for complaints of abdominal pain, 
especially early in the course of treatment. 
6. 
Patients with concurrent RA should be monitored throughout the 
infusion and rituximab ahould be discontinued in the event of a 
serious or life-threatening cardiac event. 
Rituximab shows no significant effect on bone marrow reserve and no 
apparent increased rate of infections in heavily pretreated, relapsed 
lymphoma patients. Prophylaxis for Tumor Lysis Syndrome (TLS) 

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should be used in patients with bulky tumor masses (> 10cm). 
Patients should be provided IV hydration and administered allopurinol 
or similar agent. Precautionary hospitalization should be made 
available for patients who experience severe infusional symptoms 
which do not resolve after discontinuation or completion of the 
infusion. Hospitalization is not mandated for these patients. This will 
be left to the discretion of the investigator.  
8.2.12 
References 
Product Information: rituximab. IDEC Corporation, December, 1998. 
Reff ME et al. Depletion of B cell in vivo by a chimeric mouse human 
monoclonal antibody to CD20. Blood 1994; 83:435-45. 
Demidem A et al. Chimeric anti-CD20 antibody (IDEC-C2B8) is 
apoptic and sensitizes drug resistant human B cell lymphomas and 
AIDS related lymphomas to the cytotoxic effect of CDDP, VP-16, and 
toxins. FASEB 1995; J9:A206. 
Maloney DG et al. Phase I clinical trial using escalating single dose 
infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2D8) in 
patients with recurrent B-cell Lymphoma. Blood 1993; 82(Suppl 
1):445a. 
Maloney DG et al. Initial report in a phase I/II multiple dose clinical 
trial of IDEC-C2B8 (chimeric anti-CD20) in relapsed B-cell lymphoma. 
Proc Am Soc Clin Oncol 1994; 13:993. 
8.3 
Bortezomib (Velcade) PS-341, NSC 681239  
Please see Package Insert for further information. 
8.3.1 
Chemical Name or Amino Acid Sequence  
N-Pyrazinecarbonyl-L-phenylalanine-L-leucine boronic acid 
8.3.2 
Other Names  
MLN341, LDP-341, Velcade®, bortezomib 
8.3.3 
Classification  
Proteasome Inhibitor 
8.3.4 
CAS Registry Number  
179324-69-7 
8.3.5 
Molecular Formula  
C19H25BN4O4 
8.3.6 
Mechanism of Action  
Inhibitors of the 26S proteasome act through multiple mechanisms to 
suppress tumor survival pathways, arrest tumor growth, tumor spread, 
and angiogenesis. By inhibiting the proteasome, bortezomib affects a 
combination of cellular regulatory mechanisms thereby providing a 
novel therapeutic approach to cancer treatment. This multiple 
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mechanistic approach potentially represents a more effective 
anticancer strategy compared to the antitumor activity afforded by 
conventional chemotherapy. The mechanisms of anti-tumor activity 
that have been established for bortezomib involve many pathways 
thought to be integral to cancer treatment strategies. The following 
observations were made in in vitro and in vivo experiments:  
· 
Directly induces apoptosis of tumor cells. 
· 
Inhibits activation of NF-ΚB in cells and in tumor 
microenvironment. 
· 
Reduces adherence of myeloma cells to bone marrow stromal 
cells. 
· 
Blocks production and intracellular signaling of IL-6 in myeloma 
cells. 
· 
Blocks production and expression of pro-angiogenic mediators. 
· 
Overcomes defects in apoptotic regulators, such as Bcl-2 
overexpression and alterations (i.e., mutations) in tumor 
suppressor p53 and loss of Apaf-1. 
· 
In MM, bortezomib is directly cytotoxic to myeloma cells and also 
modulates the micro-environment via inhibition of NF-KB. 
8.3.7 
How Supplied 
Drug Orders: 
Drug is available in sterile, single use vials containing 3.5 mg of 
bortezomib. Please refer to Section 8.3.8 for instructions on preparing 
the drug for injection. 
Initial Orders:  
Following submission of the required documents and patient 
randomization to Arms B or D, a supply of Bortezomib may be 
ordered from UVI, Inc. Institutions must electronically submit the 
completed E1411 Bortezomib Drug Request Form (Appendix XV and 
available on the ECOG Web Site, www.ecog.org) to UVI, Inc at 
mdubois@uintavision.com. 
When ordering Bortezomib for Arms B and D, please see below for 
the recommended time table for drug requests. A total of 2 shipments 
are recommended for patients on Arm B and D. Recommended time 
points for drug requests are as follows: 
Shipment # 
Patient Treatment Time Point 
1 
Cycles 1-3 
2 
Cycles 4-6 
Please indicate the number of vials needed on the E1411 Bortezomib 
Drug Request Form (Appendix XV). 
NOTE: 
Vials of bortezomib must be ordered in multiples of 4. 

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Institutions should allow 3 business days for receipt of the Bortezomib 
from the date the drug request is received by UVI, Inc. Shipments will 
be made from UVI, Inc. Drug orders received by 2PM EST Monday 
through Thursday will be processed for shipment that day. Approved 
orders will be delivered onsite Tuesday through Friday. 
There will be no weekend or holiday delivery of drugs. 
Reorders: See table above for recommended time points for 
submitting drug requests for patients on Arms B and D. Institutions 
should keep in mind that shipments take 3 business days from the 
date the drug request is received by UVI, Inc. Reorders using the 
E1411 Bortezomib Drug Request Form (Appendix XV) should be 
emailed to UVI, Inc, at mdubois@uintavision.com.  
NOTE: 
A supply of individual vials of bortezomib must be ordered 
in multiples of 4. Once approved by UVI, Inc, the drug will 
be received on site within 3 business days. Shipments will 
be made from UVI, Inc. Drug orders received by 2PM EST 
Monday through Thursday will be processed for shipment 
that day. Approved orders will be delivered onsite Tuesday 
through Friday. 
There will be no weekend or holiday delivery of drugs. 
Drug Inventory Records: Investigational Product Records at 
Investigational Site(s): It is the responsibility of the Investigator to 
ensure that a current record of investigational product disposition is 
maintained at each study site where investigational product is 
inventoried and disposed. Records or logs must comply with 
applicable regulations and guidelines. 
Drug Destruction and Return: 
All unused bortezomib must be returned to Millennium.  Sites are 
advised to fax a completed E1411 Clinical Trial Material Return 
Request Form (Appendix XV) to 617-444-1477. Millennium will 
provide a call tag for free pick up of the bortezomib to be returned, as 
well as instructions on preparing the package for pick up.  
Please maintain appropriate records of the return, including dates and 
quantities. 
8.3.8 
Preparation  
Drug is available in sterile, single use vials containing 3.5 mg of 
bortezomib. Each vial of bortezomib for Injection should be 
reconstituted under a laminar flow biological cabinet (hood) within 
eight hours before dosing with 3.5 mL of normal (0.9%) saline, 
Sodium Chloride Injection USP, so that the reconstituted solution 
contains bortezomib at a concentration of 1 mg/mL. For SC use, 
reconstitute with 1.4 mL of normal (0.9%) saline, Sodium Chloride 
Injection USP, so that the reconstituted solution contains bortezomib 
at a concentration of 2.5 mg/mL for subcutaneous administration. 
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them from light. Dissolution is completed in approximately 10 
seconds. The reconstituted solution is clear and colorless, with a final 
pH of 5 to 6. Reconstituted bortezomib should be administered 
promptly and in no case more than 8 hours after reconstitution. All 
materials that have been used for preparation should be disposed of 
according to standard practices. A log must be kept of all disposed 
materials. 
8.3.9 
Storage  
Vials containing lyophilized bortezomib for Injection should be stored 
according to the label requirements. For the United States, store at 
USP Controlled Room Temperature which is 25ºC (77ºF); excursions 
permitted from 15 to 30ºC (59 to 86ºF). For Europe, do not store 
above 30ºC (86ºF). To date, stability data indicate that the lyophilized 
drug product is stable for at least 18 months when stored under the 
recommended conditions. Stability studies are ongoing, and 
Millennium Pharmaceuticals, Inc. will notify the investigator should this 
information be revised during the conduct of the study. 
Bortezomib is cytotoxic. As with all cytotoxic drugs, caution is required 
when preparing and handling bortezomib solutions. Cytotoxic drugs 
should only be handled by staff specially trained in the safe handling 
of such preparations. The use of gloves and other appropriate 
protective clothing is recommended. In case of skin contact, wash the 
affected area immediately and thoroughly with soap and water for at 
least 15 minutes. If product contacts eye, immediately flush eye 
thoroughly with water for at least 15 minutes. Always contact a 
physician after any form of body contact. All materials that have been 
used for preparation should be disposed of according to standard 
practices. A log must be kept of all disposed materials. 
8.3.10 
Dose Specifics  
Bortezomib will be given at a dose of 1.6 mg/m² on days 1 and 8 of 
each cycle for patients randomized to receive BVR induction. Dose 
escalation is not allowed in any patient, and there must be at least 72 
hours between each dose of bortezomib. 
8.3.11 
Route of Administration  
Intravenous or subcutaneous (SC). Note different reconstitution 
methods, concentration and volume of administration for the different 
routes. 
8.3.12 
Method of Administration 
IV push over 3-5 seconds. 
SC, thigh or abdomen. 
8.3.13 
Incompatibilities  
Bortezomib is metabolized by cytochrome P-450 CYP3A4 and 
CYP2D6 and may interact with other drugs which are either inducers 
or inhibitors of these isoenzymes. Examples of enzyme-inducing 
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agents - phenytoin, carbamazepine, phenobarbital, rifampin and 
rifabutin - may decrease serum concentrations of bortezomib, thereby 
diminishing the therapeutic efficacy. Enzyme-inhibiting drugs such as 
erthromycin, clarithromycin, ketoconazole, itraconazole, voriconazole, 
fluconazole, diltiazem and cyclosporine may increase serum 
concentrations of bortezomib, thereby increasing the risk of toxicity. 
Specialized references should be consulted when attempting to 
predict drug interactions. To date, there are no clinical studies to 
address drug interactions with bortezomib. 
8.3.14 
Special Handling  
Shelf life surveillance of the intact vials is ongoing. The solution as 
reconstituted is stable for 43 hours at room temperature. 
CAUTION: The single-use lyophilized dosage form contains no 
antibacterial preservatives. Therefore, it is advised that the 
reconstituted product be discarded 8 hours after initial entry. 
8.3.15 
Side Effects  
Please refer to the CAEPR in Section 5.3.3. 
8.3.16 
Nursing/Patient Implications  
Patients and nurses should share side-effects with treating clinician so 
they can be treated if appropriate.  
1. 
Monitor for signs of myelosuppression such as infection, 
bleeding or shortness of breath. 
2.  Evaluate for gastrointestinal toxicity providing antiemetics as 
appropriate and monitor bowel habits. 
3. 
Counsel the patient regarding the risk of peripheral neuropathy 
and that it is likely to be dose-related. Patients who have 
received neurotoxic chemotherapy in the past (e.g. Vinca 
alkaloids, taxanes, etc.) may be at higher risk for this 
complication.  
4. 
Have patient promptly report any vision changes. 
5. 
Assess SC injection sites for signs of inflammation. 
8.3.17 
References  
Bortezomib Investigator Drug Brochure. Millennium Pharmaceuticals. 
2003. 
Richardson P, Barlogie B, Berenson J, et al. A Phase II multicenter 
study of the proteasome inhibitor bortezomib (Velcade, formerly 
PS341) in multiple myeloma patients with relapsed/refractory disease. 
Proc Am Soc Hematology 2002 #385. 
Chris Fausel, Pharm.D. 317-278-3402 

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8.4 
Lenalidomide (NSC 703813) 
For further information on lenalidomide, please refer to the approved package 
insert. 
8.4.1 
Other names 
IMiDTM compound CC-5013, Revlimid® (formerly RevimidTM ) 
8.4.2 
Classification 
Immunomodulatory drug  
8.4.3 
Mode of Action 
Lenalidomide, a thalidomide analog, is an immunomodulatory agent 
with a spectrum of activity that is not fully characterized.  In vitro, it 
inhibits secretion of the pro-inflammatory cytokines TNF-α, IL-1β, and 
IL-6 and increases secretion of the anti-inflammatory cytokine IL-10.  It 
also induces T-cell proliferation, IL-2 and IFN-γ production in vitro. 
8.4.4 
Storage and Stability 
Storage: 
The capsules should be stored at room temperature (15-
30°C) away from moisture and direct sunlight. 
Stability: 
Refer to package labeling for expiration date. 
8.4.5 
Dose Specifics 
Patients on Arm G and H will receive lenalidomide at 15 mg orally on 
days 1 through 21 on 28 day cycles (i.e., days 22 to 28 to stop/not 
take lenalidomide) during consolidation therapy. Only enough 
lenalidomide for 1 cycle of therapy may be provided to the patient 
each cycle.  Dose reductions (for adverse events) are discussed in 
Section 5.4.4.1 and Table 8). 
Patients with creatinine clearance of ≥ 30 mL/min but < 50 mL/min 
should be started at lenalidomide 10mg daily on Days 1-21 of each 
28-day cycle (these patients could be escalated once to 15mg daily 
on Days 1-21 of each 28-day cycle if they are tolerating lenalidomide 
well – the escalation should occur at the start of a cycle). For these 
patients who start on 10mg daily, de-escalation will be allowed to 5mg 
(dose level -2), and then 5mg every other day (dose level -3). Once a 
subject’s dose has been reduced, no dose re-escalation is permitted. 
Patients with creatinine clearance of < 30 mL/min by Cockroft-Gault 
formula at registration to step 2 will not be given lenalidomide. If, 
however, this develops while on step 2 treatment, lenalidomide dose 
should be decreased to 5mg daily on Days 1-21 of each 28-day cycle 
(these patients could be escalated once to 10mg daily on Days 1-21 
of each 28-day cycle if they are tolerating lenalidomide well – the 
escalation should occur at the start of a cycle). For these patients who 
start on 5mg daily, de-escalation will be allowed to 5mg every other 
day (dose level -3). Once a subject’s dose has been reduced, no dose 
re-escalation is permitted. 
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8.4.6 
Route of Administration 
Oral. Clinical studies have shown that lenalidomide administration 
coincident with food intake appears to delay absorption to some degree, 
although the extent of absorption is not altered.  Therefore, lenalidomide 
can be taken with or without food. 
8.4.7 
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. 
Administration of lenalidomide in monkeys showed no effects on the 
activities of CYP1A, CYP2B, CYP2C, CYP2E, CYP3A, or CYP4A.  
8.4.8 
Availability 
Drug Orders: 
REMS Program 
Lenalidomide will be provided to patients on Arms G and H for the 
duration of their participation in this trial at no charge to them or their 
insurance providers.  Lenalidomide will be provided in accordance 
with the REMS program of Celgene Corporation. Per standard REMS 
requirements all physicians who prescribe lenalidomide for research 
subjects enrolled into this trial, and all research subjects randomized 
to Arms C and D who then proceed on to Arms G and H of this trial, 
must be registered in and comply with all requirements of the 
REMS™ program. 
Scheduling Considerations: 
Lenalidomide cannot be shipped to patients until all of the steps 
outlined below have been completed.  Due to the multiple steps 
involved in ordering lenalidomide we ask that sites allow adequate 
time for order processing to ensure patient treatment is not delayed.   
For initial orders, steps 1 through 4 can be completed anytime after 
randomization to Arms C or D.  These steps register the patient and 
physician into the REMS program. Once it is determined the patient is 
eligible to proceed on to Arms G or H sites can complete the 
remaining steps.  Step 5 begins the prescription process and all 
subsequent steps must be completed within 7 days. 

