Conditions: Multiple Myeloma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1
Healthy volunteers: no

Brief summary:
This phase III trial studies how well lenalidomide in combination with ixazomib works compared to lenalidomide alone in treating patients with evidence of residual multiple myeloma after stem cell transplantation. Lenalidomide may help shrink or slow the growth of multiple myeloma. Ixazomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving lenalidomide and ixazomib together may work better than giving lenalidomide alone in treating patients with evidence of residual multiple myeloma after a stem cell transplantation.

Detailed description:
PRIMARY OBJECTIVE:

I. To evaluate whether escalating maintenance therapy with the addition of ixazomib citrate (ixazomib) to lenalidomide improves overall survival (OS) among patients who are minimal residual disease (MRD) positive after approximately 1 year of lenalidomide maintenance following an early stem cell transplant (=\< 12 months from diagnosis).

SECONDARY OBJECTIVES:

I. To establish whether progression-free survival (PFS) is superior with the addition of ixazomib to lenalidomide maintenance.

II. To evaluate best response on treatment and compare response rates between arms.

III. To evaluate the safety profile of ixazomib added to lenalidomide and compare toxicity rates between arms.

EXPLORATORY OBJECTIVES:

I. To measure treatment exposure and adherence. II. To estimate treatment duration, duration of response and time to progression.

PATIENT-REPORTED OUTCOMES (PRO) OBJECTIVES:

I. To quantify the extent to which the addition of ixazomib to lenalidomide maintenance contributes to neuropathy and associated physical and functional impairments. (Primary) II. To assess the impact of the addition of ixazomib to lenalidomide maintenance on disease control and associated physical and functional well-being. (Primary) III. To evaluate time to worsening and recovery rate related to neuropathy. (Secondary) IV. To evaluate time to improvement and response rate related to disease control. (Secondary) V. To evaluate attributes of select patient reported treatment-emergent symptomatic adverse events (Patient-Reported Outcomes - Common Terminology Criteria for Adverse Events \[PRO-CTCAE\]) longitudinally and compare responses with provider-reported adverse events. (Exploratory) VI. To measure the likelihood of medication adherence and examine the relationship with treatment exposure. (Exploratory) VII. To assess correlation among patient reported outcome measures and association with clinical outcomes. (Exploratory) VIII. To tabulate PRO compliance and completion rates. (Exploratory)

IMAGING OBJECTIVES:

I. To evaluate the association between baseline fludeoxyglucose F-18 (18F-FDG)-positron emission tomography (PET)/computed tomography (CT) and patient outcomes.

II. To compare overall survival (OS) with the addition of ixazomib to lenalidomide among baseline 18F-FDG PET/CT-positive and 18F-FDG PET/CT -negative subgroups.

III. To compare the change in quantitative 18F-FDG PET/CT parameters over time with the addition of ixazomib to lenalidomide.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive lenalidomide orally (PO) once daily (QD) on days 1-28 and ixazomib citrate PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and positron emission tomography (PET) and computed tomography (CT) scan at screening and on study as well as undergo collection of blood samples throughout the trial.

ARM B: Patients receive lenalidomide PO QD on days 1-28 and a placebo PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and PET and CT scan at screening and on study as well as undergo collection of blood samples throughout the trial.

After completion of study treatment, patients are followed up every 3 months if \< 2 years from study entry, every 6 months if 2-5 years from study entry, then every 12 months for up to 10 years from study entry.

Arms:
arm 1: Patients receive lenalidomide PO QD on days 1-28 and ixazomib citrate PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and PET and CT scan at screening and on study as well as undergo collection of blood samples throughout the trial. arm 2: Patients receive lenalidomide PO QD on days 1-28 and a placebo PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and PET and CT scan at screening and on study as well as undergo collection of blood samples throughout the trial.

Interventions: intervention 1: Biospecimen Collection intervention 2: Bone Marrow Aspirate intervention 3: Bone Marrow Biopsy intervention 4: Computed Tomography intervention 5: Ixazomib Citrate intervention 6: Lenalidomide intervention 7: Placebo Administration intervention 8: Positron Emission Tomography intervention 9: Quality-of-Life Assessment intervention 10: Questionnaire Administration
Intervention descriptions: intervention 1: Undergo collection of blood samples intervention 2: Undergo bone marrow aspirate intervention 3: Undergo bone marrow biopsy intervention 4: Undergo CT scan intervention 5: Given PO intervention 6: Given PO intervention 7: Given PO intervention 8: Undergo PET scan intervention 9: Ancillary studies intervention 10: Ancillary studies

Protocol document:
Prot_SAP_000.pdf: 
EAA171
1
Optimizing Prolonged Treatment In Myeloma Using MRD 
Assessment (OPTIMUM)
STUDY CHAIR:
Shaji Kumar, MD
STUDY STATISTICIAN:
Susanna Jacobus, ScM
STUDY CO-CHAIR:
IMAGING STATISTICIAN:
IMAGING CO-CHAIR:
LABORATORY CO-CHAIR:
COMMUNITY CO-CHAIR:
CANCER CONTROL AND SURVIVORSHIP 
COMMITTEE CHAIR:
MYELOMA COMMITTEE IMAGING CHAIR:
Ajay Nooka, MD, MPH
Bradley S. Snyder, MS
Lale Kostakoglu, MD, MPH
Shaji Kumar, MD
Matthias Weiss, MD, PhD
Lynne Wagner, PhD
Lale Kostakoglu, MD, MPH
MYELOMA COMMITTEE CHAIR:
S. Vincent Rajkumar, MD
Version Date: January 4, 2023
STUDY PARTICIPANTS
ACTIVATION DATE
ALLIANCE / Alliance for Clinical Trials in Oncology
June 1, 2021
NRG / NRG Oncology
Addendum #1 (Pre-Activation)
SWOG / SWOG
Addendum #2 (Pre-Activation)
Addendum #3
Addendum #4
NCTN STUDY CHAMPIONS
SWOG: Jing Christine Ye, MD, University of 
Michigan
Addendum #5
ALLIANCE: Edward Faber, DO, MS, Oncology 
Hematology Care, Inc.
Agents
IND#
NSC#
Supply
Ixazomib/Placebo
767907
NCI supplied
Lenalidomide
N/A
703813
Commercially available
IND Sponsor: DCTD, NCI
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Table of Contents 
Schema ...................................................................................................................... 6 
1. Introduction ........................................................................................................ 7 
1.1 
Background ............................................................................................... 7 
1.2 
Rationale for the Trial ............................................................................. 11 
1.3 
Choice of Intervention ............................................................................ 13 
1.4 
Patient Reported Outcomes Component ............................................... 15 
1.5 
Imaging Component ................................................................................ 17 
2. Objectives ......................................................................................................... 19 
2.1 
Primary Objective .................................................................................... 19 
2.2 
Secondary Objectives .............................................................................. 19 
2.3 
Exploratory Objectives ............................................................................ 19 
2.4 
Patient-Reported Outcomes (PRO) Objectives ....................................... 19 
2.5 
Imaging Objectives .................................................................................. 20 
3. Selection of Patients ......................................................................................... 21 
3.1 
Step 0 Pre-Registration ........................................................................... 21 
3.2 
Step 1 Randomization ............................................................................. 22 
4. Registration and Randomization Procedures ................................................... 26 
4.1 
Step 0 Pre-Registration ........................................................................... 29 
4.2 
Step 1 Randomization ............................................................................. 30 
4.3 
Additional Requirements ........................................................................ 31 
4.4 
Emergency Unblinding ............................................................................ 35 
4.5 
Instructions for Patients Who Do Not Start Assigned Protocol Treatment35 
5. Treatment Plan ................................................................................................. 36 
5.1 
Administration Schedule ......................................................................... 36 
5.2 
Lenalidomide Fertility Instructions ......................................................... 36 
5.3 
Adverse Event Reporting Requirements ................................................. 37 
5.4 
Comprehensive Adverse Events and Potential Risks Lists ...................... 48 
5.5 
Dose Modifications ................................................................................. 58 
5.6 
Supportive Care ....................................................................................... 62 
5.7 
Duration of Therapy ................................................................................ 65 
5.8 
Duration of Follow-up ............................................................................. 66 
6. Measurement of Effect ..................................................................................... 67 
6.1 
Response Considerations ........................................................................ 67 
6.2 
Response Categories ............................................................................... 68 
6.3 
Patient Reported Outcomes Measurement ............................................ 71 
7. Study Parameters .............................................................................................. 76 
7.1 
Therapeutic Parameters (for both arms of the study) ............................ 76 
8. Drug Formulation and Procurement ................................................................. 79 
8.1 
MLN9708 (Ixazomib citrate) .................................................................... 79 
8.2 
Lenalidomide ........................................................................................... 84 


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9. Statistical Considerations .................................................................................. 87 
9.1 
Study Design ............................................................................................ 87 
9.2 
Study Endpoints ...................................................................................... 87 
9.3 
Statistical Analysis Plan ........................................................................... 89 
9.4 
Sample Size Considerations .................................................................... 95 
9.5 
Projected Accrual .................................................................................... 95 
9.6 
Randomization Scheme........................................................................... 95 
9.7 
Gender and Ethnicity .............................................................................. 95 
10. Specimen Submissions ...................................................................................... 97 
10.1 Submissions to the Mayo Clinic Myeloma Reference Laboratory .......... 97 
10.2 Use of Specimens in Research ................................................................ 98 
10.3 ECOG-ACRIN Sample Tracking System .................................................... 99 
10.4 Sample Inventory Submission Guidelines ............................................... 99 
11. Laboratory Research Studies .......................................................................... 100 
11.1 Assessment of Minimal Residual Disease ............................................. 100 
11.2 Lab Data Transfer Guidelines ................................................................ 100 
12. Imaging Correlative Studies ............................................................................ 102 
12.1 18Fluorodeoxyglucose (FDG) PET/CT .................................................... 102 
13. Electronic Data Capture .................................................................................. 106 
13.1 Records Retention ................................................................................. 106 
14. Patient Consent and Peer Judgment .............................................................. 106 
15. References ...................................................................................................... 107 
Appendix I  Patient Thank You Letter .................................................................... 112 
 Appendix II  Patient Medication Calendar ............................................................ 113 
Appendix III  CRADA/CTA ....................................................................................... 115 
Appendix IV  ECOG Performance Status ............................................................... 117 
Appendix V  Instructions for Reporting Pregnancies on a Clinical Trial ................ 118 
 Appendix VI  Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines 
and Acceptable Birth Control Methods .......................................................... 121 
Appendix VII  Myeloma Tumor Biology Kit ............................................................ 126 
 


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STUDY CHAIR 
Shaji Kumar, MD 
Division of Hematology 
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
Phone: (507) 284-5096 
Fax: (507) 266-4972 
E-mail: kumar.shaji@mayo.edu 
 
STUDY CO-CHAIR 
Ajay Nooka, MD, MPH 
Winship Cancer Institute 
Emory University 
1365-C Clifton Road Northeast, Suite C3012 
Atlanta, GA 30322 
Phone: (404) 778-0655 
Fax: (404) 778-4389 
E-mail: anooka@emory.edu 
 
 
 
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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For study data 
submission: 
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 > 
Regulatory Submission) 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 1-866-651-
2878 or 
CTSURegHelp@coccg.org to 
receive further instruction and 
support. 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-CTSU 
(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 by phone or 
email : 1-888-823-5923, or 
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. 
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the CTSU Regulatory Support System (RSS). 
For clinical questions (i.e., patient eligibility or treatment-related) Contact the Study PI of the 
Coordinating Group. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail: 
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative. 
 
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Schema
P
R
E
-
R
E
G
I
S
T
R
A
T
I
O
N
1. Eligibility status for Step 1 randomization will be determined by either central MRD assessment at Mayo Clinic or local immunofixation test results.
2. Treatment is blinded. Confirmation of randomization will indicate that patient is on Arm X.
3. For patients with creatinine clearance 30-60 mL/min lenalidomide dose will be reduced to 5 mg PO daily.
Step 0
Step 1
Stratification
x Molecular based risk 
stratification by IMWG criteria: 
high vs. standard
x Prior lenalidomide maintenance 
dose: 10 mg vs. > 10 mg
1 cycle = 28 days
Accrual Goal: Step 0 = 840 patients, Step 1 = 510 MRD positive patients
R
A
N
D
O
M
I
Z
A
T
I
O
N
MRD Analysis1
MRD positive
MRD negative
Off-study
Arm A2
Lenalidomide3: 
10 mg PO daily days 1-28
Ixazomib: 
4mg PO days 1, 8, 15
Arm B2
Lenalidomide3: 
10 mg PO daily days 1-28
Placebo: 
4mg PO days 1, 8, 15
Continue treatment until 
progression or 
unacceptable toxicity
Continue treatment until 
progression or 
unacceptable toxicity
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1. 
Introduction 
1.1 
Background 
The treatment approaches for myeloma have undergone dramatic transformation 
over the past decade with the introduction of several new classes of effective 
drugs, often used in combination to achieve the maximum response. Prior 
treatment approaches in transplant-eligible patients consisted of a defined 
duration of induction therapy with a doublet followed by a single stem cell 
transplant (SCT) and observation, yielding a median of 2-3 years of myeloma 
disease control. The current approach typically includes an induction therapy 
utilizing a triplet combination that includes a proteasome inhibitor and an 
immunomodulatory drug (IMiD), followed by a single SCT and post-transplant 
maintenance with or without a brief consolidation phase.1-3 This change in 
strategy has led to a near doubling of the progression free survival (PFS) in this 
patient group. Sequential approaches as well as newer drug combinations also 
have led to unprecedented depth of response in myeloma, with a substantial 
majority of patients achieving a complete response (CR) or better to therapy. 
However, patients continue to relapse despite reaching a CR, reflecting the 
inadequacy of this measurement in detecting a substantial burden of residual 
tumor cells. As a result, it became apparent that newer, more sensitive 
approaches to tumor burden assessment are needed and this led to the 
development of flow cytometry or Next-Generation Sequencing based 
approaches, which can detect tumor burden to a sensitivity of 1 in 105 to 106 
cells. 
New International Myeloma Working Group (IMWG) response criteria: Given 
the impact of minimal residual disease (MRD) results on the outcomes in 
myeloma and more importantly, the relative lack of sensitivity of conventional 
electrophoretic methods of protein measurement, the IMWG recently updated the 
response criteria to include MRD assessment (Table 1).4 The revised criteria, 
including either one of the two most prevalent methods as equally acceptable, 
instead focuses on the level of tumor burden that defines MRD negativity. While 
there is early data showing that 10-6 provides a better outcome compared with 10-
5, the latter was selected for the definition given the importance of having access 
to techniques that can be used everywhere. The revised criteria also 
incorporated imaging, given that disease can be present outside the marrow 
space and this can have an impact on the outcomes as shown by the French trial 
(IFM2009), where both PET negativity and marrow MRD negativity at 10-5 had a 
better outcome than either being positive. Finally, the concept of sustained MRD 
as an additional measure of response stability has been introduced as part of the 
MRD criteria. 


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Table 1. Revised IMWG Response Criteria 
Response subcategory 
Revised IMWG Response criteria 
MRD negativity criteria requires 
conventional CR 
Sustained MRD 
negative 
MRD negative in the marrow and by imaging as 
defined below, confirmed one year apart. Subsequent 
evaluations can be used to further specify the duration 
of negativity (e.g., MRD negative @ 5 years etc.) 
Flow MRD-
negative 
Absence of phenotypically aberrant clonal plasma cells 
by next-generation flow cytometry on bone marrow 
aspirates with a minimum sensitivity of 1 in 105 
nucleated cells or higher 
Sequencing 
MRD negative 
Absence of clonal plasma cells by next generation 
sequencing on bone marrow aspirates with a minimum 
sensitivity of 1 in 105 nucleated cells or higher 
Imaging MRD-
negative 
MRD negative as defined by Next-generation flow or 
Next-generation sequencing PLUS  
Disappearance of every area of increased tracer 
uptake found at baseline or a preceding PET/CT 
The value of MRD negativity has been studied in multiple phase II and III studies 
and a table summarizing the results is shown below. These studies clearly 
demonstrate a prognostic value for this measurement (Table 2). 
Table 2: Studies utilizing MRD detection and outcomes based on MRD status 
Study/ Design 
N 
MRD (-) 
Outcomes 
Paiva et al5: Newly 
diagnosed MM patients 
from GEM2000 
(VBMCP/VBAD 
induction plus ASCT]). 
MRD status by MFC 
was determined at day 
100 after SCT. 
295 
42% 
PFS (median 71 vs 37 months, P < 
.001) and OS (median not reached vs 
89 months, P = .002) were longer in 
patients who were MRD negative at 
day 100 after SCT. 
Rawstron et al6: MRC 
IX trial of newly 
diagnosed MM: 
Intensive pathway with 
CTD vs. CVAD followed 
by SCT  
397 
62% 
Median PFS for MRD (+) of 15.5 
months vs. 28.6 months for MRD (-) 
patients (P<0.001). Median OS of 
59.0 months in MRD (+) vs. 80.6 
months in MRD (-) patients (P = 0.02) 
Rawstron et al6: MRC 
IX trial of newly 
diagnosed MM: non-
intensive pathway (MP 
vs. CTDa) 
245 
15% 
MRD (+) at end of induction 
associated with non-significantly 
inferior PFS (7.4 vs. 10.5 months). 
Puig et al7: GEM2000 
(VBMCP/VBADx6 
followed by SCT), 
GEM05 (transplant-
102 
51% 
MRD (-) had significantly longer PFS, 
both in intensively treated patients 
(45 vs 27 months, P=0.02) and in 
non-intensively treated patients (NR 


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Table 2: Studies utilizing MRD detection and outcomes based on MRD status 
Study/ Design 
N 
MRD (-) 
Outcomes 
eligible patients: 
VBMCP/VBAD plus Btz 
in the last two cycles, 
thal/dex or btz/thal/dex; 
elderly patients: six 
induction cycles with 
VMP or VTP). 
vs 27 months P=0.002) 
Sarasquete et al8: MM 
patients who had 
achieved CR after SCT 
24 
53% 
Improved PFS for MRD (-) (27 vs. 
10months, P=0.05). 
Paiva et al9: Transplant-
ineligible MM patients 
who had achieved 
>75% reduction in the 
M-component after 
induction 
102 
30% 
Achieving MRD-negativity translated 
into superior PFS and TTP compared 
with conventional CR or stringent CR 
(without clonality assessment on 
trephine biopsy). 
Paiva et al10: Newly 
diagnosed MM patients 
from GEM2000 and 
GEM2005MENOS65 
achieving CR at day 
100 after SCT. 
241 
64% 
The presence of baseline high-risk 
cytogenetics and persistent MRD at 
day 100 after ASCT were the only 
independent factors that predicted 
unsustained CR 
Roussel11: Phase II 
study with three 
induction cycles 
followed by SCT, 
consolidation, and 1-
year lenalidomide 
maintenance 
31 
68% 
Estimated 100% relapse-free survival 
at 3-years for MRD-negative patients 
Puig et al7: GEM2000 
(VBMCP/VBADx6 
followed by ASCT), 
GEM05 (transplant-
eligible patients: 
VBMCP/VBAD plus Btz 
in the last two cycles, 
thal/dex or btz/thal/dex; 
elderly patients: six 
induction cycles with 
VMP or VTP). 
102 (241) 
47% 
MRD (-) patients had significantly 
longer PFS, both in the intensively 
treated patient group (54 vs 27 
months, P=0.001) and in the non-
intensively treated cases (NR vs. 31 
months, P=0.029) 
Korthals et al12: 
Induction: 2 to 4 cycles 
of idarubicin and dex 
followed by ASCT 
53 (70) 
49% 
Median EFS in the low-MRD group 
was significantly longer than in the 
high-MRD group (35 vs. 20 months; P 
= .001). OS was significantly longer 
for the low-MRD group (70 vs. 45 


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Table 2: Studies utilizing MRD detection and outcomes based on MRD status 
Study/ Design 
N 
MRD (-) 
Outcomes 
mos; P = 0.04). 
Putkonen et al13: 
Patients with myeloma 
who had achieved 
CR/near-to-CR after 
autologous or 
allogeneic stem cell 
transplantation 
30 (37) 
57% 
Low/negative MRD after SCT was a 
significant predictive factor for the 
prolongation of PFS (70 vs. 19 
months; P = 0.003) 
Martinez Lopez et al14: 
Patients enrolled in the 
GEM2000 protocol: six 
cycles of 
VBCMP/VBAD followed 
by SCT. 
53 (88) 
53% 
PFS of 68% in MRD (-) vs. 28% for 
MRD (+) patients; P = 0.001 
Ladetto et al15: 4 cycles 
of bortezomib, 
thalidomide and 
dexamethasone 
consolidation after SCT 
39 
18% 
Improved PFS; 100% vs. 77% at 6 
months (grouped by median tumor 
load median as detected by ASO RQ-
PCR (P=0.02) 
Sarasquete et al8: MM 
patients who had 
achieved CR after SCT 
24 (32) 
29% 
Improved PFS for MRD (-) (34 vs. 15 
months, P=0.04)  
Martinelli et al16: 
Patien17ts in CR 
following autologous or 
allogeneic SCT 
44 (50) 
27% 
MRD (-) patients had a significantly 
lower relapse rate (41% v 16%; P 
<0.05) and longer relapse-free 
survival than MRD+ cases (35 v 110 
months; P <0.005).  
In addition, a recent meta-analysis of several studies highlights the impact of 
MRD negativity on PFS and overall survival (OS), both in all patients as well as in 
those patients in a conventional CR.18 In this analysis of published literature 
(1990-2016), 14 studies (n = 1273) provided data on the impact of MRD on PFS, 
and 12 studies (n = 1100) provided data on the impact of MRD on OS. Results 
were reported specifically in patients who had achieved conventional CR in 5 
studies for PFS (n = 574) and 6 studies for OS (n = 616). Achievement of MRD-
negative status following treatment was associated with a significant 
improvement in progression-free survival (hazard ratio [HR], 0.41; 95% CI, 0.36-
0.48; N = 1273). Overall survival was also significantly prolonged in MRD-
negative patients (HR, 0.57; 95% CI, 0.46-0.71; N = 1100). In looking specifically 
at CR patients, there was improvement in PFS (HR, 0.44; 95% CI, 0.34-0.56; 
P < .001) as well as OS (HR, 0.47; 95% CI, 0.33-0.67; P < .001). 
All these studies clearly show the prognostic value of achieving MRD negativity 
with the current therapies. Based on this prognostic potential, the FDA has 
recently approved the next-generation sequencing (NGS) assay to detect MRD, 
in patients with multiple myeloma (MM). However, it remains unclear if MRD 


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should be the target of therapy and if therapeutic decisions can be based on the 
MRD status of individual patients. The continuing improvements in therapy and 
consequent deep responses has led to an urgency in defining the role of MRD in 
myeloma. 
1.2 
Rationale for the Trial 
The mainstream adoption of MRD represents years of work demonstrating the 
clinical relevance of achieving an MRD state after any given therapy. The 
available data demonstrate the prognostic value of this response state and its 
potential for a regulatory endpoint given the long period of time required to reach 
median progression and overall survival with the new therapies used in MM. So, 
two important questions with respect to MRD in MM have been answered: First, 
for a given patient achieving MRD negative status with therapy will translate to 
better outcomes and can be used for prognostication. Second, and for a group of 
patients, a higher proportion of patients achieving MRD will translate to better 
survival thus allowing for comparisons of different types of therapy, lending itself 
to be a valid regulatory endpoint. The most significant question for the patient 
and the physician in the clinic, however, is to determine what to do with the MRD 
result for a given patient, as the achievement of MRD is a composite outcome of 
the therapy employed and the disease biology for a given patient. Our goal is to 
prove that if a patient is MRD positive, changing therapy to convert this patient to 
MRD negative status will translate to a better outcome for the given patient, thus 
taking biology out of the equation. This requires carefully designed phase III 
trials, as is the case with the current trial design. The current trial will be able to 
ask critical questions as to whether acting on the MRD status will improve the 
depth of response, prolong disease control and most importantly overall survival 
for a given patient. 
Also, this trial design will give us a unique opportunity to study the kinetics of 
relapse from MRD in patients with MM. This information is crucial as we make 
progress in the field. Once we achieve a high proportion of MRD negative state 
with the improved therapies, the question which will need to be addressed is the 
timing of retreatment for disease recurrence: whether this should be started at 
the reemergence of MRD positivity or at the time of biochemical relapse? This 
study by virtue of the design and serial MRD assessment and imaging 
assessment will provide the necessary information that will drive the design of 
future studies. It is possible that early intervention in these patients, at the time of 
MRD conversion, may have a better long-term impact, akin to the hypothesis 
currently being studied in smoldering multiple myeloma (SMM). 
The fundamental question that this trial is designed to address can be stated very 
clearly - Does escalating therapy based on the MRD positive status after a 
defined duration of therapy alter the outcomes in patients with myeloma? This is 
the most important question we face in this disease today.4,19 If the MRD is 
negative, do we stop therapy? If the MRD is positive, do we escalate therapy? 
The former question is going to be addressed through a clinical trial of 
daratumumab and lenalidomide vs. lenalidomide maintenance that is being 
planned through the cooperative groups. The study that we propose will 
complement this trial and help answer the second question. In order to answer 
this question with certainty, we require a homogenous group of patients who 
have received similar treatments, in whom we can test the MRD status using a 
well-defined method, and who can then be randomized to either continue with the 


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same treatment or alter the treatment approach. The control arm treatment 
should be considered the standard of care (SOC) in the population being studied. 
Among patients with myeloma who are eligible to undergo autologous peripheral 
blood stem cell transplant, the current SOC is to initiate therapy with a triplet 
combination (typically an IMiD and a proteasome inhibitor containing 
combination) and continue for three to four cycles, followed by autologous SCT 
and lenalidomide maintenance, typically continued until progression.1-3,20,21 
Lenalidomide maintenance as SOC: Maintenance approaches have become 
SOC in myeloma, both in the transplant and non-transplant setting. While the 
maintenance approach in the non-transplant setting remains less well defined, 
multiple phase III trials as well as a meta-analysis of the three largest trials have 
clearly shown OS and PFS improvement with lenalidomide maintenance post-
autologous stem cell transplant.1-3,20,21 Lenalidomide was recently approved by 
FDA for use in the maintenance setting based on these data. 
Unanswered question regarding duration of maintenance: However, 
significant confusion remains in terms of the ideal duration of maintenance in this 
setting. The original French trial limited the duration to 2 years due to concerns 
about second primary malignancies. The US trial continued until progression– 
this is one of the reasons often quoted for the difference in the survival 
outcomes. An ongoing clinical trial (E1A11, ENDURANCE) is asking this 
question in the non-transplant setting. Understanding the impact of MRD 
negativity on the outcomes and how that interacts with the duration of 
maintenance will be critical to improve our understanding of this question. 
Assessing for MRD status at the end of 1 year of maintenance and randomizing 
the patients to either continuing the current therapy or intensifying the therapy by 
adding another drug class to lenalidomide will provide a clean design to answer 
this clinically important question.  
We elected to utilize next generation flow cytometry (NGF) using the Euroflow 
approach for MRD assessment.4,22 The main reason for selecting this approach, 
instead of an NGS based approach for this trial, is the ability to interpret the 
assay without having a baseline specimen, which we believe will be difficult given 
that the patient is enrolled on trial at around the end of 12-18 months of therapy 
(induction, SCT and 6-12 months of maintenance) and marrow will have small 
numbers of plasma cells. 
The proposed design has several unique strengths. The natural history of 
patients receiving lenalidomide maintenance for one year or indefinitely is well 
known based on several large clinical trials. The expected MRD status at the end 
of one year of maintenance has been defined recently in a large French 
randomized trial of VRD induction followed by transplant and one year of 
lenalidomide maintenance, where MRD assessment was systematically 
undertaken in a majority of patients. The control arm of indefinite lenalidomide 
maintenance is fully supported by the available data from phase III trials as well 
as a recent meta-analysis of the phase III trials which demonstrated an overall 
survival outcome improvement with the maintenance approach compared with 
observation. A similar study in the US (IFM/DFCI) essentially replicates the 
design of the French trial with a crucial difference being lenalidomide 
maintenance is indefinite until progression (NCT01208662). Evaluation of the OS 
benefit for escalating therapy in patients with persistent MRD will immediately 


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make the results highly relevant for clinical practice, and will transform MRD 
assessment from a prognostic tool to an important clinical tool. 
Finally, we will use a double blind, placebo-controlled design, allowing for an 
unbiased estimate of the clinical benefit and the impact on PRO metrics. 
We plan to evaluate multiple secondary endpoints in this trial including several 
exploratory approaches. In addition to standard response rates and PFS, we will 
explore the ability of an additional agent to produce MRD negativity in patients 
who have not been able to achieve MRD negativity while taking a single drug for 
12 months. This will provide important information regarding the clonal 
heterogeneity and the differential effect of two classes of drugs on two clones, as 
can be learned from the accompanying genetic studies. This trial will prove to be 
a rich resource in asking some important future exploratory questions regarding 
the biology of the disease. 
1.3 
Choice of Intervention 
Ixazomib in myeloma: Ixazomib is the first oral proteasome inhibitor to enter 
clinical practice and is currently approved for use in combination with 
lenalidomide in patients with relapsed myeloma. Ixazomib citrate (MLN9708), 
which has been formulated for oral (PO) administration, is a small molecule 
proteasome inhibitor.23-25 It is the citrate ester of the biologically active boronic 
acid form, ixazomib (MLN2238). In water or aqueous systems, ixazomib citrate 
rapidly hydrolyzes to ixazomib. Similar to bortezomib, ixazomib potently, 
reversibly, and selectively inhibits the 20S proteasome. However, in contrast to 
bortezomib, it has a shorter dissociation half-life (t1/2) that may contribute to 
increased tissue distribution. Bortezomib has a slowly reversible dissociation rate 
from the red blood cell proteasome, while ixazomib demonstrates a more rapidly 
reversible dissociation rate from the blood but sustained effects on bone marrow 
and tumor proteasomes suggesting better tissue distribution. Ixazomib has been 
studied in several phase I and phase I/II studies evaluating both twice-weekly 
and weekly dosing schedules. In the twice-weekly dosing schedule, ixazomib is 
given on Days 1, 4, 8, and 11 of a 21-day cycle; in the weekly dosing schedule, 
the drug is given on Days 1, 8, and 15 of a 28-day cycle. To date, the 
development of oral ixazomib has focused on multiple myeloma [relapsed and/or 
refractory and newly diagnosed] and a related plasma cell dyscrasia, systemic 
light chain (AL) amyloidosis. 
In Study C16005, ixazomib was given weekly (Days 1, 8, and 15), in combination 
with lenalidomide (Days 1-21), and dexamethasone (Days 1, 8, 15, and 22) in a 
28-day cycle.26 Patients with newly diagnosed MM were enrolled and treated with 
oral ixazomib (days 1, 8, and 15) plus lenalidomide 25 mg (days 1-21) and 
dexamethasone 40 mg (days 1, 8, 15, 22) for up to twelve 28-day cycles, then 
maintenance therapy with ixazomib (same schedule) every 28 days until 
progression. Patients could undergo stem cell collection after three cycles and 
discontinue for autologous stem cell transplant (ASCT) after six cycles. Overall, 
65 patients were enrolled, 15 in Phase I and 50 in Phase II. Patients received a 
median of six cycles (range 1-19) with 27 (42%) remaining on treatment as of 
November 2012. Of those who have undergone stem cell mobilization, a median 
yield was 11.3 x 106 CD34+ cells/Kg (range 5-28). Ixazomib maximum tolerated 
dose (MTD) was established as 2.97 mg/m2 and RP2D was selected as 2.23 
mg/m2; RP2D translates to a 4.0 mg fixed dose based on population PK results. 
Among the 64 evaluable patients, the overall response rate was 92%, including 