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Sites should educate patients that they must register in and comply 
with all requirements of the REMS™ program including the patient 
survey and patient education in order for drug orders to be approved. 
Shipments will be made from Biologics, Inc. Monday through 
Thursday for delivery Tuesday through Friday.  Upon approval of drug 
orders, patients will receive lenalidomide via FedEx in 1-2 business 
days.  Please note that lenalidomide will be shipped directly to 
patients. 
There will be no weekend or holiday delivery of drugs. 
Prescriptions must be filled within 7 days and only enough 
lenalidomide for one cycle of therapy will be supplied to the patient 
each cycle.   
No Starter Supplies are available for this protocol.   
Strengths Available and Order Recommendations: 
Lenalidomide is available as a 5mg, 10mg or 15 mg capsule for oral 
administration.  For this study, the maximum daily dose of 
lenalidomide is 15mg, given to patients on Arms G and H, on days 1 
through 21 of each cycle.  Only enough lenalidomide for one cycle of 
therapy will be supplied to the patient at a time.   
If the patient is dosed at 15 mg, you may order one of the following 
combinations per cycle: 
Capsule Strength 
Quantity needed for one cycle 
15mg 
21 pills 
                         OR 
5mg 
Plus 
10mg 
21 pills 
Plus 
21 pills 
                         OR     
5mg 
63 pills 
Initial Orders:   
Please note that lenalidomide cannot be shipped to patients until 
all of the following steps have been completed.  Steps 1 through 
4 can be completed at anytime after randomization to Arms C or 
D.  These steps register the patient and physician into the REMS 
program. Once it is determined the patient is eligible to proceed 
on to Arms G or H sites can complete the remaining steps.  Step 
5 begins the prescription process and all subsequent steps must 
be completed within 7 days. 
1. Prescribing physician registers in the REMS program by 
completing the Prescriber Enrollemnt Form and submit this form 
electronically through www.CelgeneRiskManagement.com or fax 
to 1-888-423-9325 
2. Patient must be randomized to Arms C or D and eligible to 
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3. Prescribing physician assists patient to enroll in the REMS 
program by obtaining and signing a Patient-Physician Agreement 
Form (PPAF) online at www.CelgeneRiskManagement.com or by 
calling the Celgene Customer Care Center for assistance at1-888-
423-5436 
4. Patient signs the appropriate PPAF and agrees to follow all the 
procedures of the commercial REMS Program.  The prescribing 
physician will then submit the PPAF to the Celgene Customer 
Care Center via mail (86 Morris Avenue, Summit, NJ 07901), 
email (customercare@celgene.com), fax (1-888-432-9325), or 
online (www.celgeneriskmanagement.com) 
5. Patient and prescriber complete a surveys as required by the 
REMS Program by calling Celgene Customer Care at 1-888-423-
5436 or utilizing the REMS online® access at www.CelgeneRisk 
Management.com. 
6. At the completion of the survey, the prescribing physician is given 
a REMS authorization number.  They complete the REMS for 
Patient Prescription Form (Appendix XIII and available on the 
ECOG Web Site) and fax it to one of the Celgene Certified 
Pharamacy Network participants (List available at 
www.celgene.com/PharmacyNetwork). 
7. Prescribing physician advises the patient that a representative 
from a REMS contract pharmacy will contact them by phone within 
24 hours. 
8. REMS contract pharmacy calls patient to conduct patient 
education. 
9. REMS contract pharmacy calls Celgene Customer Care for 
confirmation number. 
10. REMS contract pharmacy approves the order and ships 
lenalidomide and FDA-approved Medication Guide directly to the 
patient.  Once the order is approved, patient will receive 
lenalidomide via FedEx in 1-2 business days. 
Reorders:   
Please note that lenalidomide cannot be shipped to patients until 
all of the following steps have been completed: 
1. Patient and prescriber complete the phone surveys as required by 
the REMS Program by calling Celgene Customer Care at 1-888-
423-5436 or utilizing the REMS online access. 
2. At the completion of the survey, the prescribing physician is given 
a REMS authorization number.  They complete the REMS for 
PatientPrescription Form (Appendix XIII and available on the 
ECOG Web Site) and fax it it to one of the Celgene Certified 
Pharamacy Network participants (List available at 
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3. Prescribing physician advises the patient that a representative 
from a REMS contract pharmacy will contact them by phone within 
24 hours. 
4. REMS contract pharmacy calls patient to conduct patient 
education. 
5. REMS contract pharmacy calls Celgene Customer Care for 
confirmation number. 
6. REMS contract pharmacy approves the order and ships 
lenalidomide and FDA-approved Medication Guide directly to the 
patient. Once the order is approved, patient will receive 
lenalidomide via FedEx in 1-2 business days. 
Scheduling Considerations: 
Lenalidomide cannot be shipped to patients until all of the steps 
above have been completed.  Due to the multiple steps involved in 
ordering lenalidomide we ask that sites allow adequate time for order 
processing to ensure patient treatment is not delayed.   
Sites should educate patients that they must register in and comply 
with all requirements of the REMS™ program including the patient 
survey and patient education in order for drug orders to be approved. 
Shipments will be made from Biologics, Inc. Monday through 
Thursday for delivery Tuesday through Friday.  Upon approval of drug 
orders, patients will receive lenalidomide via FedEx in 1-2 business 
days.  Please note that lenalidomide will be shipped directly to 
patients. 
There will be no weekend or holiday delivery of drugs. 
Prescriptions must be filled within 7 days and only enough 
lenalidomide for one cycle of therapy will be supplied to the patient 
each cycle.   
Drug Inventory Records: 
Investigational Product Records at Investigational Site(s):  It is the 
responsibility of the Investigator to ensure that a current record of 
investigational product disposition is maintained at each study site 
where investigational product is inventoried and disposed.  Records or 
logs must comply with applicable regulations and guidelines. 
Drug Destruction and Return: 
Sites are to instruct patients to return any unused lenalidomide to 
Celgene for destruction. Instructions for return of drug are included 
with each shipment of lenalidomide and instruct patients to call 
Celgene Customer Care at 1-888-423-5436 to begin the return 
process.  Once notified, Celgene will provide patients with a pre-paid 
UPS label to return unused lenalidomide to the company. 
8.4.9 
Side Effects 
Please refer to the CAEPR in Section 1.1.1. 

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8.4.10 
Nursing/ Patient Implications 
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. This should be 
discussed prior to each course of treatment. 
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 
4. All subjects who receive lenalidomide are required to have deep 
vein thrombosis (DVT) prophylaxis during lenalidomide therapy. 
Subjects with a history of a thrombotic vascular event are required 
to have full anticoagulation, therapeutic doses of low molecular 
weight heparin or warfarin to maintain an INR between 2.0–3.0, or 
any other accepted full anticoagulation regimen (e.g. direct 
thrombin inhibitors or Factor Xa inhibitors) with appropriate 
monitoring for that agent. All subjects without a history of a 
thromboembolic event are required to take a daily aspirin (81mg 
or 325 mg) for DVT prophylaxis. Subjects who are unable to 
tolerate aspirin should receive low molecular weight heparin 
therapy or warfarin treatment or another accepted full 
anticoagulation regimen. Refer to Section 5.5.4. 
5. Counsel patient to report abnormal sensations in hands or feet, 
such as decreased sensation or dysesthesia.  Paresthesias are 
often noted early before neuropathy develops. 
6. Advise patient to immediately report rashes or fever. 
7. Advise patient to take dose at the same time each day. 
8.4.11 
Lenalidomide Fertility Instructions 
Before starting study drug: 
Female Subjects 
· 
Females of childbearing potential (FCBP) must have two negative 
pregnancy tests (sensitivity of at least 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. 
· 
Will be warned that sharing study drug is prohibited and will be 
counseled about pregnancy precautions and potential risks of fetal 
exposure. 
· 
Must agree to abstain from donating blood during study 
participation and for at least 28 days after discontinuation from the 
study. 
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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. 
· 
Will be warned that sharing study drug is prohibited and will be 
counseled about pregnancy precautions and potential risks of fetal 
exposure. 
· 
Must agree to abstain from donating blood, semen, or sperm 
during study participation and for at least 28 days after 
discontinuation from the study. 
During study participation and for 28 days following discontinuation 
from the study: 
All Subjects 
· 
No more than a 28-day supply of study drug will be dispensed at a 
time. 
· 
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. 
Female Subjects 
· 
Pregnancy tests must occur within 10-14 days prior to the start of 
the study drug and again within 24 hours prior to initiation of the 
first cycle of lenalidomide. 
· 
FCBP with regular cycles must agree to have pregnancy tests 
weekly for the first 28 days of study participation and then every 
28 days while on study, at study discontinuation, and at day 28 
following discontinuation from the study. If menstrual cycles are 
irregular, the pregnancy testing must occur weekly for the first 28 
days and then every 14 days while on study, at study 
discontinuation, and at days 14 and 28 following discontinuation 
from the study. 
· 
In addition to the required pregnancy testing, the Investigator must 
confirm with FCBP that she is continuing to use two reliable 
methods of birth control at each visit. 
· 
Counseling about pregnancy precautions and the potential risks of 
fetal exposure must be conducted at a minimum of every 28 days. 
During counseling, subjects must be reminded to not share study 
drug and to not donate blood. 

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· 
Pregnancy testing and counseling must be performed if a subject 
misses her period or if her pregnancy test or her menstrual 
bleeding is abnormal. Study drug treatment must be discontinued 
during this evaluation. 
· 
Females must agree to abstain from breastfeeding during study 
participation and for at least 28 days after discontinuation from the 
study 
Male Subjects 
· 
Counseling about the requirement for latex condom use during 
sexual contact with females of childbearing potential and the 
potential risks of fetal exposure must be conducted at a minimum 
of every 28 days. During counseling, subjects must be reminded 
to not share study drug and to not donate blood, sperm, or semen. 
· 
If pregnancy or a positive pregnancy test does occur in a study 
subject or the partner of a male study subject during study 
participation, study drug must be immediately discontinued.  
· 
Men should continue pregnancy precautions for at least 2 months 
after stopping drug (lenalidomide). 
8.4.12 
References 
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. 
Richardson P, Jagannath S, Schlossman R, et al. A Multi-center, 
Randomized, Phase II 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. 
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). 
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. 
8.5 
Rituxan Hycela 
NOTE: 
Please note that Rituxan Hycela (rituximab and hyaluronidase human) 
injection for SC use will be allowed during step 2 of this study (arms 
E-H). Please see the package insert for more information. 
8.5.1 
Description 
Rituxan Hycela (rituximab and hyaluronidase human) is a colorless to 
yellowish, clear to opalescent solution. 
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8.5.2 
Storage and Stability 
Rituxan Hycela should be stored in the refrigerator at 2°C–8°C (36°F–
46°F) in the original carton to protect from light. Do not freeze. 
Once transferred from the vial into the syringe, if not used 
immediately, store the solution of rituximab/hyaluronidase in the 
refrigerator at 2°C–8°C (36°F–46°F) up to 48 hours and subsequently 
for 8 hours at room temperature up to 30°C (86°F) in diffuse light. 
8.5.3 
Dose Specifics 
Rituxan Hycela injection for SC use may be administered for rituximab 
maintenance at 1400mg/23,400 Units SC every 8 weeks (+/- 1 week). 
However, patients must receive at least one full dose of Rituximab by 
IV infusion prior to receiving Rituxan Hycela SC. Please refer to the 
commercial package insert. 
8.5.4 
Route of Administration 
Inject Rituxan Hycela into the subcutaneous tissue of the abdomen 
over approximately 5-7 minutes and never inject into areas where the 
skin is red, bruised, tender or hard, or areas where there are moles or 
scars. No data are available on performing the injection at other sites 
of the body. 
NOTE: 
Please note that Rituxan Hycela (rituximab and 
hyaluronidase human) is ready to use for SC injection only. 
Please see Package Insert for further information. 
8.5.5 
Availability 
Commercially available: 
Injection: 1400 mg rituximab and 23,400 Units hyaluronidase human 
per 11.7 mL (120mg/2,000 Units per mL) in a single-dose vial. 
Injection: 1600 mg rituximab and 26,800 Units hyaluronidase human 
per 13.4 mL (120mg/2,000 Units per mL) in a single-dose vial. 
8.5.6 
Side Effects 
Please see Package Insert for further information. 
8.5.7 
Nursing/Patient Implications 
Rituximab/hyaluronidase is compatible with polypropylene and 
polycarbonate syringe material and stainless-steel transfer and 
injection needles. 
To avoid clogging the needle, attach the injection needle to the 
syringe immediately prior to administration. 
 

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9. 
Statistical Considerations 
9.1 
Primary Endpoints 
The goals of the study are to determine if either bortezomib (Velcade, V,) added 
to an induction regimen of rituximab/ bendamustine (RB) or lenalidomide (L) 
added to rituximab (R) maintenance is associated with improved outcome in 
patients with MCL and to identify arms suitable for evaluation in the Phase 3 
setting. 372 patients, of whom 360 are expected to be eligible and treated, will be 
stratified for balancing purposes according to MIPI risk status (low risk vs. 
intermediate vs. high risk) and age (< 60 vs. ≥ 60), and enrolled over 45 months 
and equally randomized to one of four arms: 
Arm A:  RB –> Arm E:  R 
Arm B:  RBV -> Arm F:  R 
Arm C:  RB -> Arm G:  LR 
Arm D:  RBV-> Arm H:  LR 
Induction Analysis of Progression-Free Survival 
We hypothesize that patients treated with RB->R will have a 2-year PFS rate of 
70%. (estimated from R-CHOP -> R data, (Dreyling personal communication). 
Patients will be stratified according to MIPI risk status, age, and consolidation 
treatment assignment. PFS for patients randomized to RB induction (Arms A and 
C) will be compared to PFS for patients randomized to RBV (Arms B and D). 
With an anticipated 23 additional months of follow-up after the end of accrual, 
there will be adequate power (93.8%) to detect a 37.4% reduction in the hazard, 
corresponding to 2-year PFS of 80%, using a stratified logrank test with 1-sided 
Type I error of 10%. Full information will exist when 149 patients have 
progressed or died. 
Consolidation Analysis of Progression-Free Survival 
The impact of lenalidomide on consolidation will be examined among all eligible 
patients beginning consolidation therapy. Patients who withdraw before starting 
consolidation will be excluded. A recent analysis after 36 months of patient 
accrual showed that only about 80.5% of patients begin consolidation treatment 
compared to the 90% initially assumed. Therefore, the sample size has been 
increased to adjust for this. For this analysis, PFS will be defined as the time 
from the start of consolidation treatment to the earliest of disease progression or 
death. Patients will be stratified according to MIPI risk status and age at the study 
entry and induction treatment assignment.  PFS for patients registered to R 
consolidation (Arms E and F) will be compared to PFS for patients randomized to 
LR consolidation (Arms G and H). 
Given 290 eligible, treated patients in the analysis, there will be 89.4% power to 
detect the same 37.4% reduction in the hazard as for the induction comparison, 
using a stratified logrank test with 1-sided Type 1 error of 10%.  Full information 
will exist when 120 eligible, treated patients have progressed or died. 
Sensitivity Analysis 
As a sensitivity analysis, an intent-to-treat (ITT) analysis will be performed to 
evaluate PFS for the consolidation therapy. All randomized patients including 
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those who drop out before consolidation therapy will be included in the analysis. 
Patients will be stratified according to MIPI risk status at study entry and 
induction treatment assignment. PFS for patients randomized to Arms A and B 
will be compared to PFS for patients randomized to Arms C and D. For purposes 
of this analysis, PFS will be counted as time from randomization. 
The purpose of the sensitivity analysis is to detect potential bias if there is a 
difference in dropout rates between the induction arms. If different results are 
obtained from the ITT analysis, the results of the primary analysis may need to 
be interpreted with caution. 
Interim Analysis 
Both phases of the study (induction and consolidation) will be monitored by the 
ECOG-ACRIN Data Monitoring Committee (DMC) for early stopping for harm and 
futility. The ‘harm’ analysis will be performed at 25% information. If the lower 
bound of a 95% confidence interval for the hazard ratio is above 1, the DMC may 
recommend dropping bortezomib in the RBV induction arms (so all patients will 
be treated with RB induction) or dropping lenalidomide in the LR consolidation 
arms (so all patients will be treated with R consolidation), and the study will 
continue with two arms for that phase. The futility analyses will be performed at 
50% and 75% information. If the estimated hazard ratio for either the induction or 
consolidation comparison is greater than 1, the DMC may recommend dropping 
bortezomib in the RBV arms or dropping lenalidomide in the LR arms, and the 
study will continue with two arms for that phase. These analyses will be done 
separately for induction and consolidation comparisons. The effect of the interim 
analyses on the operating characteristics is fairly small. 
9.2 
Secondary Endpoints 
Analysis of PET-documented Complete Response 
PET-documented CR (complete disappearance of enhancing regions) will be 
assessed first at the end of induction. Information from patients on the two RB 
arms and on the two RBV arms will be pooled for comparing the CR rate 
between the two induction regimens. This analysis will be conducted using 
Fisher’s exact test with 10% one-sided Type I error adjusting for MIPI risk status. 
With 180 patients per treatment group, there will be 93.4% power to detect an 
improvement in the PET-documented CR rate from 50% to 65% with the addition 
of bortezomib. 
Patients who did not achieve PET-documented CR (PET positive) at the end of 
induction and begin consolidation therapy will continue to be followed for the 
emergence of PET-documented CR after 6 cycles of consolidation therapy. 
Information from patients on the two LR arms and on the two R arms will be 
pooled for comparing the proportion of patients converting to PET-documented 
CR after 6 cycles of consolidation therapy between the two consolidation 
regimens. This analysis will include patients with PET-documented residual 
disease after induction who proceed to consolidation therapy. Assuming 50% will 
have induction CRs and another 19.5% will not proceed to consolidation because 
of progression and other reasons, we expect 30.5% of patients (27.5 per arm for 
each of the 4 arms) will have a PET scan after 6 cycles of consolidation therapy. 
With 64 patients in each group (LR vs. R), there will be 88% power to detect an 
improvement in the proportion of patients converting to PET-documented CR 
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from 15% to 35% with the addition of lenalidomide, using Fisher’s exact test with 
10% one-sided Type I error adjusting for MIPI risk status at study entry and 
induction treatment assignment.  
Section 9.4 and Section 9.6 outline statistical considerations for toxicity and QOL 
objectives. All other secondary objectives will primarily be descriptive. 
9.3 
Subset Analysis for Patients Aged 60 Years and Older 
A subset analysis of the primary and secondary endpoints will be done for 
patients aged 60 years and older. We anticipate approximately 80% (N=288) of 
patients will be ≥ 60 years old. For the induction analysis, PFS will be compared 
between RB induction (Arms A and C) and RBV induction (Arms B and D), 
stratified according to MIPI risk status, age and consolidation treatment 
assignment. Using the same hypotheses as for the whole population, there will 
be 89.2% power to detect the same 37.4% reduction in the hazard, using a 
stratified logrank test with 1-sided Type 1 error of 10%. Full information will exist 
when 119 patients have progressed or died. For the consolidation analysis, PFS 
will be compared between R consolidation (Arms A and B) and LR consolidation 
(Arms C and D), stratified according to MIPI risk status at the study entry, age 
and induction treatment assignment. Assuming 232 patients started consolidation 
treatment and are included in the analysis, there will be 83.7% power to detect 
37.4% reduction in the hazard, using a stratified logrank test with 1-sided Type 1 
error of 10%. Full information will exist when 96 eligible, treated patients have 
progressed or died. 
PET-documented complete response and other secondary endpoints will also be 
evaluated in this subset of patients. 
9.4 
Toxicity 
Toxicity will be continuously monitored throughout the study. All patients who 
receive treatment, regardless of eligibility, will be assessed for toxicity. Assuming 
that toxicity data is available on all 93 treated patients per arm, the 90% 
confidence interval for the true probability of observing a toxicity of Grade 4 or 
higher will be no wider than 18%. Below are probabilities of observing at least 
one rare toxicity in patients under different true underlying toxicity rates. 
True Rare  
Toxicity Rate 
Probability of Observing at least 
One Occurrence 
.01 
0.61 
.02 
0.85 
.03 
0.94 
.04 
0.98 
.05 
0.99 
9.5 
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 
reports prepared for the ECOG-ACRIN group meeting (except that for double 
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blind studies, the DMC may review unblinded toxicity data, while only pooled or 
blinded data will be made public). 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 Policy can be 
obtained from the ECOG-ACRIN Operations Office – Boston. 
9.6 
Quality of Life 
Patient-reported quality of life, as measured by the FACT-General scale, the 
FACT-lymphoma subscale, the FACT-Fatigue subscale and the FACT/GOG-Ntx 
neurotoxicity subcale, will be assessed at baseline, at the end of induction 
therapy, after 6 cycles of consolidation therapy, at the conclusion of consolidation 
therapy, at time of progression, and annually for 5 years. 
9.6.1 
To evaluate the extent and severity of neuropathy associated with the 
addition of bortezomib to induction treatment, the change in 
FACT/GOG-Ntx score from baseline to the end of induction will be 
examined in patients treated with RB (Arms A+C) and patients treated 
with RBV (Arms B+D), respectively. The table below shows the mean 
change of the score from baseline that can be detected with 90% 
power using a two-sided Wilcoxon signed rank test with Type I error of 
5%, assuming different proportions of patients who complete the 
questionnaires at both time points. Assuming 80% of eligible, treated 
patients will have measurements at both time points, there will be 
90% power to detect a 0.28 SD change from baseline to the end of 
induction within each group.  
% of patients who 
complete the QOL 
questionnaires at 
both time points 
Number of patients 
in each treatment 
group (RB or RBV) 
Change from baseline that 
can be detected with 90% 
power in each group in 
terms of standard 
deviation (SD) 
90% 
162 
0.26 SD 
80% 
144 
0.28 SD 
70% 
126 
0.30 SD 
60% 
108 
0.32 SD 
If statistically significant changes from baseline to the end of induction 
are noted in either treatment group, the difference in change of the 
score from baseline between patients treated with RBV and RB will be 
examined. The table below shows the differences in change of the 
score that can be detected with 90% power using a two-sided 
Wilcoxon rank sum test with Type I error of 5%, assuming different 
proportions of patients who complete the questionnaires at both time 
points. Assuming 80% of eligible, treated patients will have 
measurements at both time points, there will be 90% power to detect 
a 0.40 SD difference between groups. 