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55% Very Good Partial Response (VGPR) and 23% CR. Median time to first 
response was 0.92 months (range 0.89-6.44). Importantly, in this trial, 25 patients 
continued on maintenance ixazomib with no additional toxicity or toxicity-related 
discontinuation, but with increasing depth of response with time. Given the data 
on proteasome inhibitor –IMiD combinations in myeloma, adding ixazomib to 
lenalidomide allows us to utilize an effective agent, and allows us to do a double-
blind study which is critical for evaluation of patient reported outcomes. 
The combination of ixazomib and lenalidomide has been studied as maintenance 
therapy post autologous SCT.27 This phase II trial enrolled 64 patients with a 
median age of 60 (range 39-74); 34 remained on therapy as of May 2017 having 
received a median of 28 cycles (range 1-51). Best overall response included 
stringent Complete Response (sCR 7.8%), CR (26.5%), VGPR (53%) and PR 
(10.9%). 29 patients had an improvement in their best overall response from their 
baseline response. The median PFS had not been reached with a median follow 
up of 37.8 months; estimated 2-year PFS is 81%. 30 patients are off study: 16 
due to progressive disease (PD), 3 at PI discretion, and 11 due to consent 
withdrawal. 22 patients had G1/2 peripheral neuropathy (PN); 6 patients had G3 
PN. 16 patients required a dose reduction to 2.4 mg for PN (8), neutropenia (3), 
hearing loss (2), rash (1), thrombocytopenia (1) and 4 patients discontinued 
ixazomib for neuropathy (2), neutropenia (1), and thrombocytopenia (1). 15 
patients had a dose reduction of Len to 10 mg for 21 days of a 28-day cycle, 
while 9 patients had a dose reduction to 5 mg for 28 days. 
We selected ixazomib as the intervention in this trial for several reasons: 
1. Ixazomib appears to be at least as effective when used in combination with 
lenalidomide and dexamethasone in newly diagnosed myeloma, when 
comparing the results of the C16005 trial with the published data with VRd. 
Patients coming on this trial would have received on average four cycles of 
bortezomib containing regimen (VRd or VCd) as induction prior to stem cell 
transplantation, and hence would be relatively PI naïve. To further allay the 
concerns of the steering committee, we have now excluded any patient who 
progressed on a bortezomib-containing regimen pre-SCT or were primary 
refractory. This is likely to be a small population considering the high 
response rate with VRd and VCd.24 
2. Ixazomib has the added advantage of being taken orally, and making it more 
convenient and acceptable for a patient who has been on oral maintenance 
for a year and now may be hesitant to come back in weekly for an injectable 
medication. An integrated analysis of ixazomib maintenance across 4 
different studies was presented recently demonstrating a continued increase 
in depth of response with continued treatment, with excellent tolerability.28 
The phase III trial of ixazomib maintenance versus placebo was recently 
announced to show a PFS benefit for ixazomib. 
3. The oral nature of the medication also allows us to do a placebo-controlled 
trial (Takeda has agreed to provide this), which will allow us to make a true 
estimate of the impact of therapy escalation on quality of life and patient 
reported outcomes. 
4. The combination of ixazomib and lenalidomide as maintenance was studied 
in a phase II trial by investigators at MD Anderson and the results presented 
recently points toward this regimen being effective and well-tolerated in the 
setting of post-transplant maintenance.27 


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5. Most importantly, this design will nicely complement the SWOG maintenance 
trial, which is examining a de-escalation of a daratumumab + lenalidomide-
based maintenance in the setting of no residual disease. This study will 
evaluate a PI and IMiD combination asking an equally relevant question of 
escalating therapy in face of residual disease. Given the three important 
therapeutic classes of current therapies, examining both a PI and IMiD 
combination as well as a monoclonal antibody (MoAb) + IMiD in this MRD 
guided treatment setting is important. 
6. Finally, use of ixazomib as the add-on for escalating treatment will also keep 
other important classes of drugs, especially daratumumab (or anti-CD38 
MoABs), in reserve for use at the time of the first relapse. 
1.4 
Patient Reported Outcomes Component 
1.4.1 
Background 
Patient-reported outcomes (PRO) that measure the impact of disease 
and treatment on well-being from a physical, functional, emotional and 
social perspective are an important part of the benefit equation. 
Health-related quality of life (QOL) assessments have been 
incorporated into prior phase III multiple myeloma clinical trials and 
have been very useful in putting the results of these phase III trials in 
perspective. In fact, one of the earliest studies to address this was the 
phase III trial comparing an early SCT to a delayed SCT.43 It was 
concluded that an early SCT was preferable based on the QOL 
estimates analyzed, which was defined as the time without symptoms 
and toxicity (Q-TWiST). More recently, there has been increased 
interest in assessing QOL among patients with MM given significant 
improvement in survival observed as well as the availability of 
different treatment options. A phase III trial of thalidomide 
maintenance evaluated QOL using the EORTC QLQ-C30 instrument 
in combination with a disease specific module. Assessments were 
performed every 2 months to 6 months then Q3 monthly to 5 years. A 
change score of 10 points from baseline was defined as clinically 
relevant. While PFS was prolonged with maintenance therapy, there 
was significant worsening of all the QOL parameters studied.35 In 
another phase III trial comparing three different bortezomib 
combinations as upfront therapy for transplant ineligible patients 
(bortezomib-dexamethasone, bortezomib-thalidomide-
dexamethasone, bortezomib-melphalan-prednisone, followed by 
bortezomib maintenance therapy), patient-reported QOL was 
recorded also using the EORTC QLQ-C30 questionnaire.44 Decline in 
QOL parameters were observed in the early phases of therapy in all 
groups with recovery over time. These results demonstrate the 
feasibility of conducting health-related QOL assessments in the 
context of multicenter clinical trials as well as its value in reaching the 
eventual conclusions. Intensifying therapy and/or prolonging duration 
of therapy comes at a price economically due to patient financial 
burden and clinically due to sub-optimal tolerability, both of which may 
impact QOL. Research exploring factors contributing to medication 
adherence and the impact of side effects and symptom burden from 
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1.4.2 
Rationale 
Patients and physicians often decide to alter therapy based on a 
variety of factors including patient age, patient and physician 
preference, response status, and toxicity from ongoing therapy. As we 
explore the concept of increasing the rate of MRD negativity by 
intensifying the therapy, it is important to assess the impact that the 
intervention has on PROs. With a comprehensive PRO evaluation, we 
will elucidate potential advantages and expand understanding at key 
clinical decision points. We hypothesize that adding ixazomib will not 
be associated with significantly worse treatment-related QOL 
compared with continuing on lenalidomide monotherapy given the 
oral, intermittent nature of ixazomib therapy. Furthermore, we 
hypothesize that longerperiods of ixazomib therapy will lower risk of 
disease progression and will  may yield improved QOL.  For this trial, 
we have chosen specific time points for primary comparison between 
arms, however, with limited QOL research in this setting we have yet 
to determine whether these are appropriate. Towards that end, it is 
also important to assess timing of QOL changes afforded with 
relatively frequent longitudinal QOL assessment. Beyond comparing 
treatment arms, we will evaluate the relationship between conversion 
from MRD-positive to MRD-negative status and change in QOL with 
the hypothesis that responders have comparatively better QOL than 
non-responders, a favorable outcome for the intervention arm. This 
assessment will have clinical translational value, as this will be one of 
the considerations as we move towards an MRD directed strategy in 
the clinic. Lastly, poor medication adherence as well as increased 
incidence and/or severity of patient reported adverse events are 
expected to be associated with lower QOL. 
QOL assessments performed every three months during the first year 
post randomization will provide valuable longitudinal data to quantify 
the impact of the different maintenance approaches on patient QOL. 
Similar measurements during year 2 will provide an insight into the 
effects of disease recurrence on QOL measurements, as there will be 
an increasing proportion of patients on the control arm who will start to 
demonstrate biochemical recurrences. To interpret these maintenance 
QOL analyses, we will capture actual treatment received over the 
given period and monitor patient-specific barriers to medication 
adherence. As well, we will measure the impact of symptom burden 
and treatment-related side effects from a patient perspective. 
Assessing PROs during maintenance will, therefore, be of critical 
importance to the evaluation of the overall benefit of this therapeutic 
strategy and its clinical utility. PRO metrics, unfortunately, depend 
heavily on patient perspective that can be altered in different ways by 
the burden of therapy and the response to therapy. A placebo-
controlled design such as the one proposed, however, enables an 
unbiased assessment of the true impact of altering therapy based on 
the MRD status. 
1.4.3 
Design 
Chosen PRO instruments are designed to capture potential side-
effects from treatment intervention, the impact of disease recurrence, 


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behavior towards taking treatment, and health-related quality of life. 
The Functional Assessment of Chronic Illness Therapy (FACIT) 
(http://www.facit.org) and the Patient-Reported Outcomes version of 
the Common Terminology Criteria for Adverse Events (PRO-CTCAE) 
(https://healthcaredelivery.cancer.gov/pro-ctcae/) measurement 
systems will be utilized. Specifically, general health-related quality of 
life will be assessed with the Functional Assessment of Cancer 
Therapy – General (FACT-G) including 2 subscales [physical well-
being (PWB) and functional well-being (FWB)].39 We will add a 
treatment-specific tool to evaluate neurotoxicity along with the 
disease-specific multiple myeloma assessment.40,70 These 
instruments have been validated and have been incorporated into our 
prior phase III MM treatment trials (E1A05, E1A06) as well as current 
phase III trials (E1A11, E3A06).31,41 More recently, data from E1A05 
showed the FACT-MM was feasible for use in clinical trials to 
measure myeloma-related functions and demonstrated acceptable 
psychometric properties. 
NCI PRO-CTCAE items will evaluate treatment-emergent side effects 
expected with ixazomib and lenalidomide. This will be coupled with 
routine provider initiated and protocol specific interval toxicity 
assessment to inform a more comprehensive assessment, both as it 
concerns intensity and frequency, of perceived and experienced side 
effects from therapy. Furthermore, side effects from prolonged 
therapy with lenalidomide and ixazomib perceived by a patient and 
captured with the NCI PRO-CTCAE may be different than when 
assessed by a provider, an analysis that has not been performed yet 
in former clinical trials involving these agents. Considering the 
importance of reliable compliance with prescribed oral therapy as it 
concerns therapeutic benefit, understanding treatment adherence is 
important. Aside from tabulating compliance with continuous, protocol 
specific lenalidomide and ixazomib therapy based on patient 
medication calendars, medication taking behavior will be evaluated 
with the Adherence Starts with Knowledge (ASK-12).42,43 The timing of 
PRO measurements will be consistent with office visits primarily 
during treatment, and will vary based on the instrument. 
1.5 
Imaging Component 
1.5.1 
Background 
Advanced imaging modalities have contributed significantly to our 
understanding of disease biology in multiple myeloma and is an 
integral component of the diagnostic criteria, differentiating 
asymptomatic precursor stages from active disease. Multiple different 
modalities have been used in myeloma studies and provide 
complementary information. 18F-FDG PET/CT allows simultaneous 
assessment of the bone, as well as presence of extramedullary 
lesions. MRI allows better assessment of the soft tissue and marrow 
involvement, especially with the use of diffusion-weighted images. 
Both baseline assessments, as well as follow-up imaging, also have 
an important prognostic role and appear to be associated with the 
survival of patients with MM. Myeloma cells, while they tend to be 


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primarily marrow-based, can be found in the extramedullary 
compartment, including the peripheral blood. As a result, imaging 
plays an important role in assessing response to therapy as well as 
identifying disease progression, both inside and outside the marrow. 
In fact, functional imaging assessment using 18F-FDG PET/CT is an 
integral part of minimal residual disease assessment in myeloma in 
addition to following foci of extramedullary disease identified prior to 
start of treatment. Ongoing studies continue to explore new modalities 
as well as novel tracers to better identify the tumor cells. 
1.5.2 
Rationale 
There is much to be learned in terms of the added value of imaging to 
the assessment of disease response and outcomes using traditional 
protein-based disease assessments. The value of PET-CT and MRI 
as tools for assessment of MRD has been assessed in the IFM2009 
trial (IMAJEM).25 That study was able to demonstrate an inferior 
survival outcome associated with persistent positivity even in the 
presence of MRD negativity in the marrow. While MRI changes were 
observed with therapy, PET-CT appeared to be more useful in the 
setting of response assessment. Other large retrospective studies 
have also examined the value of PET-CT. This trial provides a unique 
opportunity to assess the prognostic impact of PET positive lesions at 
the end of a year of maintenance, and how that may be impacted by 
the randomized intervention. It also provides a unique opportunity to 
examine the incremental value of PET-CT to marrow-based MRD 
testing and the impact of discrepant findings in the marrow and the 
extramedullary compartment. Another area that has not been studied 
well is the kinetics of relapse, especially in the extramedullary 
compartment. This trial, which will be enriched in a group of patients 
at higher-than-average risk of relapse (MRD-positive), will allow us to 
study the kinetics of extramedullary relapse in the context of 
biochemical relapse. Importantly, this will give us a unique opportunity 
to validate the currently proposed criteria for PET-CT assessment.29  
1.5.3 
Design 
18F-FDG PET/CT is currently considered a standard imaging modality 
for initial assessment, as part of MRD assessment and for 
identification of relapsed disease. Patients in this trial will undergo 
baseline 18F-FDG PET/CT, as well as 18F-FDG PET/CT at 12 and 24 
cycles from study entry, in addition to those done for MRD 
confirmation. The serial imaging studies will be centrally reviewed, 
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2. 
Objectives 
2.1 
Primary Objective 
2.1.1 
To evaluate whether escalating maintenance therapy with the addition 
of ixazomib to lenalidomide improves overall survival (OS) among 
patients who are MRD positive after approximately 1 year of 
lenalidomide maintenance following an early stem cell transplant (≤ 12 
months from diagnosis). 
2.2 
Secondary Objectives 
2.2.1 
To establish whether progression-free survival (PFS) is superior with 
the addition of ixazomib to lenalidomide maintenance. 
2.2.2 
To evaluate best response on treatment and compare response rates 
between arms. 
2.2.3 
To evaluate the safety profile of ixazomib added to lenalidomide and 
compare toxicity rates between arms. 
2.3 
Exploratory Objectives 
2.3.1 
To measure treatment exposure and adherence. 
2.3.2 
To estimate treatment duration, duration of response and time to 
progression. 
2.4 
Patient-Reported Outcomes (PRO) Objectives 
2.4.1 
Primary PRO Objectives 
2.4.1.1 
To quantify the extent to which the addition of ixazomib to 
lenalidomide maintenance contributes to neuropathy and 
associated physical and functional impairments. 
2.4.1.2 
To assess the impact of the addition of ixazomib to 
lenalidomide maintenance on disease control and 
associated physical and functional well-being.  
2.4.2 
Secondary PRO Objectives 
2.4.2.1 
To evaluate time to worsening and recovery rate related to 
neuropathy.  
2.4.2.2 
To evaluate time to improvement and response rate 
related to disease control.  
2.4.3 
Exploratory PRO Objectives 
2.4.3.1 
To evaluate attributes of select patient reported treatment-
emergent symptomatic adverse events (PRO-CTCAE) 
longitudinally and compare responses with provider-
reported adverse events. 
2.4.3.2 
To measure the likelihood of medication adherence and 
examine the relationship with treatment exposure. 
2.4.3.3 
To assess correlation among patient reported outcome 
measures and association with clinical outcomes. 


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2.4.3.4 
To tabulate PRO compliance and completion rates. 
2.5 
Imaging Objectives 
2.5.1 
To evaluate the association between baseline 18F-FDG PET/CT and 
patient outcomes. 
2.5.2 
To compare overall survival (OS) with the addition of ixazomib to 
lenalidomide among baseline 18F-FDG PET/CT-positive and 18F-FDG 
PET/CT -negative subgroups. 
2.5.3 
To compare the change in quantitative 18F-FDG PET/CT parameters 
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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: 
CTEP Policy does not allow for the issuance of waivers to any protocol 
specified criteria 
(http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm). 
Therefore, all eligibility criteria listed in Section 3 must be met, without 
exception. The registration of individuals who do not meet all criteria listed in 
Section 3 can result in the participant being censored from the analysis of the 
study, and the citation of a major protocol violation during an audit. All 
questions regarding clarification of eligibility criteria must be directed to the 
Group's Executive Officer (EA.ExecOfficer@jimmy.harvard.edu) or the 
Group's Regulatory Officer (EA.RegOfficer@jimmy.harvard.edu). 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician. 
NOTE: 
This study involves pre-registration and randomization. Bone marrow 
specimen must be submitted for central MRD assessment and results will 
determine Step 1 eligibility. Patients will not be randomized without MRD 
results. 
3.1 
Step 0 Pre-Registration 
3.1.1 
Patient must be ≥ 18 years of age. 
3.1.2 
Patient must be previously diagnosed with multiple myeloma (MM) 
and be on lenalidomide maintenance with ≥ 5mg daily for at least 6 
months and no more than 18 months after an early autologous stem 
cell transplantation (SCT ≤ 12 months of diagnosis). Patient must not 
be off lenalidomide maintenance therapy for more than 30 days prior 
to start of treatment on Step 1 of this protocol. 
3.1.3 
Patient must be able to undergo a diagnostic bone marrow aspirate 
following pre-registration to Step 0. 
NOTE: 
A bone marrow aspirate specimen must be submitted to 
Mayo Clinic Hematology Laboratory for central assessment 
of Minimal Residual Disease (MRD) status to confirm 
patient’s eligibility for Step 1 randomization. 
Rev. Add3 
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Mayo Clinic will forward results to the submitting institution within 
three (3) business days of receipt of the bone marrow specimen. 
3.1.4 
Patient must have an ECOG performance status 0, 1, or 2. 
3.1.5 
Patient must not have primary refractory or progressive disease on a 
proteasome inhibitor-based regimen during induction therapy prior to 
stem cell transplant. 
3.1.6 
Patient must not be on other concurrent chemotherapy, or any 
ancillary therapy considered investigational.  
NOTE: 
Bisphosphonates are considered to be supportive care 
rather than therapy and are allowed while on protocol 
treatment. 
3.1.7 
Patient must not have uncontrolled psychiatric illness or social 
situations that would limit compliance with study requirements. 
3.1.8 
Patient must not have another malignancy requiring treatment or have 
received treatment within two years before pre-registration or 
previously diagnosed with another malignancy and have any evidence 
of residual disease. Patients with non-melanoma skin cancer or 
carcinoma in situ of any type are not excluded if they have undergone 
complete resection. 
3.1.9 
Patient must have been able to maintain at least 5mg daily dose of 
lenalidomide without growth factor support. 
3.1.10 
Patient must not have known gastrointestinal (GI) disease or GI 
procedure that could interfere with the oral absorption or tolerance of 
ixazomib or lenalidomide including difficulty swallowing. 
3.1.11 
Human immunodeficiency virus (HIV)-infected patients on effective 
anti-retroviral therapy with undetectable viral load within 6 months are 
eligible for this trial. 
3.1.12 
Patient must not have known hepatitis B surface antigen-positive 
status or known or suspected active hepatitis C infection, but testing 
specifically for the trial is not required. 
 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 
3.2 
Step 1 Randomization  
3.2.1 
Patient must meet all eligibility criteria in Section 3.1 at the time of 
Step 1 randomization. 
3.2.2 
Patient must not be off lenalidomide maintenance therapy for more 
than 30 days prior to start of treatment on Step 1 of this protocol. 
Rev. Add3 
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Rev. Add3 
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3.2.3 
Patient must have evidence of residual disease by central MRD 
testing or by presence of monoclonal protein in serum or urine. 
3.2.4 
Patient must have SPEP, UPEP, and serum FLC performed ≤ 28 
days prior to randomization. 
Serum M-protein by SPEP __________ (g/dL)  
Date of Test: ________ 
Urine M-protein light chain excretion by UPEP_____ (mg/24hr)  
Date of Test: ________  
NOTE: 
UPEP (on a 24-hour collection) is required, no substitute 
method is acceptable. Urine must be followed monthly if 
the baseline urine M-spike is ≥ 200 mg/24 hr. Please note 
that if both serum and urine M-components are present, 
both must be followed in order to evaluate response. 
Serum Free Light Chain 
Kappa FLC __________ (mg/dL) or __________ (mg/L); 
Lambda FLC __________ (mg/dL) or __________ (mg/L); 
Kappa/lambda ratio __________  
Date of Test: ________ 
3.2.5 
Patient must have the following laboratory levels obtained ≤ 14 days 
prior to randomization: 
3.2.5.1 
Hemoglobin ≥ 8 g/dL 
Hemoglobin:__________ Date:__________ 
3.2.5.2 
Untransfused platelet count ≥ 75,000 cells/mm3 
Platelet:__________ Date:__________ 
3.2.5.3 
Absolute neutrophil count (ANC) ≥ 1000 cells/mm3 
ANC:__________ Date:__________  
3.2.5.4 
Calculated creatinine clearance ≥ 30 mL/min 
Creatinine clearance:__________ Date:__________ 
3.2.5.5 
Total bilirubin ≤ 1.5 times the upper limit of normal (ULN) 
Total bilirubin:________ ULN:________ Date:__________  
3.2.5.6 
SGPT (ALT) and SGOT (AST) ≤ 3 times the upper limit of 
normal (ULN) 
SGPT (ALT):________ ULN:_________ Date:__________ 
SGOT (AST):________ ULN:________ Date:__________ 
3.2.6 
Patient must not have Grade 2 or higher peripheral neuropathy or 
grade 1 peripheral neuropathy with pain per CTCAE. 
3.2.7 
Patient must not have uncontrolled intercurrent illness. 
3.2.8 
Patient must not have Grade 2 or higher diarrhea per CTCAE in the 
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3.2.9 
Patient must not have been on systemic treatment, within 14 days 
before the first dose of ixazomib, with strong CYP3A inducers (such 
as rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, 
phenobarbital), or use of St. John's wort. 
3.2.10 
Patient must agree to register into the mandatory Revlimid REMS® 
program and be willing and able to comply with the requirements of 
Revlimid REMS®. Refer to Section 8.2.8 of the protocol for more 
information on the Revlimid REMS® Program. 
3.2.11 
Patient must not be pregnant due to potential harm to the fetus from 
ixazomib and lenalidomide. All patients of childbearing potential must 
have a blood test or urine study with a sensitivity of at least 25 
mIU/mL within 10-14 days prior to the first dose of lenalidomide and 
again within 24 hours prior to the first dose of lenalidomide. Patients 
of childbearing potential must also agree to ongoing pregnancy testing 
while on treatment. A patient of childbearing potential is defined as 
anyone, regardless of sexual orientation or whether they have 
undergone tubal ligation, who meets the following criteria: 1) has 
achieved menarche at some point, 2) has not undergone a 
hysterectomy or bilateral oophorectomy, or 3) has not been naturally 
postmenopausal (amenorrhea following cancer therapy does not rule 
out childbearing potential) for at least 24 consecutive months (i.e., has 
had menses at any time in the preceding 24 consecutive months). 
Please see Appendix VI: Risks of Fetal Exposure, Pregnancy Testing 
Guidelines and Acceptable Birth Control Methods. 
Patient of childbearing potential (Y/N)? _______ 
Date of blood test or urine study: _________ 
Result (positive/negative): __________ 
3.2.12 
Patients of childbearing potential must either abstain from sexual 
intercourse for the duration of their participation in the study or agree 
to use TWO acceptable methods of birth control, one highly effective 
method and one additional effective method AT THE SAME TIME for 
1) at least 28 days before starting study treatment; 2) while 
participating in the study; 3) during dose interruptions; and 4) for at 
least 90 days after the last dose of protocol treatment. Patients must 
also agree to not breastfeed during this same time period. Men must 
agree to either abstain from sexual intercourse for the duration of their 
participation in the study or use a latex condom during sexual contact 
with a partner of childbearing potential while participating in the study 
and for 90 days after the last dose of protocol treatment even if they 
have had a successful vasectomy. Patients must also agree to 
abstain from donating sperm while on study treatment and for 28 days 
after the last dose of protocol treatment even if they have had a 
successful vasectomy. All patients must agree to abstain from 
donating blood during study participation and for at least 28 days after 
the last dose of protocol treatment. 
 
 
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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. 
Registration and Randomization Procedures 
Cancer Therapy Evaluation Program Investigator 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 at 
https://ctepcore.nci.nih.gov/iam. In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must 
complete their annual registration using CTEP’s web-based Registration and Credential 
Repository (RCR) at https://ctepcore.nci.nih.gov/rcr. 
RCR utilizes five person registration types. 
x 
IVR — MD, DO, or international equivalent; 
x 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level 
researchers (e.g., PhD); 
x 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications such as the Roster Update Management System [RUMS], OPEN, Rave, 
acting as a primary site contact, or with consenting privileges; 
x 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored 
trials; and 
x 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
RCR requires the following registration documents: 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
D 
D 
 
 
 
Financial Disclosure Form 
D 
D 
D 
 
 
NCI Biosketch (education, 
training, employment, license, 
and certification) 
D 
D 
D 
 
 
GCP training 
D 
D 
D 
 
 
Agent Shipment Form (if 
applicable) 
D 
 
 
 
 
CV (optional) 
D 
D 
D 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and Cancer Trials Support Unit (CTSU) 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: 
x 
Added to a site roster 
x 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
x 
Act as the site-protocol PI on the IRB approval 
x 
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL) 
In addition, all investigators act as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the 
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DTL must be rostered at the enrolling site with a participating organization. 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. 
Cancer Trials Support Unit Registration Procedures 
Permission to view and download this protocol and its supporting documents is restricted 
and is based on person and site roster assignment housed in the CTSU Regulatory 
Support System (RSS).  
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval: 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must accept 
the NCI CIRB review to activate new studies at the site after March 1, 2019. Local IRB 
review will continue to be accepted for studies that are not reviewed by the CIRB, or if 
the study was previously open at the site under the local IRB. International sites should 
continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory 
Office following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for 
Local Context (SSW) to the CIRB using IRB Manager to indicate their intent to open the 
study locally. The NCI CIRB’s approval of the SSW is automatically communicated to the 
CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB 
approvals across their Signatory Network. Site preferences can be set at the network or 
protocol level. Questions about establishing site preferences can be addressed to the 
CTSU Regulatory Office by email or calling 1-888-651-CTSU (2878). 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria in order for the processing of the 
IRB/REB approval record to be completed: 
x 
Holds an active CTEP status; 
x 
Active status at the site(s) on the IRB/REB approval (applies to US and Canadian 
sites only) on at least one participating organization’s roster; 
x 
If using NCI CIRB, active on the NCI CIRB roster under the applicable CIRB 
Signatory Institution(s) record; 
x 
Includes the IRB number of the IRB providing approval in the FDA Form 1572 in the 
RCR profile;  
x 
Lists all sites on the IRB/REB approval as Practice Sites in the FDA Form 1572 in 
the RCR profile; and 
x 
Holds the appropriate CTEP registration type for the protocol. 
Additional Requirements: 
Additional site requirements to obtain an approved site registration status include: 
x 
An active Federal Wide Assurance (FWA) number; and 
x 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO). 
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x 
An active roster affiliation with the NCI CIRB roster under at least one CIRB 
Signatory Institution (US sites only); and 
x 
Compliance with all protocol-specific requirements (PSRs). 
Downloading Site Registration Documents: 
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted to institutions and its associated investigators and 
staff on a participating roster. To view/download site registration forms: 
x 
Log in to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password; 
x 
Click on Protocols in the upper left of the screen 
x 
Enter the protocol #number in the search field at the top of the protocol tree; or 
x 
Click on the By Lead Organization folder to expand then select ECOG-ACRIN, 
and protocol number EAA171. 
x 
Click on Documents, Protocol Related Documents, and use the Document Type filter 
and select Site Registration, to download and complete the forms provided. (Note: 
For sites under the CIRB, IRB data will load automatically to the CTSU.) 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU members’ website. 
To access the Regulatory Submission Portal, log in to the CTSU members’ website, go 
to the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately by phone or email: at 1-866-651-
CTSU (2878), or CTSURegHelp@coccg.org in order to receive further instruction and 
support. 
Delegation of Tasks Log (DTL) 
Each site must complete a protocol-specific Delegation of Tasks Log (DTL) using the 
DTL application in the Delegation Log section on the CTSU members’ website. The 
Clinical Investigator (CI) is required to review and electronically sign the DTL prior to the 
site receiving an Approved site registration status and enrolling patients to the study. To 
maintain an approved site registration status the CI must re-sign the DTL at least 
annually and when a new version of the DTL is released; and activate new task 
assignments requiring CI sign-off. Any individual at the enrolling site on a participating 
roster may initiate the site DTL. Once the DTL is submitted for CI approval, only the 
designated DTL Administrators or the CI may update the DTL. Instructions on 
completing the DTL are available in the Help Topics button in the DTL application and 
include a Master Task List, which describes DTL task assignments, CI signature, and 
CTEP registration requirements. 
Checking Your Site’s Registration Status: 
Site’s registration status may be verified on the CTSU members’ website. 
x 
Click on Regulatory at the top of the screen; 
x 
Click on Site Registration; and 
x 
Enter the site’s 5-character CTEP Institution Code and click on Go 
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x 
Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
NOTE: 
The status given only reflects institutional compliance with site registration 
requirements as outlined within the protocol. 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 Step 1 randomization. 
Treatment should start within fourteen (14) days after Step 1 randomization.  
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the LPOs registration/randomization systems or the Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment. 
OPEN will populate the patient enrollment data in NCI’s clinical data management 
system, Medidata Rave. 
Requirements for OPEN access: 
x 
A valid CTEP-IAM account; 
x 
To perform enrollments or request slot reservations: Must be on an LPO roster, 
ETCTN corresponding roster, or participating organization roster with the role of 
Registrar. Registrars must hold a minimum of an Associate Plus (AP) registration 
type; 
x 
If a Delegation of Tasks Log (DTL) is required for the study, the registrars must hold 
the OPEN Registrar task on the DTL for the site; and 
x 
Have an approved site registration for the protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their FDA Form 1572 in RCR. If a DTL is required for the study, the IVR or 
NPIVR must be assigned the appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
x 
Patient has met all eligibility criteria within the protocol stated timeframes; and  
x 
All patients have signed an appropriate consent form and HIPAA authorization form.  
NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. You may print this confirmation for 
your records. 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
4.1 
Step 0 Pre-Registration 
To proceed to randomization, patients must have central MRD testing performed 
by Mayo Clinic. 
NOTE: 
Patients who are only pre-registered must not begin treatment. 
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The following information is to be provided at the time of pre-registration to the 
trial: 
4.1.1 
Protocol Number 
4.1.2 
Site/Investigator Identification  
x 
Institution CTEP ID 
x 
Treating Investigator 
x 
Consenting Person 
x 
Site Registrar 
x 
Network Group Credit 
x 
Credit Investigator 
4.1.3 
Patient Identification 
x 
Patient’s initials (first and last) 
x 
Patient’s Hospital ID and/or Social Security number 
x 
Patient demographics 
x 
Gender 
x 
Birth date (mm/dd/yyyy) 
x 
Race 
x 
Ethnicity 
x 
Nine-digit ZIP code 
x 
Method of payment 
x 
Country 
4.1.4 
Eligibility Verification 
Patients must meet all of the eligibility requirements listed in Section 
3.1. 
4.1.5 
Additional Requirements 
4.1.5.1 
Patients must provide a signed and dated, written informed 
consent form. 
NOTE: 
Copies of the consent are not collected by the ECOG-
ACRIN Operations Office – Boston. 
4.1.5.2 
Bone marrow aspirate must be submitted to Mayo Clinic 
following pre-registration as indicated in Section 10 for 
determination of MRD status. Mayo Clinic will forward 
results to the submitting institution within three (3) business 
days of receipt of the bone marrow. 
4.2 
Step 1 Randomization 
The following information is to be provided at the time of randomization to the 
trial: 
4.2.1 
Protocol Number  
4.2.2 
Site/Investigator Identification 
x 
Institution CTEP ID 
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x 
Treating Investigator 
x 
Consenting Person 
x 
Site Registrar 
x 
Network Group Credit 
x 
Credit Investigator 
4.2.3 
Patient Identification 
x 
Patient’s initials (first and last) 
x 
Patient’s Hospital ID and/or Social Security number 
x 
Patient demographics 
x 
Gender 
x 
Birth date (mm/dd/yyyy) 
x 
Race 
x 
Ethnicity 
x 
Nine-digit ZIP code 
x 
Method of payment 
x 
Country 
4.2.4 
Eligibility Verification 
Patients must meet all of the eligibility requirements listed in Section 
3.2. 
4.2.5 
Stratification Factors 
x 
Molecular-based risk: high vs. standard 
x 
Prior lenalidomide maintenance dose:  5 mg, 10 mg, > 10 mg 
x 
< 12 months maintenance and > 12 months maintenance 
4.3 
Additional Requirements 
4.3.1 
Quality of life forms are to be submitted as indicated in Section 6.3. 
4.3.2 
Revlimid REMS Program 
Lenalidomide will be provided in accordance with the Revlimid 
REMS® program of Celgene Corporation. Per standard Revlimid 
REMS® requirements all physicians who prescribe lenalidomide for 
research patients enrolled into this trial, and all research patients must 
be registered in and comply with all requirements of the Revlimid 
REMS® program. Refer to Section 8.2.8 of the protocol for more 
information on the Revlimid REMS® Program. 
4.3.3 
Medidata Rave 
Medidata Rave is a clinical data management system being used for 
data collection for this l trial/study. Access to the trial in Rave is 
controlled through the CTEP-IAM system and role assignments. 
Requirements to access Rave via iMedidata: 
x 
A valid CTEP-IAM account; and 
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x 
Assigned a Rave role on the LPO or PO roster at the enrolling site 
of: Rave CRA, Rave Read Only, Rave CRA (LabAdmin), Rave 
SLA, or Rave Investigator. 
Rave role requirements: 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum 
of an Associate Plus (AP) registration type; 
x 
Rave Investigator role must be registered as an Non-Physician 
Investigator (NPIVR) or Investigator (IVR); and 
x 
Rave Read Only role must have at a minimum an Associates 
(A) registration type 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for 
registration types and documentation required. 
This study has a Delegation of Tasks Log (DTL). Therefore, those 
requiring write access to Rave must also be assigned the appropriate 
Rave tasks on the DTL. 
Upon initial site registration approval for the study in Regulatory 
Support System (RSS), all persons with Rave roles assigned on the 
appropriate roster will be sent a study invitation email from iMedidata. 
To accept the invitation, site staff must either click on the link in the 
email or log in to iMedidata via the CTSU members’ website under 
Data Management > Rave Home and click to accept the invitation in 
the Tasks pane located in the upper right corner of the iMedidata 
screen. Site staff 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 eLearning link in the Tasks pane 
located in the upper right corner of the iMedidata screen. If an 
eLearning is required for a study and has not yet been taken, the link 
to the eLearning will appear under the study name in the Studies pane 
located in the center of the iMedidata screen; once the successful 
completion of the eLearning has been recorded, access to the study 
in Rave will be granted, and a Rave EDC link will replace the 
eLearning link under the study name.  
Site staff that have not previously activated their iMedidata/Rave 
account at the time of initial site registration approval for the study in 
RSS will receive a separate invitation from iMedidata to activate their 
account. Account activation instructions are located on the CTSU 
website in the Data Management section under the Rave resource 
materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on 
the CTSU members’ website in the Data Management > Rave section 
at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-
888-823-5923 or by email at ctsucontact@westat.com. 
4.3.4 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff 
to manage unanswered queries and form delinquencies, monitor data 
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The DQP is located on the CTSU members’ website under Data 
Management. The Rave Home section displays a table providing 
summary counts of Total Delinquencies and Total Queries. DQP 
Queries, DQP Delinquent Forms, DQP Form Status and the DQP 
Reports modules are available to access details and reports of 
unanswered queries, delinquent forms, and timeliness reports. 
Review the DQP modules on a regular basis to manage specified 
queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and 
have access to the CTSU website. Staff that have Rave study access 
can access the Rave study data using a direct link on the DQP. 
To learn more about DQP use and access, click on the Help icon 
displayed on the Rave Home, DQP Queries, DQP Delinquent Forms, 
DQP Form Status, and DQP Reports modules. 
4.3.5 
Imaging Submission Using Transfer of Images and Data 
Transfer of Images and Data (TRIAD) is the American College of 
Radiology’s (ACR) image exchange application. TRIAD provides sites 
participating in clinical trials a secure method to transmit images. 
TRIAD anonymizes and validates the images as they are transferred. 
TRIAD Access Requirements: 
x 
A valid CTEP-IAM account.  
x 
Registration and Credential Repository (RCR) registration type of: 
Associate (A), Associate Plus (AP), Non-Physician Investigator 
(NPIVR), or Investigator (IVR) registration type. Refer to the CTEP 
Registration Procedures section for instructions on how to request 
a CTEP-IAM account and complete registration in RCR. 
x 
TRIAD Site User role on an NCTN or ETCTN roster. 
All individuals on the Imaging and Radiation Oncology Core provider 
roster have access to TRIAD and may submit images for credentialing 
purposes, or for enrollments to which the provider is linked in OPEN. 
TRIAD Installation: 
To submit images, the individual holding the TRIAD Site User role will 
need to install the TRIAD application on their workstation. TRIAD 
installation documentation is available at 
https://triadinstall.acr.org/triadclient/. 
This process can be done in parallel to obtaining your CTEP-IAM 
account and RCR registration. 
For questions, contact TRIAD Technical Support staff via email 
TRIAD-Support@acr.org or 1-703-390-9858. 
Image Submission and Quality Assurance Review: 
Standard of Care (SOC) 18F-FDG Whole Body PET/CT imaging 
should ideally use the same scanner and should be used 
consistently across all imaging time points for the same patient 
if possible. If the same scanner is not available, equipment that 
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For 18F FDG PET CT imaging time from 18F-FDG injection to 
beginning of PET CT acquisition will be 60 minutes +/- 10 
minutes. This is to be adhered to for all PET CT scanners and 
study time points. 
Upon arrival at the PET facility for their 18F-FDG Whole Body scan, 
confirm that the patient is properly prepared for the imaging study per 
institutional guidelines including but not limited to: 
The patient is fasting for at least 4 hours but should be hydrated with 
plain water. 
The time between injection of 18F-FDG and imaging should be 60 
minutes +/- 10 minutes. 
The patient’s weight and height are measured and recorded (not 
verbally relayed by the subject). 
The pre-injection blood glucose level is in accordance with institutional 
guidelines (typically < 200 mg/dL, measured ideally within one hour of 
18F-FDG injection). If the serum glucose is out of the expected range, 
the study should be rescheduled. The referring physician or primary 
physician of the subject should be contacted to optimize blood 
glucose control.  
In diabetic patients, insulin injection is not administered for at least 6 
hours before the injection of 18F-FDG. In patients on oral anti-diabetic 
medications, these drugs must be taken as planned before the 
injection of 18F-FDG. 
The patient should be off steroids for at least 24 hours and if on 
intravenous glucose/dextrose, they should be stopped for 6 hours. 
All imaging time points for repeat PET imaging should ideally use the 
same scanner and the same imaging parameters as used for the 
baseline PET study. 
There are several sources for SOC guidelines for 18F-FDG Whole 
Body PET/CT scans. For this study, the following should serve as the 
minimum requirement to be used locally: 
http://jnm.snmjournals.org/content/47/6/1059.long. 
All imaging time points should be submitted to the ACR Core 
Laboratory via TRIAD for Image Quality Assurance (IQA) review. 
Imaging should be submitted within three (3) business days from 
the time of acquisition to ensure rapid review and prompt 
feedback of any discrepancies from the Core Lab. 
Upon image receipt, a Core Lab Imaging Technologist will perform an 
IQA review of the image data to ensure that all imaging is intact and 
has been submitted in its entirety (i.e., primary PET AC, PET NAC 
and CTAC series), the recommended imaging parameters were 
followed, and the exam is of adequate image quality. In the event that 
an exam is deemed non-compliant or is missing critical DICOM tags 
used for SUV analysis (i.e., weight, height and time of injection), a 
Core Lab Imaging Technologist will issue a query within the Medidata 
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Rave data management system. Sites are expected to resolve data 
queries within seven (7) business days. 
NOTE: 
Please refrain from anonymizing the DICOM header of 
any exam prior to uploading into the TRIAD 
application. Custom DICOM editing can exclude an exam 
from the final analysis, due to the omission of technical 
data elements. These elements include, but are not limited 
to, the study date, scanner station name, scanner serial 
number, patient height and weight and any scan 
acquisition parameter. TRIAD has been uniquely 
configured to locate and scrub all PHI from the exam’s 
DICOM header, during the image transfer to ensure the 
anonymity of our trial patients. 
4.4 
Emergency Unblinding 
The information provided below is for the use by a physician, nurse, CRA or 
pharmacist treating the patient. These contact numbers should not be used by 
patients. Patients should be instructed to call their doctor’s office in the event of 
an emergency or adverse event that may result in the need to unblind the patient. 
In the event of an emergency or severe adverse reaction necessitating 
identification of the medication for the welfare of the patient, please contact the 
EA Drug Team at DrugOrder@ecog-acrin.org during business hours (9am-4pm 
M-F Eastern Time) or AnswerConnect at 1-866-296-8940 outside of those hours.  
The request will require the protocol number (i.e., EAA171), the patient ID 
number (5-digit number), patient initials, patient step, your contact information, as 
well as the reason for unblinding.  ECOG-ACRIN staff may contact you for further 
details in-order to determine the validity of the request and will work to obtain the 
required approvals to unblind the patient.  Once approved, a staff member will 
provide the unblinded treatment identity.  Note that if a patient is unblinded, they 
must discontinue protocol treatment. 
NCI CTEP should also be notified of a request for unblinding. 
4.5 
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 through Medidata 
Rave according to the schedule in the EAA171 Forms Completion Guidelines. 
However, laboratory, patient reported outcomes, and imaging correlatives 
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5. 
Treatment Plan 
5.1 
Administration Schedule 
NOTE: 
All patients should be on at least 81 mg acetylsalicylic acid (ASA) 
daily while receiving lenalidomide. Please see Section 5.6.16 for 
additional information regarding thromboprophyaxis. 
5.1.1 
Arm X (Arms A and B) 
NOTE: 
Patients are randomized to Arm A (lenalidomide and 
ixazomib) or Arm B (lenalidomide and placebo) but will be 
identified as on Arm X as this is a blinded trial. 
Lenalidomide: 10 mg PO daily days 1-28 
NOTES: 
For patients with creatinine clearance 30-60 mL/min 
lenalidomide dose will be reduced to 5 mg PO daily. 
Lenalidomide may be taken with or without food. Capsules 
must not be crushed, chewed, or opened.  
Please refer to Section 8.2 for additional Lenalidomide 
administration details. 
Ixazomib/Placebo: 4 mg PO days 1, 8, and 15 
Repeat cycle every 28 days until disease progression or unacceptable 
toxicity. 
NOTES: 
Ixazomib/Placebo capsule(s) must be taken on an empty 
stomach, 1 hour before or 2 hours after food. Capsule(s) 
must be swallowed whole with water. Do not open or break 
capsules.  
Missed or delayed doses can be taken only if the next 
scheduled dose is ≥ 72 hours away. A missed dose should 
not be taken within 72 hours of the next scheduled dose. If 
vomiting occurs after taking a dose, the patient should not 
repeat the dose. Resume dosing at the time of the next 
scheduled dose. 
Please refer to Section 8.1 for additional Ixazomib/Placebo 
administration details. 
5.2 
Lenalidomide Fertility Instructions 
NOTE: 
Please also see Appendix VI “Lenalidomide 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 Revlimid REMS® 
program, and be willing and able to comply with the requirements of Revlimid 
REMS®. Patients of childbearing potential must have a negative serum or urine 
pregnancy test with a sensitivity of at least 25 mIU/mL within 10 to 14 days prior 
to the first dose of lenalidomide and again within 24 hours of starting each new 
cycle. Patients of childbearing potential must either commit to continued 
abstinence from heterosexual intercourse or begin TWO acceptable methods of 
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birth control, one highly effective method and one additional effective method AT 
THE SAME TIME, 1) at least 28 days before starting lenalidomide; 2) while 
participating in the study; 3) during dose interruptions; and 4) for at least 28 days 
after the last dose of lenalidomide.  
Patients of childbearing potential must also agree to ongoing pregnancy testing 
as outlined in Appendix VI. Patients must also agree to not breastfeed during this 
same time period. Male patients must agree to either abstain from sexual 
intercourse for the duration of their participation in the study or use a latex 
condom during sexual contact with a partner of childbearing potential while 
participating in the study and for 28 days after the last dose of protocol treatment 
even if they have had a successful vasectomy. 
Patients must also agree to abstain from donating sperm while on study 
treatment and for 28 days after the last dose of protocol treatment even if they 
have had a successful vasectomy. All patients must agree to abstain from 
donating blood during study participation and for at least 28 days after the last 
dose of protocol treatment. 
5.3 
Adverse Event Reporting Requirements 
All adverse events described throughout this protocol and all reportable 
adverse events on this protocol will be graded using the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. 
All appropriate treatment areas should have access to a copy of the CTCAE 
version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the 
CTEP website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.ht
m). 
Clinician graded CTCAE is the AE (adverse event) safety standard. PRO-CTCAE 
items are to complement CTCAE reporting. Patients will respond to PRO-CTCAE 
items but no protocol directed action will be taken. PRO-CTCAE is not intended 
for expedited reporting, real time review or safety reporting. 
5.3.1 
Purpose 
Adverse event (AE) data collection and reporting, which are a 
required part of every clinical trial, are done so investigators and 
regulatory agencies can detect and analyze adverse events and risk 
situations to ensure the safety of the patients enrolled, as well as 
those who will enroll in future studies using similar agents. 
5.3.2 
Routine Reporting of Adverse Events (Medidata Rave) 
Adverse events are reported in a routine manner at scheduled times 
during a trial using the Medidata Rave clinical data management 
system. Please refer to Section 4.3.3 of the protocol for more 
information on how to access the Medidata Rave system and the 
EAA171 forms packet for instructions on where, when and what 
adverse events are to be reported routinely on this protocol.  
Symptomatic Adverse Events reported by patients through PRO-
CTCAE are not safety reporting and may be presented with other 
routine AE data. 
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5.3.3 
Expedited Reporting of Adverse Events (CTEP-AERS) 
In addition to routine reporting, certain adverse events must be also 
reported in an expedited manner for timelier monitoring of patient 
safety and care. The remainder of this section provides information 
and instructions regarding expedited adverse event reporting. 
5.3.4 
Terminology 
x 
Adverse Event (AE): Any untoward medical occurrence associated 
with the use of an agent in humans, whether or not considered agent 
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. 
x 
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 protocol 
treatment. 
Unlikely 
The AE is doubtfully related to protocol 
treatment. 
Possible 
The AE may be related to protocol treatment. 
Probable 
The AE is likely related to protocol treatment. 
Definite 
The AE is clearly related to protocol treatment. 
x 
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. 
x 
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. 
x 
Hospitalization (or prolongation of hospitalization): For AE 
reporting purposes, a hospitalization is defined as an inpatient 
hospital stay equal to or greater than 24 hours. 
x 
Life Threatening Adverse Event: Any AE that places the patient at 
immediate risk of death from the AE as it occurred. 
x 
Serious Adverse Event (SAE): Any adverse event occurring at any 
dose that results in ANY of the following outcomes: 
x 
Death 
x 
A life-threatening adverse event  
x 
Inpatient hospitalization or prolongation of existing hospitalization 
(for ≥ 24 hours).  
x 
A persistent or significant incapacity or substantial disruption of 
the ability to conduct normal life functions.  
x 
A congenital anomaly/birth defect.  
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x 
Important Medical Events (IME) that may not result in death, be 
life threatening, or require hospitalization may be considered 
serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
x 
SPEER (Specific Protocol Exceptions to Expedited Reporting): A 
subset of AEs within the CAEPR that contains a list of events that are 
protocol specific exceptions to expedited reporting. If an AE meets the 
reporting requirements of the protocol, and it is listed on the SPEER, it 
should ONLY be reported expeditiously if the grade being reported 
exceeds the grade listed in the parentheses next to the event. 
5.3.5 
Expedited Adverse Event Reporting Procedure 
The Rave Cancer Therapy Evaluation Program Adverse Event 
Reporting System (CTEP-AERS) Integration enables evaluation of 
Adverse Events (AE) entered in Rave to determine whether they 
require expedited reporting and facilitates entry in CTEP-AERS for 
those AEs requiring expedited reporting. Sites must initiate all AEs for 
this study in Medidata Rave. 
Sites must initiate all AEs for this study in Medidata Rave. 
Pre-treatment AEs: AEs that occur after informed consent is signed 
and prior to start of treatment are collected in Medidata Rave using 
the Pre-treatment Adverse Event form. Pre-existing medical 
conditions (formerly referred to as baseline AEs) identified during 
baseline assessment are not considered AEs and therefore should 
not be reported on the Pre-treatment Adverse Event form. If these 
pre-existing conditions worsen in severity, the investigator must 
reassess the event to determine if an expedited report is required. 
Whether or not an expedited report is required, the worsened event 
should be reported as a routine AE. 
Treatment-emergent AEs: All AEs that occur after start of treatment 
are collected in Medidata Rave, using the Adverse Event form, which 
is available for entry at each treatment course or reporting period and 
is used to collect AEs that start during the period or persist from the 
previous reporting period. AEs that occur 30 Days after the Last 
Administration of the Investigational Agent/Intervention are collected 
using the Late Adverse Event form. 
Prior to sending AEs through the rules evaluation process, site staff 
should verify the following on the Adverse Event form in Rave: 
x 
The reporting period (course/cycle) is correct and 
x 
AEs are recorded and complete (no missing fields) and the form is 
query free. 
NOTE: 
The CRA reports AEs in Rave at the time the Investigator 
learns of the event. 
NOTE: 
If the CRA modifies an AE, it must be re-submitted for 
rules evaluation. 
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Upon completion of AE entry in Medidata Rave, the CRA submits the 
AE for rules evaluation by completing the Expedited Reporting 
Evaluation form. Both NCI and protocol-specific reporting rules 
evaluate the AEs submitted for expedited reporting. A report is 
initiated in CTEP-AERS using information entered in Medidata Rave 
for AEs that meet reporting requirements. The CRA completes the 
report by accessing CTEP-AERS via a direct link on the Medidata 
Rave Expedited Reporting Evaluation form. Contact the CTSU Help 
Desk at 1-888-823-5923 or by email at ctsucontact@westat.com if 
you have any issues submitting an expedited report in CTEP-AERS. 
In the rare occurrence that internet connectivity is lost, a 24-hour 
notification is to be made to CTEP by telephone at: 
x 
(301-897-7497). 
Once internet connectivity is restored, the 24-hour notification that 
was phoned in must be entered immediately into CTEP-AERS using 
the direct link from Medidata Rave. 
Additional information about the CTEP-AERS integration is available 
on the CTSU members’ website: 
x 
Study specific documents: Protocols > Documents> Protocol 
Related Documents> Adverse Event Reporting; and 
x 
Additional resources: Resources > CTSU Operations Information> 
User Guides & Help Topics. 
NCI requirements for SAE reporting are available on the CTEP 
website. 
x 
NCI Guidelines for Investigators: Adverse Event Reporting 
Requirements is available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applicatio
ns/docs/aeguidelines.pdf 
 


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5.3.6 
Steps to determine if an adverse event is to be reported in an 
expedited manner – Arms A and B (Note: Since this is a blinded 
study, the treatment arm code (TAC) will appear as Arm X in the 
CTEP-AERS system.) 
Guidelines for reporting adverse events OCCURRING WHILE ON 
PROTOCOL TREATMENT AND WITHIN 30 DAYS of the last 
administration of the investigational agent(s). 
x 
Site must determine if an event meets expedited reporting 
requirements so that the AE will be entered into Medidata Rave, 
triggering a CTEP-AERS report, within the mandated timeframes 
outlined in Section 5.3.7. 
x 
Do not initiate the CTEP-AERS report via the CTEP-AERS 
website. 
x 
We encourage all sites to confirm the Rules Engine assessment 
with the charts and tables below. 
x 
Once the CTEP-AERS is completed, ECOG-ACRIN, the NCI, and 
all appropriate regulatory agencies will be notified of the event in 
an expeditious manner. 
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Determine if the event meets the 
definition of a Serious Adverse 
Event (SAE) as outlined by the six 
criteria in the top portion of the 
table below in Section 5.3.7. 
Yes 
No 
Identify the type and 
grade of the event 
using the CTCAE. 
Determine if the patient 
was hospitalized for  
≥ 24 hours for the event. 
With this information, review the 
chart in Section 5.3.7 to determine 
if event requires expedited 
reporting. 
Refer to Section 5.3.8 to 
determine if the event 
meets the protocol 
specific reporting 
requirements for this 
study. If so, report the 
event in Medidata Rave 
so a CTEP-AERS report 
will be initiated with a link 
to complete it. 
Refer to Section 5.3.8 to determine 
if the event meets the protocol 
specific reporting requirements for 
this study. If so, report the event in  
Medidata Rave so a CTEP-AERS 
report will be initiated with a link to 
complete it. 
Is the event 
reportable? 
No 
Yes 
Refer to Section 5.3.8 to determine if the event meets the 
criteria as an exception to reporting on this protocol. If it 
does not, report the event in Medidata Rave so a CTEP-
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5.3.6.1 
Guidelines for reporting adverse events OCCURRING 
GREATER THAN 30 DAYS after the last administration of 
the investigational agent(s). 
If the adverse event meets the definition of a Serious 
Adverse Event (SAE) as outlined by the six criteria in the 
top portion of the table below in Section 5.3.7, OR the 
protocol specific requirements in Section 5.3.8, AND has 
an attribution of possible, probably or definite, the following 
events require reporting as follows: 
Expedited 24-hour notification followed by complete 
report within 5 calendar days for: 
x 
All Grade 4 and Grade 5 AEs 
NOTE: 
Any death occurring greater than 30 days after 
the last dose of investigational agent with an 
attribution of possible, probable or definite must 
be reported in CTEP-AERS accessed via 
Medidata Rave even if the patient is off study. 
Expedited 10 calendar day reports for: 
x 
Grade 2 adverse events resulting in hospitalization or 
prolongation of hospitalization 
x 
Grade 3 adverse events   
5.3.7 
Expedited Reporting Requirements for Arm X (Arms A and B) on 
protocol EAA171 
Investigational Agents: Ixazomib/Placebo  
Commercial Agents: Lenalidomide  
When an investigational agent(s) is used in combination with a 
commercial agent(s), the combination is considered to be 
investigational and expedited reporting of adverse events follow the 
guidelines for investigational agents. 
Late Phase II and Phase III Studies 
Expedited Reporting Requirements for Adverse Events that Occur on 
Studies under an IND within 30 Days of the Last Administration of the 
Investigational Agent/Intervention.1 
NOTE: 
Footnote 1 instructs how to report serious adverse events 
that occur more than 30 days after the last administration 
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FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1. 
Death 
2. 
A life-threatening adverse event  
3. 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4. 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5. 
A congenital anomaly/birth defect.  
6. 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI 
in CTEP-AERS accessed via Medidata Rave within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar 
Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE: Protocol-specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
x 
“24-Hour; 5 Calendar Days” – The AE must initially be reported in CTEP-AERS accessed via 
Medidata Rave within 24 hours of learning of the AE, followed by a complete expedited report within 
5 calendar days of the initial 24-hour report. 
x 
“10 Calendar Days” – A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1 Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
x 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
x 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
x 
Grade 3 adverse events 
 


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5.3.8 
Additional instructions, requirements and exceptions for protocol 
EAA171 
Additional Instructions 
x 
For instructions on how to specifically report events that result in 
persistent or significant disability/incapacity, congenital anomaly, 
or birth defect events in CTEP-AERS accessed via Medidata 
Rave, 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. 
x 
Reporting a death on study: A death occurring while on study 
treatment or within 30 days of the last dose of study 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. 
 
EAA171 specific expedited reporting requirements: 
x 
Pregnancies: Pregnancies and suspected pregnancies 
(including a positive or inconclusive pregnancy test, regardless of 
age or disease state) occurring while the female patient is on 
ixazomib/placebo or lenalidomide, or within 28 days of the female 
patient’s last dose of ixazomib/placebo or lenalidomide, are 
considered immediately reportable events. The pregnancy, 
suspected pregnancy, or positive/ inconclusive pregnancy test 
must be reported in CTEP-AERS accessed via Medidata Rave 
within 24 hours of the Investigator’s knowledge. Please refer to 
Appendix V for detailed instructions on how to report the 
occurrence of a pregnancy as well as the outcome of all 
pregnancies. 
 
EAA171 specific expedited reporting exceptions: 
For study Arm X (Arms A and B), the adverse events listed below do 
not require expedited reporting: 
x 
If an AE meets the reporting requirements of the protocol, and it 
is listed on the SPEER, it should ONLY be reported expeditiously 
if the grade being reported exceeds the grade listed in the 
parentheses next to the event.  


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5.3.9 
Other recipients of adverse event reports and supplemental data 
DCTD/NCI will notify ECOG-ACRIN/pharmaceutical collaborator(s) of 
all AEs reported to the FDA. Any additional written AE information 
requested MUST be submitted to BOTH the NCI and ECOG-ACRIN. 
Adverse events determined to require expedited reporting 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. 
5.3.10 
Second Primary Cancer Reporting Requirements 
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 utilizing the agent Lenalidomide must be 
reported as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Report the diagnosis expeditiously by initially reporting it 
PROMPTLY upon learning of the secondary malignancy on the 
Adverse Event Form or Late Adverse Event Form in the 
appropriate Treatment Cycle or Post Registration folder in 
Medidata Rave. Once the adverse event is entered into Rave, the 
Rules Engine on the Expedited Reporting Evaluation Form will 
confirm whether or not the second primary requires expedited 
reporting. The CTEP-AERS report must then be initiated directly 
from the Expedited Reporting Evaluation Form in Medidata Rave. 
Do not initiate the CTEP-AERS report via the CTEP-AERS 
website. 
Report under a.) leukemia secondary to oncology chemotherapy, 
b.) myelodysplastic syndrome, c.) treatment related secondary 
malignancy or d) Neoplasms Other, malignant (grade 3 or 4) 
NOTE: 
When reporting attribution on the AE form, assess 
the relationship between the secondary 
malignancy and the current protocol treatment 
ONLY (and NOT relationship to anti-cancer agent 
received either before or after protocol treatment). 
NOTE: 
We encourage all sites to confirm the Rules Engine 
assessment with the Second Primary reporting 
requirements outlined in this section. 
3. Report the diagnosis via http://ctep.cancer.gov. 
4. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 
5. 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 
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NOTE: 
All new malignant tumors must be reported in 
CTEP-AERS accessed via Medidata Rave 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: 
x 
Tumor pathology 
x 
History of prior tumors 
x 
Prior treatment/current treatment including duration 
x 
Any associated risk factors or evidence regarding how long the 
tumor may have been present 
x 
When and how the tumor was detected 
x 
Molecular characterization or cytogenetics or the original tumor (if 
available) and of any new tumor 
x 
Tumor treatment and outcome (if available). 
NOTE: 
The ECOG-ACRIN 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 ECOG-ACRIN 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 in CTEP-AERS or by the ECOG-ACRIN 
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5.4 
Comprehensive Adverse Events and Potential Risks Lists 
5.4.1 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
MLN9708 (Ixazomib citrate, NSC 767907) 
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. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), 
appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted 
below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/do
cs/aeguidelines.pdf for further clarification. Frequency is provided 
based on 1122 patients. Below is the CAEPR for MLN9708 (Ixazomib 
citrate). 
NOTE: 
Report AEs on the SPEER ONLY IF they exceed the grade 
noted in parentheses next to the AE in the SPEER.  If this 
CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
Version 2.1, March 26, 20221 
 
Adverse Events with Possible 
Relationship to MLN9708 (Ixazomib citrate) 
(CTCAE 5.0 Term) 
[n= 1122] 
 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) Rare but Serious (<3%)   
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
  
 
 
Thrombotic 
thrombocytopenic purpura   
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Constipation 
 
  
Diarrhea 
 
 
 Diarrhea (Gr 2) 
Nausea 
 
 
 Nausea (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS   
 
 
Edema limbs 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever 
 
 Fever (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatobiliary disorders - 
Other (hepatotoxicity)2 
  
INFECTIONS AND INFESTATIONS 
  
 
Upper respiratory 
 
 Upper respiratory infection (Gr 2) 
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Adverse Events with Possible 
Relationship to MLN9708 (Ixazomib citrate) 
(CTCAE 5.0 Term) 
[n= 1122] 
 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
infection 
INVESTIGATIONS 
  
 
Neutrophil count 
decreased 
 
 Neutrophil count decreased (Gr 
2) 
 
Platelet count decreased  
 Platelet count decreased (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Headache 
 
  
 
Nervous system 
disorders - Other 
(peripheral neuropathies 
NEC, peripheral 
neuropathy, peripheral 
motor neuropathy) 
 
 
Nervous system disorders - 
Other (peripheral neuropathies 
NEC, peripheral neuropathy, 
peripheral motor neuropathy) (Gr 
2) 
 
Peripheral sensory 
neuropathy 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
  
 
Dyspnea 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
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 Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity 
have each been reported in <1% of patients treated with MLN9708. Events of liver impairment have 
been reported. Monitor hepatic enzymes regularly and adjust dosing for Grade 3 or 4 symptoms. 
Adverse events reported on MLN9708 (Ixazomib citrate) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that MLN9708 
(Ixazomib citrate) caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia 
CARDIAC DISORDERS - Myocardial infarction 
EYE DISORDERS - Blurred vision; Retinal detachment 
GASTROINTESTINAL DISORDERS - Enterocolitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Disease progression; 
Flu like symptoms; Malaise 
HEPATOBILIARY DISORDERS - Bile duct stenosis 
INFECTIONS AND INFESTATIONS - Bronchial infection; Fungemia; Infections and infestations 
- Other (Parainfluenza Infection); Lung infection; Pharyngitis; Sepsis; Shingles; Sinusitis 


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INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Injury, poisoning and 
procedural complications - Other (femoral neck fracture); Spinal fracture 
INVESTIGATIONS - Aspartate aminotransferase increased; Lymphocyte count decreased; 
White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypokalemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Muscle 
weakness lower limb; Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (non-Hodgkin’s 
lymphoma); Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other 
(plasma cell myeloma); Tumor pain 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysgeusia 
PSYCHIATRIC DISORDERS - Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchial obstruction 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythema multiforme; Pruritus 
VASCULAR DISORDERS - Hypotension 
VASCULAR DISORDERS - Hypotension; Vasculitis 
NOTE: 
MLN9708 (Ixazomib citrate) 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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5.4.2 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Lenalidomide (Revlimid, NSC 703813) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) 
provides a single list of reported and/or potential adverse events (AE) 
associated with an agent using a uniform presentation of events by 
body system. Refer to the “CTEP, NCI Guidelines: Adverse Event 
Reporting Requirements” 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/do
cs/aeguidelines.pdf for further clarification. Frequency is provided 
based on 4081 patients. Below is the CAEPR for lenalidomide (CC-
5013). 
Version 2.8, June 27, 20191 
 
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 
 
Rev. Add1 


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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%) 
Fatigue 
 
 
 
Fever 
 
 
Generalized edema 
 
 
Non-cardiac chest pain 
 
 
Pain 
 
HEPATOBILIARY DISORDERS 
 
 
Hepatic failure 
 
 
Hepatobiliary disorders - Other 
(cholestasis) 
IMMUNE SYSTEM DISORDERS 
 
 
Allergic reaction 
 
 
Anaphylaxis 
 
 
Immune system disorders - Other 
(angioedema) 
 
 
Immune system disorders - Other 
(graft vs. host disease)3 
INFECTIONS AND INFESTATIONS 
 
Infection4 
 
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 
 


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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%) 
 
Hypomagnesemia 
 
 
Hyponatremia 
 
 
Hypophosphatemia 
 
 
Iron overload 
 
 
 
Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
 
 
Back pain 
 
 
Bone pain 
 
 
Generalized muscle weakness 
 
 
Muscle cramp 
 
 
Myalgia 
 
 
Pain in extremity 
 
 
 
Rhabdomyolysis5 
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 
 


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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%) 
 
Psychiatric disorders - Other (mood 
altered) 
 
RENAL AND URINARY DISORDERS 
 
 
Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Cough 
 
 
Dyspnea 
 
 
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 (pyoderma gangrenosum) 
 
 
 
Stevens-Johnson syndrome 
 
 
Toxic epidermal necrolysis 
SURGICAL AND MEDICAL PROCEDURES 
 
 
Surgical and medical procedures - 
Other (impaired stem cell 
mobilization)8 
VASCULAR DISORDERS 
 
Hematoma 
 
 
Hypertension 
 
 
Hypotension 
 
 
Peripheral ischemia 
 
 
Thromboembolic event9 
 
 
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. 