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% of patients who 
complete the QOL 
questionnaires at 
both time points 
Number of patients 
in each treatment 
group (RB or RBV) 
Difference between groups 
that can be detected with 
90% power in terms of 
standard deviation (SD) 
90% 
162 
0.37 SD 
80% 
144 
0.40 SD 
70% 
126 
0.43 SD 
60% 
108 
0.46 SD 
Strategies to minimize the impact of missing assessments will include 
a prospective reminder system through which enrolling sites will be 
notified in advance of patients’ upcoming assessment schedules.   
9.6.2 
To evaluate the extent and severity of fatigue associated with the 
addition of lenalidomide to consolidation treatment, the FACT-Fatigue 
score will be examined. To ensure patients are comparable at the 
beginning of consolidation, we will first examine the change in the 
FACT-Fatigue score in the induction phase. If there are no significant 
changes in FACT-Fatigue score from baseline to the end of induction 
in either treatment group (RB or RBV), and no significant differences 
in FACT-Fatigue score at the end of induction between arms, the 
patients treated with LR consolidation will be pooled and those treated 
with R consolidation will be pooled (otherwise, each arm will be 
analyzed individually). The change in FACT-Fatigue score from the 
end of induction to after 6 cycles of consolidation will be examined in 
patients treated with R consolidation and patients treated with LR 
consolidation, respectively. Considering that about 19.5% of patients 
will not begin consolidation therapy, and the proportion of patients 
who complete questionnaires usually decreases over the course of 
the study, we assuming 60% of patients will have measurements at 
both time points. There will be 87.0% power to detect a 0.34 SD 
change from end of induction to after 6 cycles of consolidation within 
each group, using a two-sided Wilcoxon signed rank test with Type I 
error of 5%. Similarly, the change in FACT-Fatigue score from the end 
of induction to the end of consolidation will be examined. 
If statistically significant changes are noted in either treatment group 
at either time point, the change in the score from the end of induction 
between patients treated with R and LR consolidation will be 
compared. Assuming 60% patients per arm with change scores and 
using a two-sided Wilcoxon rank sum test with Type I error of 5%, 
there will be about 87.0% power to detect a 0.48 SD difference 
between the groups. 
If there are differences between groups in QOL at the end of 
induction, each arm may be considered individually in the evaluation 
of QOL during consolidation. In this case, assuming 60% of patients 
with repeated measurements, there will be adequate (77.080%) 
power to detect a 0.42 SD change from the end of induction within 
each arm. 

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9.6.3 
To evaluate the effects of the addition of bortezomib and lenalidomide 
on global patient-reported health-related quality of life, the FACT-
General score will be examined at baseline, at the end of induction, 
after 6 cycles of consolidation and at the end of consolidation. The 
analysis will be similar to the one outlined in 9.5.1 and 9.5.2.  
9.6.4 
To evaluate the effects of bortezomib-related neuropathy on global 
patient-reported health-related quality of life, the FACT-General 
scores will be compared between patients with and without 
neuropathy. First, median of the FACT/GOG-Ntx score at the end of 
induction will be calculated among patients treated with RBV. Patients 
with FACT/GOG-Ntx scores above median will be categorized into 
‘neuropathy’ group and those with scores below median will be 
categorized into ‘no neuropathy’ group. The FACT-General scores at 
the end of induction will then be compared between groups with and 
without neuropathy, using a two-sided Wilcoxon rank sum test with 
Type I error of 5%. In addition, the FACT-General scores at later 
times (following 6 cycles of consolidation therapy etc) will be 
compared between the two groups to assess the long term effects of 
neuropathy on QOL. The comparisons will be stratified by 
consolidation treatment assignment. Repeated measures analysis 
techniques will also be utilized. 
9.6.5 
To evaluate the response of lymphoma-specific symptoms to 
treatment, the FACT-lymphoma scores will be examined at each time 
point, and compared between different treatment groups. The analysis 
will be similar to the one outlined in 9.5.1 and 9.5.2.  
9.6.6 
To describe the trajectory of overall health-related quality of life, 
lymphoma symptoms, neuropathy, and fatigue prior to, during and 
following treatment, the FACT-General score, the FACT-lymphoma 
score, the FACT-Fatigue score and the FACT/GOG-Ntx score will be 
examined at each time point. Besides comparing these QOL scores 
between treatment groups at each time point, repeated measures 
analysis techniques will also be utilized to examine the treatment 
effect, time effect, and potential interaction on QOL score over time. 
The method of Schluchter for jointly modeling QOL scores and 
survival will be explored in an attempt to account for the possibility of 
informative missingness (66).  
9.7 
Selection of Optimal Regimen(s) 
There were no power or sample calculations for this section. 
9.8 
Imaging Correlative Studies 
Imaging by FDG-PET will be done pretreatment (PET-0), after cycle 3 (PET-3), 
and after cycle 6 (PET-6). 
9.8.1 
There were no power or sample size calculations for this section. 

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9.9 
Lab Correlative Studies (FFPE tissues) 
We assume that lab data will be available from 90% of patients (n=324). We will 
consider a transformation of Ki67 data to improve the normality and variance 
stabilization of its distribution. 
9.9.1 
A Cox regression model will be fitted to predict PFS by the expression 
levels of the five genes of proliferation markers that were discovered 
by Hartmann et al (2008) (55). The association between Ki-67 
proliferation index and the risk score from the fitted prediction model 
will be assessed by scatter plot and correlation coefficient estimate. A 
regression analysis with a two-sided alpha=5% will have 95% power 
to detect a Pearson correlation of 0.2. 
9.9.2 
Ki67 index will be associated with PFS by Cox regression method. 
Suppose that the whole patient population has 75% 2-year PFS with 
exponential distribution. With 324 patients accrued for 40 months and 
2 years of additional follow-up, with two-sided alpha=5%, Cox 
regression has 90% power to detect a hazard ratio of 1.35 between 
two patient groups with Ki67 index values of one standard deviation 
away. We will conduct multivariate analysis to investigate if Ki67 is a 
prognostic factor independent of MIPI. The analysis will be conducted 
when 117 events (progressions or deaths) are observed. Similar 
analyses will be conducted to associate Ki67 index with CR and OR 
using two-sample t-test for univariate analysis and logistic regression 
for multivariate analysis. Treatment assignment will also be included 
in the multivariate analyses if it is significant on the clinical outcomes.  
9.9.3 
Expression of SOX11 by IHC will be correlated with OR and PFS 
similarly as Ki67 index. miRNA profiling will be associated with 
response and PFS using prediction-validation method based on 10-
fold cross validation. The gradient lasso algorithm (Sohn et al 2009) 
will be used to fit a prediction model based on Cox regression model 
(67). This algorithm will reduce the number of genomic markers. A 
prediction model for OR will be estimated by replacing the objective 
function of the gradient lasso algorithm for the likelihood function of 
logistic regression. The validity of the fitted prediction model will be 
assessed by calculating the p-value using permutation method. 
9.10 
Minimal Residual Disease (MRD) Correlative Studies 
There are several analysis steps of the samples. First, DNA sequences that are 
likely to be uniquely present in a particular patient’s cells based on the 
sequencing of B cell rearrangements will be identified from samples in which 
cancer cells are found at high levels, such as bone marrow aspirate or diagnostic 
biopsy. After identifying patient specific malignant clones, numbers of cells that 
are likely to be of tumor origin in circulation and in marrow at baseline and 
subsequent timepoints will be identified by molecular counting techniques.  
To determine whether the number of malignant cells in circulation predict the 
number of cells in marrow, graphic display and Spearman's rank correlation 
coefficient will be used. MRD status will be assigned for blood and bone marrow 
separately for each paired sample, and the concordance will be assessed. The 
analysis will be done at diagnosis, and at follow up assessment. 

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To determine whether the number of malignant cells in circulation or in marrow at 
the end of induction correlate with CR or 2-year PFS, the number of malignant 
cells will be compared between CR vs. non-CR, and between those who are 
progression-free at 2 years vs. those who are not, using Wilcoxon rank-sum tests 
with one-sided Type I error of 10%. We expect that blood samples will be 
collected in approximately 90% of patients at baseline, and 90% of these patients 
will have blood samples at the end of induction (292 samples). For bone marrow 
samples, we expect 80% of patients with positive marrow initially and 40% with 
follow-up bone marrow biopsies. That will give us an approximately 144 bone 
marrow samples at the end of induction. Assuming 50% of patients will achieve 
CR after induction, we will have adequate power (90%) to detect an effect size of 
0.31 (0.31 standard deviation difference) in number of malignant cells between 
CR and non-CR with 292 blood samples, and an effect size of 0.44 with 144 
bone marrow samples. Assuming 70% of patients will be progression-free at 2 
years, we will have adequate power (90%) to detect an effect size of 0.34 in 
number of malignant cells between those who are progression-free at 2 years vs. 
those who are not, with 292 blood samples, and an effect size of 0.48 with 144 
bone marrow samples. 
The association between MRD level and progression-free survival will be 
evaluated using Cox proportional hazards models, adjusting for important clinical 
covariates. If an association is identified, recursive partitioning and/or maximum 
likelihood methods will be used to identify a useful cut point for distinguishing 
patients with good/poor PFS outcomes. A similar analysis will be done for flow 
cytometry outcomes. Positive predictive value (PPV) and negative predictive 
value (NPV) of these tests will be estimated. Since PPV and NPV are estimated 
from a data selected classification, cross validation will be performed to adjust for 
the bias from optimizing the classification rule.   
To determine whether there is a lower level of residual disease among patients 
randomized to RBV as compared with RB, the number of malignant cells in 
circulation and in marrow at the end of induction will be compared between these 
two treatment groups, using Wilcoxon rank-sum test with one-sided Type I error 
of 10%. We will have adequate power (90%) to detect an effect size of 0.31 in 
number of malignant cells between the RBV group and RB group with 292 blood 
samples, and an effect size of 0.44 with 144 bone marrow samples. To 
determine whether there is a higher rate of MRD- among patients randomized to 
RBV as compared with RB, MRD status in circulation and in marrow will be 
assessed at the end of induction for patients in each treatment group. Assuming 
overall rate of MRD- is 30%, with 292 blood samples (146 each group), we will 
have 90% power to detect a difference in MRD- rate between RBV group and RB 
group from 22% to 38%, using Fisher’s exact test with one-sided Type I error of 
10%. The following table summarizes differences in MRD- rate between groups 
that can be detected with 292 blood samples and 144 bone marrow samples 
assuming different overall rate of MRD-. 

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Overall rate 
of MRD- 
Differences in MRD- rate that can 
be detected with 292 blood samples 
(146 each group) 
Differences in MRD- rate that can 
be detected with 144 marrow 
samples (72 each group) 
20% 
13% vs. 27% 
10% vs. 30% 
30% 
22% vs. 38% 
19% vs. 41% 
40% 
31% vs. 49% 
28% vs. 52% 
50% 
41% vs. 59% 
37% vs. 63% 
Similarly, the number of malignant cells and proportion of MRD- will be compared 
between patients treated with LR maintenance and those treated with R 
maintenance, using Wilcoxon rank-sum test and Fisher’s exact test respectively 
with one-sided Type I error of 10%. 
To compare the two methods of MRD detection - molecular techniques and flow 
cytometry  as prognostic markers for outcome, the predictive value of the MRD 
for CR and for 2-year PFS will be analyzed using receiver operating 
characteristics (ROC) curves for different cut-off values. The areas under the 
ROC curves (AUC) for these two methods will be compared using the method of 
Delong et al (1988) (69). 
To explore whether MRD relapse signals clinical relapse and in what time frame, 
patients who are MRD- at the end of induction will be identified. Time to MRD 
relapse will be calculated from the end of induction to the time when patients 
become MRD+. Time to clinical relapse will also be calculated from the end of 
induction. The associations between time to MRD relapse and time to clinical 
relapse will be investigated using an estimator of Kendall’s τ under bivariate 
censoring. 
An interim analysis of MRD assay is planned per agreement between ECOG-
ACRIN and Sequenta. The concordance between MRD level in peripheral blood 
(and marrow when possible) as measured by the Sequenta assay and the level 
obtained using flow cytometry will be evaluated after the first 100 patients have 
undergone induction therapy and been measured for MRD by both Sequenta and 
Mayo Clinic Lymphoma Lab. Also, the association between MRD level and PFS 
will be evaluated after the first 100 patients have been followed for 2 years. 
These analyses will be pooled over treatment arm, so no results by treatment will 
be included. The study investigators have agreed in principle to the release of 
these results while the study is ongoing.  However, to assure that results of this 
analysis do not unintentionally compromise the primary objectives of the study, 
the release of the analyses must be approved by the DMC and the investigators 
will be given the opportunity to review and approve any abstracts, presentations 
or manuscripts prior to release. 

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9.11 
Gender and Ethnicity  
Based on previous data, the anticipated accrual in subgroups defined by gender 
and race is shown in the following table.  Mantle cell lymphoma is more common 
in males, and based on published research (Armitage et al, 1998) and accrual to 
previous studies, we expect accrual to reflect this higher prevalence. 
Gender and Minority Accrual Estimates for Proposed Study (Accrual Goal=372) 
 
Sex/Gender 
Total 
Females 
Males 
Ethnic Category 
 
 
 
Hispanic or Latino 
9 
10 
19 
Not Hispanic or Latino 
145 
208 
353 
Ethnic Category: Total of all subjects 
154 
218 
372 
Racial Category 
 
 
 
American Indian or Alaskan Native 
1 
2 
3 
Asian 
1 
2 
3 
Black or African American 
8 
11 
19 
Native Hawaiian or other Pacific Islander 
1 
2 
3 
White 
143 
201 
344 
Racial Category: Total of all subjects 
154 
218 
372 
 
 

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10. 
Centralized Review 
NOTE: Submitted scans and specimens must be entered and tracked via the ECOG-
ACRIN Sample Tracking System (STS). See Section 10.3.  
NOTE: Details on data and image acquisition, and processing and evaluation of FDG-
PET/CT scans are outlined in Appendix IX (FDG-PET/CT IMAGING). 
NOTE:  An informed consent must be signed prior to the submission of any samples 
including mandatory diagnostic reviews, laboratory studies and/or banking. 
Samples for 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. 
10.1 
FDG-PET/CT Scan Imaging 
10.1.1 
PET/CT Imaging Time Points 
The following PET/CT scans will be collected digitally: 
· 
Baseline 
NOTE: 
The baseline PET/CT scan must be obtained ≤ 28 days 
prior to randomization. 
NOTE: 
Diagnostic CT scans of the neck/chest/abdomen/pelvis 
must be performed if PET/CT scan cannot be obtained 
at baseline due to timing constraints, insurance or 
reimbursement issues, or other reasons, and must be 
documented in the patient’s chart. 
· 
Post Cycle Three (3) 
NOTE: 
The interim FDG-PET/CT scan (if and when available) 
after three (3) cycles of induction therapy will be 
obtained at least 12 days after the administration of the 
3rd cycle of induction therapy. 
· 
Post Cycle Six (6) – End of Induction 
NOTE: 
The post completion of induction therapy FDG-PET/CT 
scan will be obtained at least 3 weeks after the 
administration of the last dose of induction therapy. 
· 
After Cycle Six (6) (week 24 ± 1 week)  of Consolidation (if PET 
(+) at end of induction) 
· 
After Cycle Twelve (12) (week 48 ± 1 week) of Consolidation 
· 
After Cycle Eighteen (18) (week 72 ± 1 week) of Consolidation 
· 
End of Consolidation 
10.1.2 
Evaluation of PET/CT Data 
All images will be read centrally by the CALGB Imaging Core 
Laboratory. 
To ensure the highest standards and consistency between different 
centers, all FDG-PET scans (baseline, interim [when available], end of 
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induction therapy (post six cycles), and six months into consolidation 
therapy) must be submitted to the CALGB Imaging Core Laboratory at 
Ohio State University Medical Center for centralized review. 
Centralized review will be performed by a member of a team of 
PET/CT readers. There will be an adjudicator from the same pool of 
reviewers in the case of disagreement. There will be one reviewer, Dr. 
Nathan Hall, who will provide back-up PET/CT reviewer services 
within the CALGB Imaging Core Laboratory. The CALGB Imaging 
Core Laboratory will transmit the scans to the expert reviewers and 
then will transmit the results to the CALGB Statistical Center.  
Questions concerning the FDG imaging procedure, interpretation of 
FDG-PET/CT scans and the definition of PET positivity should be 
directed to: 
Lale Kostakoglu, MD, MPH 
E1411 Imaging Co-Chair 
Tel: (212) 241-6319 
Fax: (212) 831-2851 
lale.kostakoglu@mssm.edu  
10.1.3 
PET/CT Data Submission 
The complete PET and CT studies must be electronically submitted to 
the CALGB Imaging Core Laboratory in digital DICOM format; any 
other formats such as Bitmap, JPG, hardcopy files, or scanned films 
are unacceptable. De-identify the patient data using institutional 
procedures to remove the patient name and medical record number 
while preserving the patient study ID number and protocol number 
separately. 
Imaging data shall be submitted to the CALGB Imaging Core 
Laboratory within no more than three (3) business days once the 
image acquisition is completed at the site.  
Images may be electronically transferred by either Web-based (a PC 
with internet access is needed) or FTP-based (a PC with both internet 
access and any FTP software installed is needed) transfer 
approaches. The standard and secure online access information will 
be provided separately through the specific trial e-mail 
E1411@ImagingCoreLab.com, per the request by participating sites 
before their first data submission. 
Once the electronic imaging data submission is done, send an e-mail 
to the CALGB Imaging Core Laboratory at 
E1411@ImagingCoreLab.com to inform them that the study has been 
completely uploaded from the institution. Please include the basic 
information of submitted data sets as follows: 
1) E1411 patient study ID number and protocol number 
2) Scan time point 
3) Date of scans 

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4) Date of first day of protocol treatment 
5) Institution name 
Institutions must send an ECOG-ACRIN 1411 PET/CT Adjunctive 
Data Sheet (Appendix XVI) to the CALGB Imaging Core Laboratory. 
NOTE: An STS shipping manifest form must be generated and 
shipped with all sample submissions.  
10.2 
Pathology Review 
Pathology materials from the original diagnostic tumor biopsy must be submitted 
for review and classification and laboratory studies.  Pathology materials from 
tumor biopsies performed while on study should be submitted for banking for 
future use. 
The clinical investigator and the submitting pathologist have the responsibility for 
submitting representative diagnostic material for review and classification. Refer 
to Appendix II (Pathology Submission Guidelines). 
10.2.1 
Materials Required For This Protocol 
10.2.2 
Forms (Submit with every pathology submission) 
· 
CALGB Pathology Material Submission Form (#3467), Parts A & 
B completed. Please identify the clinical status of the submitted 
material (i.e., pretreatment as opposed to remission and relapse). 
· 
A copy of the surgical pathology report 
· 
Immunophenotypic studies, if available 
· 
Sample Tracking System Shipping Manifest Form 
In addition to the surgical pathology report, if immunophenotypic 
studies have been performed at the home institution, it is necessary 
that these be forwarded as well.  
10.2.3 
Biological Material Submissions: 
If blocks cannot be submitted, 12 unstained slides, two or more 4mm 
mega cores and an H&E are required. The Alliance Biorepository at 
Ohio State does provide institutions with the dermal punch coring 
instruments needed to extract the cores required for this study. Please 
contact the Alliance Biorepository at Ohio State to order the kit. 
If your institutions’ pathologist requires further instruction, has 
questions regarding coring, or in the event there is not enough tissue 
to fulfill the alternative submission, please contact the Alliance 
Biorepository at Ohio State at (614) 293-7073 or 
path.calgb@osumc.edu 
10.2.3.1 
MANDATORY  
· 
Paraffin embedded tumor block from the original biopsy 
NOTE: 
Submission of pathology materials for central 
review is mandatory in order for the patient to 
be considered evaluable. Failure to submit 
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pathology materials may render the case 
unevaluable. 
NOTE: 
The original tumor biopsy submitted at baseline 
will also be used for the optional laboratory 
studies outlined in Section 11 for those patients 
who have consented to participate. 
10.2.3.2 
From patients who answer “Yes” to “I agree to provide 
additional specimens for research.” 
· 
Tumor blocks from any diagnostic biopsies performed 
while on study. 
10.2.4 
Shipping Procedures  
ECOG-ACRIN and SWOG Sites: 
Access to the shipping account for shipments to the ECOG-ACRIN 
Central Biorepository and Pathology Facility (CBPF) at MD Anderson 
can now be obtained by logging onto fedex.com with an account 
issued by the ECOG-ACRIN CBPF. For security reasons, the account 
number will no longer be given out in protocols, over the phone, or via 
email. If your site needs to have an account created, please contact 
the ECOG-ACRIN CBPF by email at eacbpf@mdanderson.org. 
Alliance sites will be reimbursed for shipping costs from Alliance. 
Ship at ambient temperature, using a cool pack during warmer 
months. 
10.2.4.1 
Submission Schedule  
➢ The required initial pathology materials must be 
submitted within one month of patient randomization.   
➢ Additional tumor biopsies should be submitted within 
one month of collection.  
Shipping Address: 
Alliance Biorepository at Ohio State 
The Ohio State University 
Innovation Center 
2001 Polaris Parkway, Lab #1315 
Columbus, OH 43240-2000 
Ph: (614) 293-7073 
Fax: (614) 293-7967 
Ship pathology samples Monday-Thusday, no Friday 
shipments, by overnight courier. 
An STS shipping manifest form must be generated and 
shipped with all sample submissions.  
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10.2.4.2 
Pathology Coordinating Office: Sample Processing and 
Routing  
· 
Slides will be cut from the original diagnostic tumor 
blocks and forwarded to Dr. David Yang for review. 
· 
Pathology samples will be routed for laboratory studies 
as outlined in Sections 11.3 and 11.4. 
· 
Blocks from patients who consented to the laboratory 
studies and/or banking of residuals for future studies: 
Four 3 mm cores will be taken from each block and 
placed into tissue microarrays (TMA). The regions of 
interest will be designated by Dr. David Yang. 
· 
Sections/slides will be forwarded to Sequenta, Inc. for 
molecular MRD analysis for those cases with no bone 
marrow. 
10.3 
ECOG-ACRIN Sample Tracking System 
It is required 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: 
Any case reimbursements associated with sample submissions 
will not be credited if samples are not logged into STS. 
Additionally, 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: 
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 
10.3.1 
Study Specific Notes 
A Generic Specimen Submission Form (#2981) will be required only if 
STS is unavailable at the time of sample submission, along with the 
Patient Information Form (Appendix XVII). Indicate the appropriate 
Lab ID # on the submission form: 
· 
0104 = Mayo Clinic Lymphoma Laboratory 
· 
0148 = Alliance Biorepositiry at Ohio State 
· 
0162 = CALGB Imaging Core Laboratory 
· 
0163 = Sequenta, Inc.  
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Retroactively enter all collection and shipping information when STS 
is available. 
10.4 
Banking  
TMAs and residual material from the blocks/slides submitted will be retained at 
the Central Repository for possible use in future approved studies.  Any residual 
blocks will be available for purposes of individual patient management on specific 
written request.  If future use is denied or withdrawn by the patient, the samples 
will be removed from consideration for use in any future study. 
 

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11. 
Correlative Studies 
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 submissions. 
See Section 10.3.  
11.1 
Submission of Blood to Mayo Clinic  
Blood samples should be shipped the day they are drawn. If you have any 
questions concerning sample collection and shipment, please contact Kim 
Henderson at (507) 284-3805 or Henderson.Kimberly@mayo.edu at the Mayo 
Clinic Lymphoma Laboratory. 
11.1.1 
Sample Submission Schedule 
Blood samples are being collected for Flow Cytometry for Minimal 
Residual Disease (MRD) to be performed by investigators at Mayo 
Clinic.  Submit 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 from ACD (yellow top tubes) should be collected at 
the following time points: 
· 
Baseline (after randomization, prior to treatment) 
· 
Post Cycle Three (3) 
· 
Post Cycle Six (6) [End of Induction] 
Blood samples are also being collected for banking for possible future 
research studies.  Submit from patients who answer “Yes” to “I agree 
to provide additional blood for research.” 
Peripheral blood from EDTA (purple top tube) and red top tube should 
be collected at: 
· 
Baseline (after randomization, prior to treatment) 
· 
Post Cycle Three (3) 
· 
Post Cycle Six (6) [End of Induction] 
11.1.2 
Sample Preparation Guidelines 
Kits are available to order for the collection of the samples, and will 
contain the supplies and instructions for collecting, processing, and 
shipping the samples. To order kits contact Kim Henderson at (507) 
284-3805 or Henderson.Kimberly@mayo.edu. Include the name of 
the contact person, phone number, and address where the kits should 
be shipped, ECOG-ACRIN protocol number, the number of kits 
needed, and if the kits need to be shipped priority overnight, otherwise 
kits will arrive in three to four working days. 
The following CBC information must be entered into STS with each 
time point: WBC and lymphocyte count.  
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Blood samples should be shipped the day they are drawn at room 
temperature (do not freeze).  Samples from multiple patients can be 
shipped together, but must be placed in separately labeled tubes and 
bags. 
All samples must be clearly labeled with the ECOG-ACRIN protocol 
number E1411, the patient’s initials (last name, first name), the 
patient's ECOG-ACRIN sequence number (If available), date of 
collection, and type of sample (PB). 
· 
Peripheral blood: Draw 7mL of whole blood into each of three (3) 
ACD yellow top tubes (provided in the kit) at each time point.  Ship 
day of collection. 
· 
Peripheral blood: Draw 10mL of whole blood into one (1) EDTA 
purple top tube (provided in the kit) at each time point.  Ship day 
of collection. 
· 
Peripheral blood: Draw 10mL of whole blood into one (1) red top 
tube (provided in the kit) at each time point.  Ship day of 
collection. 
11.1.3 
Shipping Procedures 
Blood samples should be mailed the day they are obtained and 
shipped overnight to arrive during normal working hours.  The 
laboratory is open to receive shipments Monday through Friday.  
Follow packing guidelines listed in the kit.  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. 
· 
Place the tubes in the absorbent holder and seal in the zip lock 
specimen bag. 
· 
Place the filled specimen bag in the Styrofoam container. 
· 
Loosely pack with paper toweling. 
· 
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 samples priority 
overnight delivery the same day collected. 
· 
Notify Federal Express for pick-up and/or leave package at the 
designated FedEx drop-off location. 
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Please e-mail Kim Henderson at Henderson.Kimberly@mayo.edu to 
notify the Mayo Clinic Lymphoma Laboratory when samples are being 
shipped. Indicate the ECOG-ACRIN protocol number, the FedEx 
tracking number, and the name and phone number of the contact 
person. The blood samples in prepared kits should be shipped to the 
following: 
Kim Henderson 
Mayo Clinic Lymphoma Laboratory 
613 Stabile 
200 First Street Southwest 
Rochester, MN 55905 
An STS shipping manifest form must be generated and shipped with 
all sample submissions.  
Blood samples from the ACD tubes will be forwarded to Dr. Curtis 
Hanson at Mayo Clinic for MRD analysis by flow as outlined in Section 
11.5 and to Dr. Sandeep Dave at Duke University for the laboratory 
studies outlined in Section 11.4. 
11.2 
Submission of Blood and Bone Marrow to Sequenta, Inc. 
Blood and bone marrow samples are being collected for Molecular Minimal 
Residual Disease (MRD) studies as outlined in Section 11.6.  Submit 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.” 
11.2.1 
Sample Submission Schedule 
Blood and bone marrow samples should be shipped the day they are 
drawn.  If you have any questions concerning sample collection and 
shipment, please contact Kim Henderson at (507) 284-3805 or 
Henderson.Kimberly@mayo.edu at the Mayo Clinic Lymphoma 
Laboratory. 
Draw 10mL of peripheral blood into one (1) EDTA (purple top tube) at 
the following time points: 
· 
Baseline (prior to treatment) 
· 
Post Cycle Three (3) 
· 
Post Cycle Six (6) [End of Induction] 
· 
Every Four (4) Months During the First Year of Maintenance 
· 
Every Six (6) Months During the Second Year of Maintenance 
· 
Twelve (12) Months After Completion of Maintenance 
Draw 3-5mL of ‘redirect’ bone marrow aspirate into one (1) EDTA (10 
mLpurple top tube) at the following time points: 
· 
Baseline (prior to treatment) 
· 
Post Cycle Six (6) [End of Induction, Patients in CR Only] 
11.2.2 
Sample Preparation Guidelines 
Kits are available to order for the collection of the samples, and will 
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contain the supplies and instructions for collecting, processing, and 
shipping the samples.  Ordering instructions are outlined in Section 
11.1.2. 
The following CBC information must be entered into STS with each 
time point: WBC and lymphocyte count.  
Blood and bone marrow samples should be shipped the day they are 
drawn at room temperature (do not freeze). Samples from multiple 
patients can be shipped together, but must be placed in separately 
labeled tubes and bags. 
All samples must be clearly labeled with the ECOG-ACRIN protocol 
number E1411, the patient’s initials (last name, first name), the 
patient's ECOG-ACRIN sequence number (If available), Sequenta 
sequence number, date of collection, and type of sample (PB,BM). 
· 
Peripheral blood: Draw 10mL of whole blood into one (1) EDTA 
purple top tube (provided in the kit) at each time point.  Ship day 
of collection.  Invert the tube eight times prior to shipment. 
· 
Bone Marrow Aspirate: One (1) EDTA purple top tube (provided in 
the kit) at each time point (while 3-5mL is recommended, any 
amount is acceptable).  Ship day of collection.   
11.2.3 
Shipping Procedures 
Blood and bone marrow samples should be mailed the day they are 
obtained and shipped overnight to arrive during normal working hours.  
The laboratory is open to receive shipments Monday through Friday.  
Follow packing guidelines listed in the kit and in Section 11.1.3.  
FRIDAY AND PRE-HOLIDAY SHIPMENTS SHOULD BE AVOIDED. 
Please e-mail the Sequenta ECOG-ACRIN Study Coordinator at 
ECOGE1411@sequentainc.com 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 and bone marrow samples in prepared kits should be 
shipped to the following: 
Sequenta, Inc. 
Attn: ECOG-ACRIN Study Coordinator 
400 East Jamie Court, Suite #301 
South San Francisco, CA 94080 
Phone: (650) 243-3900 
An STS shipping manifest form must be generated and shipped with 
all sample submissions.  
11.3 
Ki67 Proliferation Index and SOX11 Expression 
We will prospectively assess two promising biomarkers that may provide 
important prognostic information in MCL.  The proliferation signature has been 
demonstrated by gene expression profiling (GEP) to be of prognostic value in 
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MCL, independent of other clinical factors.36 While assessment of this signature 
is difficult in routine practice, a global assessment of proliferation using an 
immunohistochemical stain for the Ki67 antigen confirms this concept.  Indeed 
Ki67 index has been shown to add value to the mantle cell international 
prognostic index (MIPI) and has been assessed retrospectively in multiple large 
patient cohorts treated with modern therapy with consistent results.37-40  Indeed 
high Ki67 predicts poor outcome in patients undergoing autologous stem cell 
transplantation.41   Recently, the transcription factor SOX11 has been reported to 
be expressed in the majority of MCL.  The function of SOX11 is poorly 
understood.  It is expressed in embryonic neuronal progenitors and in 
mesenchymal cells in many developing organs and its absence appears lethal in 
knock out mouse experiments.  It is also highly expressed in MCL nuclei, a 
pattern that appears relatively specific in B-cell lymphoma.42,43  The prognostic 
significance of SOX11 is uncertain; however, GEP studies now suggest that lack 
of SOX11 is associated with favorable outcome and indolent behavior in MCL.11   
We will assess Ki67 and SOX11 in tissue microarrays (1mm dia. cores) via 
immunohistochemistry using automated immunostainers as described 
previously.41,45  Staining will be assessed by image analysis using the Aperio 
slide scanner and analysis software for nuclear staining quantitation.   
11.4 
miRNA Profiling 
We will further assess the role of microRNAs as prognostic markers in patients 
with mantle cell lymphoma. MicroRNAs are 18-22 nucleotide-long RNA 
molecules that regulate the expression of genes. There is an increasing 
recognition of the role of microRNAs in malignancies.46-48 Lymphoma is among 
the few malignancies known to be causally associated with microRNA 
deregulation3. MicroRNAs have also shown promise as diagnostic and prognostic 
biomarkers in a variety of malignancies.46,49  Intact microRNAs can be isolated 
from tissues preserved using standard paraffin-embedded methods50,51, making it 
easier to translate to clinical use.  
We have recently elucidated the microRNA transcriptome of normal and 
malignant B cells52 and identified over 200 new microRNAs.  We have developed 
a custom microarray that comprises all the known microRNAs from every species 
(virus to human), as well as the 279 microRNAs that we discovered.  Thus, our 
microarray provides a comprehensive platform for the identification of microRNA 
expression in lymphomas.  We will assess the expression of microRNAs and 
their relationship to prognosis in patients with mantle cell lymphoma. Available 
cases will be divided into equal sized training and validation sets.  Small RNAs 
from the biopsy tissue will be labeled and hybridized to the microarray, the 
images scanned, normalized and log2- transformed using methods well-
established in our laboratory.  We will evaluate the association of progression-
free and overall survival using methods similar to those we have described 
previously53.  We will develop a multivariate predictor based on microRNA 
expression based on the training set cases and only the optimal model will be 
validated using the independent test set cases.  
Additional exploratory studies will be performed on the same tissue to help 
determine the mechanistic basis of microRNA expression and the associated 
target genes.  Polymorphisms have been shown to be an important cause of 
altered microRNA expression and target interaction54.  We will use standard 