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


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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 
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 


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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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5.5 
Dose Modifications 
NOTE: Dose modifications are based on adverse events, which are possibly, 
probably or definitely related to drug. More than one dose reduction per 
cycle may occur. 
Patients experiencing grade 3 or 4 AE’s that are possibly, probably or definitely 
related to a particular agent(s) requiring dose modifications as per the tables 
below will have that particular agent(s) held until resolution of the AE. If AE 
improves to baseline or ≤ grade 1 prior to next scheduled dose, treatment should 
be restarted with a one dose level reduction for the causative drug for the 
remainder of the cycle. The next cycle will then continue with this reduced dose 
level. Patients experiencing grade 3 or 4 AEs that are possibly, probably or 
definitely related to a particular agent(s) which occur on or after the last treatment 
day of a cycle, will have that particular agent(s) reduced by one dose level 
beginning with the next cycle. 
NOTE: If the AE is attributed to a specific drug, only that drug needs dose 
reduction. If the AE is possibly attributed to more than one agent, the 
more likely agent can be first reduced, and then the other drug if the 
toxicity recurs. If both drugs are equally likely to have contributed to the 
toxicity, reduce the ixazomib/placebo first. 
Once a patient’s dose has been reduced, no dose-re-escalation is permitted 
unless it is clear that the drug was not responsible for the toxicity that led to the 
dose reduction. 
A delay of up to 14 days is allowed between cycles. Any delay beyond 14 days 
should be discussed with the study chair. If treatment has been delayed for > 8 
weeks due to treatment related toxicity, the patient will go off study treatment. A 
treatment delay of greater than 14 days, but no longer than 60 days, is allowed if 
the delay is unrelated to study treatment. 
If ixazomib/placebo is held for toxicity, the patient may restart drug during the 
same cycle provided there are additional doses left in the cycle. 
If there is a delay in obtaining lenalidomide for start of a new cycle, the cycle can 
be delayed until it is available in order to allow all drugs to be started at the same 
time. However, if the cycle has already started, treatment may continue and 
lenalidomide should be started when it becomes available and continue for the 
remaining days of lenalidomide as per cycle. 
PRO-CTCAE data should not be used for determining dose delays or dose 
modifications or any other protocol directed action. 
5.5.1 
Ixazomib/Placebo Treatment Adjustment 
See table below for ixazomib/placebo treatment adjustment steps 
Ixazomib/Placebo Treatment Adjustment Steps 
Starting Dose 
4 mg days 1, 8, 15 every 28 days 
Dose Level -1 
3 mg days 1, 8, 15 every 28 days 
Dose Level -2 
2.3 mg days 1, 8, 15 every 28 days 
Dose Level -3 
Discontinue 
Rev. Add3 


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5.5.2 
Lenalidomide Treatment Adjustment 
See table below for lenalidomide treatment adjustment steps 
Lenalidomide (CC-5013) Treatment Adjustment Steps 
Starting Dose 
(For CrCl 30-60 ml/min) 
5 mg daily for 28 days 
10 mg daily for 28 days 
Dose Level -1 
5 mg daily for 21 days 
every 28 days 
10 mg daily for 21 days 
every 28 days 
Dose Level -2 
2.5 mg daily for 28 days 
5 mg daily for 28 days 
Dose Level -3 
2.5 mg every other day for 
28 days 
2.5 mg daily for 28 days 
Dose Level -4 
Discontinue 
2.5 mg every other day for 
28 days 
5.5.3 
Dose Modifications for Ixazomib/Placebo and Lenalidomide Based on 
Toxicity 
At retreatment and Day 2-21 of Cycle 
 
NCI CTCAE Grade 
If attributed to Lenalidomide 
If attributed to 
Ixazomib/Placebo 
Sustained (≥ 7 days) 
≥ Grade 3 neutropenia 
or 
≥ Grade 3 neutropenia 
associated with fever 
(temperature ≥ 38.5º C) 
or Grade 4 neutropenia 
Hold (interrupt dose) and follow CBC on 
days of scheduled ixazomib/placebo 
doses. If the toxicity resolves to baseline 
or ≤ grade 2 prior to Day 14 restart 
lenalidomide at next lower dose level and 
continue the cycle until Day 14. Start next 
cycle at the reduced dose level. 
If neutropenia is the only toxicity for which 
a dose reduction is required, G-CSF may 
be used and the lenalidomide dose 
maintained. 
Hold (interrupt dose) and follow 
CBC on days of scheduled 
ixazomib/placebo doses. If the 
toxicity resolves to baseline or  
≤ grade 2, restart 
ixazomib/placebo at next lower 
dose level and continue for rest 
of cycle as per protocol. Start 
next cycle at the reduced dose 
level. 
Sustained (≥ 7 days) 
≥ Grade 3 
thrombocytopenia or ≥ 
Grade 3 
thrombocytopenia with 
bleeding or grade 4 
thrombocytopenia 
 
Hold (interrupt dose) and follow CBC on 
days of scheduled ixazomib/placebo 
doses. If the toxicity resolves to baseline 
or ≤ grade 2 prior to Day 14 restart 
lenalidomide at next lower dose level and 
continue the cycle until Day 14. Start next 
cycle at the reduced dose level. 
Hold (interrupt dose) and follow 
CBC on days of scheduled 
ixazomib/placebo doses. If the 
toxicity resolves to baseline or  
≤ grade 2, restart 
ixazomib/placebo at next lower 
dose level and continue for rest 
of cycle as per protocol. Start 
next cycle at the reduced dose 
level. 


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At retreatment and Day 2-21 of Cycle 
 
NCI CTCAE Grade 
If attributed to Lenalidomide 
If attributed to 
Ixazomib/Placebo 
Infection ≥ grade 2 (with 
normal neutrophil count) 
Hold (interrupt dose) and observe. If the 
toxicity resolves to baseline or ≤ grade 1 
prior to Day 14 restart lenalidomide at 
next lower dose level and continue the 
cycle until Day 14. Start next cycle at the 
reduced dose level. 
Hold (interrupt dose) and follow 
CBC on days of scheduled 
ixazomib/placebo doses. If the 
toxicity resolves to baseline or  
≤ grade 1, restart 
ixazomib/placebo at next lower 
dose level and continue for rest 
of cycle as per protocol. Start 
next cycle at the reduced dose 
level. 
Non-blistering rash 
Grade 2-3 
Hold (interrupt dose) and observe. If the 
toxicity resolves to baseline or ≤ grade 1 
prior to Day 14 restart lenalidomide at 
next lower dose level and continue the 
cycle until Day 14. Start next cycle at the 
reduced dose level. 
Hold (interrupt dose) and 
observe. If the toxicity resolves 
to baseline or ≤ grade 1, restart 
ixazomib/placebo at next lower 
dose level and continue for rest 
of cycle as per protocol. Start 
next cycle at the reduced dose 
level. 
Grade 4 
Discontinue lenalidomide and do not 
resume. 
 
Desquamating 
(blistering) rash - any 
Grade 
Discontinue lenalidomide. 
Start next cycle at the reduced 
dose level. 
Erythema multiforme ≥ 
Grade 3 
Discontinue lenalidomide. 
Start next cycle at the reduced 
dose level. 
Sinus bradycardia/ other 
cardiac Arrhythmia 
Grade 2 
Hold (interrupt dose) and observe. If the 
toxicity resolves to baseline or ≤ grade 1 
prior to Day 14 restart lenalidomide at 
next lower dose level and continue the 
cycle until Day 14. Start next cycle at the 
reduced dose level. 
No dose modifications 
required 
Grade 3-4 
Discontinue lenalidomide. 
 
Allergic reaction or 
Hypersensitivity 
Grade 2-3 
Hold (interrupt dose) and observe. If the 
toxicity resolves to baseline or ≤ grade 1 
prior to Day 14 restart lenalidomide at 
next lower dose level and continue the 
cycle until Day 14. Start next cycle at the 
reduced dose level. 
Hold (interrupt dose) and 
follow on days of 
scheduled 
ixazomib/placebo doses. 
If the toxicity resolves to 
baseline or ≤ grade 1, 
restart ixazomib/placebo 
at next lower dose level 
and continue for rest of 
cycle as per protocol. 
Start next cycle at the 
reduced dose level. 


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At retreatment and Day 2-21 of Cycle 
 
NCI CTCAE Grade 
If attributed to Lenalidomide 
If attributed to 
Ixazomib/Placebo 
Grade 4 
Discontinue lenalidomide. 
Discontinue 
ixazomib/placebo and do 
not resume. 
Constipation  
Grade 1-2 
Initiate bowel regimen and maintain dose 
level. 
Initiate bowel regimen 
and maintain dose level. 
≥ Grade 3 
Hold (interrupt dose) and observe. If the 
toxicity resolves to baseline or ≤ grade 1 
prior to Day 14 restart lenalidomide at 
next lower dose level and continue the 
cycle until Day 14. Start next cycle at the 
reduced dose level. 
 
Renal Function 
CrCl < 30 mL/min* 
Hold (interrupt dose) and observe. If the 
toxicity resolves to baseline or ≤ grade 1 
prior to Day 14 restart lenalidomide at 
next lower dose level and continue the 
cycle until Day 14. Start next cycle at the 
reduced dose level. 
No dose modifications 
required 
Venous 
Thrombosis/embolism 
≥ Grade 3 
Hold (interrupt) dose and start 
anticoagulation; restart at investigator’s 
discretion after adequate anticoagulation 
(maintain dose level). 
No dose modifications 
required.  
Nervous system toxicity 
 
Peripheral neuropathy 
Grade 1 or 2 without 
pain 
 
Reduce dose of 
ixazomib/placebo to the 
next lower dose level. If a 
patient is already at the 
lowest drug level, go off 
treatment. 
Grade >2 or grade 2 
with pain 
Reduce dose of lenalidomide to the next 
lower dose level. If a patient is already at 
the lowest drug level, go off treatment. 
Discontinue 
ixazomib/placebo until 
toxicity resolves or 
returns to baseline. When 
toxicity resolves, re-
initiate ixazomib/placebo 
at the next lower dose 
level. If a patient is 
already at the lowest drug 
level, go off treatment. 
Grade 4 
Reduce dose of lenalidomide to the next 
lower dose level. If a patient is already at 
the lowest drug level, go off treatment. 
Discontinue 
ixazomib/placebo 
Hyperthyroidism or 
Hypothyroidism 
Omit lenalidomide for remainder of cycle, 
evaluate etiology, and initiate appropriate 
therapy. Restart lenalidomide next cycle 
(decrease dose by one dose level). 
No dose modifications 
required 


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At retreatment and Day 2-21 of Cycle 
 
NCI CTCAE Grade 
If attributed to Lenalidomide 
If attributed to 
Ixazomib/Placebo 
Any other ≥ grade 3 non-
hematologic toxicity 
assessed as at least 
possibly related to the 
drugs (nausea, emesis 
and diarrhea included 
only if the grade persists 
despite maximal 
supportive care) 
Hold (interrupt dose) and observe if 
toxicity is thought to be at least possible 
related to lenalidomide. If the toxicity 
resolves to baseline or ≤ grade 2 prior to 
Day 14 restart lenalidomide at next lower 
dose level and continue the cycle until 
Day 14. Start next cycle at the reduced 
dose level. 
Hold (interrupt dose) if 
toxicity is thought to be at 
least possible related to 
ixazomib/placebo. If the 
toxicity resolves to 
baseline or  
≤ grade 2, restart 
ixazomib/placebo at next 
lower dose level and 
continue for rest of cycle 
as per protocol. Start next 
cycle at the reduced dose 
level. 
* Creatinine clearance calculation can be made using standard methods, but the same method 
should be used for the entire duration of the study. 
5.6 
Supportive Care 
5.6.1 
All supportive measures consistent with optimal patient care will be 
given throughout the study. 
5.6.2 
Oral hydration 
Patients are encouraged to drink at least 6 to 8 cups of liquid per day. 
5.6.3 
Disallowed concurrent treatment 
The following treatments are not permitted during the trial: 
x 
Any other investigational treatment 
x 
Any other systemic anti-neoplastic therapy including, but not 
limited to, immunotherapy, hormonal therapy or monoclonal 
antibody therapy 
x 
Any external beam radiotherapy 
5.6.4 
Nausea and/or vomiting 
Standard anti-emetics including 5-hydroxytryptamine 3 serotonin 
receptor antagonists are recommended for emesis if it occurs once 
treatment is initiated; prophylactic anti-emetics may also be 
considered at the physician’s discretion. Dexamethasone should not 
be administered as an anti-emetic. Fluid deficit should be corrected 
before initiation of study drug and during treatment. 
5.6.5 
Blood products and growth factors 
Blood products and growth factors should be utilized as clinically 
warranted and following institutional policies and recommendations. 
The use of growth factors should follow published guidelines of the 
Journal of Clinical Oncology, Vol 24, No 18 (June 20), 2006: pp. 2932-
2947. Erythropoietic agents, or other agents that may increase the 
risk of thrombosis, such as estrogen containing therapies, should be 


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used with caution after making a benefit-risk assessment in patients 
receiving lenalidomide. 
5.6.6 
Diarrhea 
Diarrhea should be managed according to clinical practice, including 
the administration of antidiarrheals such as loperamide once 
infectious causes are excluded. Fluid intake should be maintained to 
avoid dehydration. Fluid deficit should be corrected before initiation of 
treatment and during treatment. Additional doses of loperamide at 2 
mg every 2-4 hours until diarrhea free (maximum 16 mg/day). 
In the event of Grade 3 or 4 diarrhea, the following supportive 
measures are allowed: hydration, octreotide, and antidiarrheals. 
If diarrhea is severe (requiring intravenous rehydration) and/or 
associated with fever or severe neutropenia (Grade 3 or 4), broad-
spectrum antibiotics must be prescribed. Patients with severe diarrhea 
or any diarrhea associated with severe nausea or vomiting should be 
hospitalized for intravenous hydration and correction of electrolyte 
imbalances. Please monitor patients carefully for development of 
ileus. 
5.6.7 
Herpes Zoster prophylaxis 
Patients may be at an increased risk of infection including reactivation 
of herpes zoster and herpes simplex viruses. Prophylaxis with 
acyclovir 400 mg PO BID should be used for all patients while on 
study therapy and for 3 months beyond the end of therapy. 
5.6.8 
Prohibited medications 
Prohibited enzyme inducers 
x 
Systemic treatment with any of the following metabolizing enzyme 
inducers should be avoided, unless there is no appropriate 
alternative medication for the patient’s use. (Rationale: If there 
were to be a drug-drug interaction with an inducer, 
ixazomib/placebo exposure would be decreased) 
Strong CYP3A inducers 
x 
Including Rifampin, rifapentine, rifabutin, carbamazepine, 
phenytoin, and phenobarbital 
Additional strong CYP3A inducers can be found at: https://drug-
interactions.medicine.iu.edu/main-table.aspx 
Excluded foods and dietary supplements include St. John’s wort. 
5.6.9 
Erythematous Rash with or without Pruritus 
Rash with or without pruritus has been reported with ixazomib, 
primarily at the higher doses tested and when given with agents 
where rash is an overlapping toxicity. The rash may range from limited 
erythematous areas, macular and/or small papular bumps that may or 
may not be pruritic over a few areas of the body, to a more 
generalized eruption that is predominately on the trunk or extremities. 
Rash has been most commonly characterized as maculopapular or 
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reported within the first three cycles of therapy. The rash is often 
transient, self-limiting, and is typically Grade 1 to 2 in severity. Rash 
can also be seen with lenalidomide, and usually responds to dose 
interruption and dose decrease. 
Symptomatic measures such as antihistamines or corticosteroids (oral 
or topical) have been successfully used to manage rash and have 
been used prophylactically in subsequent cycles. The use of a topical, 
IV, or oral steroid (e.g., prednisone ≤10 mg per day or equivalent) is 
permitted. Management of a Grade 3 rash may require intravenous 
antihistamines or corticosteroids. Administration of ixazomib/placebo 
(and/or other causative agent if given in combination) should be 
modified per protocol and re-initiated at a reduced level from where 
rash was noted (also, per protocol). 
In line with clinical practice, dermatology consult and biopsy of Grade 
3 or higher rash or any SAE involving rash is recommended. 
Prophylactic measures should also be considered if a patient has 
previously developed a rash (e.g., using a thick, alcohol-free emollient 
cream on dry areas of the body or oral or topical antihistamines). A 
rare side effect is Stevens-Johnson Syndrome, a severe and 
potentially life-threatening rash marked by skin peeling and mouth 
sores, which should be managed symptomatically according to 
standard medical practice. Punch biopsies for histopathological 
analysis are encouraged at the discretion of the investigator. 
5.6.10 
Thrombocytopenia 
Blood counts should be monitored regularly as outlined in the protocol 
with additional testing obtained according to standard clinical practice. 
Thrombocytopenia may be severe but has been manageable with 
platelet transfusions according to standard clinical practice. 
Ixazomib/placebo and lenalidomide administration should be modified 
as noted as per dose modification recommendations in the protocol 
when thrombocytopenia occurs (see Section 5.5). Therapy can be 
reinitiated at a reduced level upon recovery of platelet counts. A rare 
risk is thrombotic thrombocytopenic purpura (TTP), a rare blood 
disorder where blood clots form in small blood vessels throughout the 
body characterized by thrombocytopenia, petechiae, fever, or possibly 
more serious signs and symptoms. TTP should be managed 
symptomatically according to standard medical practice. 
5.6.11 
Neutropenia 
Blood counts should be monitored regularly as outlined in the protocol 
with additional testing obtained according to standard clinical practice. 
Neutropenia may be severe but has been manageable. Growth factor 
support is not required but may be considered according to standard 
clinical practice. Ixazomib/placebo administration should be modified 
as noted as per dose modification recommendations in the protocol 
when neutropenia occurs. Therapy can be reinitiated at a reduced 
level upon recovery of ANCs. 


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5.6.12 
Fluid deficit 
Dehydration should be avoided since ixazomib may cause vomiting, 
diarrhea, and dehydration. Patients should be encouraged to maintain 
adequate fluid intake. Acute renal failure has been reported in patients 
treated with ixazomib, commonly in the setting of the previously noted 
gastrointestinal toxicities and dehydration. Fluid deficit should be 
corrected before initiation of study drug and as needed during 
treatment to avoid dehydration. 
5.6.13 
Hypotension 
Symptomatic hypotension and orthostatic hypotension with or without 
syncope have been reported with ixazomib. Blood pressure should be 
closely monitored while the patient is on study treatment and fluid 
deficit should be corrected as needed, especially in the setting of 
concomitant symptoms such as nausea, vomiting, diarrhea, or 
anorexia. Patients taking medications and/or diuretics to manage their 
blood pressure (for either hypo- or hypertension) should be managed 
according to standard clinical practice, including considerations for 
dose adjustments of their concomitant medications during the course 
of the trial. Fluid deficit should be corrected before initiation of study 
drug and as needed during treatment to avoid dehydration. 
5.6.14 
Posterior Reversible Encephalopathy Syndrome 
One case of posterior reversible encephalopathy syndrome, which 
ultimately resolved, has been reported with ixazomib. This condition is 
characterized by headache, seizures and visual loss, as well as 
abrupt increase in blood pressure. Diagnosis may be confirmed by 
magnetic resonance imaging (MRI). If the syndrome is diagnosed or 
suspected, symptom-directed treatment should be maintained until 
the condition is reversed by control of hypertension or other instigating 
factors. 
5.6.15 
Transverse Myelitis 
Transverse myelitis has also been reported with ixazomib. It is not 
known if ixazomib causes transverse myelitis; however, because it 
happened to a patient receiving ixazomib, the possibility that ixazomib 
may have contributed to transverse myelitis cannot be excluded. 
5.6.16 
Thromboprophylaxis 
All patients should be on at least 81 mg ASA daily while receiving 
lenalidomide. If they are unable to take ASA or are at high risk of VTE 
per investigator assessment, full dose anticoagulation is 
recommended. 
5.7 
Duration of Therapy  
Patients will receive protocol therapy unless: 
x 
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 instructions in the 
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x 
Patient withdraws consent. 
x 
Patient experiences unacceptable toxicity. 
x 
Non-protocol therapies are administered. 
x 
Patient experiences disease progression. 
5.8 
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 10 years from the date of randomization. All 
patients must also be followed through completion of all protocol therapy. 
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6. 
Measurement of Effect 
6.1 
Response Considerations 
The International Myeloma Working Group (IMWG) uniform response criteria will 
be adapted to assess response to therapy in this trial.4,44 Since patients are 
entering the study at end of defined duration of therapy, and baseline disease 
parameters may not be known, we will limit the assessments to categories that 
are independent of baseline values (i.e., MRD negative, sCR, CR, and VGPR as 
defined below). 
6.1.1 
Terms and Definitions 
6.1.1.1 
M-Protein 
Synonyms include M-spike, monoclonal protein, myeloma 
protein, monoclonal paraprotein, M-component. 
6.1.1.2 
Free Light Chain (FLC) Estimation 
Currently carried out using the serum FLC assay (Freelite, 
The Binding Site Limited, UK). Patients with kappa/lambda 
FLC ratio < 0.26 are defined as having monoclonal lambda 
FLC and those with ratios > 1.65 as having a monoclonal 
kappa FLC. The monoclonal light chain isotype is 
considered the involved FLC isotype, and the opposite 
light chain type as the uninvolved FLC type. 
6.1.1.3 
Response Terms: 
Only the following response terms will be used in this 
study: Sustained MRD negative (MRD-), Flow MRD-, 
Sequencing MRD-, Imaging Plus MRD-, stringent complete 
response (sCR), complete response (CR), very good 
partial response (VGPR), and progression (PD). Partial 
response or stable response categories are not being used 
in the current study. 
See Section 6.2 for definitions. 
6.1.1.4 
Response Evaluation and Confirmation 
In order to assess hematologic response categories of 
sCR, CR and VGPR, assessment of serum M-protein, 
serum immunoglobulin free light chain and urine M-protein 
will need to be performed as applicable. Confirmation of 
these results must be made by verification on two 
consecutive determinations. 
A second confirmatory bone marrow is not required to 
confirm response in any case. 
Radiographic studies are not required to satisfy these 
response requirements; however, if radiographic studies 
were performed there should be no evidence of 
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6.1.1.5 
Bone Progression 
Caution must be exercised to avoid rating progression or 
relapse on the basis of variation of radiologic technique 
alone. Compression fracture does not exclude continued 
response and may not indicate progression. 
When progression is based on skeletal disease alone, it 
should be discussed with the study chair before removing 
the patient from the study. 
6.1.2 
Monoclonal Protein Considerations 
Serum M protein level is quantitated using densitometry on serum 
protein electrophoresis (SPEP) except in cases where the SPEP is 
felt to be unreliable. 
x 
M-proteins migrating in the β-region (usually IgA M-proteins) 
x 
Cases in which the M-protein is so large and narrow on agarose 
(some specimens > 4 g/dL) that they underestimate the actual 
immunoglobulin level (by greater than 1500 mg/dL) due to 
technical staining properties of the agarose gel 
x 
Cases in which there are multiple peaks of same M-protein 
(aggregates or dimers) 
If SPEP is not available or felt to be unreliable (above examples) for 
routine M-protein quantitation, then quantitative immunoglobulin levels 
derived from nephelometry or turbidometry can be accepted. 
However, this must be explicitly reported at baseline, and only 
nephelometry can be used for that patient to assess response. SPEP 
derived M-protein values and quantitative nephelometric 
immunoglobulin values cannot be used interchangeably. 
Urine M-protein measurement is estimated using 24-hour urine 
protein electrophoresis (UPEP) only. Random or 24-hour urine tests 
measuring kappa and lambda light chain levels are not reliable and 
are not allowed. 
6.2 
Response Categories 
6.2.1 
IMWG MRD Negativity Category 
Requires a complete response as defined in Section 6.2.2. MRD tests 
should be initiated only at the time of suspected complete response. 
MRD requires no known evidence of progressive or new bone lesions 
if radiographic studies were performed. However, radiographic studies 
are not required to satisfy these response requirements except for the 
requirement of 18F-FDG PET if imaging MRD-negative status is 
reported. 
6.2.1.1 
Sustained MRD Negative 
MRD negativity in the marrow (NGF or NGS, or both) and 
by imaging as defined below, confirmed minimum of 1 year 
apart. Subsequent evaluations can be used to further 
specify the duration of negativity (e.g., MRD-negative at 5 
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6.2.1.2 
Flow MRD Negative 
Absence of phenotypically aberrant clonal plasma cells by 
NGF on bone marrow aspirates using the EuroFlow 
standard operation procedure for MRD detection in 
multiple myeloma (or validated equivalent method) with a 
minimum sensitivity of 1 in 105 nucleated cells or higher 
6.2.1.3 
Sequencing MRD Negative 
Absence of clonal plasma cells by NGS on bone marrow 
aspirates in which presence of a clone is defined as less 
than two identical sequencing reads obtained after DNA 
sequencing of bone marrow aspirates using the ClonoSEQ 
platform (or validated equivalent method) with a minimum 
sensitivity of 1 in 105 nucleated cells or higher 
6.2.1.4 
Imaging Plus MRD Negative 
MRD negativity as defined by NGF or NGS plus 
disappearance of every area of increased tracer uptake 
found at baseline or a preceding PET/CT or decrease to 
less than mediastinal blood pool SUV or decrease to less 
than that of surrounding normal tissue 
6.2.2 
Standard IMWG Response Category 
6.2.2.1 
Stringent Complete Response (sCR) 
CR as defined below plus all of the following: 
x Normal serum FLC ratio at two consecutive times and  
x Absence of clonal cells in bone marrow by 
immunohistochemistry or 2- to 4- color flow cytometry.a 
x Presence/absence of clonal cells is based upon the κ/λ 
ratio. An abnormal κ/λ ratio by immunohistochemistry 
requires a minimum of 100 plasma cells for analysis. An 
abnormal ratio reflecting presence of an abnormal clone 
is κ/λ ratio of 4:1 or 1:2. 
6.2.2.2 
Complete Response (CR) 
Patients who have complete disappearance of an M-
protein and no evidence of myeloma in the bone marrow 
are considered to have complete response. To be 
considered CR, patients must meet all of the following 
criteria: 
x 
Negative immunofixation on the serum and urine 
x 
Disappearance of any soft tissue plasmacytomas 
x 
≤ 5% plasma cells in bone marrow 
x 
If the only measurable disease is FLC, a normal FLC 
ratio of 0.26-1.65 
6.2.2.3 
Very Good Partial Response (VGPR) 
x 
Serum M-protein detectable by immunofixation but not 
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x 
Urine M-protein < 100 mg/24 hours  
6.2.2.4 
Progression (PD) 
Patients will be considered to have met progression if one 
of the following criteria is met. The investigation that 
qualified as progression should be repeated and verified 
on a subsequent occasion only if treating physician deems 
it clinically necessary. 
Increase of ≥ 25% from lowest value reported in 
x 
Serum M-component and/or (the absolute increase 
must be ≥ 0.5 g/dL). 
x 
Urine M-component and/or (the absolute increase must 
be ≥ 200 mg/ 24 hours. 
x 
Only in patients without measurable serum and urine M 
protein levels: the difference between involved and 
uninvolved FLC levels. The absolute increase must be 
> 10 mg/dL. 
x 
If the only measurable disease is bone marrow, bone 
marrow plasma cell percentage: the absolute % must 
be ≥ 10%. 
x 
Development of new bone lesions or soft tissue 
plasmacytomas or ≥ 50% increase from nadir in the 
size (SPD) of existing bone lesions or soft tissue 
plasmacytoma or ≥ 50% increase in the longest 
diameter of a previous lesion > 1cm in short axis. 
Plasmacytoma measurements should be taken from 
the CT portion of the PET/CT, or MRI scans, or 
dedicated CT scans where applicable. For patients with 
only skin involvement, skin lesions should be 
measured with a ruler. Measurement of tumor size will 
be determined by the sum of the products of the 
maximal perpendicular diameters of measured lesions 
(SPD). 
6.2.2.5 
Clinical Relapse 
One or more of the following direct indicators of increasing 
disease and/or end-organ dysfunction that are considered 
related to the underlying plasma cell proliferative disorder 
with no alternate explanation: 
x 
Development of new soft tissue plasmacytomas or 
bone lesions on skeletal survey, magnetic resonance 
imaging, or other imaging 
x 
Definite increase in the size of existing plasmacytomas 
or bone lesions. A definite increase is defined as a 
50% (and at least 1 cm) increase as measured serially 
by the sum of the products of the cross-diameters of 
the measurable lesion 
x 
Hypercalcemia (>11.5 mg/dL; >2.875mM/L) 


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x 
Decrease in hemoglobin of more than 2 g/dL (1.25mM) 
or to less than 10 g/dL 
x 
Rise in serum creatinine by more than or equal to 2 
mg/dL (≥177mM/L) 
6.3 
Patient Reported Outcomes Measurement 
Patient reported outcomes assessments are required for English-speaking 
patients. 
6.3.1 
PRO Instruments 
FACT 
Health-related QOL will be assessed with three instruments: 1) the 
FACT-General (G) functional well-being (FWB) and physical well-
being (PWB) subscales.39 Each FACT-G subscale has 7 items. The 
14 items are based on a 5-point Likert scale (0-4) resulting in a score 
ranging from 0 to 56 points with a higher score indicating better 
health-related QOL; 2) The FACT/GOG-Neurotoxicity Trial Outcomes 
Index (FACT/GOG-Ntx TOI) comprised of the FWB and PWB 
subscales plus the neurotoxicity subscale which has 11 items, 
summing to a score of 0-100;70 and 3) the FACT-Multiple Myeloma 
Trial Outcomes Index (FACT-MM TOI) comprised of the FWB and 
PWB subscales plus the multiple myeloma subscale which has 14 
items, summing to a score of 0-112 for the instrument.40 The 
anticipated time to complete is roughly 8-10 minutes. 
NCI PRO-CTCAE 
NCI PRO-CTCAE items will be administered to allow patients to self-
report symptomatic adverse events experienced on treatment. In its 
current version (dated 6/22/2018), there are 80 symptomatic AE terms 
included in the PRO-CTCAE item library which draw directly from the 
CTCAE, the standardized safety assessment lexicon for cancer 
clinical trials. Items correspond to 5 attributes measured [frequency 
(F), severity (S), interference (I), presence/absence (P) and amount 
(A)] based on multiple choice questions. Response for each attribute 
except P which is binary is on a 5-point Likert scale with 5 indicating 
‘almost constantly’ frequency, ‘very severe’ severity, ‘very much’ 
amount or ‘very much’ interference. For each attribute, recall is the 
past 7 days. Attributes measured for each symptomatic AE varies and 
comprise the PRO-CTCAE item library. 
For this study, 23 symptomatic AEs summing to 38 items have been 
selected as presented below. There are 10 symptomatic AEs which 
are assessed using one item, 11 symptomatic AEs which are 
assessed using two items, and 6 symptomatic AEs which are 
assessed using three items. The types of items in order of prevalence 
include severity (n=18 symptomatic AEs), interference (n=9 
symptomatic AEs), frequency (n=7 symptomatic AEs), present/not 
present (n=4 symptomatic AE), and amount (none). The anticipated 
time to complete should be approximately 10 minutes. 
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PRO-CTCAE Symptomatic 
AE (Attributes) 
CTCAE Term – System Organ Class 
Dry Mouth (S) 
Dry mouth - Gastrointestinal disorders 
Taste Changes (S) 
Dysgeusia - Nervous system disorders 
Nausea (FS) 
Nausea - Gastrointestinal disorders 
Vomiting (FS) 
Vomiting - Gastrointestinal disorders 
Heartburn (FS) 
Dyspepsia - Gastrointestinal disorders 
Bloating (FS) 
Bloating - Gastrointestinal disorders 
Constipation (S) 
Constipation - Gastrointestinal disorders 
Diarrhea (F) 
Diarrhea - Gastrointestinal disorders 
Swelling (FSI) 
Edema limbs - General disorders and 
administration site conditions 
Rash (P) 
Rash maculo-papular - Skin and 
subcutaneous tissue disorders 
Skin Dryness (S) 
Dry skin - Skin and subcutaneous tissue 
disorders 
Itching (S) 
Pruritus - Skin and subcutaneous tissue 
disorders 
Hives (P) 
Urticaria - Skin and subcutaneous tissue 
disorders 
Sensitivity to Light (P) 
Photosensitivity - Skin and subcutaneous 
tissue disorders 
Numbness and Tingling (SI) 
Peripheral sensory neuropathy - Nervous 
system disorders 
Dizziness (SI) 
Dizziness - Nervous system disorders 
Blurred Vision (SI) 
Blurred vision - Eye disorders 
Concentration (SI) 
Concentration Impairment - Nervous system 
disorders 
Memory (SI) 
Memory impairment - Nervous system 
disorders 
Muscle Pain (FSI) 
Myalgia - Musculoskeletal and connective 
tissue disorders 
Insomnia (SI) 
Insomnia - Psychiatric disorders 
Fatigue (SI) 
Fatigue - General disorders and 
administration site conditions 
Bruising (P) 
Bruising - Injury, poisoning and procedural 
complications 
Adherence Starts with Knowledge Scale 
The Adherence Starts with Knowledge Scale (ASK-12) will be used to 
assess the likelihood that a patient is taking oral medications per 
protocol.43 The 12-item questionnaire was derived from the 
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asthma, congestive heart failure or diabetes.42 In this study, the ASK-
12 had good internal consistency (Cronbach’s coefficient alpha=0.75), 
and test-retest reliability (intraclass correlations (ICC)=0.79). The 
ASK-12 which elicits the same type of information as the Morisky 
Medication Adherence Scale (MMAS) also demonstrated convergent 
validity through strong correlation with MMAS-4 (Spearman 
correlation r = 0.74; p < 0.001). The ASK-12 titled ‘Taking Medicine-
What Gets in the Way?’ is segmented into three sections: 
inconvenience/forgetfulness (3 items), treatment beliefs (4 items) and 
behavior (5 items). Response for each item is on a 5-point Likert scale 
(1-5) with the total score ranging from 12-60 and a higher score 
representing less likelihood of medication adherence. The anticipated 
time to complete is roughly 3-4 minutes. 
6.3.2 
Patient-Reported Outcomes Assessment Schedule 
PRO time-points overlap with protocol-specified clinic visits. The NCI 
PRO-CTCAE will be assessed at baseline and the beginning of each 
cycle on study therapy up to two-years. The FACT-G (PWB+FWB), 
Ntx and MM are first administered at baseline prior to starting 
treatment for evaluation of change longitudinally. The FACT-G 
(PWB+FWB), Ntx and MM then will be administered every three 
cycles for the first 24 cycles (beginning of cycles 4, 7, 10, 13, 16, 19, 
22 and 25) and every six cycles thereafter up to completion of 48 
cycles (beginning of cycles 31, 37, 43, 49), and at treatment 
discontinuation prior to completing 48 cycles. During long-term follow-
up, there will be 4 quarterly assessments for one year. The ASK-12 
will be assessed every six cycles on treatment up to completion of 48 
cycles (beginning of cycles 7, 13, 19, 25, 31, 37, 43, and 49). 
Assessment 
Timepoint1,2 
Questionnaires to be Administered 
Study Cycle 
FACT-G, Ntx 
and MM3 
PRO-CTCAE 
ASK-12 
Baseline 
Within 28 days 
prior to Step 1 
registration 
X 
X 
 
On Treatment 
Cycles 2-3 
 
X 
 
Cycle 4 
X 
X 
 
Cycles 5-6 
 
X 
 
Cycle 7 
X 
X 
X 
Cycles 8-9 
 
X 
 
Cycle 10 
X 
X 
 
Cycles 11-12 
 
X 
 
Cycle 13 
X 
X 
X 
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Assessment 
Timepoint1,2 
Questionnaires to be Administered 
Study Cycle 
FACT-G, Ntx 
and MM3 
PRO-CTCAE 
ASK-12 
Cycles 14-15 
 
X 
 
Cycle 16 
X 
X 
 
Cycles 17-18 
 
X 
 
Cycle 19 
X 
X 
X 
Cycles 20-21 
 
X 
 
Cycle 22 
X 
X 
 
Cycles 23-24 
 
X 
 
Cycle 25 
X 
X 
X 
Cycle 31 
X 
 
X 
Cycle 37 
X 
 
X 
Cycle 43 
X 
 
X 
Cycle 49 
X 
 
X 
Long Term Follow-Up4 
3 months post-tx 
X 
 
 
6 months post-tx 
X 
 
 
9 months post-tx 
X 
 
 
1-year post-tx  
X 
 
 
1 +/- 7 days if appointments on the scheduled date are missed, the 
questionnaires will be mailed electronically to participants who will be asked 
to complete the questionnaires and return answers by electronic mail to the 
clinic. After 7 days, clinic or research staff may contact participants by 
telephone and ask participants to complete the questionnaire over the 
telephone reading their answers to the staff person. This approach will 
approximate the completion of PROs in clinic as closely as possible. 
2. Assessments to be completed at beginning of the cycle +/- 7 days. 
3 FACT-G, Ntx and FACT-MM measures are included on one paper form. 
FACT-G, Ntx and MM will also be assessed at treatment discontinuation 
prior to 48 cycles 
4 Months post-treatment with respect to the date of discontinuation of 
treatment. 
6.3.3 
Patient-Reported Outcomes Additional Instructions 
All questionnaires will be administered as a paper survey, with the aim 
that the patient completes questionnaires at the time of scheduled 
study clinic visits. 
The patient should be instructed to respond to the questionnaires in 
terms of his or her experience during the timeframe specified on each 
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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 questionnaires as long as the staff person 
does not influence the patient’s responses. 
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 or she is feeling. If a question was not answered, the 
patient should be asked if he or she would like to answer it. The 
patient should always have the option to refuse. If the patient cannot 
complete a questionnaire, or if the patient refuses to complete a 
questionnaire, the reason should be noted according to the 
instructions in the EAA171 Forms Completion Guidelines. 
If appointments on the scheduled date are missed, the questionnaires 
will be mailed electronically to participants who will be asked to 
complete the questionnaires and return answers by electronic mail to 
the clinic. After 7 days, clinic or research staff may contact 
participants by telephone and ask participants to complete the 
questionnaire over the telephone reading their answers to the staff 
person. This approach will approximate the completion of PROs in 
clinic as closely as possible. 
NOTE: 
When delivering questionnaires to patients by electronic 
mail or over the telephone, please document the process 
of distribution and completion carefully and thoroughly in 
the medical record in case of an audit review. 
PRO-CTCAE items will be administered sometimes coincident with 
other study PRO measures following procedures for PRO 
administration as described above. PRO-CTCAE items will be 
administered prior to clinic visits, or prior to participant’s discussion of 
disease status and treatment side effects with health-care 
professionals. This is modeled after NCI PRO-CTCAE study 
procedures employed in other clinical trial validation studies. 
Clinicians will be instructed to complete clinician-rated treatment 
toxicities (CTCAE) prior to reviewing PRO-CTCAE ratings. This will 
minimize the extent to which PRO-CTCAE responses introduce a bias 
to clinician CTCAE ratings. PRO-CTCAE are currently undergoing 
validation and thus exploratory in nature, therefore, at this point 
should not be used to inform clinician CTCAE ratings. Clinicians will 
be instructed to review PRO-CTCAE items after clinician toxicity 
ratings have been completed to identify any patient-reported 
symptoms and toxicities that warrant clinical attention. Supportive 
care measures to manage treatment toxicities are described in 
Section 5.6. 
 
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7. 
Study Parameters 
7.1 
Therapeutic Parameters (for both arms of the study) 
1. Pre-study scans and x-rays used to assess all measurable or non-measurable sites of disease must be done ≤ 4 
weeks prior to randomization. 
2. Pre-study CBC (with differential and platelet count) must be done ≤ 14 days prior to randomization. 
3. All required pre-study chemistries, as outlined in Section 3, must be done ≤ 14 days prior to randomization – unless 
specifically required on Day 1 as per protocol. 
Schedule of events 
Biological Specimen Submission: MANDATORY for Minimal Residual Disease Assessment 
 
Following Pre-Registration 
Submit to: 
Bone Marrow Aspirate (1) 6mL ACD 
(yellow top) tube10 
X 
Mayo Clinic 
 
Study Parameters 
Tests and Procedures 
Prior to 
randomization 
(≤ 28 days 
unless 
otherwise 
noted) 
At the end of 
each cycle 
Annually 
At study 
discontinuation 
or progression 
(whichever 
comes first) 
28 days after 
discontinuation 
of treatment 
Post 
Treatment to 
10 years from 
study entry9 
History and Exam, Performance Status, 
Height16 and Weight 
X 
X 
 
X 
 
 
CBC with Differential1 
X 
X 
 
X 
 
 
Chemistry Labs2 
X 
X 
 
X 
 
 
Beta-2 Microglobulin 
X 
 
 
 
 
 
LDH 
X 
 
 
 
 
 
SPEP3 
X 
X 
 
X 
 
X 
Serum M-protein Immunofixation 
X13 
X7 
 
 
 
X7 
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Study Parameters 
Tests and Procedures 
Prior to 
randomization 
(≤ 28 days 
unless 
otherwise 
noted) 
At the end of 
each cycle 
Annually 
At study 
discontinuation 
or progression 
(whichever 
comes first) 
28 days after 
discontinuation 
of treatment 
Post 
Treatment to 
10 years from 
study entry9 
24 hr UPEP3 
X 
X 
 
X 
 
X 
24 hr Urine M-protein Immunofixation 
X13 
X7 
 
 
 
X7 
Serum Free Light Chain Assay 
X 
X7 
 
X 
 
X15 
Serum Immunoglobulin G, A, M 
X 
X 
 
X 
 
X 
Bone Marrow Aspirate and/or Biopsy 
X 
 
X11 
 
 
 
18F-FDG PET/CT 
X8 
X12 
 
 
 
 
Serum or Urine Pregnancy Test4 
X 
X 
 
X 
X 
 
Adverse Event Assessment 
X 
X 
 
 
X 
 
PRO Assessment5 
See Section 6.3.2 
MRD  
See above: Biological Specimen Submission table 
Registration to Revlimid REMS®14 
X 
 
 
 
 
 
Patient Medication Calendar6 
 
X 
 
 
 
 
1. Baseline CBCs (with differential and platelet count) which includes WBC, ANC, Platelets, and Hgb must be done ≤ 14 days prior to 
randomization. CBCs required for protocol therapy must be done < 4 days prior to the treatment cycle. 
2. Chemistry includes sodium, potassium, calcium, blood urea nitrogen (BUN), creatinine, creatinine clearance, glucose, alkaline phosphatase, 
total bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Magnesium and phosphorus are not required but should 
be tested as clinically indicated.  
3. Assessment is required if used to assess disease response. To confirm VGPR or higher response, both serum and urine M-components must 
be evaluated. 
4. Patients of childbearing potential must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 to 14 
days prior to starting lenalidomide. It is recommended to perform the pregnancy test as close to the date of randomization as possible in case 
there are drug shipment and treatment start date delays. A negative serum or urine pregnancy test must be repeated within 24 hours of starting 
lenalidomide and with each new cycle. Patients must also 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, for 1) at least 28 
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days before starting study treatment; 2) while participating in the study; 3) during dose interruptions; and 4) for at least 90 days after the last 
dose of protocol treatment. Patients of childbearing potential with regular or no menstrual cycles must agree to have pregnancy tests weekly for 
the first 28 days of study participation and then every 28 days while on study, at study discontinuation, and at day 28 following discontinuation 
from the study. If menstrual cycles are irregular, the pregnancy testing must occur weekly for the first 28 days and then every 14 days while on 
study, at study discontinuation, and at days 14 and 28 following discontinuation from the study. Men must agree to use a latex condom during 
sexual contact with a partner of childbearing potential while participating in the study and for 90 days after the last dose of protocol treatment 
even if they have had a successful vasectomy. See Appendix VI: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth 
Control Methods 
5. Please refer to Section 6.3.2 for the PRO assessment schedule.  
6. The Patient Medication Calendar must be completed for each cycle of treatment to record ixazomib/placebo and lenalidomide capsules taken. 
Please see Appendix II: Patient Medication Calendar.  
7. Serum and urine immunofixation and serum FLC only need to be repeated to confirm sCR or CR. 
8. Within 8 weeks of pre-registration Step 0. 
9. Follow-up post-treatment till progression. After progression, follow for survival for a maximum of 10 years. Every 3 months if patient is < 2 years 
from randomization, every 6 months if patient is 2-5 years from randomization, every 12 months if patient is 5 years or more from randomization. 
No specific requirements if patient is more than 10 years from randomization. 
10. All specimens must be entered and tracked via the online ECOG-ACRIN Sample Tracking System (STS). See Section 10.3 
11. End of cycles 12, 24, 36 and 60 (± 6 weeks) only 
12. End of cycles 12 and 24 (± 6 weeks) only 
13. Institutions must upload immunofixation test results via Medidata Rave to determine eligibility status for Step 1 randomization. 
14. Please refer to Section 8.2.8 and www.celgeneriskmanagement.com for information about the Revlimid REMS® program. 
15. As clinically indicated. 
16. Height is only required at baseline (prior to randomization) and does not need to be repeated. 
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8. 
Drug Formulation and Procurement 
Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and 
research staff through the PMB OAOP application. Access to OAOP requires the 
establishment of a CTEP IAM account and the maintenance of an “active” account 
status, a “current” password and active person registration status. Questions about IB 
access may be directed to the PMB IB Coordinator via email. 
Useful Links and Contacts 
x 
CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/ 
x 
NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov 
x 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
x 
PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP 
x 
CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  
x 
CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov  
x 
IB Coordinator: IBCoordinator@mail.nih.gov  
x 
PMB email: PMBAfterHours@mail.nih.gov 
x 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) 
8.1 
MLN9708 (Ixazomib citrate) 
8.1.1 
Other Names  
Ixazomib ML0070120, MLN2238 citrate ester, Ninlaro® 
8.1.2 
Classification 
Proteasome inhibitor 
8.1.3 
Mode of Action 
Ixazomib/placebo is a reversible proteasome inhibitor. 
Ixazomib/placebo preferentially binds and inhibits the chymotrypsin-
like activity of the beta 5 subunit of the 20S proteasome. It induced 
apoptosis of multiple myeloma cell lines in vitro. 
8.1.4 
Storage and Stability 
Storage: Store ixazomib/placebo capsules between 2º – 30ºC (36º – 
86ºF). Ixazomib/placebo should remain in the blister and carton 
provided until use. Do not freeze or store above 30°C. 
If a storage temperature excursion is identified, promptly return 
ixazomib/placebo capsules to 2º – 30ºC (36º – 86ºF) and quarantine 
the supplies. Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the 
excursion) to PMBAfterHours@mail.nih.gov for determination of 
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Stability: Stability studies are ongoing. 
8.1.5 
Dose Specifics 
Ixazomib/placebo will be administered at a dose of 4 mg on days 1, 8, 
and 15 of each cycle. 
8.1.6 
Preparation  
No specific preparation is required. 
NOTE: 
Ixazomib/placebo is an anticancer drug. As with other 
potentially toxic compounds, caution should be exercised 
when handling ixazomib/placebo. It is recommended to 
wear gloves and protective garments during preparation 
when dispensed in clinic. Please refer to published 
guidelines regarding the proper handling and disposal of 
anticancer agents. 
8.1.7 
Route of Administration 
Ixazomib/placebo will be administered orally. 
8.1.8 
Method of Administration 
Take capsule(s) on an empty stomach, 1 hour before or 2 hours after 
food. Swallow whole capsules with water. Do not open or break 
capsules. 
Missed or delayed dose can be taken only if the next scheduled dose 
is ≥ 72 hours away. A missed dose should not be taken within 72 
hours of the next scheduled dose. If vomiting occurs after taking a 
dose, the patient should not repeat the dose. Resume dosing at the 
time of the next scheduled dose. 
8.1.9 
Availability 
Clinical Supplies: Ixazomib (NSC 767907) and matching placebo will 
be provided free of charge by Takeda and distributed by the 
Pharmaceutical Management Branch (PMB), Cancer Therapy 
Evaluation Program (CTEP), Division of Cancer Treatment and 
Diagnosis (DCTD), National Cancer Institute (NCI). 
Ixazomib and matching placebo will be supplied in blister cards 
containing 3 capsules each. 
Each blinded, patient-specific blister card will be labeled with: 
x 
the protocol number (i.e., “EAA171”) 
x 
the blister card number (i.e., “blister card 1 of 2” or “blister card 2 
of 2”) 
x 
the number of capsules (i.e., “3 capsules”) 
x 
the patient ID number (e.g.,"99999", which represents the unique 
patient identifier assigned at registration) 
x 
the patient initials (i.e., first initial, middle, last initial [e.g., "FML"]) 
x 
the agent identification (i.e., “Ixazomib 4 mg or placebo capsule”, 
“Ixazomib 3 mg or placebo capsule” or “Ixazomib 2.3 mg or 
placebo capsule”) 
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x 
a blank line for the pharmacist to enter the patient’s name 
x 
administration instructions (i.e., “Take one capsule on days 1, 8 
and 15 of each 28-day cycle.”) 
x 
storage instructions [i.e., “Store between 2º – 30º C (36º – 86º 
F).”] 
x 
emergency contact instructions 
x 
a Julian date 
The Julian date indicates the day the bottle was labeled and shipped 
and is composed of the last two digits of the calendar year (e.g., 2019 = 
19, 2020 = 20) and a day count (e.g., January 1 = 001, December 31 = 
365). For example, a bottle labeled and shipped on January 1, 2019 
would have a Julian date of ‘19001’ and a bottle labeled and shipped on 
December 31, 2019 would have a Julian date of ‘19365’. The Julian 
date will be used by PMB for recalls. When a lot expires, PMB will 
determine the last date the expired lot was shipped and will recall all 
bottles (i.e., both Ixazomib and Placebo) shipped on or before that date 
thus eliminating any chance of breaking the blind. The Julian Date – 
Order number (e.g., 21352-0003) from the patient-specific label 
must be used as the Lot number on the NCI Oral DARF. 
BLINDED AGENT ORDERS: No blinded starter supplies will be 
available for this study. 
Patients will be registered and randomized through OPEN and assigned 
patient ID number. This number must recorded by the registering 
institution at the time of registration for proper clinical supply dispersion. 
Once a patient has been registered, ECOG-ACRIN will electronically 
transmit a clinical drug request for that patient to the PMB. This request 
will be entered and transmitted by ECOG-ACRIN the day the patient is 
registered and will be processed by PMB the next business day and 
shipped the following business day. If a patient is registered on Monday, 
ECOG-ACRIN would enter a clinical drug request for that patient on 
Monday and PMB would process that request on Tuesday and ship the 
drug on Wednesday. Sites could expect to receive their order 
approximately Thursday or Friday. Shipments to United States sites can 
be expedited (i.e., receipt on Thursday in example above) by the 
provision of an express courier account name and number to ECOG-
ACRIN at the time the patient is registered/randomized. 
The initial patient-specific supply will be enough to complete 8 weeks of 
treatment (2 x 3-capsule blister cards). The supplies will be sent to the 
registering investigator / drug shipment investigator at the time of 
registration and should arrive within 5 to 7 business days. Subsequent 
orders for blinded, patient-specific supplies must be requested by the 
Principal Investigator (or his/her authorized designee[s]) for EAA171 at 
each participating institution using the PMB On-line Agent Order 
Processing (OAOP) program. The assigned patient ID number (e.g., 
999999) and the patient initials (e.g., "FML") should be entered in the 
"Patient or Special Code" field. A separate order is required for each 
patient ID number (e.g., 999999) being ordered. All drug orders should 
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be shipped directly to the physician responsible for treating the patient. 
Requests can be placed 6 weeks after the last shipment is received. 
DOSE ADJUSTMENTS: Starter supplies for dose reductions will 
not be provided. If the patient is dose reduced from the original 4 mg or 
placebo dose, an agent request must be submitted by the site through 
the OAOP application. Ixazomib/placebo 3 mg and 2.3 mg dose 
adjustments will be ordered through OAOP only at the time of the dose 
reduction. The patient-specific blister cards of the dose adjusted 
supplies will be enough to complete 8 weeks of treatment (2 x 3-capsule 
blister cards). Requests for additional supplies can be placed 6 weeks 
after the last shipment is received. 
Pharmaceutical Management Branch (PMB) policy requires that agent 
be shipped directly to the institution where the patient is to be treated. 
The CTEP-assigned protocol number and patient ID must be used for 
ordering all CTEP-supplied investigational agents for this study. The 
responsible investigator must be registered with CTEP, DCTD through 
an annual submission of FDA Form 1572 (Statement of Investigator), 
NCI BioSketch, Agent Shipment Form (ASF), and Financial Disclosure 
Form (FDF). 
Active CTEP-registered investigators and investigator-designated 
shipping designees and ordering designees must submit agent requests 
through the PMB Online Agent Order Processing (OAOP) application. 
Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” 
account status and a “current” password. For questions about drug 
orders, transfers, returns, or accountability, call or email PMB at any 
time. Refer to the PMB's website for specific policies and guidelines 
related to agent management. 
Transfer of Ixazomib/Placebo: Ixazomib/placebo may not be 
transferred from one patient to another patient or from one protocol to 
another protocol. PMB does not permit the transfer of agents between 
institutions (unless prior approval from PMB is obtained). 
Ixazomib/placebo supplied for this study may not be used outside the 
scope of this protocol. To obtain an approval for transfer, investigators 
should complete and submit to the PMB (PMBAfterHours@mail.nih.gov) 
a Transfer Investigational Agent Form available on the NCI home page 
(http://ctep.cancer.gov) or call the PMB at 240-276-6575. The 
participating institution should also inform the ECOG-ACRIN of the 
transfer by transferring the patient in TUMS. 
Return of Ixazomib/Placebo: At the completion of accrual and 
treatment, all unused (unopened) blister packs of ixazomib/placebo 
must be returned to the PMB. When it is necessary to return study drug 
(e.g., unused blister packs remaining when the protocol is closed to 
accrual and treatment at a participating clinical site, unopened expired 
blister packs, or supplies remaining after a patient goes off of protocol 
treatment), investigators should return the ixazomib/placebo to the PMB 
using the NCI Return Agent Form available on the NCI home page 
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Supplies remaining from dispensed blister cards should be documented 
on the patient-specific NCI Investigational Agent Accountability Record 
Form for Oral Agents. On the correct dispensing row, document the date 
returned and the quantity, then destroy on site in accordance with 
institutional policy. 
Agent Inventory Records: The investigator, or a responsible party 
designated by the investigator, must maintain a careful record of the 
receipt, dispensing and final disposition of all agents received from the 
PMB using the appropriate NCI Investigational Agent (Drug) 
Accountability Record (DARF) available on the CTEP forms page. Store 
and maintain separate NCI Investigational Agent Accountability Records 
for each patient, agent, strength, formulation and ordering investigator 
on this protocol. Please note that the Julian Date – Order number 
(e.g., 21352-0003) from the patient-specific label must be used as 
the Lot number on the NCI Oral DARF. 
Questions about drug orders, transfers, returns, or accountability 
should be addressed to the PMB by calling (240) 276-6575 Monday 
through Friday between 8:30am and 4:30pm Eastern Time. You may 
also contact the PMB via e-mail at PMBAfterHours@mail.nih.gov. 
8.1.10 
Side Effects  
See Section 5.4.1 for the Comprehensive Adverse Event and 
Potential Risks (CAEPR) list. 
8.1.11 
Potential Drug Interactions 
Ixazomib/placebo is metabolized by CYP3A4 (42.3%), 1A2 (26.1%), 
2B6 (16%), 2C8 (6%), 2D6 (4.8%), 2C19 (4.8%), and 2C9 (<1%). Co-
administration of ixazomib/placebo with clarithromycin did not result in 
a clinically significant change in the systemic exposure of 
ixazomib/placebo. Co-administration of ixazomib/placebo with 
rifampin decreased ixazomib/placebo Cmax by 54% and AUC by 
74%. Therefore, avoid concomitant administration of ixazomib/placebo 
with strong CYP3A4 inducers (such as rifampin, phenytoin, 
carbamazepine, and St. John’s Wort).  
Ixazomib/placebo is neither a time-dependent nor a reversible inhibitor 
of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. Ixazomib/placebo did 
not induce CYP1A2, CYP2B6, and CYP3A4/5 activity or 
corresponding immunoreactive protein levels. Ixazomib/placebo is not 
expected to produce drug-drug interactions via CYP inhibition or 
induction. 
Ixazomib/placebo is a low affinity substrate of P-gp. Ixazomib/placebo 
is not a substrate of BCRP, MRP2 or hepatic OATPs. 
Ixazomib/placebo is not an inhibitor of P-gp, BCRP, MRP2, 
OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2-K. 
Hence, ixazomib/placebo is not expected to cause transporter-
mediated drug-drug interactions. 
8.1.12 
Patient Implications 
There are no human data available regarding the potential effect of 
ixazomib/placebo on pregnancy or development of the embryo or 
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fetus. Based on clinical data, ixazomib/placebo caused embryo-fetal 
toxicity in pregnant rats and rabbits at doses resulting in exposures 
that were slightly higher than those observed in patients receiving the 
recommended dose. Patients should avoid becoming pregnant while 
being treated with ixazomib/placebo. Patients of childbearing potential 
and patients who are sexually active with a partner of childbearing 
potential must use effective contraceptive measures during and for 90 
days following treatment. 
It is not known whether ixazomib/placebo or its metabolites are 
present in human milk. Many drugs are present in human milk and as 
a result, there could be a potential for adverse events in nursing 
infants. Patients should discontinue nursing while receiving 
ixazomib/placebo. 
8.2 
Lenalidomide 
Please refer to the commercial package insert for complete drug and toxicity 
information. 
8.2.1 
Other Names 
CC-5013, Revlimid™, CDC-501 
8.2.2 
Classification 
Immunomodulatory Agent 
8.2.3 
Mode of Action 
Lenalidomide, a thalidomide analog, is an immunomodulatory agent 
with a spectrum of activity that is still under investigation. Some of its 
effects include inhibition of inflammation, inhibition of angiogenesis, 
inhibition of hematopoetic tumor cell proliferation, modulation of stem 
cell differentiation and upregulation of T cell and NK cell responses. 
8.2.4 
Storage and Stability 
Storage: Store capsules at room temperature (25°C). Excursions are 
permitted (to 15-30°C). 
Stability: Refer to the package labeling for expiration date. 
8.2.5 
Dose Specifics 
Lenalidomide will be administered at a dose of 10 mg on days 1-28. 
8.2.6 
Preparation 
No preparation is required. 
Only a one cycle (28-day) supply may be dispensed at one time. 
8.2.7 
Route of Administration 
Take lenalidomide by mouth with or without food. Do not crush, chew 
or open capsules. 
8.2.8 
Availability 
Lenalidomide will be provided in accordance with Celgene 
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REMS® program requirements, all physicians who prescribe 
lenalidomide for research patients enrolled into this trial, and all 
research patients enrolled into this trial, must be registered in, and 
must comply with, all requirements of the Revlimid REMS® program. 
Further information about the Revlimid REMS® program is available 
at www.celgeneriskmanagement.com. 
Celgene distributes lenalidomide 2.5 mg and 5 mg hard gelatin 
capsules in tamper-evident, child-resistant, opaque, high density 
polyethylene (HDPE) bottles with HDPE caps. 
The capsules also contain anhydrous lactose, microcrystalline 
cellulose, croscarmellose sodium, and magnesium stearate. 
8.2.9 
Side Effects 
See Section 5.4.2 for the Comprehensive Adverse Event and 
Potential Risks (CAEPR) list. 
8.2.10 
Potential Drug Interactions 
Periodic monitoring of digoxin levels is recommended during 
coadministration with lenalidomide. 
Monitor patients receiving concomitant warfarin per standard practice 
guidelines. 
Lenalidomide is not a substrate of human CYP enzymes, nor is it an 
inhibitor or inducer. 
8.2.11 
Nursing/Patient Implications 
Risks Associated with Pregnancy 
Lenalidomide is structurally related to thalidomide. Thalidomide is a 
known human teratogenic active substance that causes severe life-
threatening birth defects. An embryofetal development study in 
animals indicates that lenalidomide produced malformations in the 
offspring of female monkeys who received the drug during pregnancy. 
The teratogenic effect of lenalidomide in humans cannot be ruled out. 
Therefore, a risk minimization plan to prevent pregnancy must be 
observed. 
Definition of patient of childbearing potential 
A patient of childbearing potential is anyone, regardless of sexual 
orientation or whether they have undergone tubal ligation, who meets 
the following criteria: 1) has achieved menarche at some point, 2) has 
not undergone a hysterectomy or bilateral oophorectomy, or 3) has 
not been naturally postmenopausal (amenorrhea following cancer 
therapy does not rule out childbearing potential) for at least 24 
consecutive months (i.e., has had menses at any time in the 
preceding 24 consecutive months). 
Before starting study drug: 
Patients of Childbearing Potential: 
x 
Patients of childbearing potential must have two negative 
pregnancy tests (minimum sensitivity of 25 mIU/mL) prior to 
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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 Investigator has verified that the results of these pregnancy 
tests are negative. 
Male Patients: 
x 
Must agree to use a latex condom during sexual contact with 
partners of childbearing potential while participating in the study 
and for at least 28 days following discontinuation from the study 
even if they have undergone a successful vasectomy. 
All Patients: 
x 
Only enough lenalidomide for one cycle of therapy may be 
dispensed with each cycle of therapy.  
x 
If pregnancy or a positive pregnancy test does occur in a study 
patient or the partner of a male patient during study participation, 
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9. 
Statistical Considerations 
9.1 
Study Design 
This is a randomized phase III study with the primary aim to evaluate whether 
intensifying maintenance therapy based on MRD positive status after 
approximately 1 year post early stem cell transplant lenalidomide maintenance 
results in prolonged overall survival (OS). OS will be compared between patients 
with MRD positive status (n=510) randomized to either ixazomib-lenalidomide 
(Arm A) or placebo-lenalidomide (Arm B). 
9.2 
Study Endpoints 
9.2.1 
Clinical Outcomes 
9.2.1.1 
Primary Endpoint 
x 
Overall survival defined as the time from randomization 
to death due to any cause, or censored at date last 
known alive 
9.2.1.2 
Secondary Endpoints 
x 
Progression-free survival defined as the time from 
randomization until the earlier of progression or death 
due to any cause, or censored at date of last disease 
evaluation (Note: Only deaths that occur within 3 
months of the last disease evaluation are considered 
events.) 
x 
Best response on treatment for eligible patients based 
on standard IMWG criteria as described in Section 6; 
Response rates for eligible patients including very good 
partial response (VGPR), complete response (CR) and 
stringent CR (sCR) at 12-, 24-, 36- and 60-cycles post-
randomization 
x 
Incidence of adverse events by worst grade and type 
for treated patients determined using CTCAE; Rates of 
worst grade 3 or higher non-hematologic toxicity and 
overall worst grade 3 or higher toxicity on treatment 
9.2.1.3 
Exploratory Endpoints 
x 
Time to progression (TTP) defined as the time from 
randomization to progression, or censored at date of 
last disease evaluation 
x 
Duration of response (DOR) defined as the time of 
observed response (VGPR or better) to the time of 
progression in the respective group of responders 
x 
Treatment duration calculated as the time from 
randomization to date off treatment, or censored at the 
date of last treatment 
x 
Cumulative dose calculated as the sum of all doses 
taken across all cycles 
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x 
Dose intensity calculated as cumulative dose received 
divided by treatment duration 
x 
Relative dose intensity calculated as the dose intensity 
divided by planned dose intensity 
9.2.2 
Patient-Reported Outcomes 
9.2.2.1 
Primary Endpoint 
x 
Change in FACT/GOG-Ntx TOI score calculated as the 
difference after completion of 12 cycles of study 
therapy from baseline 
x 
Change in FACT-MM TOI score calculated as the 
difference after completion of 24 cycles of study 
therapy from baseline 
9.2.2.2 
Secondary Endpoints 
x 
Levels and changes from baseline of all instruments  
x 
Time to worsening of FACT/GOG-Ntx TOI defined as 
the time from baseline to a decrease of 8 points (MID), 
respectively, or censored at the date of last 
assessment 
x 
FACT/GOG-Ntx TOI recovery rate in the patients 
experiencing a MID decrease, the proportion of 
patients with the FACT/GOG-Ntx TOI score returning 
to baseline level 
x 
Time to improvement of the FACT-MM TOI defined as 
the time from baseline to an increase of 10 points 
(MID), respectively, or censored at the date of last 
assessment 
x 
FACT-MM TOI response rate defined as the proportion 
of patients experiencing a MID improvement since 
baseline at each assessment time point 
9.2.2.3 
Exploratory Endpoints 
x 
Presence, frequency, interference, amount and/or 
severity of select PRO-CTCAEs tabulated at each 
cycle 
x 
ASK-12 scores at each assessment time point 
x 
PRO compliance rate defined as the proportion of 
patients who submit the given PRO instrument among 
those eligible at each time point which excludes those 
missing by design (due to death or disease 
progression, early treatment discontinuation) 
x 
PRO completion rate defined as the proportion of 
patients who complete given PRO instrument based on 
the instrument’s scoring system among those eligible 
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9.3 
Statistical Analysis Plan 
9.3.1 
Primary Clinical Analysis 
The primary analysis will be on an intention to treat (ITT) basis 
considering the randomized treatment assignment irrespective of 
treatment received. OS will be estimated using the Kaplan-Meier (KM) 
method and compared using a stratified log-rank test. Stratified cox 
proportional hazards regression will produce a treatment hazard ratio 
(HR) estimate (ixazomib-lenalidomide/placebo-lenalidomide). Interim 
analyses for efficacy will be conducted. The design incorporates a 
group sequential monitoring plan with 6 interim analyses (IA) and one 
final analysis for the OS comparison between arms. Based on accrual 
and failure rate assumptions in the sample size calculation (Section 
9.4), interim analyses are expected to occur from 3y to 5.5y after 
randomization and the final analysis at full information (179 deaths) is 
expected to occur after 6y of follow-up. Critical values as presented 
below in Table 1 are based on the Lan-DeMets error spending rate 
function corresponding to the truncated version of O’Brien-Fleming 
boundaries to preserve the overall type I error rate. At each interim 
analysis, the null hypothesis of equal OS on the two arms will be 
tested against the 1-sided alternative of increased OS on the 
ixazomib-lenalidomide arm. The p-value from a 1-sided stratified log-
rank test will be compared to the level of nominal significance 
associated with these critical values. If the boundary is crossed at an 
IA, there is sufficient evidence of efficacy to stop the study in favor of 
the alternative hypothesis. The DSMC then would consider stopping 
the study early. 
Table 1 
Analysis 
Study 
Time 
(years) 
Information 
Time (%) 
Failures 
under 
Alternative 
Critical 
Value 
Nominal 
Significance 
1 
3.0 
35% 
63 
3.2905 
0.0005 
2 
3.5 
47% 
84 
3.1768 
0.0007 
3 
4.0 
59% 
105 
2.7443 
0.0030 
4 
4.5 
70% 
126 
2.4984 
0.0062 
5 
5.0 
81% 
145 
2.3232 
0.0101 
6 
5.5 
91% 
162 
2.1904 
0.0142 
7 
6.0 
100% 
179 
2.0858 
0.0185 
Coupled with the interim analysis for early stopping for superiority of 
ixazomib-lenalidomide (Arm A), the study will be monitored for harm 
and inefficacy. At 35% information, the DSMC may consider stopping 
the study early for harm if the lower bound of a 95% confidence 
interval for the HR is above 1.0. Interim inefficacy monitoring is 
planned to start after approximately 47% of full information becomes 
available with repeated analysis at each semi-annual DSMC meeting. 
The Linear 20% Inefficacy Boundary (LIB20), an approach described 
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not at least a small trend in favor of the alternative hypothesis starting 
at this time. Specifically, at each interim analysis, if the estimated HR 
is larger than the cutoff value given in the LIB20 boundary (Table 2), 
the DSMC then would consider stopping the study early for lack of 
efficacy. 
Table 2 
Information 
Proportion 
Cutoff Hazard 
Ratio 
47% 
1.004 
59% 
0.984 
70% 
0.965 
81% 
0.947 
91% 
0.931 
100% 
0.917 
9.3.2 
Secondary Clinical Analyses 
Progression-Free Survival (PFS) 
An important secondary aim is to evaluate whether a response-
adapted strategy translates into superior progression-free survival for 
patients switching to more-intensive treatment. PFS will be estimated 
using the KM method and compared using the stratified log-rank test. 
Median PFS on the control arm is assumed to be 18 months based on 
results from recent clinical trials. Assuming exponential distribution of 
failures, this study is design to detect a 44% increase in median PFS 
to 26 months on the experimental arm. This corresponds to a 
treatment HR approximating 0.70 [monthly hazard rate 0.0385 versus 
0.0267]. At 1-sided 2.5% type I error, there is approximately 90% 
power using a log-rank test to detect this HR given 510 patients 
uniformly accrued over 3.5y with full information of 319 PFS events at 
4.5y (accrual end plus one year). The actual timing of this PFS 
analysis will depend on accrual. The analysis will not be done before 
one year after the last patient is randomized. No interim analyses for 
the PFS comparison will be conducted. The study team will also not 
consider or declare the experimental arm to be a success based on 
the PFS endpoint alone. 
Response 
Response will be tabulated by category. Response rates (sCR, CR, 
VGPR) will be compared using the chi-squared test for proportions. It 
is hypothesized that the ixazomib-lenalidomide arm will have higher 
response rates. Ineligible patients are excluded from the analysis and 
unevaluable patients are counted in the denominator. Sensitivity 
analyses will exclude unevaluable patients from the rate calculations. 
Given 255 patients per arm, there is over 90% to detect a difference 
of 15% in VGPR rates at 1-sided 2.5% significance assuming a 52.5% 
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Toxicity 
We will monitor the toxicities experienced by all treated patients. 
Interim analyses of toxicity are performed twice yearly for all ECOG-
ACRIN studies. Expedited reporting of certain adverse events is 
required, as described in Section 5.3. We are specifically interested in 
comparing the rates of worst grade 3 or higher non-hematologic 
treatment-related events using the chi-squared test for proportions. It 
is likely that the ixazomib-lenalidomide arm will have moderately 
higher toxicity rates than the placebo-lenalidomide arm. The grade 3 
or higher treatment-related non-hematologic rate on the placebo-
lenalidomide arm is estimated to be around 36% based on reported 
toxicity rates on the lenalidomide arm of the CALGB maintenance 
trial. Assuming 1-sided 2.5% significance, there is 84% power to 
detect a difference in grade 3 or higher treatment-related non-
hematologic rates of 13% (ixazomib-lenalidomide arm 49% rate) with 
all enrolled patients treated. The maximum width of a 95% CI for a 
rate of a given toxicity on either treatment arm is 13%. As exploratory, 
global grade 3 or higher treatment-related non-hematologic rates will 
be evaluated within age subgroups dichotomized at 65 years. We also 
plan to examine comprehensively adverse events experienced by 
study participants using the Tox-T method which has been validated 
as a tool to assess adverse events in other NCTN trials.46 
9.3.3 
Exploratory Clinical Endpoints 
Time to Progression and Duration of Response 
TTP and DOR in each arm will be estimated using the Kaplan-Meier 
method. 
Treatment Exposure 
Treatment exposure to the oral medications lenalidomide and 
ixazomib will be quantified using patient medication calendars. 
Cumulative dose, dose intensity, and relative dose intensity will be 
calculated overall and by cycle. Data will be summarized by treatment 
arm with descriptive statistics and graphically over time. Treatment 
duration in each arm will be estimated using the Kaplan-Meier 
method. Patients will be classified into dichotomous groups based on 
a 75% relative dose intensity cutoff (< 75% vs ≥ 75% represents poor 
vs good treatment adherence). The proportion of patients with poor 
lenalidomide treatment adherence will be compared between arms 
using the chi-squared test for proportions. In addition, multivariable 
logistic regression analysis will be conducted to identify the baseline 
factors associated with calculated good treatment adherence. We will 
conduct one interim analysis to monitor treatment adherence to 
ixazomib. Specifically, the treatment adherence rate at 18 months will 
be measured by ixazomib relative dose intensity at or exceeding 75% 
(“good” treatment adherence). This analysis is expected to occur at 
2.5 years from randomization when 72 patients (29% of target 
accrual) have reached potentially 18 months of assigned ixazomib 
therapy. If the treatment adherence rate is at least 80% we would 
consider this acceptable while a treatment adherence rate of 65% is 
considered evidence that adherence to ixazomib is unacceptable. If 
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54 or more patients achieve target treatment adherence exceeding 
75% over 18 months, then the study will continue. If the true treatment 
adherence rate is 65%, the probability of concluding treatment 
adherence is acceptable is 0.05 (type I error). If the true treatment 
adherence rate is 80%, the probability of concluding treatment 
adherence is acceptable is 0.88 (power). 
9.3.4 
Patient-Reported Outcomes (PRO) Endpoints 
PRO compliance and completion rates will be tabulated at each 
collection time point and overall separately for the FACT-G (FWB and 
PWB subscales), FACT-Ntx, FACT-MM, ASK-12 and PRO-CTCAE 
instruments. 
Health-Related Quality of Life (QOL) 
To assess the impact of treatment and disease on health-related 
QOL, there are two co-primary endpoints: change in FACT/GOG-Ntx 
TOI from baseline to end of cycle 12 post-randomization (beginning of 
cycle 13 assessment) and change in FACT-MM TOI from baseline to 
end of cycle 24 (beginning of cycle 25 assessment) post 
randomization. The FACT-G (FWB and PWB subscales), Ntx and MM 
will be administered at the beginning (day 1)of every 3 cycles for the 
first 24 cycles (beginning of cycles 4, 7, 10, 13, 16, 19, 22 and 25) and 
every 6 cycles thereafter (up to completion of 48 cycles of therapy 
(beginning of cycles 31, 37, 43, and 49), or at treatment 
discontinuation prior to completion of 48 cycles of therapy. During 
long-term follow-up/post-treatment end, there will be four quarterly 
assessments for 1 year. We hypothesize that treatment with ixazomib 
will not result in a significant difference in the FACT/GOG-Ntx TOI 
over the first 12 cycles and that improved PFS will result in higher 
FACT-MM TOI scores by end of 24 cycles. All patients who receive at 
least one dose of study drug and complete the QOL assessment at 
both time points are eligible. Power calculations are based on t-tests 
comparing the two treatment arms for the change in score with a 2-
sided 0.05 alpha split between these comparisons. In an unselected 
group of MM patients being treated with oral therapy (n=118), the 
FACT-MM TOI had a standard deviation (SD) of approximately 21 
points. The FACT-Ntx TOI has a reported SD of 14-16.70 We propose 
using a general effect size measure of half standard deviation to 
establish the minimally important difference (MID).47,69 We therefore 
will establish a MID of 10 for the FACT-MM TOI and 8 for the FACT-
Ntx TOI. We assume 90% and 81% of patients are alive by year 1 and 
2, respectively, as well as a 10% drop-out rate resulting in potential 
patients of n=414 and n=373 for each analysis. Sensitivity for the 
proportion assumed to submit the questionnaire at both time points 
(compliance rates of 60% and 80%), allowing for a range of 
instrument variability and assuming different correlation (0.6, 0.4) 
between repeated measures was performed (Table 3). The difference 
in the FACT-Ntx TOI mean change score over 12 cycles of treatment 
between the ixazomib-lenalidomide arm and the placebo-lenalidomide 
arm that can be detected with 80% power at 2-sided 0.025 
significance level ranges from 3.7-6.9 points as shown below. The 
difference in the FACT-MM TOI mean change score over 24 cycles of 