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methods such as Northern Blot, real-time PCR, immunohistochemistry and 
sequencing for these studies to identify the role of polymorphisms on microRNA 
and target expression.  We will also analyze the association of the identified 
polymorphisms with overall and progression-free survival, in conjunction with 
microRNA expression.  
The end-result of this study would be a comprehensive identification of 
microRNAs that are associated with response to treatment and potential 
mechanistic insights into the deregulation of microRNA and its target gene 
expression.  
This work will require the equivalent of one core biopsy and a tube of blood 
(ACD, yellow top tube) from patients.  
These assays will be performed by Sandeep Dave, M.D. at Duke University. 
11.5 
6-Color Flow Cytometry for Minimal Residual Disease 
This is a commercial assay that requires 6mL of ACD blood. The technique 
detects minimal residual disease. It has been demonstrated to be comparable to 
molecular techniques in CLL but has not been tested in MCL. The assay will use 
antibody to kappa, lambda, CD5, CD20, CD45, and CD19. The results will be 
read by Dr. Curtis Hanson of Mayo Hematopathology and results sent to ECOG-
ACRIN where they will be merged with clinical data and compared with molecular 
techniques performed by Sequenta, Inc. The technique provides a quantitative 
result. 
11.6 
Molecular Minimal Residual Disease  
This is an assay that detects the cancer-specific IgH rearrangement by deep 
sequencing.  For each patient the cancer-specific IgH rearrangement can be 
identified through the assessment of a diagnostic sample.  The diagnostic 
sample can be the positive lymph node (frozen or archived FFPE), bone marrow 
(aspirate or clot), or Peripheral Blood Mononuclear Cell (PBMC) preparation. In 
E1499 and E1405, circulating MCL cells were detectable in 88% of samples in 
the central flow cytometry laboratory (Dr. E. Paietta; unpublished data). All the 
IgH sequences are amplified from the diagnostic samples and the product is 
subjected to DNA sequencing.  The cancer-specific sequence is expected to be 
present at high frequency (>10%) in contrast to most other sequences present at 
very low level (<0.1%).  The cancer-specific sequence is then readily identified 
for each patient.  Minimal residual disease in follow up samples can then be 
assessed by determining the level of that sequence in the sample.  This is done 
by amplifying all the IgH sequences from the relevant samples and subjecting the 
product to deep sequencing (1M reads or more).  The level of the cancer-specific 
sequence can then be determined at very high sensitivity and specificity.   
11.7 
Banking  
Upon completion of the analysis, the residuals and/or derivatives of blood and 
bone marrow samples collected for the laboratory studies will be retained at an 
ECOG-ACRIN designated repository for possible use in ECOG-ACRIN approved 
future studies. If future use is denied or withdrawn by the patient, the samples will 
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11.8 
Sample Inventory Submission Guidelines  
Inventories of all samples collected, aliquoted, and used on the above mentioned 
laboratory studies and/or banking will be submitted electronically by secure web 
application to the ECOG-ACRIN Operations Office – Boston upon request by any 
laboratory holding and/or using any samples associated with this study. 
11.9 
Lab Data Transfer Guidelines  
The data collected or generated on the above mentioned laboratory studies will 
be submitted electronically by secure web application to the ECOG-ACRIN 
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12. 
Electronic Data Capture 
Please refer to the E1411 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed exclusively in Medidata Rave. 
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. Reports are due January 31, April 30, 
July 31 and October 31. 
13. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
14. 
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42. Penzo-Mendez AI. Critical roles for SoxC transcription factors in development and 
cancer. Int J Biochem Cell Biol. 2010;42:425-428. 
43. Wang X, Asplund AC, Porwit A et al. The subcellular Sox11 distribution pattern 
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Haematol. 2008;143:248-252. 
44. Fernandez V, Salamero O, Espinet B et al. Genomic and gene expression profiling 
defines indolent forms of mantle cell lymphoma. Cancer Res. 2010;70:1408-1418. 

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45. Mozos A, Royo C, Hartmann E et al. SOX11 expression is highly specific for mantle 
cell lymphoma and identifies the cyclin D1-negative subtype. Haematologica. 
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46. Klapper W, Hoster E, Determann O et al. Ki-67 as a prognostic marker in mantle cell 
lymphoma-consensus guidelines of the pathology panel of the European MCL 
Network. J Hematop. 2009. 
47. Jung SH, Owzar K, George SL.  A multiple testing procedure to associate gene 
expression levels with survival.  Stat Med, 2005; 24: 3077-3088. 
48. Malumbres R, Chen J, Tibshirani R et al. Paraffin-based 6-gene model predicts 
outcome in diffuse large B-cell lymphoma patients treated with R-CHOP. Blood. 
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49. Doleshal M, Magotra AA, Choudhury B et al. Evaluation and validation of total RNA 
extraction methods for microRNA expression analyses in formalin-fixed, paraffin-
embedded tissues. J Mol Diagn. 2008;10:203-211. 
50. Lu J, Getz G, Miska EA et al. MicroRNA expression profiles classify human cancers. 
Nature. 2005;435:834-838. 
51. Nicoloso MS, Sun H, Spizzo R et al. Single-nucleotide polymorphisms inside 
microRNA target sites influence tumor susceptibility. Cancer Res. 2010;70:2789-
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52. Hartmann E, Fernandez V, Moreno V et al. Five-gene model to predict survival in 
mantle-cell lymphoma using frozen or formalin-fixed, paraffin-embedded tissue. J 
Clin Oncol. 2008;26:4966-4972. 
53. Marcucci G, Radmacher MD, Maharry K et al. MicroRNA expression in 
cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358:1919-1928. 
54. He L, Thomson JM, Hemann MT et al. A microRNA polycistron as a potential 
human oncogene. Nature. 2005;435:828-833. 
55. Calin GA, Ferracin M, Cimmino A et al. A MicroRNA signature associated with 
prognosis and progression in chronic lymphocytic leukemia. N Engl J Med. 
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56. Xi Y, Nakajima G, Gavin E et al. Systematic analysis of microRNA expression of 
RNA extracted from fresh frozen and formalin-fixed paraffin-embedded samples. 
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57. Jima DD, Zhang J, Jacobs C et al. Deep sequencing of the small RNA 
transcriptome of normal and malignant human B cells identifies hundreds of novel 
microRNAs. Blood. 2010;116:e118-e127. 
58. Dave SS, Wright G, Tan B et al. Prediction of survival in follicular lymphoma based 
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59. Cella D, Cashy J, Kutikova L, Burgess MF, Lin BK et al. Development of a measure 
of health-related quality of life for non-Hodgkin’s lymphoma clinical research: The 
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characteristics and reversibility of peripheral neuropathy during treatment of 
advanced multiple myeloma with bortezomib. Journal of Clinical Oncology 2006; 24: 
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63. Webster K, Cella D, Kutikova L, Gauthier J, Liepa A, Bowman L. and Gregory S. 
Measuring quality of life (QOL) in patients with non-Hodgkin’s lymphoma (NHL): The 
Functional Assessment of Cancer Therapy – Lymphoma (FACT-Lym). Quality of 
Life Research 2005; 14: 1650. 
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Erratum in Hoster et al. A new prognostic index (MIPI) for patients with advanced 
stage mantle cell lymphoma. Blood. 2008; 111: 558-565. 
66. Schluchter MD. Methods for the analysis of informatively censored longitudinal data. 
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67. Sohn I, Kim J, Jung SH and Park C. Gradient lasso for Cox proportional hazards 
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68. Pott C, Hoster E, Delfau-Larue MH, et al. Molecular remission is an independent 
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69. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or 
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Prospective comparison of subcutaneous versus intravenous administration of 
bortezomib in patients with multiple myeloma. Haematologica 93(12) 1908-1911, 
2008. 
72. Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, 
Rekhtman G, Masliak Z, Robak T, Shubina A, Arnulf B, Kropff M, Cavet J, Esseltine 
DL, Feng H, Girgis S, van de Velde H, Deraedt W, Harousseau JL. Subcutaneous 
versus intravenous administration of bortezomib in patients with relapsed multiple 
myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncology 12(5):431-
440, 2011 

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NCI Update Date: June 13, 2012 
146 
Intergroup Randomized Phase II Four Arm Study In Patients With Previously Untreated 
Mantle Cell Lymphoma Of Therapy With: Arm A = Rituximab+ Bendamustine Followed By 
Rituximab Consolidation (RB → R); Arm B = Rituximab + Bendamustine + Bortezomib 
Followed By Rituximab Consolidation (RBV→ R), Arm C = Rituximab + Bendamustine 
Followed By Lenalidomide + Rituximab Consolidation (RB → LR) or Arm D = Rituximab + 
Bendamustine + Bortezomib Followed By Lenalidomide + Rituximab Consolidation  
(RBV → LR) 
Appendix I 
 
Informed Consent Template for Cancer Treatment Trials (English Language) 
[Deleted in Addendum #3] 
INFORMED CONSENT INTENTIONALLY REMOVED FROM 
PROTOCOL DOCUMENT 
Appendix I was removed from the protocol document in Addendum #3 and is posted as a 
separate document on the ECOG website. This was removed from the protocol to comply 
with NCI formatting guidelines. 
 
Rev. 12/13 

ECOG-ACRIN 
E1411 
Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
147 
Intergroup Randomized Phase II Four Arm Study In Patients With Previously Untreated 
Mantle Cell Lymphoma Of Therapy With: Arm A = Rituximab+ Bendamustine Followed By 
Rituximab Consolidation (RB → R); Arm B = Rituximab + Bendamustine + Bortezomib 
Followed By Rituximab Consolidation (RBV→ R), Arm C = Rituximab + Bendamustine 
Followed By Lenalidomide + Rituximab Consolidation (RB → LR) or Arm D = Rituximab + 
Bendamustine + Bortezomib Followed By Lenalidomide + Rituximab Consolidation  
(RBV → LR) 
Appendix II 
 
Pathology Submission Guidelines 
The following items are included in Appendix II: 
1. Guidelines for Submission of Pathology Materials  
(instructional sheet for Clinical Research Associates [CRAs]) 
2. Instructional memo to submitting pathologists 
3. List of Required Materials for E1411 
4. CALGB Pathology Submission Form (#3467) 
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ECOG-ACRIN 
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Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
148 
Guidelines for Submission of Pathology Materials 
The following items should always be included when submitting pathology materials to the 
ECOG-ACRIN Pathology Coordinating Office: 
· 
Institutional Surgical Pathology Report 
· 
Pathology materials (see attached List of Required Material) 
· 
CALGB Pathology Material Submission Form (#3467) 
Instructions: 
1. Place the Patient ID label provided by the ECOG-ACRIN Operations Office – Boston in Part 
A of the CALGB Pathology Material Submission Form (#3467). 
If a label is not available, TYPE or PRINT the following information in Part A of the form: 
Patient's name (last, first) 
Protocol number 
Protocol case number (the patient's ECOG-ACRIN sequence number; for 
intergroup studies, include both the ECOG-ACRIN and other group's sequence 
numbers) 
Patient's hospital number 
Institution 
Affiliate (if appropriate) 
2. Complete blank areas of the pathologist's instructional memo and forward it, along with the 
List of Required Material and the CALGB Pathology Material Submission Form (#3467), to 
the appropriate pathologist. 
3. The pathologist should return the required pathology samples and surgical pathology 
reports, along with the completed CALGB Pathology Material Submission Form (#3467) 
(Part B completed). If any other reports are required, they should be obtained from the 
appropriate department at this time. 
4. Keep a copy of the CALGB Pathology Material Submission Form (#3467) for your records. 
(The original should be sent to the Alliance Biorepository at Ohio State.) 
5. Double-check that ALL required forms, reports and pathology samples are included in the 
package to the Alliance Biorepository at Ohio State. (See appropriate List of Required 
Material.)  
Pathology specimens submitted WILL NOT be processed by the Alliance 
Biorepository at Ohio State until all necessary items are received. 
6. Mail pathology materials to: 
Alliance Biorepository at Ohio State 
The Ohio State University 
Department of Pathology 
Innovation Centre 
2001 Polaris Parkway 
Columbus, OH 43240 
Phone: (614) 293-7073 
Fax: (614) 293-7967 
Email: path.calgb@osumc.edu 
 
If you have any questions concerning the above instructions or if you anticipate any problems in 
meeting the pathology material submission deadline of one month, contact the Pathology 
Coordinator at the Alliance Biorepository at Ohio State by telephone (614) 293-7073 or by fax 
(614) 293-7697. 
Rev. 12/13, 8/15 
Rev. 12/13 
Rev. 12/13 
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ECOG-ACRIN 
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Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
149 
LIST OF REQUIRED MATERIAL 
E1411: Intergroup Randomized Phase II Four Arm Study In Patients With Previously 
Untreated Mantle Cell Lymphoma Of Therapy With: Arm A = Rituximab+ 
Bendamustine Followed By Rituximab Consolidation (RB → R); Arm B = Rituximab 
+ Bendamustine + Bortezomib Followed By Rituximab Consolidation (RBV→ R), 
Arm C = Rituximab + Bendamustine Followed By Lenalidomide + Rituximab 
Consolidation (RB → LR) or Arm D = Rituximab + Bendamustine + Bortezomib 
Followed By Lenalidomide + Rituximab Consolidation (RBV → LR) 
Baseline (MANDATORY) 
1. CALGB Pathology Material Submission Form (#3467) – Parts A & B completed. [or 
appropriate pathology submission form] 
2. Institutional pathology report (must be included with EVERY pathology submission). 
3. Required Pathology Materials: 
· 
Paraffin embedded tumor block from the original biopsy  
NOTE:  
Submission of pathology materials for central review is mandatory in order for 
the patient to be considered evaluable. Failure to submit pathology materials 
may render the case unevaluable. 
NOTE: 
The original tumor biopsy submitted at baseline will also be used for the 
optional laboratory studies for those patients who have consented to 
participate. Since blocks are being used for laboratory studies, in some cases 
the material may be depleted and, therefore, the block may not be returned. 
NOTE: 
If blocks cannot be submitted, 12 unstained slides, two or more 4mm mega 
cores and an H&E are required. The Alliance Biorepository at Ohio State 
does provide institutions with the dermal punch coring instruments needed to 
extract the cores required for this study. Please contact the Alliance 
Biorepository at Ohio State to order the kit. 
If your institutions’ pathologist requires further instruction, has questions 
regarding coring, or in the event there is not enough tissue to fulfill the 
alternative submission, please contact the Alliance Biorepository at Ohio 
State at (614) 293-7073 or path.calgb@osumc.edu 
On Study Tumor Biopsies (from consenting patients) 
1. CALGB Pathology Material Submission Form (#3467) – Parts A and B completed. [or 
appropriate pathology submission form] 
2. Institutional pathology report (must be included with EVERY pathology submission). 
3. Pathology Materials: 
· Tumor blocks from any diagnostic biopsies performed while on study. 
 