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treatment between the ixa-lenalidomide arm and the placebo-
lenalidomide arm that can be detected with 80% power at 2-sided 
0.025 significance level ranges from 5.8-10.0 points. All of the 
scenarios show the target MID for each comparison or smaller can be 
detected with satisfactory power and thus we will be able to show a 
significant difference in QOL if it occurs. 
Table 3 
 
 
 
Differences in FACT-Ntx TOI 
Subscale Mean Change Score 
(power=80%, 2-sided 
alpha=0.025) 
Standard 
Deviation 
(SD) 
Correlation 
SD of 
change 
60% 
compliance     
(n=124/arm) 
80% 
compliance     
(n=164/arm) 
From Baseline to 12 Cycles Post Randomization 
 
12.0 
0.6 
10.7 
4.2 
3.7 
 
0.4 
13.1 
5.2 
4.5 
14.0 
0.6 
12.5 
4.9 
4.3 
 
0.4 
15.3 
6.0 
5.3 
16.0 
0.6 
14.3 
5.6 
4.9 
 
0.4 
17.5 
6.9 
6.0 
 
 
 
Differences in FACT-MM TOI 
Mean Change Score 
(power=80%, 2-sided 
alpha=0.025) 
Standard 
Deviation 
(SD) 
Correlation 
SD of 
change 
60% 
compliance 
(n=112/arm) 
80% 
compliance 
(n=148/arm) 
From Baseline to 24 Cycles Post Randomization 
 
18.0 
0.6 
16.1 
6.7 
5.8 
 
0.4 
19.7 
8.2 
7.1 
20.0 
0.6 
17.9 
7.4 
6.4 
 
0.4 
21.9 
9.1 
7.9 
22.0 
0.6 
19.7 
8.2 
7.1 
 
0.4 
24.1 
10.0 
8.7 
Sensitivity analysis will be conducted to retain patients who 
discontinued treatment early and missing their FACT-Ntx TOI score 
after 12 cycles of treatment (beginning of cycle 13 assessment) using 
their QOL score at early treatment discontinuation for the analysis. 
For the FACT-MM TOI analysis after 24 cycles of treatment 
(beginning of cycle 25 assessment) the long-term follow-up 
assessment closest to 2 years from randomization will be used if 
patients are not on treatment. Descriptive statistics (mean, SD, 
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changes for the set of health-related QOL evaluations including the 
FACT/GOG-Ntx TOI, FACT-MM TOI and FACT-G (FWB and PWB 
subscales). Levels and changes will also be assessed graphically. 
Linear mixed effects models will be used to perform repeated 
measured regression analysis with the assumed covariance matrix 
maximizing Akaike information criteria. Models with treatment, 
assessment time, and treatment by assessment time interaction with 
and without other predictors will be fit. If there is substantial 
missingness, we will analyze the data according to the methods 
described in Schluchter and Schluchter, Greene and Beck. These 
methods consider missingness informative by jointly modeling 
longitudinal QOL score and survival time to dropout. 
There are two key secondary health-related QOL analysis comparing 
treatment arms: Time to worsening of the FACT/GOG-Ntx TOI and 
time to improvement of the FACT-MM TOI. Time to worsening of the 
FACT/GOG-Ntx TOI and time to improvement of the FACT-MM TOI 
will be analyzed with the KM method and compared using the log-rank 
test. We will establish significance as alpha=1.67% based on 
Bonferroni adjustment (5% divided over 3 comparisons). We will 
provide rates on each arm including exact binomical 95% confidence 
intervals for the FACT/GOG-Ntx TOI recovery rate and FACT-MM TOI 
response rate. 
As exploratory, correlation between time to worsening of symptoms 
with PFS and OS will be assessed with Kendall’s Tau adjusted for 
censored observations. 
Finally, we will evaluate whether patients with poor treatment 
adherence based on medication calendars and lower likelihood of 
medication adherence based on ASK-12 scores have lower QOL 
scores [the FACT/GOG-Ntx TOI, FACT-MM TOI and FACT-G (FWB 
and PWB subscales)] after 12- and 24-cycles of treatment. Linear 
regression analysis at these 2 time points separately will be 
conducted with QOL score as outcome and treatment adherence 
group as the main effect adjusting for baseline QOL score along with 
other disease and demographic characteristics. 
PRO-CTCAE 
Analyses related to the PRO-CTCAE are exploratory. Descriptive 
statistics will be used to summarize selected PRO-CTCAEs tabulated 
at each cycle overall and by arm. We will map PRO-CTCAEs with 
provider reported AEs and evaluate differences in incidence and worst 
severity. PRO-CTCAE ratings will further be evaluated in relation to 
patient bother by treatment side effects (FACT-GP5 item, “I am 
bothered by treatment side effects”) to identify the toxicities that are 
most highly associated with treatment tolerability issues. 
Medication Adherence Scale 
Analyses related to the ASK-12 are exploratory. Descriptive statistics 
will be used to summarize ASK-12 scores tabulated every 6 cycles on 
study therapy. The ASK-12 is reported to have a mean (standard 
deviation) of 27.5 (7.2). Differences between arms will be evaluated 
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based on the t-test (or Wilcoxon rank sum test). Patients will also be 
classified into high versus low likelihood of medication adherence 
groups according to tertile distributions (lowest tertile vs second and 
top). The relationship between likelihood of medication adherence and 
calculated treatment adherence dichotomous groups will be evaluated 
in 2x2 tables. In addition, multivariable logistic regression analysis will 
be conducted to identify the baseline factors associated with low 
likelihood of medication adherence over 12- and 24-cycles of 
treatment. 
9.4 
Sample Size Considerations 
OS will be estimated based on the KM method and compared between arms 
using the stratified log-rank test. All survival estimates are from randomization, 
which would be ~18 months from start of initial therapy. Median OS for the 
control arm was estimated to be 5.5 years (y) considering expectations in this 
setting for an unselected cohort as well as results from the previously mentioned 
meta-analysis according to post-treatment MRD status.3 Based on the log-rank 
test, there is approximately 80% power at 1-sided 2.5% significance to detect a 
difference in 4y OS from 60.4% to 72.2% reflecting an approximate 35% 
reduction in hazard [treatment HR=0.65] assuming 510 patients uniformly 
accrued over 3.5y and 179 deaths at full information (6y). 
9.5 
Projected Accrual 
This study aims to screen 840 patients to pre-registration Step 0 at an accrual 
rate of 20 patients per month/240 patients per year for an accrual duration of 
3.5y. With an allowance of 15% for patients not yielding high quality specimens 
for MRD analysis, it is expected that 714 patients will have MRD measured. MRD 
status is anticipated to be split 75% positive/25% negative resulting in 536 MRD 
positive patients and 178 MRD negative patients. Some drop-out (5%) between 
marker evaluation and enrollment to Step 1 treatment is also anticipated resulting 
in an estimated 510 patients randomized to Arm A or Arm B with 1:1 allocation. 
Patients with MRD negative disease status based on NGF and immunofixation 
results will not be registered to the treatment phase. 
9.6 
Randomization Scheme 
Patients are randomized in equal allocation to ixazomib-lenalidomide or placebo-
lenalidomide and stratified by molecular risk status by International Myeloma 
Working Group (IMWG) criteria: standard or high risk, prior lenalidomide 
maintenance dose: 5 mg,10 mg, or >10 mg, prior maintenance duration: < 12 
months or > 12 months. Treatment will be assigned using permuted blocks within 
strata with dynamic balancing by main ECOG-ACRIN institution.33 
9.7 
Gender and Ethnicity 
Based on observed data from E1A11 the anticipated accrual in subgroups 
defined by gender and race is expected to parallel the newly diagnosed setting 
as follows: 
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DOMESTIC PLANNED ENROLLMENT REPORT (TREATMENT) 
Racial Categories 
Ethnic Categories 
Total 
 
Not Hispanic or Latino 
Hispanic or Latino 
 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
2 
4 
0 
0 
6 
Asian 
6 
4 
0 
0 
10 
Native Hawaiian or Other 
Pacific Islander 
2 
0 
0 
0 
2 
Black or African 
American 
27 
29 
0 
0 
56 
White 
147 
255 
17 
17 
437 
More Than One Race 
0 
0 
0 
0 
0 
Total 
184 
292 
17 
17 
510 
The accrual targets in individual cells are not large enough for definitive 
treatment comparisons to be made within these subgroups. Therefore, overall 
accrual to the study will not be extended to meet individual subgroup accrual 
targets. 
Study Monitoring 
This study will be monitored by the ECOG-ACRIN Data Safety Monitoring 
Committee (DSMC). The DSMC meets twice each year. For each meeting, all 
monitored studies are reviewed for safety and progress toward completion. When 
appropriate, the DSMC will also review interim analyses of outcome data. Copies 
of the toxicity reports prepared for the DSMC meetings are included in the study 
reports prepared for the ECOG-ACRIN group meeting (except that for double 
blind studies, the DSMC 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 DSMC 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 DSMC. Any DSMC 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 DSMC Policy can be 
obtained from the ECOG-ACRIN Operations Office – Boston. 
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10. 
Specimen Submissions 
Following pre-registration (Step 0), diagnostic bone marrow aspirates must be submitted 
to Mayo Clinic Hematology Laboratory for the central Minimal Residual Disease (MRD) 
assessment as described in Sections 1.1 and 11. The institution will be notified of the 
results within three (3) business days of receipt of the bone marrow specimen.  
All specimens must be clearly labeled with the ECOG-ACRIN protocol number 
(EAA171), the patient’s initials (last name, first name) and ECOG-ACRIN patient 
sequence number, the collection date, and specimen type. 
It is required that all specimens submitted on this trial be entered and tracked via the 
ECOG-ACRIN Sample Tracking System (STS) [Section 10.3]. An STS shipping manifest 
form is to be included with every submission. 
10.1 
Submissions to the Mayo Clinic Myeloma Reference Laboratory 
Myeloma Tumor Biology Kits are available to order and will include materials 
necessary for the preparation and shipment of the specimens. To order kits 
contact Stacey Lehman at the Mayo Clinic Myeloma Reference Laboratory at 
(507) 284-3805 or email Lehman.Stacey@mayo.edu. Include the name of the 
contact person, phone number, address where kits should be shipped, ECOG-
ACRIN protocol number (EAA171), 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. 
Any questions concerning specimen collection and shipment can be directed to 
Stacey Lehman at (507) 284-3805 or Lehman.Stacey@mayo.edu. 
10.1.1 
Sample Submission Schedule 
Bone marrow specimens are to be submitted as indicated below: 
Biological Materials1 
Following Pre-registration 
MANDATORY for Minimal Residual Disease Assessment 
Bone Marrow Aspirate (1) 6mL ACD 
(yellow top) tube 
X 
1. Kits are being provided for the collection and shipment of the bone 
marrow specimens. 
10.1.2 
Sample Preparation Guidelines 
Bone Marrow Aspirate 
This redirect bone marrow aspirate should be drawn at the same time 
that the bone marrow aspiration/biopsy is being done for clinical and 
diagnostic purposes and should be done through the same skin 
puncture site that the clinical specimen was obtained. 
x 
Draw 6mL of “redirect” bone marrow aspirate into one (1) ACD 
(yellow top) vacutainer tube provided in the Myeloma Tumor 
Biology Kit. Please use the first or second pull for these tubes. 
Ship the day of collection. 
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10.1.3 
Shipping Procedures 
If your shipment was not logged into the ECOG-ACRIN STS, please 
call Stacey Lehman at (507) 284-3805 or email 
Lehman.Stacey@mayo.edu to notify the laboratory when specimens 
are being shipped. Indicate the ECOG-ACRIN protocol number 
(EAA171), the FedEx tracking number, and name and phone number 
of the contact person. 
Bone marrow aspirates should be sent fresh, the day of collection, at 
ambient temperature (do not freeze) and shipped overnight to arrive 
during normal working hours. Specimens from multiple patients may 
be shipped together, but must be placed in separately labeled tubes 
and bags. 
Follow the packing guidelines listed in the kit. If specimens are sent 
late in the week and will arrive on the weekend, please note "Saturday 
Delivery" on the Federal Express form. 
FRIDAY AND PREHOLIDAY SHIPMENTS SHOULD BE AVOIDED. 
Packing instructions: 
x 
Place the slightly thawed Kool-PAK in the bottom of Styrofoam 
container (Kool-PAK should be frozen at least 24 hours in 
advance). Allow the frozen ice pack to thaw at room temperature 
for 2–3 hours before preparing the specimens for shipment. 
x 
Place absorbent toweling on top of the Kool-PAK. 
x 
Place specimens in their individual plastic bags provided, wrap in 
paper toweling and place them in the Styrofoam container and 
close the lid. Do not place the specimens directly on the ice pack. 
x 
Place the Styrofoam container and the Sample Tracking System 
Shipping Manifest Form within the cardboard mailing sleeve. 
x 
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 the same day collected. 
x 
Notify Federal Express for pick-up and/or leave package at the 
designated FedEx drop-off location. 
The specimens in prepared kits should be shipped to the following 
address: 
Stacey Lehman 
Mayo Foundation 
221 4th Avenue SW 
613 Stabile 
Rochester, MN 55905 
An STS shipping manifest form must be generated and shipped 
with all specimen submissions. 
10.2 
Use of Specimens in Research 
Specimens will be distributed to investigators at Mayo Clinic Hematology 
Laboratory for the laboratory research studies defined in Section 11. 


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Specimens from patients who consented to allow their specimens to be used for 
future approved research studies will be retained in an ECOG-ACRIN designated 
central repository. 
Specimens submitted will be processed to maximize their utility for current and 
future research projects. 
If future use is denied or withdrawn by the patient, the specimens will be 
removed from consideration for use in any future research study. Specimens will 
be destroyed per guidelines of the respective repository. 
10.3 
ECOG-ACRIN Sample Tracking System 
It is required (barring special circumstances) that all specimens submitted on 
this trial be entered and tracked using the ECOG-ACRIN Sample Tracking 
System (STS). As of June 2007, 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 specimens 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst. 
Important: Please note that the STS software creates pop-up windows, so you 
will need to enable pop-ups within your web browser while using the software. A 
user manual and interactive demo are available by clicking this link: 
http://www.ecog.org/general/stsinfo.html. Please take a moment to familiarize 
yourself with the software prior to using the system. 
An STS generated shipping manifest must be generated and shipped with all 
specimen submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu. 
Study Specific Notes 
Generic Specimen Submission Form (#2981v3), along with the Mayo Clinic 
Patient Information Form (Appendix VII), will be required only if STS is 
unavailable at time of specimen submissions. Notify the laboratory of the 
shipment by faxing a copy of the completed form to the laboratory. 
Retroactively enter all specimen collection and shipping information when STS is 
available. 
10.4 
Sample Inventory Submission Guidelines 
Inventories of all specimens submitted from institutions will be tracked via the 
ECOG-ACRIN STS and receipt and usability verified by the receiving laboratory. 
Inventories of specimens forwarded and utilized for the approved laboratory 
research studies will be submitted by the laboratory to the ECOG-ACRIN 
Operations Office - Boston on a monthly basis in an electronic format defined by 
the ECOG-ACRIN Operations Office - Boston. 


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11. 
Laboratory Research Studies 
These analyses will be performed at the Hematology Laboratory at Mayo Clinic 
Rochester, MN under the direction of Dr. Shaji Kumar. 
11.1 
Assessment of Minimal Residual Disease 
11.1.1 
MRD – Next Generation Flow Cytometry Methods 
Next generation flow cytometry (NGF) MRD assessment is conducted 
with multiparameter flowcytometry. The reagents for the MRD 
assessment will utilize the MM MRD kit (cytognos # MM-MRD, 
Salamanca). Analysis will follow the Euroflow approach using Infinicyt 
software as outlined by Flores-Montero et al. 22 The methodology has 
been described before and will be used without additional 
modification. Briefly, it utilizes an 8-color flow approach using two 
tubes, one with cytoplasmic light chains assessment on permeabilized 
cells. Four milliliters (ml) BM aspirate will be lysed using a fixative free 
erythrocyte lysing solution (# CYT-BL (10X), Cytognos, Salamanca, 
Spain). Per manufacturers guidelines, up to two ml of marrow will be 
suspended in 50 ml of freshly made 1X lyse and gently mixed for 15 
minutes. After centrifugation, the supernant is aspirated and the pellet 
resuspended in 2 ml of Staining Buffer (SB - PBS /0.09% Azide /0.5% 
BSA). The tube is then filled to 50 ml with staining buffer and 
centrifuged. Two ml of SB are used to resuspend one pellet and 
combined with the pellet in the second tube. The cell suspension is 
transferred to a 12 X 75 tube. After centrifugation, the supernant is 
aspirated and the pellet is resuspended in 0.5 ml of SB. The 
suspension is diluted with SB not to exceed 107 per ml. Up to 10 
million cells are added to tube 1 and tube 2. Both tubes are stained for 
30 minutes at room temperature, in the dark with multi epitope CD38 
FITC/CD138 V450/CD45 Percp 5.5 /CD19 PE-Cy7 in both tubes for 
plasma cell (PC) gating. To determine PC phenotype both tube 1 and 
2 contain CD27-BV510 and CD56-PE; tube 1 also includes CD117 
APC and CD81 APC C750. After incubation, tube 1 is resuspended 
for 10 minutes in BD FACs Lyse. The pellet is resuspended in 0.5 ml 
SB and held until run on the flow cytometer. Tube 2 is further 
processed for cytoplasmic light chain staining (Kappa APC /Lambda 
APC-C750) with a fix and perm step. After centrifugation, the pellet is 
resuspended in 0.5 ml SB and held until run on the flow cytometer. 
The bone marrow quality will be determined by assessing for 
expected normal marrow cells. Normal and neoplastic plasma cells 
will be reported as percentage of all CD38/138/45 gated cells. The 
report will include the total number of cells analyzed, PC 
immunophenotype (including clonality), and plasma cell (normal and 
abnormal) percentages and event (abnormal plasma cell) count to 
determine MRD negative or positive status. 
11.2 
Lab Data Transfer Guidelines 
The data collected on the above-mentioned laboratory research studies will be 
submitted electronically using a secured data transfer to the ECOG-ACRIN 


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Operations Office - Boston by the investigating laboratories on a quarterly basis 
or per joint agreement between ECOG-ACRIN and the Investigator. 