Rev. 12/13 
Rev. 12/13 
Rev. 12/13 
Rev. 12/13 
Rev. 8/15 

 
150 
MEMORANDUM 
TO:  ____________________________________  
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair 
ECOG-ACRIN Laboratory Science and Pathology Committee 
DATE:  
 
SUBJECT: Submission of Pathology Materials for E1411: Intergroup Randomized Phase II 
Four Arm Study In Patients With Previously Untreated Mantle Cell Lymphoma Of 
Therapy With: Arm A = Rituximab+ Bendamustine Followed By Rituximab 
Consolidation (RB → R); Arm B = Rituximab + Bendamustine + Bortezomib 
Followed By Rituximab Consolidation (RBV→ R), Arm C = Rituximab + 
Bendamustine Followed By Lenalidomide + Rituximab Consolidation (RB → LR) or 
Arm D = Rituximab + Bendamustine + Bortezomib Followed By Lenalidomide + 
Rituximab Consolidation (RBV → LR) 
 
The patient named on the attached CALGB Pathology Material Submission Form (#3467) has 
been entered onto an ECOG-ACRIN protocol by ______________________________ (ECOG-
ACRIN Investigator).  This protocol requires the submission of pathology materials for pathology 
review, laboratory studies and banking for future research. 
Please complete PART B of the Submission Form. Keep a copy for your records and return the 
completed Submission Form, the surgical pathology report(s), the slides and/or blocks and any 
other required material (see List of Required Material) to the Clinical Research Associate (CRA).  
The CRA will forward all required pathology material to the Alliance Biorepository at Ohio State. 
Blocks and/or slides submitted for this study will be retained at the Central Repository for future 
studies.  Blocks will be returned upon written request for purposes of patient management. 
Please note: Since blocks are being used for laboratory studies, in some cases the material 
may be depleted, and, therefore, the block may not be returned. 
If you have any questions regarding this request, please contact the Alliance Biorepository at 
Ohio State at (614) 293-7073 or by fax (614) 293-7697.  The ECOG-ACRIN CRA at your 
institution is: 
Name: ________________________________________  
Address: _______________________________________  
Phone: ________________________________________  
 
Thank you. 
Rev. 12/13 
Rev. 12/13, 
8/15 

Form #3467 
CALGB DIAGNOSTIC PATHOLOGY MATERIAL SUBMISSION FORM 
151 
Instructions: 
This form is a required part of pathology submission. Please complete and submit along with all 
pathology materialand corresponding pathology reports requested by the protocol. See list of required 
materials as specified in EACH protocol. 
Tel. 614-293-7073 
Fax 614-293-7967 
PART A: To Be Completed By Data Manager/CRA 
DO NOT USE INITIALS – Submit Patient’s FULL Name 
 
(The Patient has authorized the use of PHI.) 
Date sample sent to CALGB  ______/______/_______ (M,D,Y) 
 
Patient’s Name: 
Data Manager _______________________________________  
 
Last _______________________ 
First ____________________  
Address  ___________________________________________  
 
ECOG Prot. No. _________  ECOG Patient Seq. No. ________  
 __________________________________________________  
 
Participating Group 
Prot. No. _______________  
Participating Group 
Patient ID No. ________________  
Telephone No. (          ) _______________________________  
 
Group __________ 
Institution _________ 
PI _____________  
Fax No. (          ) _____________________________________  
 
Step No. ________ 
Affiliate _________  
Email address  ______________________________________  
 
ECOG-ACRIN Parent Prot. No. __  
Seq. No. ______________  
PART B: 
TO BE COMPLETED BY DATA MANAGER/CRA AND SUBMITTING PATHOLOGIST 
 
 
 
 
 
 
 
 
Complete for 
Slides/Vials 
Status* 
(See Below) 
Date Specimen 
Collected (M/D/Y) Disease Site 
Number of 
Slides/Vials 
Specimen ID  
Numbers 
Type of 
Stain 
 
 
 
/        / 
 
 
 
 
 
 
 
/        / 
 
 
 
 
 
Complete for 
Blocks/Punch 
Status* 
(See Below) 
Date Specimen 
Collected (M/D/Y) Disease Site 
Number of 
Blocks/Punch 
Specimen ID  
Numbers 
Fixative 
 
 
 
/        / 
 
 
 
 
 
 
 
/        / 
 
 
 
 
 
*Status: Please identify the clinical status of the sample.  
List all that apply: 
 
 
1. Original diagnostic material 
5. Post-surgery biopsy/tissue 
 
Submitting Pathologist _____________________ 
2. AML/MDS diagnosis 
6. Relapse/recurrence 
 
Telephone No. (          ) ____________________ 
3. Pre-protocol treatment 
biopsy/tissue 
7. Remission/response 
 
 
Address  ________________________________ 
4. Post-protocol treatment 
biopsy/tissue 
8. Other, specify: ______________  
 
  _________________________  
 
 _______________________________________ 
Did the patient consent to participate in the storage of samples for future research? 
Yes 
No 
MATERIAL RETURN (All materials will be retained by the ECOG PCO unless return is requested here.) 
Does the submitting institution’s policy require the return of any submitted material (blocks, H&E slides, etc.)? 
  Yes 
No 
If so, please indicate which materials must be returned ______________________________________________________________  
All materials will be returned to the submitting pathologist unless an alternate address is indicated here ______________________  
If materials were not able to be submitted for this protocol and its correlative studies, please circle the 
reason for non-submission. 
Federal/State Regulations ____  Hospital/Institutional Policy _____ Insufficient Tissue _____  Other ______  (Specify) _________  
Pathologist or Investigator’s Signature __________________________________________________________________________ 
Investigator:  Keep a copy for your files and submit original form to the destination specified in protocol. 
2/05 
 
Rev. 12/13 

ECOG-ACRIN 
E1411 
Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
152 
Intergroup Randomized Phase II Four Arm Study In Patients With Previously Untreated 
Mantle Cell Lymphoma Of Therapy With: Arm A = Rituximab+ Bendamustine Followed By 
Rituximab Consolidation (RB → R); Arm B = Rituximab + Bendamustine + Bortezomib 
Followed By Rituximab Consolidation (RBV→ R), Arm C = Rituximab + Bendamustine 
Followed By Lenalidomide + Rituximab Consolidation (RB → LR) or Arm D = Rituximab + 
Bendamustine + Bortezomib Followed By Lenalidomide + Rituximab Consolidation  
(RBV → LR) 
Appendix III 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can be 
downloaded from the ECOG web site at http://www.ecog.org. As this is a personal letter, 
physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN and the 
NCI to increase awareness of the importance of clinical trials and improve accrual and follow-
through. We appreciate your help in this effort. 
____________________________________________________________________________ 
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study.  Many questions remain 
unanswered in cancer. 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 you will receive high quality, complete care.  I and my research staff will maintain 
very close contact with you.  This will allow me 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” throughout, we 
thank you again and look forward to helping you. 
 
 
Sincerely, 
 
 
 
[PHYSICIAN NAME] 
Rev. 12/13 
Rev. 4/14 

ECOG-ACRIN 
E1411 
Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
153 
Intergroup Randomized Phase II Four Arm Study In Patients With Previously Untreated 
Mantle Cell Lymphoma Of Therapy With: Arm A = Rituximab+ Bendamustine Followed By 
Rituximab Consolidation (RB → R); Arm B = Rituximab + Bendamustine + Bortezomib 
Followed By Rituximab Consolidation (RBV→ R), Arm C = Rituximab + Bendamustine 
Followed By Lenalidomide + Rituximab Consolidation (RB → LR) or Arm D = Rituximab + 
Bendamustine + Bortezomib Followed By Lenalidomide + Rituximab Consolidation  
(RBV → LR) 
Appendix IV 
 
Patient Pill Calendar 
 
 
Pill Calendar Directions 
1. Take your scheduled dose of each pill. 
2. If you forget, the missed pills will not be taken later. 
3. Please bring the empty bottle or any leftover tablets and your  
pill calendar to your next clinic visit. 
 
 
Rev. 12/13 

ECOG-ACRIN 
E1411 
Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
154 
Patient Pill Calendar for Lenalidomide 
This is a calendar on which you are to record the time and number of tablets you take each day.  
You should take your scheduled dose of each pill. Note the times and the number of tablets 
that you take each day.  If you develop any side effects, please record them and anything you 
would like to tell the doctor in the space provided.  Bring any unused tablets and your completed 
pill calendar to your doctor’s visits. 
 
DAY  
Date 
Time pills taken 
Number of 
pills taken 
Use the space below 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.) 
Month 
Day 
Year 
AM 
PM 
AM 
PM 
1 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
 
16 
 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
 
22 
No lenalidomide dose on this day 
 
23 
No lenalidomide dose on this day 
 
24 
No lenalidomide dose on this day 
 
25 
No lenalidomide dose on this day 
 
26 
No lenalidomide dose on this day 
 
27 
No lenalidomide dose on this day 
 
28 
No lenalidomide dose on this day 
 
Patient. Signature: ____________________________________ Date: ___________________ 
 

ECOG-ACRIN 
E1411 
Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
155 
Intergroup Randomized Phase II Four Arm Study In Patients With Previously Untreated 
Mantle Cell Lymphoma Of Therapy With: Arm A = Rituximab+ Bendamustine Followed By 
Rituximab Consolidation (RB → R); Arm B = Rituximab + Bendamustine + Bortezomib 
Followed By Rituximab Consolidation (RBV→ R), Arm C = Rituximab + Bendamustine 
Followed By Lenalidomide + Rituximab Consolidation (RB → LR) or Arm D = Rituximab + 
Bendamustine + Bortezomib Followed By Lenalidomide + Rituximab Consolidation  
(RBV → LR) 
Appendix V 
 
ECOG Performance Status 
 
 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction 
 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature e.g. light house work, office work. 
 
PS 2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and 
about more than 50% of waking hours. 
 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
 
PS 4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair. 
 
Rev. 12/13 

ECOG-ACRIN 
E1411 
Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
156 
Intergroup Randomized Phase II Four Arm Study In Patients With Previously Untreated 
Mantle Cell Lymphoma Of Therapy With: Arm A = Rituximab+ Bendamustine Followed By 
Rituximab Consolidation (RB → R); Arm B = Rituximab + Bendamustine + Bortezomib 
Followed By Rituximab Consolidation (RBV→ R), Arm C = Rituximab + Bendamustine 
Followed By Lenalidomide + Rituximab Consolidation (RB → LR) or Arm D = Rituximab + 
Bendamustine + Bortezomib Followed By Lenalidomide + Rituximab Consolidation  
(RBV → LR) 
Appendix VI 
 
Risks of Fetal Exposure, Pregnancy Testing Guidelines  
and Acceptable Birth Control Methods 
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. 
All study participants must be registered into the mandatory RMES® program, and be willing 
and able to comply with the requirements of REMS®. 
Criteria for females 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). 
Counseling 
For a female of childbearing potential, lenalidomide is contraindicated unless all of the following 
are met (i.e., all females of childbearing potential must be counseled concerning the following 
risks and requirements prior to the start of lenalidomide study therapy):  
· 
She understands the potential teratogenic risk to the unborn child 
· 
She understands the need for effective contraception, without interruption, 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: 
Rev. 12/13 

ECOG-ACRIN 
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· 
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 study therapy):  
· 
She acknowledges that she understands the hazards and necessary precautions associated 
with the use of lenalidomide 
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 study therapy): 
· 
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.   
Contraception 
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two reliable 
forms of contraception simultaneously or to practice complete abstinence from heterosexual 
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) 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) 
− 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, as outlined below. 
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Female Patients: 
FCBP must have two negative pregnancy tests (sensitivity of at least 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 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 drug 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 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 a female partner of a male subject taking investigational product becomes pregnant, the 
male subject taking lenalidomide should notify the Investigator, and the pregnant female 
partner should be advised to call their healthcare provider immediately. 
Additional precautions 
· 
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 therapy and for at least 28 days following 
discontinuation of study drug. 
· 
Male patients should not donate blood, semen or sperm during therapy or for at least 28 
days following discontinuation of study drug. 
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· 
Only enough study drug for one cycle of therapy may be dispensed with each cycle of 
therapy. 
 

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Intergroup Randomized Phase II Four Arm Study In Patients With Previously Untreated 
Mantle Cell Lymphoma Of Therapy With: Arm A = Rituximab+ Bendamustine Followed By 
Rituximab Consolidation (RB → R); Arm B = Rituximab + Bendamustine + Bortezomib 
Followed By Rituximab Consolidation (RBV→ R), Arm C = Rituximab + Bendamustine 
Followed By Lenalidomide + Rituximab Consolidation (RB → LR) or Arm D = Rituximab + 
Bendamustine + Bortezomib Followed By Lenalidomide + Rituximab Consolidation  
(RBV → LR) 
Appendix VII 
 
Mantle Cell Lymphoma International Prognostic Index (MIPI) 
A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma 
bloodjournal.hematologylibrary.org. See Section 4.1.5.1 for MIPI Calculator link. 
 
Using data of 455 advanced stage MCL patients treated within 3 clinical trials, we examined the 
prognostic relevance of IPI and FLIPI and derived a new prognostic index (MCL international 
prognostic index, MIPI) of overall survival (OS). 
According to the MIPI, patients were classified into 
· 
low risk (44% of patients, median OS not reached), 
· 
intermediate risk (35%, 51 months), and 
· 
high risk groups (21%, 29 months), 
based on the 4 independent prognostic factors: 
· 
age, 
· 
performance status,   
· 
lactate dehydrogenase (LDH), and 
· 
leukocyte count.   
· 
Cell proliferation (Ki-67) was exploratively analyzed as an important biologic marker and 
showed strong additional prognostic relevance. 
The MIPI is the first prognostic index particularly suited for MCL patients and may serve as an 
important tool to facilitate risk-adapted treatment decisions in patients with advanced stage 
MCL. 
Reference: 
(Blood. 2008;111: 558-565) 
Using data of 455 advanced stage MCL patients treated within 3 clinical trials, we examined the 
prognostic relevance of IPI and FLIPI and derived a new prognostic index (MCL international 
prognostic index, MIPI) of overall survival (OS). Statistical methods included Kaplan-Meier 
estimates and the log-rank test for evaluating IPI and FLIPI and multiple Cox regression for 
developing the MIPI. IPI and FLIPI showed poor separation of survival curves. According to the 
MIPI, patients were classified into low risk (44% of patients, median OS not reached), 
intermediate risk (35%, 51 months), and high risk groups (21%, 29 months), based on the 4 
independent prognostic factors: age, performance status, lactate dehydrogenase (LDH), and 
leukocyte count. Cell proliferation (Ki-67) was exploratively analyzed as an important biologic 
marker and showed strong additional prognostic relevance. The MIPI is the first prognostic 
index particularly suited for MCL patients and may serve as an important tool to facilitate risk-
adapted treatment decisions in patients with advanced stage MCL 
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Intergroup Randomized Phase II Four Arm Study In Patients With Previously Untreated 
Mantle Cell Lymphoma Of Therapy With: Arm A = Rituximab+ Bendamustine Followed By 
Rituximab Consolidation (RB → R); Arm B = Rituximab + Bendamustine + Bortezomib 
Followed By Rituximab Consolidation (RBV→ R), Arm C = Rituximab + Bendamustine 
Followed By Lenalidomide + Rituximab Consolidation (RB → LR) or Arm D = Rituximab + 
Bendamustine + Bortezomib Followed By Lenalidomide + Rituximab Consolidation  
(RBV → LR) 
Appendix VIII 
 
Modified Ann Arbor Staging System 
 
Stage I  
Involvement of a single lymph node region. 
 
Stage II  
Involvement of 2 or more lymph node regions on the same side of the 
diaphragm. 
 
Stage III   
Involvement of lymph node regions on both sides of the diaphragm. 
 
Stage IV  
Diffuse or disseminated involvement of one or more extra lymphatic 
organs or tissues, with or without associated lymph node involvement. 
 
 
The subscript E (e.g., IIE or IIIE) is used to denote involvement of an extra lymphatic site 
primarily or by direct extension, rather than hematogenous spread, as in the case of a 
mediastinal mass extending to involve the lung. 
 
The presence of (B) or absence of (A) fever, night sweats, and/or unexplained loss of 
10% or more body weight in the 6 months prior to admission are denoted by the 
corresponding suffix letters B and A. 
 