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12. 
Imaging Correlative Studies 
12.1 
18Fluorodeoxyglucose (FDG) PET/CT 
Advanced imaging modalities are playing an increasingly important role in the 
diagnosis, risk stratification and response assessment of myeloma. 18F-FDG 
PET/CT allows simultaneous assessment of the bone marrow, as well as 
presence of extramedullary lesions. Both baseline assessments as well as follow 
up imaging have an important prognostic role and appear to be associated with 
survival. Myeloma cells, while they tend to be primarily marrow based, can be 
found in the extramedullary compartment, including the peripheral blood. As a 
result, imaging plays an important role in assessing response to therapy, as well 
as in identifying disease progression, both inside and outside the bone marrow. 
In fact, functional imaging assessment using 18F-FDG PET/CT is an integral part 
of minimal residual disease assessment in myeloma, in addition to following foci 
of extramedullary disease identified prior to start of treatment. 
12.1.1 
Imaging Schedule 
All registered patients from both the ixazomib/lenalidomide arm and 
the placebo/lenalidomide arm are expected to undergo 18F-FDG 
PET/CT as SOC at the following time points: 
x 
Prior to initiation of randomized study mandated therapy [referred 
to as the baseline scan]. The baseline scan can be done prior to 
study registration, as long as it is within 8 weeks of pre-registration 
step 0 
x 
After completion of 12 cycles of study mandated therapy (± 6 
weeks) [referred to as the year 1 scan] 
x 
After completion of 24 cycles of study mandated therapy (± 6 
weeks) [referred to as the year 2 scan] 
All 18F-FDG PET/CT images are to be submitted via TRIAD as 
outlined in Section 4.3.5. 
12.1.2 
Criteria for defining abnormal 18F-FDG PET/CT 
The primary 18F-FDG PET/CT reading will be performed using IMWG 
PET criteria, where a negative PET is described as disappearance of 
every area of increased tracer uptake found at disease sites on the 
baseline 18F-FDG PET/CT, or a preceding 18F-FDG PET/CT, or 
decrease to less than that seen in mediastinal blood pool SUV.4 
However, other criteria including IMPETUS and IMAJEM trial criteria 
will also be applied as exploratory analyses to determine if a better 
reading scheme can be established with respect to accuracy in the 
prediction of patient outcome.29,45 
12.1.3 
Imaging Aims and Statistics 
There are three imaging aims in this correlative study, which will be 
based on central review of the acquired 18F-FDG PET/CT scans, and 
which are distinguished into primary and secondary. 
Imaging aims which involve patient outcomes (overall survival or 
progression-free survival) will be conducted at full information. In 
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addition, reporting of imaging aims will not be done prior to reporting 
of the respective primary or secondary therapy endpoints. 
12.1.3.1 
Primary imaging aim 
[1] To evaluate the association between baseline 18F-
FDG PET/CT and patient outcomes. 
The primary imaging aim consists of evaluating the 
association between baseline 18F-FDG PET/CT and patient 
outcomes, and seeks to address the question of whether 
abnormal 18F-FDG PET/CT findings at baseline (i.e., after 
approximately 1 year of lenalidomide maintenance 
following an early stem cell transplant) are prognostic of 
poorer progression-free survival (PFS) and overall survival 
(OS). The potential association will be analyzed using both 
quantitative and qualitative 18F-FDG PET/CT parameters. 
Quantitatively, the association between baseline SUV-
based quantitative 18F-FDG PET/CT parameters (SUVmax, 
SUVpeak, MTV, TLG) and PFS will be analyzed through 
Cox regression. PFS will be defined as the time from 
randomization until the earlier of progression or death due 
to any cause. SUV-based quantitative 18F-FDG PET/CT 
(qPET) parameters will be analyzed as continuous 
covariates, and adjustment will be made for potential 
confounders, including patient age and the randomization 
stratification factors. In addition, we will formally test 
whether this association differs by study arm through a 
statistical interaction term between the qPET parameter 
and study arm. If this interaction is not significant at the 
0.05 level, then a single overall hazard ratio will be 
estimated for the entire study cohort. We assume that up 
to 10% of patients may not receive the 18F-FDG PET/CT at 
baseline or may have an uninterpretable scan. 
Standardizing each qPET parameter to have mean 0 and 
standard deviation 1, and assuming the R-square of each 
qPET parameter with other covariates is no more than 0.4, 
the proposed sample size of 510 patients (459 evaluable) 
has power of 82% to detect a hazard ratio as low as 1.25 
per standard deviation increase in the qPET parameter, 
when the progression event rate is 0.6. If the observed 
progression event rate over the duration of the trial is 
higher than 0.6, the power will correspondingly increase 
(e.g., power=85% for a progression event rate of 0.65). A 
two-sided Cox regression with a type I error rate of 0.05 
was used for this computation (PASS 16). In addition, for 
further clinical utility, we will explore estimating an optimal 
threshold for each baseline qPET parameter using 
recursive partitioning in a conditional inference framework, 
with 95% confidence interval derived using the bootstrap 
technique.50 Finally, since a marker displaying an 
independent, strong association may not necessarily 
contribute meaningfully to improved classification, we will 
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also examine the ability of each baseline qPET parameter 
to serve as a prognostic marker in discriminating patients 
which progress within 2 years and 3 years of the start of 
study mandated therapy using time-dependent (cumulative 
sensitivity/dynamic specificity) ROC analysis.51,52 Area 
under the time-dependent ROC curve [AUC(t)] will be 
estimated using the NNE method proposed by 
Heagerty.53,54 
Qualitative criteria are described in protocol Section 12.1.2. 
These criteria will be used to dichotomize the baseline 18F-
FDG PET/CT scans as either negative or positive, where 
analyses using the IMPETUS and IMAJEM criteria are 
considered exploratory. The association between a 
positive/abnormal baseline 18F-FDG PET/CT scan and 
PFS will be assessed through Kaplan-Meier curves with 
the log-rank test. An adjusted analysis will also be 
conducted using a Cox regression model, with adjustment 
for potential confounders, including patient age and the 
randomization stratification factors. In addition, we will 
formally test whether this association differs by study arm 
through a statistical interaction term between 18F-FDG 
PET/CT positivity and study arm. If this interaction is not 
significant at the 0.5 level, then a single overall hazard 
ratio will be estimated for the entire study cohort. It is 
anticipated that between 50-70% of patients will have a 
positive 18F-FDG PET/CT scan at baseline. Assuming 60% 
of patients have a positive 18F-FDG PET/CT scan at 
baseline, the proposed sample size of 510 patients (459 
evaluable) yields 87% power at a type I error rate of 0.05 
to detect a difference in median PFS between 18F-FDG 
PET/CT-positive and 18F-FDG PET/CT-negative patients 
as low as 7 months (19 vs. 26 months, respectively, 
assuming 3 years of accrual time and 4.5 years of patient 
follow-up; PASS 16). 
Similar analyses will be conducted for the OS outcome. OS 
will be defined as the time from randomization until death 
or the date last known alive. 
The 18F-FDG PET/CT images will be collected centrally 
and archived for future research analysis. All data and 
results will be anonymized. 
12.1.3.2 
Secondary imaging aims 
[2] To compare overall survival (OS) with the addition 
of ixazomib to lenalidomide among baseline 18F-FDG 
PET/CT-positive and 18F-FDG PET/CT-negative 
subgroups. 
This secondary imaging aim consists of a subgroup 
analysis of the trial primary endpoint, and will assess for 
heterogeneity of treatment effect by baseline 18F-FDG 
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would suggest that the effectiveness of ixazomib treatment 
could be increased by targeting patients with the 
appropriate baseline 18F-FDG PET/CT status.55 
Heterogeneity of treatment effect will be assessed at full 
information, using a two-sided statistical test for interaction 
between study arm (ixazomib/lenalidomide vs. 
placebo/lenalidomide) and baseline 18F-FDG PET/CT 
status (positive/abnormal vs. negative) in a Cox regression 
model.56,57 If the statistical test for interaction is not 
significant at the 0.05 level, we will conclude that there is 
not sufficient evidence for heterogeneity of treatment 
effect; if the statistical test for interaction is significant, 
estimated treatment hazard ratios for OS (ixazomib arm vs. 
placebo arm) will be reported separately for baseline 18F-
FDG PET/CT-positive and 18F-FDG PET/CT-negative 
subgroups, along with the corresponding 95% confidence 
intervals. OS will be defined as the time from 
randomization until death or the date last known alive. 
We anticipate between 50-70% of patients will have a 
positive 18F-FDG PET/CT scan at baseline. Sensitivity of 
the findings will be examined by adjusting the Cox model 
for patient age and the randomization stratification factors. 
[3] To compare the change in quantitative 18F-FDG 
PET/CT parameters over time with the addition of 
ixazomib to lenalidomide. 
This secondary imaging aim consists of comparing the 
change in 18F-FDG PET/CT parameters over time across 
study arms and seeks to address the question of whether 
adding ixazomib to lenalidomide results in sharper 
decreases in 18F-FDG uptake (as measured by 18F-FDG 
PET/CT) compared to lenalidomide plus placebo, thus 
giving evidence of greater disease control. 
The difference in qPET parameters from the baseline 18F-
FDG PET/CT to the year 1 18F-FDG PET/CT will be 
reported by study arm. An analysis of covariance 
(ANCOVA) model will be used to test for a treatment effect 
on each qPET parameter, where the baseline qPET 
parameter value and an indicator for study arm are 
included as covariates, with the qPET parameter at year 1 
as the model outcome.59-61 Sensitivity of the findings will be 
examined by additionally adjusting the ANCOVA model for 
the randomization stratification factors (, as this would be 
expected to further improve precision of the study arm 
comparison.62 
In addition, longitudinal profiles of each qPET parameter 
from the baseline 18F-FDG PET/CT through the year 2 18F-
FDG PET/CT will be compared across study arm through 
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Assuming that up to 15% of patients may not have either 
the baseline 18F-FDG PET/CT scan performed or the year 
1 18F-FDG PET/CT scan performed, or may have one or 
more of these scans uninterpretable, the proposed sample 
size of 510 patients (434 evaluable, 217 per study arm) 
has power of 80% using ANCOVA at a type I error rate of 
0.05 to detect a difference in year 1 mean SUVmax 
between arms as low as 2.0, with only moderate 
correlation between the baseline and year 1 SUVmax (R-
squared=0.45) and common standard deviation as large as 
10.0 (PASS 16). Larger correlation between baseline and 
year 1 SUVmax and/or smaller standard deviation of 
SUVmax would result in greater power. 
13. 
Electronic Data Capture 
Please refer to the EAA171 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed in Medidata Rave and TRIAD. 
Data for this study will be submitted via the Data Mapping Utility (DMU). Cumulative 
protocol- and patient-specific data will be submitted weekly to CTEP electronically via 
the DMU. DMU Light reporting consists of Patient Demographics, On/Off Treatment 
Status, Abbreviated Treatment and Course information, and Adverse Events as 
applicable. Instructions for setting up and submitting data via DMU are available on the 
CTEP Website: https://ctep.cancer.gov/protocolDevelopment/dmu.htm. 
NOTE: 
All adverse events (both routine and serious) that meet the protocol 
mandatory reporting requirements must be reported via DMU in addition to 
expedited reporting of serious adverse events via CTEP-AERS. 
13.1 
Records Retention 
FDA regulations (21 CFR 312.62) require clinical investigators to retain all trial-
related documentation, including source documents, long enough to allow the 
sponsor to use the data to support marketing applications. 
This study will be used in support of a US marketing application (New Drug 
Application), all records pertaining to the trial (including source documents) must 
be maintained for: 
x 
two years after the FDA approves the marketing application, or 
x 
two years after the FDA disapproves the application for the indication being 
studied, or 
x 
two years after the FDA is notified by the sponsor of the discontinuation of 
trials and that an application will not be submitted. 
Please contact the ECOG-ACRIN Operations Office – Boston prior to destroying 
any source documents. 
14. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
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15. 
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Bortezomib/Thalidomide/Prednisone (VTP) as Induction Therapy Followed by 
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Bortezomib/Prednisone (VP) in Elderly Untreated Patients with Multiple Myeloma 
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44. Niesvizky R, Flinn IW, Rifkin RM, et al. Patient-Reported Quality of Life In Elderly, 
Newly Diagnosed Multiple Myeloma Patients Treated with Bortezomib-Based 
Regimens: Results From the Phase 3b UPFRONT Study. ASH Annual Meeting 
Abstracts. 2010;116(21):3026. 


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45. Moreau P, Attal M, Caillot D et al. Prospective evaluation of magnetic resonance 
imaging and [18F]fluorodeoxyglucose positron emission tomography-computed 
tomography at diagnosis and before maintenance therapy in symptomatic patients 
with multiple myeloma included in the IFM/DFCI 2009 trial: results of the IMAJEM 
study. J Clin Oncol. 2017;35(25):2911-18. 
46. Thanarajasingam G, Atherton PJ, Novotny PJ, Loprinzi CL, Sloan JA, Grothey A. 
Longitudinal adverse event assessment in oncology clinical trials: the Toxicity over 
Time (ToxT) analysis of Alliance trials NCCTG N9741 and 979254 Lancet Oncol 
2016; 17:663-70. 
47. Norman GR, Sloan JA, Wyrwich KW. Interpretation of changes in health-related 
quality of life: the remarkable universality of half a standard deviation. Med Care. 
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48. Yost KJ, Eton DT. Combining distribution- and anchor-based approaches to 
determine minimally important differences: The FACT experience. Eval Health Prof 
2005; 28:172-91. 
49. Cella D, Hahn EA, Dineen K. Meaningful change in cancer-specific quality of life 
scores: differences between improvement and worsening. Qual Life Res. 2002; 
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50. Hothorn T, Hornik K, Zeileis A.  Unbiased recursive partitioning: a conditional 
inference framework.  Journal of Computational and Graphical Statistics 2006. 
51. Pepe MS, Janes H, Longton G, et al. Limitations of the odds ratio in gauging the 
performance of a diagnostic, prognostic, or screening marker. J Epidemiol. 2004; 
159(9):882-90. 
52. Steyerberg WE, Vickers AJ, Cook NR, et al. Assessing the performance of prediction 
models: A framework for traditional novel measures. Epidemiol. 2009; 21:128-38. 
53. Heagerty PJ, Lumley T, Pepe MS. Time-dependent ROC curves for censored 
survival data and a diagnostic marker. Biometrics. 2000; 56(2):337-44. 
54. Blanche P, Dartigues JF, Jacqmin-Gadda H. Review and comparison of ROC curve 
estimators for a time-dependent outcome with marker-dependent censoring. Biom J. 
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55. VanderWeele TJ, Knol, MJ.  On the interpretation of subgroup analyses in 
randomized trials: heterogeneity versus secondary interventions.  Ann Intern Med 
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56. Assmann SF, Pocock SJ, Enos LE, Kasten LE. Subgroup analyses and other 
(mis)uses of baseline data in clinical trials. Lancet 2000. 
57. Wang R, Lagakos JW, Ware JH, Hunter DJ, Drazen JM. Statistics in medicine – 
reporting of subgroup analyses in clinical trials. NEJM 2007. 
58. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or 
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59. Vickers AJ, Altman DG. Analysing controlled trials with baseline and follow up 
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61. Neter, J, Kutner MH, Nachtsheim CJ, Wasserman W.  Applied Linear Statistical 
Models, 4th edition (textbook). 
62. Raab GM, Day S, Sales J.  How to select covariates in include in the analysis of a 
clinical trial.  Controlled Clinical Trials 2000. 
63. Fitzmaurice GM, Laird NM, Ware JH.  Applied Longitudinal Analysis, 2nd edition 
(textbook). 
64. Vickers AJ, Cronin AM, Begg CM. One statistical test is sufficient for assessing new 
predictive markers. BMC Medical Research Methodology 2011. 
65. Pepe MS, Kerr KF, Longton G, Wang Z. Testing for improvement in prediction model 
performance. Stat Med 2013. 
66. Steyerberg EW, Harrell FE, Borsboom GJJM, Eijkemans MJC, Vergouwe Y, 
Habbema JDF. Internal validation of predictive models: efficiency of some 
procedures for logistic regression analysis. Journal of Clinical Epidemiology 2001. 
67. Harrell FE. Regression modeling strategies, 2nd edition. Textbook 
68. Pencina MJ, D’Agostino RB, Steyerberg EW.  Extensions of net reclassification 
improvement calculations to measure usefulness of new biomarkers.  Stat Med 
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69. Gupta S, Abouzaid S, et al. Assessing the Effect of Adherence on Patient-reported 
Outcomes and Out of Pocket Costs Among Patients With Multiple Myeloma Clinical 
Lymphoma, Myeloma & Leukemia March 2018. 
70. Calhoun EA,Welshman EE, Chang CH, Lurain JR, Fishman DA, Hunt TL, Cella D. 
Psychometric evaluation of the Functional Assessment of Cancer Therapy 
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receiving systemic chemotherapy. Int J Gynecol Cancer. 2003 Nov-Dec;13(6):741-8. 
71. Freidlin B, Korn EL, Gray R. A general inefficacy interim monitoring rule for 
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Appendix I 
 
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 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 hope to 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 ECOG-ACRIN, we thank you again and look forward to 
helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 


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Appendix II 
 
Patient Medication Calendar 
 
Medication Calendar Directions 
1. Take your scheduled dose of each medication. 
2. Ixazomib/Placebo: Take capsule(s) on an empty stomach, 1 hour before or 2 hours 
after food. Swallow whole capsules with water. Do not break or open the capsules. 
3. Lenalidomide: Take capsule by mouth with or without food. Do not crush, chew or 
open the capsules.  
4. Missed or delayed doses can be taken only if the next scheduled dose is ≥ 72 hours 
away. A missed dose should not be taken within 72 hours of the next scheduled 
dose. If vomiting occurs after taking a dose, do not repeat the dose. Resume dosing 
at the time of the next scheduled dose. 
5. Please bring the empty carton or any leftover medication and your  
medication calendar to your next clinic visit. 
 
 
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Patient Medication Calendar 
This is a calendar on which you are to record the time and number of capsules you take each 
day. You should take your scheduled dose of each capsule. Note the times and the number 
of capsules 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 capsules and 
your completed medication calendar to your doctor’s visits. 
Patient Initials (L, F): __________      Patient Study ID: __________      Cycle #: __________ 
DAY 
DATE 
TIME 
# CAPSULES 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.) 
Ixazomib/Placebo 
Capsules 
Lenalidomide 
Capsules 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
 
10 
 
 
 
 
 
11 
 
 
 
 
 
12 
 
 
 
 
 
13 
 
 
 
 
 
14 
 
 
 
 
 
15 
 
 
 
 
 
16 
 
 
 
 
 
17 
 
 
 
 
 
18 
 
 
 
 
 
19 
 
 
 
 
 
20 
 
 
 
 
 
21 
 
 
 
 
 
22 
 
 
 
 
 
23 
 
 
 
 
 
24 
 
 
 
 
 
25 
 
 
 
 
 
26 
 
 
 
 
 
27 
 
 
 
 
 
28 
 
 
 
 
 


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


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


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Appendix IV 
 
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 housework, 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. 
 


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Appendix V 
 
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 ixazomib/placebo 
or lenalidomide, or within 28 days of the female patient’s last dose of ixazomib/placebo or 
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? 
For this study, a pregnancy, suspected pregnancy (including a positive or inconclusive 
pregnancy test) must be initially reported on the Adverse Event Form or Late Adverse Event 
Form in the appropriate Treatment Cycle or Post Registration folder in Medidata Rave. Once 
the adverse event is entered into Rave, the Rules Engine on the Expedited Reporting 
Evaluation Form will confirm whether or not the pregnancy requires expedited reporting. The 
CTEP-AERS report must then be initiated directly from the Expedited Reporting Evaluation 
Form in Medidata Rave. Do not initiate the CTEP-AERS report via the CTEP-AERS website. 
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? 
x 
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” 
x 
The pregnancy must be reported within the timeframe specified in the Adverse Event 
Reporting section of the protocol for a grade 3 event. 
x 
The start date of the pregnancy should be reported as the calculated date of conception.  
x 
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? 
x 
The Investigator must follow the female patient until completion of the pregnancy and 
must report the outcome of the pregnancy and neonatal status in CTEP-AERs accessed 
via Medidata Rave.  
x 
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 – 
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x 
It is recommended the female patient be referred to an obstetrician-gynecologist, 
preferably one experienced in reproductive toxicity for further evaluation and counseling.  
How should the outcome of a pregnancy be reported? 
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 and 
separate CTEP-AERs report should be initiated (via Medidata Rave) reporting the outcome 
of the pregnancy. 
What constitutes an abnormal outcome? 
An abnormal outcome is defined as any pregnancy that results in the birth of a child with 
persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions (formerly referred to as disabilities), congenital anomalies, or birth defects. For 
assistance in recording the grade or category of these events, please contact the CTEP 
AEMD Help Desk at 301-897-7497 or aemd@tech-res.com, for it will need to be discussed 
on a case by case basis.   
Reporting a Pregnancy Loss 
A pregnancy loss is defined in CTCAE as “A death in utero.” 
For this study, it must be initially reported on the Adverse Event Form or Late Adverse Event 
Form in the appropriate Treatment Cycle or Post Registration folder in Medidata Rave. Once 
the adverse event is entered into Rave, the Rules Engine on the Expedited Reporting 
Evaluation Form will confirm whether or not the adverse event requires expedited reporting. 
The CTEP-AERS report must then be initiated directly from the Expedited Reporting 
Evaluation Form in Medidata Rave. Do not initiate the CTEP-AERS report via the CTEP-
AERS website. The pregnancy loss must be reported as a 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 newborn 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, AND any infant death after 28 days that 
is suspected of being related to the in utero exposure to ixazomib/placebo or lenalidomide, 
must be initially reported on the Adverse Event Form or Late Adverse Event Form in the 
appropriate Treatment Cycle or Post Registration folder in Medidata Rave. Once the event 
is entered into Rave, the Rules engine on the Expedited Reporting Evaluation Form will 
confirm whether or not the event requires expedited reporting. The CTEP-AERS report must 
then be initiated directly from the Expedited Reporting Evaluation Form in Medidata Rave. 
Do not initiate the CTEP-AERS report via the CTEP-AERS website. The neonatal death 
must be reported as a 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. 
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Additional Required Forms: 
When submitting CTEP-AERs reports for pregnancy, pregnancy loss, or neonatal loss, the 
CTEP 'Pregnancy Information Form' must be completed and faxed along with any 
additional medical information to CTEP (301-897-7404). This form is available on CTEP's 
website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/PregnancyReport
Form.pdf) 


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Appendix VI 
 
Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable 
Birth Control Methods 
1.1. 
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. A teratogenic effect of lenalidomide in humans cannot be ruled out. 
Therefore, a pregnancy prevention program must be followed. 
1.1.1. Definition of a Patient of Childbearing Potential 
A patient of childbearing potential is anyone who: 1) has achieved menarche at 
some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) 
has not been naturally postmenopausal (amenorrhea following cancer therapy 
does not rule out childbearing potential) for at least 24 consecutive months (i.e., 
has had menses at any time in the preceding 24 consecutive months). 
1.1.2. Definition of a Patient Not of Childbearing Potential 
Patients who do not meet the above definition of a patient of childbearing 
potential should be classified as Patient Not of Childbearing Potential. 
1.2. 
Counseling 
1.2.1. Patients of Childbearing Potential 
For a patient of childbearing potential, lenalidomide is contraindicated unless all 
of the following are met (i.e., all patient of childbearing potential must be 
counseled concerning the following risks and requirements prior to the start of 
lenalidomide): 
x 
Patients understand the potential teratogenic risk to the unborn child 
x 
Patients understand the need for effective contraception, without interruption, 
28 days before starting lenalidomide, throughout the entire duration of 
lenalidomide, during dose interruptions and for at least 28 days after the last 
dose of lenalidomide 
x 
Patients understand and agree to inform the Investigator if a change or stop 
of method of contraception is needed 
x 
Patients must be capable of complying with effective contraceptive measures 
x 
Patients are informed and understand the potential consequences of 
pregnancy and the need to notify her study doctor immediately if there is a 
risk of pregnancy 
x 
Patients understand the need to commence lenalidomide as soon as it is 
dispensed following a negative pregnancy test 
x 
Patients understand and accept the need to undergo pregnancy testing 
based on the frequency outlined in this plan (Section 1.4 below) and in the 
Informed Consent 
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x 
Patients acknowledge that they understand the hazards lenalidomide can 
cause to an unborn fetus and the necessary precautions associated with the 
use of lenalidomide. 
The Investigator must ensure that a patient of childbearing potential: 
x 
Complies with the conditions of the pregnancy prevention plan, including 
confirmation that they have an adequate level of understanding 
x 
Acknowledges the aforementioned requirements. 
1.2.2. Patients Not of Childbearing Potential 
For a patient not of childbearing potential, lenalidomide is contraindicated unless 
all of the following are met (i.e., all patients not of childbearing potential must be 
counseled concerning the following risks and requirements prior to the start of 
lenalidomide): 
x 
Patients acknowledge they understand the hazards lenalidomide can cause 
to an unborn fetus and the necessary precautions associated with the use of 
lenalidomide. 
1.2.3. Males 
Traces of lenalidomide have been found in semen. 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): 
x 
Male patients understand the potential teratogenic risk if engaged in sexual 
activity with a pregnant partner or a partner of childbearing potential. 
x 
Male patients understand the need for the use of a condom even if they have 
had a vasectomy, if engaged in sexual activity with a pregnant partner or a 
partner of childbearing potential. 
x 
Understand the potential teratogenic risk if the patient donates semen or 
sperm. 
1.3. 
Contraception 
1.3.1. Patients of Childbearing Potential 
Patients of childbearing potential enrolled in this protocol must agree to use two 
reliable forms of contraception simultaneously or to practice complete abstinence 
(True abstinence is acceptable when this is in line with the preferred and usual 
lifestyle of the patient. Periodic abstinence [e.g., calendar, ovulation, 
symptothermal or post-ovulation methods] and withdrawal are not acceptable 
methods of contraception.) from heterosexual contact during the following time 
periods related to this study: 1) for at least 28 days before starting lenalidomide; 
2) while taking lenalidomide; 3) during dose interruptions; and 4) for at least 28 
days after the last dose of lenalidomide. 
The two methods of reliable contraception must include one highly effective 
method and one additional effective (barrier) method. If the below contraception 
methods are not appropriate for the patient of childbearing potential, they must 
be referred to a qualified provider of contraception methods to determine the 
medically effective contraception method appropriate to the patient. The following 
are examples of highly effective and additional effective methods of 
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x 
Examples of highly effective methods: 
x 
Intrauterine device (IUD) 
x 
Hormonal (birth control pills, injections, implants, levonorgestrel-releasing 
intrauterine system [IUS], medroxyprogesterone acetate depot injections, 
ovulation inhibitory progesterone-only pills [e.g., desogestrel]) 
x 
Tubal ligation 
x 
Partner’s vasectomy 
x 
Examples of additional effective methods: 
x 
Male condom 
x 
Diaphragm 
x 
Cervical Cap 
Because of the increased risk of venous thromboembolism in patients with 
multiple myeloma taking lenalidomide and dexamethasone, combined oral 
contraceptive pills are not recommended. If a patient is currently using combined 
oral contraception the patient should switch to another one of the highly effective 
methods listed above. The risk of venous thromboembolism continues for 4 to 6 
weeks after discontinuing combined oral contraception. The efficacy of 
contraceptive steroids may be reduced during co-treatment with dexamethasone. 
Implants and levonorgestrel-releasing intrauterine systems are associated with 
an increased risk of infection at the time of insertion and irregular vaginal 
bleeding. Prophylactic antibiotics should be considered particularly in patients 
with neutropenia. 
1.3.2. Male Patients 
Male patients must practice complete abstinence (True abstinence is acceptable 
when this is in line with the preferred and usual lifestyle of the patient. Periodic 
abstinence [e.g., calendar, ovulation, symptothermal or post-ovulation methods] 
and withdrawal are not acceptable methods of contraception.) or agree to use a 
condom during sexual contact with a pregnant partner or a partner of 
childbearing potential while taking lenalidomide, during dose interruptions and for 
at least 28 days after the last dose of lenalidomide, even if they have undergone 
a successful vasectomy. 
1.4. 
Pregnancy Testing 
Medically supervised pregnancy tests with a minimum sensitivity of 25mIU/mL must be 
performed for patients of childbearing potential. 
Patients of childbearing potential must have two negative pregnancy tests (sensitivity of 
at least 25mIU/mL) prior to starting lenalidomide. The first pregnancy test must be 
performed within 10 to 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 
patient may not receive lenalidomide until the study doctor has verified that the results of 
these pregnancy tests are negative. 
Patients of childbearing potential 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 taking lenalidomide, at study discontinuation, and at Day 28 following the last 
dose of lenalidomide. 


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Patients of childbearing potential with irregular menstrual cycles must agree to have 
pregnancy tests weekly for the first 28 days of study participation and then every 14 
days while taking lenalidomide, at study discontinuation, and at Days 14 and 28 
following the last dose of lenalidomide. 
1.5. 
Pregnancy Precautions for Lenalidomide Use 
1.5.1. Before Starting Lenalidomide 
1.5.1.1 
Patients of Childbearing Potential 
Patients of childbearing potential must have two negative pregnancy 
tests (sensitivity of at least 25mIU/mL) prior to starting lenalidomide. 
The first pregnancy test must be performed within 10 to 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 
patient may not receive lenalidomide until the study doctor has 
verified that the results of these pregnancy tests are negative. 
Patients of childbearing potential must use two reliable forms of 
contraception simultaneously, or practice complete abstinence (True 
abstinence is acceptable when this is in line with the preferred and 
usual lifestyle of the patient. Periodic abstinence [e.g., calendar, 
ovulation, symptothermal or post-ovulation methods] and withdrawal 
are not acceptable methods of contraception.) from heterosexual 
contact for at least 28 days before starting lenalidomide. 
1.5.1.2. 
Male Patients 
Male patients must agree to practice complete abstinence (True 
abstinence is acceptable when this is in line with the preferred and 
usual lifestyle of the patient. Periodic abstinence [e.g., calendar, 
ovulation, symptothermal or post-ovulation methods] and withdrawal 
are not acceptable methods of contraception.) or agree to use a 
condom during sexual contact with a pregnant partner or a partner of 
childbearing potentialwhile taking lenalidomide, during dose 
interruptions and for at least 28 days after the last dose of 
lenalidomide, even if he has undergone a successful vasectomy. 
1.5.2. During and After Study Participation 
1.5.2.1 
Patients of Childbearing Potential 
x 
Patients of childbearing potential 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 taking 
lenalidomide, at study discontinuation, and at Day 28 following the 
last dose of lenalidomide. 
x 
Patients of childbearing potential with irregular menstrual cycles 
must agree to have pregnancy tests weekly for the first 28 days of 
study participation and then every 14 days while taking 
lenalidomide, at study discontinuation, and at Days 14 and 28 
following the last dose of lenalidomide. 
x 
At each visit, the Investigator must confirm with the patient of 
childbearing potential that they are continuing to use two reliable 


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methods of birth control if not committing to complete abstinence, 
or confirm commitment to complete abstinence. 
x 
If a patient of childbearing potential considers the need to change 
or to stop a method of contraception, the Investigator must be 
notified immediately. 
x 
Counseling about pregnancy precautions and the potential risks of 
fetal exposure must be conducted at a minimum of every 28 days. 
x 
If pregnancy or a positive pregnancy test does occur in a patient, 
lenalidomide must be immediately discontinued. 
x 
Pregnancy testing and counseling must be performed if a patient 
misses their period or if her pregnancy test or their menstrual 
bleeding is abnormal. Lenalidomide must be discontinued during 
this evaluation. 
x 
Patients must agree to abstain from breastfeeding while taking 
lenalidomide and for at least 28 days after the last dose of 
lenalidomide. 
1.5.2.2. 
Male Patients 
x 
Must practice complete abstinence (True abstinence is acceptable 
when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence [e.g., calendar, ovulation, 
symptothermal or post-ovulation methods] and withdrawal are not 
acceptable methods of contraception.) or use a condom during 
sexual contact with a pregnant partner or a partner of childbearing 
potential while taking lenalidomide, during dose interruptions and 
for at least 28 days after the last dose of lenalidomide, even if he 
has undergone a successful vasectomy. 
x 
Must not donate semen or sperm while receiving lenalidomide, 
during dose interruptions or for at least 28 days after the last dose 
of lenalidomide. 
x 
Counseling about pregnancy precautions and the potential risks of 
fetal exposure must be conducted at a minimum of every 28 days. 
x 
If pregnancy or a positive pregnancy test does occur in the partner 
of a male patient while taking lenalidomide, the Investigator must 
be notified immediately. 
1.5.3. Additional Precautions 
x 
Patients should be instructed to never give lenalidomide to another person. 
x 
Patients should be instructed to return any unused capsules to the study 
doctor. 
x 
Patients should not donate blood while receiving lenalidomide, during dose 
interruptions and for at least 28 days after the last dose of lenalidomide. 
x 
No more than a 28-day lenalidomide supply may be dispensed with each 
cycle of lenalidomide. 
 