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Intergroup Randomized Phase II Four Arm Study In Patients With Previously Untreated 
Mantle Cell Lymphoma Of Therapy With: Arm A = Rituximab+ Bendamustine Followed By 
Rituximab Consolidation (RB → R); Arm B = Rituximab + Bendamustine + Bortezomib 
Followed By Rituximab Consolidation (RBV→ R), Arm C = Rituximab + Bendamustine 
Followed By Lenalidomide + Rituximab Consolidation (RB → LR) or Arm D = Rituximab + 
Bendamustine + Bortezomib Followed By Lenalidomide + Rituximab Consolidation  
(RBV → LR) 
Appendix IX 
 
FDG-PET Imaging, Interpretation, PET and CT Data Submission, and Semi-quantitative 
Analysis 
 
PET/CT Imaging Timelines 
The following PET/CT and IC contrast CT scans will be collected digitally for archival: 
· The baseline PET/CT scan and the diagnostic CT scan must be obtained ≤ 28 days prior 
to registration. In the case of a patient who already had a baseline FDG-PET/CT scan at 
an outside facility, the quality of the PET/CT scan must be approved by the CALGB 
Imaging Core Lab before the enrollment of the patient to E1411. Furthermore, these 
patients will not be included in the quantitative evaluations. The FDG PET/CT study can 
be performed by combining the intravenous contrast enhanced diagnostic CT study into 
one PET/CT study. 
· The interim FDG-PET/CT scan (if and when available) after 3 cycles of induction therapy 
will be obtained at least 12 days after the administration of the 3rd cycle of induction 
therapy (post 3 cycles). If the baseline PET/CT study is performed using a protocol 
combining the intravenous contrast enhanced diagnostic CT into one study then all 
subsequent PET/CT studies should be performed following the same methodology to 
avoid variability in SUVmax among FDG PET/CT studies within the same patient. 
· The post completion of induction therapy FDG-PET/CT scan and diagnostic CT scan will 
be obtained at least 3 weeks after the administration of the last dose of induction therapy 
(post 6 cycles). If the baseline PET/CT study is performed using a protocol combining 
the intravenous contrast enhanced diagnostic CT into one study then all subsequent 
PET/CT studies should be performed following the same methodology to avoid variability 
in SUVmax among FDG PET/CT studies within the same patient.   
· The interim consolidation FDG-PET/CT scan (if PET (+) at end of treatment) should be 
obtained six (6) months into consolidation.  If the baseline PET/CT study is performed 
using a protocol combining the intravenous contrast enhanced diagnostic CT into one 
study then all subsequent PET/CT studies should be performed following the same 
methodology to avoid variability in SUVmax among FDG PET/CT studies within the 
same patient.    
· The final FDG-PET/CT scan should be obtained at the completion of consolidation.  If 
the baseline PET/CT study is performed using a protocol combining the intravenous 
contrast enhanced diagnostic CT into one study then all subsequent PET/CT studies 
should be performed following the same methodology to avoid variability in SUVmax 
among FDG PET/CT studies within the same patient. 
o All interim (when available) and post-therapy PET/CT and IV contrast CT scans 
should be performed on the same scanner with the same specifications as those 
performed at baseline. Ideally, the IV contrast CT scan should be done on the same 
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day following the PET/CT scan. Alternatively, if the baseline FDG PET/CT was done 
with a protocol combining the IV contrast CT into the FDG PET/CT protocol (namely, 
FDG PET/CT is performed with IV contrast on board with a diagnostic CT), then the 
interim PET/CT study should be done using the same protocol. However, if the IV 
contrast CT is obtained on a separate day, the time difference between PET/CT and 
IV contrast CT should not exceed 15 days at baseline and should not exceed 7 days 
after any cycle of therapy. In the case of a patient who already had a baseline FDG-
PET/CT scan at an outside facility, the quality of the PET/CT scan must be approved 
by the CALGB Imaging Core Lab before the enrollment of the patient to E1411. 
Furthermore, these patients will not be included in the quantitative evaluations. 
o For reproducible and accurate results, post-therapy PET/CT scans should be 
acquired using the same FDG uptake time (post-injection interval) as the pre-therapy 
scan. The difference in waiting period after injection of FDG between the baseline 
and interim (when available) or post-therapy PET/CT scans should not exceed 10 
minutes for maintaining consistency and ensuring accuracy for quantitative studies. 
o Patient CT scans should follow institutional standards for oral and IV contrast. Scans 
of the chest, abdomen, and pelvis should be obtained at all time points, and scans of 
the neck should be obtained if it is deemed involved at baseline. 
PET/CT Data Acquisition 
All data acquisitions and reconstructions will be performed on a PET/CT system. A 
phantom study will be performed to standardize all PET/CT systems prior to the initiation of 
the protocol. 
o Prior to FDG Injection and During Uptake Period 
Patients must fast for at least four hours before the PET/CT scan. Oral hydration is 
strongly encouraged prior to and during injection of 18F-FDG (250-500mL water can be 
given PO during the uptake period) and during the uptake period after administration of 
18F-FDG. IV furosemide (10 mg) may be administered (but is not mandatory) to 
increase urinary elimination of the tracer and minimize image artifacts caused by urinary 
stasis in the abdomen and pelvis. Intravenous fluids containing dextrose or parenteral 
feeding should be withheld for at least 6 hours prior to the injection of 18F-FDG. No 
steroid administration is allowed for at least 7 days prior to FDG-PET imaging. Active 
exercise should be discouraged for at least 24 hours prior to the study. Muscle stress, 
tension, chewing, and movement during the uptake period should be minimized to 
decrease muscle uptake. Patients should not speak during the injection and uptake 
period. Interviews with the patient should be withheld until after completion of the 
imaging study. 
The blood glucose level should be checked before the 18F-FDG injection. Blood sugar 
(measured by glucometer) must be less than 200 mg/dL at the time of the FDG-PET/CT 
study. If the blood glucose level is greater than 200 mg/dL, the FDG-PET/CT imaging 
should be rescheduled. If the blood glucose level still exceeds 200 mg/dL on the 
following scheduled day for PET scanning, the patient will not be included in the trial. 
Insulin administration immediately before the PET/CT study to reduce the glucose levels 
is not allowed. Patients with diabetes should continue to adhere to their oral agents or 
insulin routines. These medications should not be administered near the 18F-FDG 
injection time. In insulin-dependent patients, insulin should be administered at least 5 
hours prior to the 18F-FDG injection. Patients with diabetes who are on diabetic 
medication should take their medication 4-5 hours prior to the test. If blood sugar 

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exceeds 150 mg/dL (but less than 200 mg/dL), a note should be made in on the case 
report form. 
Metallic objects should be removed from the patients whenever possible. Patients 
should be kept in a warm waiting room prior to 18F-FDG injection to avoid brown 
adipose tissue uptake. In anxious and claustrophobic patients, administration of oral 
diazepam (0.06-0.10 mg/kg) is recommended 30-40 minutes prior to the initiation of the 
imaging study. 
Weight (kg), height (cm), blood glucose (mg/dL), and the date and time of chemotherapy 
and colony stimulating administration (e.g., GCSF, GMCSF) will be recorded prior to the 
injection of 18F-FDG. 
5-20 mCi of 18F-FDG will be administered (depending on the PET/CT scanner and the 
manufacturer’s recommendations) IV, depending on the manufacturer’s 
recommendation. A 10-20mL saline flush is recommended in reducing the venous 
retention of 18F-FDG. The patient must wait for at least 60 minutes prior to the initiation 
of the PET/CT acquisition for all PET/CT scans (both pre-and post-therapy scans). The 
wait period should be kept within a maximum of 10 minutes among patients. The wait 
period must not exceed 80 minutes at baseline. It is NOT acceptable to start imaging 
with wait periods of less than 60 minutes and longer than 80 minutes for both pre- 
and post-therapy PET/CT scans. The time difference between baseline and other PET 
studies should not be > 10 minutes. A time difference of > 15 minutes between PET/CT 
studies is NOT acceptable. 
The imaging will start after voiding the bladder. 150-200mL of water must be given to the 
patient immediately prior to the study acquisition before they are positioned on the table 
to distend stomach and avoid physiologic stomach uptake. 
PET/CT Image Acquisition 
Patients will be positioned on the table in a headfirst, supine position with arms elevated 
above the head to reduce beam-hardening artifacts at the level of the liver. A separate head 
and neck imaging will be pursued for those whose primary disease site is in the neck with 
the arms positioned along the side. The use of oral contrast is at the discretion of each 
facility. However, IV-contrast dedicated CT acquisition should follow PET imaging with non-
contrast low-dose CT to avoid variations in FDG uptake in the blood pool and the tumor that 
is caused by the IV contrast agent. The low dose CT associated with PET should be 
acquired using a current of not less than 80 mA/second. Nonetheless, if the baseline 
PET/CT study is performed using a protocol combining the intravenous contrast enhanced 
diagnostic CT into one study then all subsequent PET/CT studies should be performed 
following the same methodology to avoid variabilities in SUVmax among FDG PET/CT 
studies within the same patient. 
It is critical that all post-therapy PET/CT scans be performed in an identical way to the 
baseline scan with the same scanner, same scanning direction (skull to thighs or thighs to 
skull) and consistent arm positioning. 
For PET imaging, six to seven contiguous volumes will be chosen, depending on the 
patient’s height, to ensure data acquisition of the entire region of interest (ROI), the level of 
the skull base to the 1/3 proximal femurs. The time/bed position should be in accordance 
with the manufacturer’s recommendations for optimal imaging. Adjacent fields of view 
should share overlapping slices. 
PET/CT Image Processing 
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Follow the manufacturer’s recommendation for image reconstruction. The emission data will 
be corrected for scatter, random coincidence events, and system dead-time using provided 
software. An iterative reconstruction (ordered subsets expectation maximization) and CT-
based attenuation correction will be used for the PET images. Reconstructions should be 
archived both with and without attenuation correction to resolve issues arising from 
potential artifacts generated by the CT-based attenuation correction procedure. 
Evaluation of PET/CT Data 
All images will be read centrally by the CALGB Imaging Core Laboratory. 
To ensure the highest standards and consistency between different centers, all FDG-PET 
scans must be submitted to the CALGB Imaging Core Laboratory at Ohio State University 
for centralized review. Response determinations must be based on the centralized review 
of the FDG-PET scan and NOT on scan assessments by local physicians.  
Centralized review will be performed by a member of a team of PET/CT readers. There will 
be an adjudicator from the same pool of reviewers in the case of disagreement. There will 
be one reviewer, Dr. Nathan Hall, who will provide back-up PET/CT reviewer services 
within the CALGB Imaging Core Laboratory. The CALGB Imaging Core Laboratory will 
transmit the scans to the expert reviewers for response determination and then will transmit 
the results to the CALGB Statistical Center.  
Determination of FDG-PET positivity or negativity will be performed using a 5-point scoring 
system on guidelines established by an international PET harmonization conference 
convened in London in May 2007 (See Appendix X). According to these guidelines, scans 
will be judged to be positive if lesions are more hypermetabolic than the liver by visual, 
qualitative inspection.  Borderline metabolism in a lesion will be considered negative in 
concordance with the policies of Gallamini and Hutchings whose studies established the 
value of early interim FDG-PET imaging (Bernard et al 2001, Watanabe et al 2010, Tateishi 
et al 2011). 
Objectives/Endpoint: Definition of Response by Metabolic Criteria 
The primary endpoints are OR, CR, and PFS in PET-6 positive and PET-6 negative groups 
(at the end of 6 cycles of induction therapy) in both the R-B-V and R-B arms of induction 
therapy, using London criteria provided in Appendix X. 
Negative PET Scan (Metabolic Responders) 
Upon qualitative evaluation, tumor FDG uptake that is less than or equal to the liver in 
target or non-target tumors, regardless of their location, the absence of new lesions that are 
deemed to be tumor, and the absence of non-target tumors will be considered negative for 
the presence of residual lymphoma (Appendix X). 
Positive PET Scan 
Upon qualitative evaluation, diffuse or focal uptake exceeding that seen in the liver in target 
or non-target tumors, regardless of their location, will be considered positive for residual 
tumor.  
Semi-quantitative Analysis 
In patients with multiple tumor sites, the six sites with the highest uptake will be designated 
as the target sites. For these lesions, SUV measurements and metabolic volumes will be 
determined at baseline, after cycle 3 (when available), at completion of induction therapy 
(post 6 cycles), as outlined below. 
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At baseline, a 3D volume of interest (VOI) will be taken over the tumor on axial, sagittal, 
and coronal multi-planar reformatting (MPR) views that visually show the most prominent 
uptake. Maximum SUV body weight (SUVbw), will be obtained over the lesion.  
Using receiver operator curves (ROC), most optimal cutoff for absolute decrease in 
metabolic volumes and maximum SUVbw, absolute uptake in the tumor/s and relative 
uptake in tumor/s versus various reference anatomic sites (liver, mediastinal blood pool, 
and background), as well as various cutoffs for post-therapy maximum SUVbw metabolic 
volumes, will be determined and compared after cycle 3 of induction and following cycle 6 
of induction (for PET negative patients). 
In patients with multiple tumor sites, the six sites correlating with the PET target lesions will 
be designated as the target sites. In each lymph node region the lesions with the highest 
uptake will be chosen. If there is any lesion that demonstrates uptake after therapy other 
than the designated target lesions, they will be non-target lesions and will be evaluated in 
the same fashion as target lesions. For all designated lesions, volumetric vs. 2 dimensional 
(2-D) measurement changes between baseline and after cycle 3 of induction and following 
cycle 6 of induction therapy will be determined from dedicated CT scans. Using receiver 
operator curves (ROC), the most optimal cutoff for absolute decrease and percent decrease 
will be determined. A combinatorial analysis will be performed incorporating the changes 
from PET data and dedicated CT data to determine if this approach increases the predictive 
value of both tests combined compared to each test alone. 
Qualitative and semi quantitative FDG-PET findings/changes, CT size changes, and 
combinatorial analyses (PET + dedicated CT data) will be compared with molecular 
parameters, and conventional parameters, including IPS in the prediction of response and 
PFS. 
Post-Induction Therapy 
At any point after therapy, the decision for biopsy of any lesion is at the discretion of the 
treating physician. After completion of induction treatment, during consolidation therapy, if 
any PET/CT data are available during or after completion of consolidation phase of therapy, 
central evaluation of PET response and PET-based prediction of survival will also be 
considered using the same objectives and evaluation strategy designed for the induction 
phase of the protocol. 
 

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Intergroup Randomized Phase II Four Arm Study In Patients With Previously Untreated 
Mantle Cell Lymphoma Of Therapy With: Arm A = Rituximab+ Bendamustine Followed By 
Rituximab Consolidation (RB → R); Arm B = Rituximab + Bendamustine + Bortezomib 
Followed By Rituximab Consolidation (RBV→ R), Arm C = Rituximab + Bendamustine 
Followed By Lenalidomide + Rituximab Consolidation (RB → LR) or Arm D = Rituximab + 
Bendamustine + Bortezomib Followed By Lenalidomide + Rituximab Consolidation  
(RBV → LR) 
Appendix X 
 
Deauville Criteria 
 
Negative Scan 
· 
Score 1  no uptake 
· 
Score 2  uptake ≤ mediastinum 
· 
Score 3  update > mediastinum and ≤ liver 
 
Positive Scan 
· 
Score 4 
 moderately  > liver 
· 
Score 5 
markedly  uptake > > liver 
 
Score X: 
New areas of update unlikely to be related to lymphoma. 
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Intergroup Randomized Phase II Four Arm Study In Patients With Previously Untreated 
Mantle Cell Lymphoma Of Therapy With: Arm A = Rituximab+ Bendamustine Followed By 
Rituximab Consolidation (RB → R); Arm B = Rituximab + Bendamustine + Bortezomib 
Followed By Rituximab Consolidation (RBV→ R), Arm C = Rituximab + Bendamustine 
Followed By Lenalidomide + Rituximab Consolidation (RB → LR) or Arm D = Rituximab + 
Bendamustine + Bortezomib Followed By Lenalidomide + Rituximab Consolidation  
(RBV → LR) 
Appendix XI 
 
[Deleted in Addendum #2] 
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Intergroup Randomized Phase II Four Arm Study In Patients With Previously Untreated 
Mantle Cell Lymphoma Of Therapy With: Arm A = Rituximab+ Bendamustine Followed By 
Rituximab Consolidation (RB → R); Arm B = Rituximab + Bendamustine + Bortezomib 
Followed By Rituximab Consolidation (RBV→ R), Arm C = Rituximab + Bendamustine 
Followed By Lenalidomide + Rituximab Consolidation (RB → LR) or Arm D = Rituximab + 
Bendamustine + Bortezomib Followed By Lenalidomide + Rituximab Consolidation  
(RBV → LR) 
Appendix XII 
 
E1411 Imaging Site Personnel Form 
 
Responsible CRA Contact 
Complete Address 
E-mail 
Phone Number 
Fax Number 
Radiology Department Contact 
Complete Address 
E-mail 
Phone Number 
Fax Number 
 
 
 
Please provide the information requested above. Provide the middle 
initial for individuals who commonly use them. Also, please add or 
correct the degree/title as necessary. This information will be 
retained by the CALGB Imaging Core Laboratory. 
 
Once completed, you may send this form to: 
 
  
CALGB Imaging Core Laboratory 
  
Attn: E1411 
  
Wright Center of Innovation 
  
The Ohio State University 
  
395 West 12th Avenue, Room 414 
  
Columbus, OH 43210 
  
Fax: (614) 293-9275 
 
Call the CALGB Imaging Core Laboratory at (614) 293-9151 with any questions.  Thank 
you for your assistance. 
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Intergroup Randomized Phase II Four Arm Study In Patients With Previously Untreated 
Mantle Cell Lymphoma Of Therapy With: Arm A = Rituximab+ Bendamustine Followed By 
Rituximab Consolidation (RB → R); Arm B = Rituximab + Bendamustine + Bortezomib 
Followed By Rituximab Consolidation (RBV→ R), Arm C = Rituximab + Bendamustine 
Followed By Lenalidomide + Rituximab Consolidation (RB → LR) or Arm D = Rituximab + 
Bendamustine + Bortezomib Followed By Lenalidomide + Rituximab Consolidation  
(RBV → LR) 
Appendix XIII 
 
RevAssist for Study Participants Clinical Trial Prescription Form 
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Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
173 
Intergroup Randomized Phase II Four Arm Study In Patients With Previously Untreated 
Mantle Cell Lymphoma Of Therapy With: Arm A = Rituximab+ Bendamustine Followed By 
Rituximab Consolidation (RB → R); Arm B = Rituximab + Bendamustine + Bortezomib 
Followed By Rituximab Consolidation (RBV→ R), Arm C = Rituximab + Bendamustine 
Followed By Lenalidomide + Rituximab Consolidation (RB → LR) or Arm D = Rituximab + 
Bendamustine + Bortezomib Followed By Lenalidomide + Rituximab Consolidation  
(RBV → LR) 
Appendix XIV 
 
E1411 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? 
1. Lenalidomide may cause birth defects (deformed babies) or death of an unborn baby. 
Lenalidomide is similar to the medicine thalidomide. It is known thalidomide causes life-
threatening birth defects. Lenalidomide has not been tested in pregnant women but may 
also cause birth defects. 
If you are a female who is able to become pregnant: 
· 
Do not take lenalidomide if you are pregnant or plan to become pregnant 
· 
for 28 days before starting lenalidomide 
· 
while taking lenalidomide  
· 
during dose interruptions of lenalidomide  
· 
for 28 days after stopping lenalidomide  
· 
Stop taking lenalidomide if you become pregnant during lenalidomide treatment 
· 
Do not breastfeed while taking lenalidomide 
· 
You must have pregnancy testing done at the following times: 
· 
within 10 – 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) 
· 
You must practice complete abstinence 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  
· 
and for 28 days after stopping Lenalidomide 
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Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
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· 
Study doctors and healthcare providers are instructed to report all cases of 
pregnancy 
If you are a male: 
It is not known if lenalidomide passes into semen.  
· 
Male patients, including those who have had a vasectomy, must use a latex condom 
during sexual intercourse with a pregnant female or a female that can become 
pregnant: 
· 
While you are taking lenalidomide   
· 
for 28 days after you stop taking lenalidomide  
· 
Male patients should not donate sperm or semen while taking lenalidomide and 
for 28 days after stopping lenalidomide.  
2.   Lenalidomide may cause a reduction in the number of white blood cells and platelets.  
This can lead to increased risk of infection and bleeding. You may need a blood 
transfusion or certain medicines if your blood counts drop too low.  You will have blood 
tests done as part of the clinical research trial in which you are participating.  This is 
discussed in the informed consent document. 
3.   Lenalidomide may cause an increased chance for blood clots in the veins and in the 
lungs. Call your study doctor or get emergency medical care right away if you get the 
following signs or symptoms: 
· shortness of breath 
· chest pain 
· arm or leg swelling 
4. Lenalidomide restrictions in sharing lenalidomide and donating blood: 
· Do not share lenalidomide with other people 
· Do not give blood while you take lenalidomide and for 28 days after stopping 
lenalidomide  
· You will get no more than a 28-day supply of lenalidomide at one time 
Additional information is provided in the informed consent form and you can ask your study 
doctor for more information. 
Rev. 12/13 

ECOG-ACRIN 
E1411 
Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
175 
Intergroup Randomized Phase II Four Arm Study In Patients With Previously Untreated 
Mantle Cell Lymphoma Of Therapy With: Arm A = Rituximab+ Bendamustine Followed By 
Rituximab Consolidation (RB → R); Arm B = Rituximab + Bendamustine + Bortezomib 
Followed By Rituximab Consolidation (RBV→ R), Arm C = Rituximab + Bendamustine 
Followed By Lenalidomide + Rituximab Consolidation (RB → LR) or Arm D = Rituximab + 
Bendamustine + Bortezomib Followed By Lenalidomide + Rituximab Consolidation  
(RBV → LR) 
Appendix XV 
 
E1411 Bortezomib Drug Request Form 
Section I (To be completed by Site)  
All shaded areas must be completed before forwarding the drug request to UVI, Inc. 
 ECOG-ACRIN Protocol Number:  E1411 
Millennium Protocol Number:  
Delivery Address 
 
Institution Name: 
CTEP ID: 
Attention To: 
Street Address: 
 
City, State, Zip Code: 
 
Shipment Must Reach Destination By: 
 (MM/DD/YY)- 
Deliveries 
are 
not 
made 
on 
Mondays, weekends or holidays) 
Pharmacy Contact Name:   
 
Pharmacy Contact Phone:      
Pharmacy Contact Fax: 
Pharmacy Contact E Mail:     
Principal Investigator Name:    
Principal Investigator Address:                        
 
 
PATIENT SEQUENCE NUMBER: 
 
ARM RANDOMIZED TO: 
STUDY DRUG: 
BORTEZOMIB 
BORTEZOMIB 
QUANTITY: 
(Quantities are 4 Vials 
Per Carton) 
SHIPMENT #  
See below or Section 8.3.7 for Shipment Time Points 
(Place check mark below) 
SHIPMENT 
TIME POINT 
 
 
#1, Cycles 1-3 
 
 
#2, Cycles 4-6 
Drug is being provided at no charge.  Site may not submit any claims or receive any reimbursement for 
any source (whether public or private) for Drug and may not be returned to Millennium (or its 
distributor) for a refund or credit.  Drug must be used solely pursuant to the Protocol.  All other uses are 
strictly prohibited.   
 
By:  ______________________________________________ 
              (Signature//Title) 
 
Name (Print): _______________________________________ 
 
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ECOG-ACRIN 
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Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
176 
PLEASE EMAIL THIS DRUG REQUEST AS AN ATTACHMENT TO mdubois@uintavision.com 
 
Section II  (To be completed by UVI, Inc) 
 
UVI, Inc. Approval:  
 
Confirm Patient on Arm B or D: 
 
UVI Personnel Name:  
 
 
          Signature: 
          
 
             Date:  
 
 
Section I (To be completed by Site) 
 
Instruction – How to Return Commercial Velcade for Investigational Use Only : 
 
1. Complete form below and fax to # 1-866-422-4797 for Millennium approval 
2. Once form is received, you will receive a Return Authorization number and call tag for free pick up 
of the VELCADE to be returned, as well as instructions on preparing your package for pick up.  
3. Upon pick up of your package, please notify your CRA/M that the Return Request has been 
completed.  
 
NOTE:  Please ensure that the VELCADE vials are adequately protected when packaging to prevent 
breakage. 
 
If you have any questions, please contact Barbara Franklin at phone #: 617-551-8985 or 
franklin@mpi.com. 
 
 
RETURN PICK UP ADDRESS 
(Address the VELCADE will be picked up 
from): 
 
 
 
 
TOTAL Amount of VELCADE Vials to Be 
Returned: 
 
__________________________vials 
  
Contact Name:   
 
 
LOT NUMBER(s):  
Phone:    
   
Fax: 
 
Email Address: 
 
Reason for Return: 
Principal Investigator Name:    
                                                
Millennium Protocol Number: 
Sub-Investigator Name (if applicable):    
 

ECOG-ACRIN 
E1411 
Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
177 
Intergroup Randomized Phase II Four Arm Study In Patients With Previously Untreated 
Mantle Cell Lymphoma Of Therapy With: Arm A = Rituximab+ Bendamustine Followed By 
Rituximab Consolidation (RB → R); Arm B = Rituximab + Bendamustine + Bortezomib 
Followed By Rituximab Consolidation (RBV→ R), Arm C = Rituximab + Bendamustine 
Followed By Lenalidomide + Rituximab Consolidation (RB → LR) or Arm D = Rituximab + 
Bendamustine + Bortezomib Followed By Lenalidomide + Rituximab Consolidation  
(RBV → LR) 
Appendix XVI 
 
E1411 PET/CT Adjunctive Data Sheet 
 
ECOG-ACRIN1411 protocol requires PET scans to start at [60-80] min post FDG injection. 
This exact same wait period of uptake must be used consistently for follow-ups with no more 
than 10 min difference from the baseline, and the wait period should be kept within a 
maximum of 10 minutes difference among patients. 
 
 
1. ECOG-ACRIN Patient ID: ________________  
Patient Initials: 
_____________________ 
2. Institution/Affiliate: ____________________________________ 
 
ECOG-ACRIN Institution ID: __________________________________ 
3. Date of PET/CT Scan (MM/DD/YYYY): _______/_______/_______ 
Time point of the study (Mark the time period on the left side and provide required date on 
the right side):  
· 
__ Baseline (≤ 28 days before randomization) 
Date of Registration: _______/_______/_______ 
· 
__ Interim (> C3D12 of induction administration) 
Date of C3D1: _______/_______/_______ 
· 
__ Final (> 3wks after admin of last induction dose) 
Date of last dose of induction: ______/______/______  
· 
Interim (> C6 of consolidation administration) 
Date of C6D1: _______/_______/_______ 
· 
__ Interim (> C12 of consolidation administration) 
Date of C12D1: _______/_______/_________  
· 
Final (> 3wks after admin of last consolidation dose) 
Date of last dose of consolidation: ______/______/______ 
4. Patient had been fasting for ____hours; Patient blood glucose level was _____ mg/dL or 
____ mmol/L 
5. Patient weight prior to dosing ______kg or ______lbs;  Patient height ____ cm or ____ft 
____ in. 
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Rev. 12/13 
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Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
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6. Location of injection side (Circle one): 
Right / Left Antecubital 
 
Right / Left Wrist 
Other, specify: 
__________________ 
7. Effective FDG Dose injected: ____ mCi or ____ MBq at the Time of Injection: 
____hh: _____mm  
Pre-injection FDG-Syringe Dose: ____ mCi or ____ MBq   at the Time of Pre-Calibration: 
____hh: _____mm 
Post-injection Residual Dose assay: ____ mCi or ____ MBq at the Time of Syringe Empty: 
____hh:____mm 
8. PET scan started at ________ minutes post FDG injection. 
9. CT of PET/CT for PET Attenuation Correction: kVp _____  mA/mAs_____  
Additional diagnostic CT was performed? Yes / No 
10. Was Oral contrast used during CT scan? Yes / No 
Was IV contrast used during CT scan? Yes / No 
11. In the past 4 weeks, has the patient received colony stimulating factors? 
No / Yes (then mark all that apply):   
Filgrastim (Neupogen®) ___ 
 
Epoetin (Aranesp®, Epogen®, Procrit®) ___ 
Pegfilgrastim(Neulasta®)___ 
Other _____________________ 
12. Model of the PET/CT scanner used for this study: 
____________________________________  
Same as the baseline?  Yes / No / N/A 
13. Was the PET imaging completed according to protocol? 
Yes / No  
If not, please explain: 
_________________________________________________________________________
__________ 
14. Site treating physician:_____________ E-Mail: __________________ 
Telephone: 
____________ 
15. Site Primary Contact:______________ E-Mail: __________________ 
Telephone: 
____________ 
16. Completed by: ___________________ Date of the form completed: 
_______/_______/_______ 
Reminder - This Form should be submitted to the CALGB Imaging Core Lab via: 
Email: ECOG1411@imagingcorelab.com 
Fax: 614-293-9275      
FTP: Contact Imaging Core Lab at the trial email 
Mail: Imaging Core Lab, The Ohio State University, Rm#414, 395 W 12th Ave, Columbus, OH 
43210 
ICL Contact Telephone: 614-293-2929 

ECOG-ACRIN 
E1411 
Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
179 
Intergroup Randomized Phase II Four Arm Study In Patients With Previously Untreated 
Mantle Cell Lymphoma Of Therapy With: Arm A = Rituximab + Bendamustine Followed 
By Rituximab Consolidation (Rb → R); Arm B = Rituximab + Bendamustine + Bortezomib 
Followed By Rituximab Consolidation (RBV → R), Arm C = Rituximab + Bendamustine 
Followed By Lenalidomide + Rituximab Consolidation (RB → LR) or Arm D = Rituximab + 
Bendamustine + Bortezomib Followed By Lenalidomide + Rituximab Consolidation  
(RBV → LR) 
Appendix XVII 
 
Blood Collection Kit Mayo Clinic Lymphoma Laboratory 
Specimen Checklist and Shipping Instructions 
** PLEASE AVOID DRAWING OR SENDING SPECIMENS ON FRIDAYS AND HOLIDAYS** 
Kit Contents: 
· 
Small Styrofoam box and cardboard mailing sleeve 
· 
Patient Information Form 
· 
FedEx Air bill with pre-printed return address 
· 
7ml ACD (yellow top) collection tubes 
· 
10ml EDTA (purple top) collection tube 
· 
10ml Red Top collection tube 
· 
Absorbent tube holder 
· 
Zip lock specimen bag 
Packing and Shipping Instructions: 
1. Collect the following specimens: 
1 
Peripheral blood – Draw: 
· 
21ml into three (3) ACD tubes 
· 
10ml in one (1) EDTA tube 
· 
10ml in one (1) Red Top tube 
2. All specimens are to be clearly labeled with the protocol number E1411, the patient’s initials 
(last, first, middle), ECOG-ACRIN sequence number (if available) and date of collection. 
3. Place the tubes in the absorbent holder and seal in the zip lock specimen bag. 
4. Place the filled specimen bag in the Styrofoam container. 
5. Loosely pack with paper toweling. 
6. Place the Styrofoam container and the Sample Tracking System manifest form within the 
cardboard mailing sleeve. 
7. 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 
via priority overnight delivery (next day delivery by 10am) the same day collected. 
8. Notify Federal Express for pick-up and/or leave package at the designated FedEx drop-off 
location. 
IMPORTANT: 
If these are baseline sample submissions being shipped prior to patient 
enrollment please call Kim Henderson at (507) 284-3805 at the Mayo Clinic 
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ECOG-ACRIN 
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Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
180 
Lymphoma Laboratory for a “Sequenta Sequence Number”.   This 
number will be the only patient identifier on the paperwork and baseline 
sample submissions to Sequenta. 
Please e-mail Kim Henderson at Henderson.Kimberly@mayo.edu to notify the laboratory when 
samples are being shipped. Indicate the ECOG-ACRIN protocol number, the FedEx tracking 
number, name and phone number of the contact person. The blood samples in prepared kits 
should be shipped to the following: 
Kim Henderson 
Mayo Clinic Lymphoma Laboratory 
613 Stabile 
200 First Street Southwest 
Rochester, MN 55905 
Patient Information Form 
It is required that samples submitted from patients participating in E1411 be entered and 
tracked via the online ECOG-ACRIN Sample Tracking System (see Section 10.3). 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):  
Hospital ID or Social Security #:  
ECOG-ACRIN Protocol #: E1411 
ECOG-ACRIN Patient Sequence 
#:  
Contact Person:  
Institution:  
Address:  
 City                                       State               Zip 
Phone #:  
FAX #:  

ECOG-ACRIN 
E1411 
Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
181 
Please indicate which samples are being shipped at this time: 
1. Baseline 
2. Post Cycle Three 
3. Post Cycle Six (End of Induction) 
Any questions concerning these samples or to obtain blood collection kits for the E1411 study, 
please contact: 
Kim Henderson 
Mayo Clinic Lymphoma Laboratory  
(507) 284-3805 
Henderson.Kimberly@mayo.edu 
Affiliates who anticipate participating in this study should please call in advance for kits. 
 

ECOG-ACRIN 
E1411 
Cancer Research Group 
Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
182 
Intergroup Randomized Phase II Four Arm Study In Patients With Previously Untreated 
Mantle Cell Lymphoma Of Therapy With: Arm A = Rituximab + Bendamustine Followed 
By Rituximab Consolidation (Rb → R); Arm B = Rituximab + Bendamustine + Bortezomib 
Followed By Rituximab Consolidation (RBV → R), Arm C = Rituximab + Bendamustine 
Followed By Lenalidomide + Rituximab Consolidation (RB → LR) or Arm D = Rituximab + 
Bendamustine + Bortezomib Followed By Lenalidomide + Rituximab Consolidation  
(RBV → LR) 
Appendix XVIII 
 
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 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 NCI’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-ACRIN 
Operations Office – Boston.  Please contact the ECOG-ACRIN 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. 
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ECOG-ACRIN 
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Version Date: May 31, 2018 
 
NCI Update Date: June 13, 2012 
183 
How should the outcome of a pregnancy be reported? 
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 AEMD Help 
Desk at aemd@tech-res.com or 301-897-7497for 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 disorder characterized by death in utero; failure of 
the product of conception to show evidence of respiration, heartbeat, or definite movement of a 
voluntary muscle after expulsion from the uterus, without possibility of resuscitation.” 
It must be reported via CTEP-AERs as Grade 4 “Pregnancy Loss” under the System Organ 
Class (SOC) “Pregnancy, puerperium and perinatal conditions”.   
A pregnancy loss 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 (301-230-0159). This form is available on CTEP's website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/PregnancyReportFor
m.pdf) 
Rev. 4/14 
Rev. Add13 
Rev. Add13