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Optimizing Prolonged Treatment In Myeloma Using MRD Assessment (OPTIMUM) 
 
Appendix VII 
 
Myeloma Tumor Biology Kit 
Specimen Checklist and Shipping Instructions 
**PLEASE AVOID DRAWING OR SENDING SPECIMENS ON FRIDAYS AND HOLIDAYS** 
Kit Contents: 
x 
5lb Styrofoam box and cardboard mailing sleeve 
x 
Patient Information Form 
x 
FedEx air bill with pre-printed return address 
x 
6mL ACD (yellow top) collection tubes 
x 
Absorbent tube holder 
x 
Zip lock biohazard specimen bags  
x 
(1) Kool-PAK. Place the ice pack in the freezer for at least 24 hours prior to specimen 
shipment. Allow the frozen ice pack to thaw at room temperature for 2-3 hours before 
preparing the specimen for shipment. 
Packing and Shipping Instructions: 
1. Collect the following specimens: 
1. Bone marrow aspirate - Draw 6mL of 'redirect' bone marrow aspirate into one (1) 
6mL ACD tube. 
2. All specimens are to be clearly labeled with the ECOG-ACRIN protocol number EAA171, 
the patient’s initials (last name, first name), ECOG-ACRIN patient sequence number, 
specimen type (BM/PB) and date of collection. 
3. Place the slightly thawed Kool-PAK in bottom of Styrofoam container. 
4. Place absorbent toweling on top of Kool-PAK. 
5. Place specimens in the plastic bags provided, wrap in paper toweling and place them in 
the Styrofoam container and close the lid. Do not place the specimens directly on the ice 
pack. 
6. Place the Styrofoam container and the Sample Tracking System shipping 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 the same day collected. 
8. Notify Federal Express for pick-up and/or leave package at the designated FedEx drop-
off location. 
The ECOG-ACRIN Sample Tracking System will automatically contact the Myeloma 
Reference Laboratory. If you did not use the ECOG-ACRIN Sample Tracking System please 
call Stacey Lehman at (507) 284-3805 or email Lehman.Stacey@mayo.edu to notify the 
laboratory when specimens are being shipped. Indicate the ECOG-ACRIN protocol number, 
the FedEx tracking number, and name and phone number of the contact person. 
The specimens in prepared kits should be shipped to the following: 


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Stacey Lehman 
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221 4th Avenue SW 
613 Stabile 
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Patient Information Form 
It is required that specimens submitted from patients participating in EAA171 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:      /        /           
Patient Initials (last name, first 
name):                 
ECOG-ACRIN Protocol #: EAA171                                                                                 
ECOG-ACRIN Patient Sequence 
#:                                                                                                
Contact Person:                                                                                                
Institution:                                                                                                
Address:  
 City                                           State                  Zip 
Phone #:                                                                                                
FAX #:  
Please indicate which specimens are being shipped at this time: 
1. Pre-Registration 
Any questions concerning these specimens or to obtain a Myeloma Tumor Biology kit, 
please contact: 
Stacey Lehman 
Mayo Clinic Myeloma Reference Laboratory 
Lehman.Stacey@mayo.edu  
(507) 284-3805 

ICF_001.pdf: 
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Research Study Informed Consent Document 
Study Title for Participants: Testing the Addition of Ixazomib/Placebo to 
Lenalidomide in Patients with Evidence of Residual Multiple Myeloma 
Official Study Title for Internet Search on 
http://www.ClinicalTrials.gov: Protocol EAA171: Optimizing Prolonged 
Treatment In Myeloma Using MRD Assessment (OPTIMUM) 
(NCT03941860) 
Version Date: January 4, 2023 
Overview and Key Information 
What am I being asked to do? 
We are asking you to take part in a research study. This study has public funding from the 
National Cancer Institute (NCI), part of the National Institutes of Health (NIH) in the United 
States Department of Health and Human Services. We do research studies to try to answer 
questions about how to prevent, diagnose, and treat diseases like cancer. 
We are asking you to take part in this research study because you have multiple myeloma. 
Taking part in this study is your choice. 
You can choose to take part or you can choose not to take part in this study. You also can 
change your mind at any time. Whatever choice you make, you will not lose access to your 
medical care or give up any legal rights or benefits. 
This document has important information to help you make your choice. Take time to read it. 
Talk to your doctor, family, or friends about the risks and benefits of taking part in the study. 
It’s important that you have as much information as you need and that all your questions are 
answered. See the “Where can I get more information?” section for resources for more 
clinical trials and general cancer information. 
Why is This Study Being Done? 
This study is being done to answer the following question: 
What are the good and bad effects of adding the study drug ixazomib to the usual approach 
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for patients with multiple myeloma? 
We are doing this study because we want to find out if this approach is better or worse than 
the usual approach for your multiple myeloma. The usual approach is defined as care most 
people get for multiple myeloma. 
What is the usual approach to my multiple myeloma? 
The usual approach for patients with multiple myeloma who are not in a study, at your stage 
of treatment, is treatment with lenalidomide after stem cell transplantation. This approach is 
approved by the Food and Drug Administration (FDA). 
What are my choices if I decide not to take part in this study? 
• You may choose to have the usual approach described above. 
• You may choose to take part in a different research study, if one is available. 
• You may choose not to be treated for cancer. 
• You may choose to only get comfort care to help relieve your symptoms and not get 
treated for your cancer. 
What will happen if I decide to take part in this study? 
If you decide to take part in this study, you will either get lenalidomide and the study drug 
called ixazomib, or you will get lenalidomide and a placebo, until your disease gets worse or 
the side effects become too severe. A placebo looks like the study drug, but contains no 
medication. You and your doctor will not know if you are getting the study drug or placebo. 
After you finish your study treatment, your doctor will continue to follow your condition for 
up to 10 years from the date you were randomly assigned to a treatment on study and watch 
you for side effects as well as your overall health. Your doctor will check on you every 3 
months after treatment if you stop the study within the first 2 years from the date you were 
randomly assigned to treatment, every 6 months after treatment if you stop the study between 
2 and 5 years after starting, and every 12 months after treatment if you stop the study after 
more than 5 years. 
What are the risks and benefits of taking part in this study? 
There are both risks and benefits to taking part in this study. It is important for you to think 
carefully about these as you make your decision. 
Risks 
We want to make sure you know about a few key risks right now. We give you more 
information in the “What risks can I expect from taking part in this study?” section. 
If you choose to take part in this study, there is a risk that the study drugs may not be as good 
as the usual approach for your cancer. 
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There is also a risk that you could have side effects from the study drugs. These side effects 
may be worse and may be different than you would get with the usual approach for your 
cancer. 
Some of the most common side effects that the study doctors know about are: 
• Development of numbness and tingling in the hands and feet 
• Fatigue 
• Decrease in blood counts 
• Increased risk of infection 
• Nausea and diarrhea 
• Skin rash 
There may be some risks that the study doctors do not yet know about. 
Benefits 
If you agree to take part in this study, there may or may not be direct medical benefit to you. 
However, it may help the study doctors understand how this study drug works. This study 
may help the study doctors learn things that may help other people in the future. 
There is evidence that ixazomib and lenalidomide are effective in shrinking your cancer or 
preventing it from returning. It is not possible to know now if the study drugs will extend 
your life compared to the usual approach. This study will help the study doctors learn things 
that will help people in the future. 
If I decide to take part in this study, can I stop later? 
Yes, you can decide to stop taking part in the study at any time. 
If you decide to stop, let your study doctor know as soon as possible. It’s important that you 
stop safely. If you stop, you can decide if you want to keep letting the study doctor know 
how you are doing. 
Your study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study. 
Are there other reasons why I might stop being in the study? 
Yes. The study doctor may take you off the study if: 
• Your health changes and the study is no longer in your best interest. 
• New information becomes available and the study is no longer in your best interest. 
• You do not follow the study rules. 
• For women: You become pregnant while on the study. 
• The study is stopped by the National Cancer Institute (NCI), Institutional Review Board 
(IRB), Food and Drug Administration (FDA), or study sponsor (ECOG-ACRIN). The 
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It is important that you understand the information in the informed consent before 
making your decision. Please read, or have someone read to you, the rest of this document. 
If there is anything you don’t understand, be sure to ask your study doctor or nurse. 
What is the purpose of this study? 
The purpose of this study is to compare the effectiveness using lenalidomide and ixazomib to 
treat your cancer to using lenalidomide and placebo. The addition of ixazomib to the 
lenalidomide you are already taking could shrink your cancer or prevent it from returning. 
But, it could also cause side effects, which are described in the risks section below.  
This study will help the study doctors find out if this different approach is better than the 
usual approach. To determine if it is better, the study doctors will be looking to see if the 
study drugs lengthen the life of patients compared to the usual approach. 
Ixazomib is already approved by the FDA for use in combination with lenalidomide for 
patients with multiple myeloma that came back after initial treatment. Lenalidomide has also 
been approved by the FDA for treatment of multiple myeloma that has relapsed after other 
therapies. There will be about 510 people taking part in this study. 
What are the study groups? 
This study has a screening step that requires a bone marrow biopsy and aspirate. 
This study has 2 study groups. You will not be told which group you are in. 
• Group 1 
If you are in this group, you will get the usual drug used to treat your multiple myeloma, 
lenalidomide, plus a study drug called ixazomib. You will get these drugs as a capsule 
you take by mouth with water on an empty stomach. You will take lenalidomide on days 
1 to 28 of each cycle and ixazomib on days 1, 8, and 15 of each cycle. Each cycle lasts 28 
days.  
There will be about 255 people in this group. 
• Group 2 
If you are in this group, you will get the usual drug used to treat your multiple myeloma, 
lenalidomide, plus a placebo. A placebo is a capsule that looks like the study drug, but 
contains no medication. You will get these drugs as a capsule you take by mouth with 
water on an empty stomach. You will take lenalidomide on days 1 to 28 of each cycle and 
the placebo on days 1, 8, and 15 of each cycle. Each cycle lasts 28 days. 
There will be about 255 people in this group. 
We will use a computer to assign you to one of the study groups. This process is called 
“randomization.” It means that your doctor will not choose and you cannot choose which 
study group you are in. You will be put into a group by chance. You will have an equal 
chance of being in Group 1 or Group 2. Neither you nor your doctor will know which group 
you are assigned to. 
Another way to find out what will happen to you during this study is to read the chart below. 
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Start reading from the top and read to the bottom, following the lines and arrows. 
You agree to take part 
in this study and sign 
this consent form. 
 
If your bone marrow has 
minimal residual disease or 
you have M-protein in your 
blood or urine, you will get 
randomized. The computer 
will put you in a study group. 
 
If your bone marrow does 
not have minimal residual 
disease and you do not have 
M-protein in your blood or 
urine, you will not continue 
on the study. Your doctor 
will discuss other choices 
with you. 
Your bone marrow is 
tested to see if you have 
minimal residual disease 
and your blood and urine 
are tested for M-protein. 
Group 1: 
Lenalidomide 
and Ixazomib 
 
Group 2: 
Lenalidomide 
and Placebo 
 


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What exams, tests, and procedures are involved in this study? 
Before you begin the study, your doctor will review the results of your exams, tests, and 
procedures. This helps your doctor decide if it is safe for you to take part in the study. If you 
join the study, you will have more exams, tests, and procedures to closely monitor your 
safety and health. Most of these are included in the usual care you would get even if you 
were not in a study. 
Listed below are exams, tests, and procedures that need to be done as part of this study to 
monitor your safety and health, but may not be included in the usual care. We will use them 
to carefully follow the effects of the study treatment, including preventing and managing side 
effects. 
Before you begin the study: 
You will need the following extra tests and procedures to find out if you can be in the 
research study: 
• Pregnancy test (if you are a patient of childbearing potential) 
• Once within 14 days of starting study treatment 
• Will be repeated on the first day of treatment, before you take the first dose of  
• study treatment 
• Blood tests 
• Imaging scan called 18Fluorodeoxyglucose positron emission tomography/computed 
tomography (abbreviated as 18F-FDG PET/CT) 
This imaging scan is part of the usual care you would get if you were not in a study. As 
part of this study, a copy of your scan will be sent to a central database to be reviewed for 
research purposes. Your name and other personal information will not be associated with 
the scan so you cannot be identified. Neither you nor your study doctor will be given the 
findings from the research review of your scan. 
• Bone marrow biopsy and aspirate 
Mandatory Bone Marrow Biopsy and Aspirate 
You will need to have a bone marrow biopsy and aspirate procedure as part of this study. 
We will ask you to undergo a bone marrow biopsy to establish the diagnosis of multiple 
myeloma and ask for a sample (approximately two (2) teaspoons) of the bone marrow 
aspirate at this time. You and your study doctor will get the results of this special testing 
in which we are looking for residual myeloma cells, called Minimal Residual Disease 
(MRD) testing. The MRD testing is being done to look for any remaining traces of 
myeloma cells. If you do have minimal residual disease (also known as MRD positive) or 
have M-protein in your blood or urine, and you meet all the study requirements, then we 
can assign you to treatment. If we find that the bone marrow specimen from your bone 
marrow biopsy and aspirate procedure does not have minimal residual disease (also 
known as MRD negative) and you do not have M-protein in your blood or urine, then 
your doctor will discuss other options for your care.  
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These results will be placed in your medical record, which may affect your care. If you 
agree to take part in the study, you may need to sign a separate consent form for the study 
biopsy at the hospital or clinic where the biopsy is done. 
If there are any leftover bone marrow samples that may possibly be stored for bio-
banking, this will be discussed in the section under “Optional Studies.” 
The results of the MRD and immunofixation testing will be used to determine if you can take 
part in this study. 
• If the MRD test results are negative and you do not have M-protein in your blood or 
urine, you will be taken off study. 
• If the MRD test results are positive or you have M-protein in your blood or urine, you 
will be registered to the study. 
NOTE: The MRD test used in this study is considered investigational. 
During the study: 
• Pregnancy test during every cycle (if you are a patient of childbearing potential) 
• Blood tests during every cycle 
• Bone marrow biopsies and/or aspirates at the end of cycles 12, 24, 36, and 60 
• Imaging scan called 18Fluorodeoxyglucose positron emission tomography/computed 
tomography (abbreviated as 18F-FDG PET/CT) at the end of cycles 12 and 24 
These imaging scans are part of the usual care you would get if you were not in a study. 
As part of this study, a copy of your scans will be sent to a central database to be 
reviewed for research purposes. Your name and other personal information will not be 
associated with the scan so you cannot be identified. Neither you nor your study doctor 
will be given the findings from the research review of your scan. 
Patient Reported Outcomes questionnaires 
If you are an English speaker and choose to take part in this study, you will be asked to 
answer questions about your quality of life. Researchers will use this information to learn 
more about how cancer treatment affects people. There are four types of questionnaires you 
will be asked to complete. You don’t have to answer any question that makes you feel 
uncomfortable. 
The first questionnaire is a question about your health, and it takes about 8-10 minutes to 
complete. You will be asked to fill out this questionnaire at the times listed below: 
• Prior to starting study treatment 
• At the end of every 3 cycles for the first 2 years of treatment (before starting cycles 4, 7, 
10, 13, 16, 19, 22, and 25) 
• At the end of every 6 cycles after the first 2 years of starting treatment up to 4 years 
(before starting cycles 31, 37, 43, and 49) 
• At early discontinuation of treatment prior to 2 years 
• 3, 6, 9, and 12 months after the end of treatment 
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The second questionnaire is about side effects commonly experienced with this study 
treatment. This questionnaire will take about 10 minutes to complete, and you will be asked 
to complete this at the times listed below: 
• Prior to starting study treatment  
• At the end of every cycle for each cycle for the first 2 years of treatments 
It is important to know that you are taking your medications properly. Therefore, we will ask 
you to fill out a third very brief questionnaire at the end of every 6 cycles while you are on 
study treatment (before starting cycles 7, 13, 19, 25, 31, 37, 43, and 49). This will take about 
3-4 minutes to complete. 
The fourth questionnaire will ask you questions about your employment, financial position, 
care support status, health insurance, and where you live. This questionnaire will help the 
study doctors learn more about factors in your life that may impact your health. This will 
take about 3-5 minutes to complete, and you will be asked to complete it at the following 
times: 
• Prior to starting study treatment 
• At the end of every 6 cycles for the first 2 years of starting treatment (before starting 
cycles 7, 13, 19, and 25) 
• At time of early discontinuation of treatment prior to 2 years of starting treatment 
If you have any serious health issues or other concerns, please talk with your doctor or nurse 
right away. 
What risks can I expect from taking part in this study? 
General Risks 
If you choose to take part in this study, there is a risk that the study drugs may not be as good 
as the usual approach at shrinking your cancer/preventing your cancer from coming back. 
You also may have the following discomforts: 
• Spend more time in the hospital or doctor’s office. 
• Be asked sensitive or private questions about things you normally do not discuss. 
• May not be able to take part in future studies. 
The study drugs used in this study could be very harmful to an unborn or newborn baby. 
There may be some risks that doctors do not yet know about. It is very important that you 
check with your study doctor about what types of birth control or pregnancy prevention to 
use during the study and for 90 days after you have completed the study. Ask your doctor 
about the risks involved with different types of contraception methods. 
Biopsy Risks 
Common side effects of a biopsy are a small amount of bleeding at the time of the procedure, 
bruising, and pain at the biopsy site. Pain can be treated with regular pain medications. 
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that describes the risks in more detail. 
Side Effect Risks 
The drugs used in this study may affect how different parts of your body work such as your 
liver, kidneys, heart, and blood. The study doctor will test your blood and let you know if 
changes occur that may affect your health. 
There is also a risk that you could have other side effects from the study drugs. 
Here are important things to know about side effects: 
1. The study doctors do not know who will or will not have side effects. 
2. Some side effects may go away soon, some may last a long time, and some may never go 
away. 
3. Some side effects may make it hard for you to have children. 
4. Some side effects may be mild. Other side effects may be very serious and even result in 
death. 
You can ask your study doctor questions about side effects at any time. Here are important 
ways to make side effects less of a problem: 
• If you notice or feel anything different, tell your study doctor. He or she can check to see 
if it is a side effect. 
• Your study doctor will work with you to treat your side effects. 
• Your study doctor may adjust the study drugs to try to reduce side effects. 
This study is looking at a combination of the usual drugs used to treat this type of cancer plus 
a study drug. This different combination of drugs may increase your side effects or may 
cause new side effects. 
There are also risks associated with blood draws that include pain, bleeding, bruising, getting 
a blood clot, and feeling faint or fainting. You may develop an infection with redness and 
irritation of the vein at the site where blood is drawn. However, these usually go away on 
their own. 
Drug Risks 
The tables below show the most common and most serious side effects doctors know about. 
Keep in mind that there might be other side effects doctors do not yet know about. If 
important new side effects are found, the study doctor will discuss these with you. 
Study Group 1 and Group 2 – Possible side effects of lenalidomide are listed in the tables 
below. This drug is part of the usual approach for treating this type of cancer: 
Possible Side Effects of Lenalidomide 
(Table 2.8 Version Date: June 27, 2019) 
COMMON, SOME MAY BE SERIOUS 
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• Anemia which may require blood transfusion 
• Constipation, diarrhea 
• Tiredness 
• Bruising, bleeding 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving lenalidomide (CC-5013), from 4 to 20 may have: 
• Infection, especially when white blood cell count is low  
• Dizziness, fainting 
• Blurred vision 
• Cloudiness of the eye, visual disturbances 
• Pain 
• Dry mouth, skin 
• Heartburn, nausea, vomiting 
• Chills, fever 
• Swelling of the body 
• Fall 
• Weight loss, loss of appetite 
• Dehydration 
• Muscle weakness 
• Abnormal unpleasant sensation, body movement 
• Changes in taste 
• Headache 
• Feeling of "pins and needles" in arms and legs 
• Numbness, tingling or pain of the arms and legs 
• Depression 
• Difficulty sleeping 
• Change in mood 
• Cough, shortness of breath 
• Nose bleed 
• Increased sweating 
• Itching, rash 
• Sores on the skin 
• High blood pressure which may cause headaches, dizziness, blurred vision 
• Low blood pressure which may cause feeling faint 
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RARE, AND SERIOUS 
In 100 people receiving lenalidomide (CC-5013), 3 or fewer may have: 
• Abnormal heartbeat 
• Heart attack, heart failure which may cause shortness of breath, swelling of ankles, and 
tiredness 
• Liver damage which may cause yellowing of eyes and skin, swelling 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat 
• Damage to organs in the body when donor cells attack host organs 
• Kidney damage which may require dialysis 
• Damage to muscle which may cause muscle pain, dark red urine 
• Cancer of bone marrow caused by chemotherapy 
• Damage to the bone marrow (irreversible) which may cause infection, bleeding, may 
require transfusions 
• Increased tumor size 
• A new cancer unrelated to an earlier cancer 
• A new cancer resulting from treatment of earlier cancer  
• Stroke which may cause paralysis, weakness 
• Damage to the lungs which may cause shortness of breath 
• Skin rash developing 1-8 weeks after a drug is given which may be accompanied by 
fever, lymph node swelling and organ failure 
• Severe skin rash with blisters and peeling which can involve mouth and other parts of 
the body 
• Difficulty stimulating enough stem cells in the bloodstream for future transplant 
Occasional adverse events such as atrial fibrillation (irregular heartbeat), myocardial 
infarction (heart attack), and congestive heart failure (condition where the heart becomes 
weak and cannot pump enough blood to the rest of the body) have been reported with the use 
of lenalidomide from clinical studies and post-marketing. 
Deep vein thrombosis and pulmonary embolism 
Lenalidomide has demonstrated an increased risk of deep vein thrombosis (DVT, blood clot 
in a larger blood vessel) and pulmonary embolism (PE, a blood clot in or around the lungs) in 
some people with certain medical conditions. The study staff will ask you about any risk 
factors you may have. If you have a history of blood clots your doctor will prescribe 
treatment with a blood thinner for the first four months of the study treatment. The doctor 
may continue to prescribe the medication or aspirin for the remainder of your course of study 
treatment. All other patients will receive (at the discretion of the treating physician) either 
oral low–dose aspirin or another treatment to prevent blood clotting during study 
participation. Patients unable or unwilling to undergo treatment for prevention of blood clots 


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will not be eligible to participate in this study. You will be instructed on the signs and 
symptoms of DVT and PE and if symptoms occur you should contact your study doctor 
promptly. 
Second new cancers 
According to researchers, patients with cancer have a higher risk of developing a second new 
cancer when compared to people without cancer although this risk is very small. In clinical 
studies of newly diagnosed multiple myeloma, a higher number of second cancers were 
reported in patients treated with induction therapy (treatment as first step to reducing number 
of cancer cells) and/or bone marrow transplant, followed by lenalidomide for a long period of 
time compared to patients treated with induction therapy and/or bone marrow transplant, and 
then placebo (a capsule containing no medication). In clinical studies of patients whose 
multiple myeloma either did not respond to treatment or returned after treatment, a higher 
number of second cancers were reported in patients previously treated with multiple 
chemotherapy regimens and radiation than the drug carfilzomib. Patients should make their 
doctors aware of their medical history and any concerns they may have regarding their own 
increased risk of other cancers. 
Other risks of Lenalidomide 
If any physician other than the study doctor prescribes medication for you for another 
condition or you are taking any over-the-counter medications or vitamins, you must inform 
the study staff. This is important because the interaction of some medications may cause 
serious side effects. 
Lenalidomide has been shown to increase the level of digoxin in the blood in some patients; 
please tell your doctor if you are taking the drug digoxin. 
Pregnancy: 
Lenalidomide is related to the drug thalidomide. Thalidomide is known to cause severe life-
threatening human birth defects. If lenalidomide is taken during pregnancy, it may cause 
birth defects or death to an unborn baby. Patients who are able to become pregnant must not 
become pregnant while taking lenalidomide. You have been informed that the risk of birth 
defects is unknown. If you are a patient who is able to become pregnant, you agree not to 
become pregnant while taking lenalidomide.  
In order to participate in this study you must also register into and follow the requirements of 
the REMS program of Celgene Corporation. This program provides education and 
counseling on the risks of fetal exposure, blood clots and reduced blood counts. You will be 
required to receive counseling every 28 days during treatment with lenalidomide, follow the 
pregnancy testing and birth control requirements of the program that are appropriate for you 
and take telephone surveys regarding your compliance with the program. 
You understand and agree to receive counseling and to comply with the pregnancy 
precaution requirements of the REVLIMID REMS® program. You will be registered in the 
REVLIMID REMS® program. 


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FOR PATIENTS WHO ARE ABLE TO BECOME PREGNANT* 
*Anyone, regardless of sexual orientation or whether they have undergone tubal ligation, 
who meets the following criteria: 1) has achieved menarche (the first occurrence of 
menstruation) at some point, 2) has not undergone a hysterectomy (the surgical removal of 
the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or 3) has not 
been naturally postmenopausal (amenorrhea following cancer therapy does not rule out 
childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in 
the preceding 24 consecutive months). 
Please read thoroughly and initial each space provided if you understand each 
statement: 
_____: I understand that birth defects may occur with the use of lenalidomide. I have been 
warned by my doctor that my unborn baby may have birth defects and can even die, if I am 
pregnant or become pregnant while I am taking lenalidomide. 
_____: I understand that I must NOT take lenalidomide if I am pregnant, breast-feeding a 
baby or able to get pregnant and not using 2 reliable methods of birth control. 
_____: If I am having sexual relations with a man, my uterus and/or both ovaries have not 
been removed, I have had at least one menstrual period in the past 24 months and/or my 
menses stopped due to treatment of my disease, I understand that I am able to become 
pregnant. I must use one highly effective method of birth control plus one additional 
effective method of birth control (contraception) at the SAME TIME. 
Highly Effective Methods 
Additional Effective Methods 
Intrauterine device (IUD) 
Latex condom 
Hormonal (birth control pills, injections, implants) 
Diaphragm 
Tubal ligation 
Cervical Cap 
Partner’s vasectomy 
 
_____: These birth control methods must be used during the following time periods related to 
this study: 1) for at least 28 days before starting lenalidomide therapy; 2) while participating 
in the study; during interruptions in therapy and 3) for at least 28 days after lenalidomide has 
been stopped. I must use these methods unless I completely abstain from heterosexual sexual 
contact. If a hormone (birth control pill, injection, patch or implant) or IUD method is not 
medically possible for me, I may use another highly effective method or two barrier methods 
AT THE SAME TIME. 
_____: I know I must have a pregnancy test done by my doctor within 10 – 14 days and 
again within 24 hours prior to starting lenalidomide therapy, even if I have not had my 
menses due to treatment of my disease or had as little as one menstrual period in the past 24 
months. If I have regular or no menstrual cycles, I will then have pregnancy tests every week 
for the first 28 days, then every 28 days while I am taking lenalidomide, again when I have 
been taken off of lenalidomide therapy and then 28 days after I have stopped taking 
lenalidomide. If I have irregular menstrual cycles, I will have pregnancy tests every week for 
the first 28 days, then every 14 days while I am taking lenalidomide, again when I have been 
taken off of lenalidomide therapy, and then 14 days and 28 days after I have stopped taking 


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lenalidomide. 
_____: I know I must immediately stop taking lenalidomide and inform my doctor, if I 
become pregnant while taking the drug, if I miss my menstrual period or have unusual 
menstrual bleeding, if I stop using 2 reliable forms of birth control, or if I think for any 
reason that I may be pregnant. I must talk to my doctor before changing any birth control 
methods. 
_____: I am not now pregnant, nor will I try to become pregnant for at least 28 days after I 
have completely finished taking lenalidomide. 
_____: I understand that lenalidomide will be prescribed only for me. I must not share it with 
ANYONE, even someone that has similar symptoms to mine. It must be kept out of reach of 
children and should never be given to anyone who is pregnant or able to have children. 
______: I agree any unused drug supply will be returned per the instructions provided by 
REMS. 
______: I know that I cannot donate blood while taking lenalidomide and for 28 days after 
stopping lenalidomide. Study patients who become pregnant will be monitored throughout 
the pregnancy and will continue to be monitored for 30 days after delivery (premature 
delivery, aborted fetus, full-term pregnancy, or no longer pregnant). 
FOR ALL MALES 
Please read thoroughly and initial each space provided if you understand each 
statement: 
_____: I understand that birth defects may occur with the use of lenalidomide. I have been 
warned by my doctor that an unborn baby may have birth defects and can even die, if anyone 
is pregnant or becomes pregnant while taking lenalidomide. 
_____: I have been told by my doctor that I must NEVER have unprotected sexual contact 
with a partner who can become pregnant. Because lenalidomide is present in small quantities 
in semen, my doctor has explained that I must completely abstain from sexual contact with 
partners who are pregnant or able to become pregnant, or I must use a latex condom every 
time I engage in any sexual contact with partners who are pregnant or may become pregnant. 
I must do this while I am taking lenalidomide and for 28 days after I stop taking 
lenalidomide, even if I have had a successful vasectomy. 
_____: I know I must inform my doctor if I have unprotected sexual contact with a partner 
who is pregnant or can become pregnant or if I think, for ANY REASON, that my sexual 
partner may be pregnant. Partners of male patients taking lenalidomide should be advised to 
call their own physician immediately if they get pregnant. 
_____: I understand that lenalidomide will be prescribed only for me. I must not share it with 
ANYONE, even someone that has similar symptoms to mine. It must be kept out of reach of 
children and should never be given to anyone who is able to have children. 
_____: I agree any unused drug supply will be returned per the instructions provided by 
REMS. 
_____: I know that I cannot donate blood, sperm or semen while taking lenalidomide and for 


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28 days after stopping lenalidomide. 
FOR PATIENTS THAT ARE NOT ABLE TO BECOME PREGNANT 
Please read thoroughly and initial each space provided if you understand each 
statement: 
_____: I understand that birth defects may occur with the use of lenalidomide. I have been 
warned by my doctor that an unborn baby may have birth defects and can even die, if anyone 
is pregnant or becomes pregnant while taking lenalidomide. 
_____: I certify that I am not now pregnant, nor am I of child bearing potential as I have been 
in a natural menopause for at least 24 months (been through the change in life without even 1 
menstrual period for the past 24 months); or I had my uterus removed (hysterectomy) or had 
both my ovaries removed (bilateral oophorectomy). 
_____: I understand that lenalidomide will be prescribed only for me. I must not share it with 
ANYONE, even someone that has similar symptoms to mine. It must be kept out of reach of 
children and should never be given to anyone who is pregnant or able to have children. 
_____: I agree any unused drug supply will be returned per the instructions provided by 
REMS. 
_____: I know that I cannot donate blood while taking lenalidomide and for 28 days after 
stopping lenalidomide. 
FOR ALL PATIENTS 
You will be counseled at least every 28 days during lenalidomide treatment and again one 
last time when you stop taking lenalidomide about not sharing lenalidomide (and other study 
drugs), the potential risks of fetal exposure, abstaining from blood and other donations, the 
risk of changes in blood counts and blood clots, and you will be reminded not to break, chew 
or open lenalidomide capsules. 
Study Group 1 – In addition to side effects listed above, people who are in Group 1 may 
also have some side effects of ixazomib. These side effects are listed below: 
Possible Side Effects of Ixazomib 
(Table Version Date: March 26, 2022) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving MLN9708 (Ixazomib citrate), more than 20 and up to 100 may 
have: 
• Diarrhea, nausea, vomiting 
• Tiredness 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving MLN9708 (Ixazomib citrate), from 4 to 20 may have: 
• Anemia which may require blood transfusion 


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OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving MLN9708 (Ixazomib citrate), from 4 to 20 may have: 
• Pain 
• Constipation 
• Fever 
• Cold symptoms such as stuffy nose, sneezing, sore throat 
• Bruising, bleeding 
• Loss of appetite 
• Headache 
• Muscle Weakness 
• Numbness, tingling or pain of the arms and legs 
• Cough, shortness of breath 
• Rash 
 
RARE, AND SERIOUS 
In 100 people receiving MLN9708 (Ixazomib citrate), 3 or fewer may have: 
• Blood clot which may cause confusion, paralysis, seizures and blindness 
• Swelling of arms, legs 
• Liver damage which may cause yellowing of the eyes and skin 
Some discomforts and risks that occur with lesser frequency (<1%) than those mentioned 
above, should be noted because they are severe, life-threatening or fatal. With limited 
experience and because these events occurred while patients were receiving other drugs as 
well, we do not know if ixazomib causes such problems. Severe, life-threatening or deadly 
conditions that may involve rash, blistering, skin peeling and mouth sores including Stevens-
Johnson Syndrome, Toxic Epidermal Necrolysis, drug reaction with eosinophilia and 
systemic symptoms (DRESS syndrome) and pemphigus vulgaris, have been reported in 
ixazomib studies when given in combination with other drugs. These rashes are disorders of 
the immune system, which differ from regular skin rashes and are generally more severe. 
In addition, posterior reversible encephalopathy syndrome has also been reported with 
ixazomib with lesser frequency (< 1%). This condition affects the brain and may cause 
headaches, changes in your vision, changes in your mental status, or seizures (fits), but is 
usually reversible. Transverse myelitis, also a rare condition (<1%), is an inflammatory 
disease causing injury to the spinal cord which has been reported in a patient receiving 
ixazomib. This condition may cause varying degrees of muscle weakness, reduced movement 
in legs, changes in the feelings of the toes and feet, unusual muscle tightness, feelings of 
pain, changes in bowel (constipation) or urinary (loss of control) function or loss of leg 
movement. In general, recovery may be partial, complete, or not at all but most patients 
experiencing transverse myelitis have good to fair recovery of symptoms. We do not know 
whether ixazomib causes transverse myelitis, however, as it happened to a patient receiving 
ixazomib, we are not able to exclude the possibility that ixazomib may have contributed to 


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transverse myelitis. 
Progressive multifocal leukoencephalopathy (PML) is a rare, serious infection of the brain 
that is caused by a virus. Persons with a weakened immune system may develop PML. PML 
can result in death or severe disability. PML has been observed rarely (<0.1 %) in patients 
taking ixazomib. It is not known whether ixazomib may contribute to the development of 
PML. 
Ixazomib should not be taken if you have ever had an allergic reaction to boron or boron 
containing products. 
The following side effects may also be a risk with ixazomib because they have been reported 
with another proteasome inhibitor, bortezomib, in patients with diseases requiring this type of 
treatment, or in patients who receive ixazomib in combination with other drugs for cancer 
treatment: 
• Reactivation of the herpes virus infection such as herpes zoster (shingles) that can 
sometimes cause local pain that may last after recovery from the skin rash and does not 
go away for some time; 
• Rapid death of cancer cells that may let large amounts of the cells into the blood that 
injure organs, such as kidneys (this is referred to as tumor lysis syndrome); 
• Worsening of your heart function (congestive heart failure) that may require additional 
drugs for treatment or hospitalization; 
• Disorders of your lung that could be serious enough to result in death 
Other Risks of MLN9708 (ixazomib citrate) 
There are some additional risks associated with MLN9708 (ixazomib citrate).  
Common risks (which occur greater than 20% of the time) include infection, a low number of 
a particular white blood cell which is important to the immune system (lymphopenia), and 
joint pain (arthralgia). 
Less likely risks (which occur 20% of the time or less) include back pain, upper respiratory 
tract infection, sensation of lightheadedness or vertigo (spinning sensation or dizziness), 
blood chemical imbalance (electrolyte imbalance), and pneumonia.  
Rare risks (which occur less than 2-3% of the time) include low or high blood pressure, a 
painful blistery red rash that is confined to one side of the body similar to chicken pox 
(Herpes zoster), esophageal ulcer, chest pain, abnormal liver tests, weight loss, fainting 
episodes, decreased level of consciousness, tremors, blood clots, inflammation of the lungs, 
increased blood pressure in the lungs, nosebleeds, changes in mood, swelling around the 
eyes, muscle aches, and an inflammatory response associated with an increase in your white 
blood cell count, fever, and a change in certain protein levels and chemistries in the body, 
Rare and serious risks also include abnormal heart rhythms, congestive heart failure, 
disorders that could affect the function of your lung that could be serious enough to result in 
death, blockage of your bowel function, and a condition that can be associated with abnormal 
neurological function and seizures (posterior reversible encephalopathy syndrome; PRES).  
Tumor lysis is another rare but serious complication that may occur if the cancer cells die too 


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quickly and includes inappropriate increase or decrease of various natural chemicals in the 
blood stream, called uric acid, phosphorus, potassium, creatinine, and calcium. Severe tumor 
lysis can result in kidney failure and may harm muscle or nerve function (tumor lysis 
syndrome). Another rare and serious risk is high creatinine which may indicate renal failure. 
The amount of creatinine (a waste product made by your body) in your blood helps your 
doctor understand how your kidneys are working. High creatinine means your kidneys are 
having trouble working well. Patients who had lost body water because of vomiting and/or 
loose stools have had high levels of creatinine indicating that the kidneys were failing to 
function adequately. In some severe situations, less kidney function may require temporary 
treatment with a machine that supports the function of the kidney (dialysis). 
Furthermore, there are some risks when MLN9708 (ixazomib citrate) is used for maintenance 
treatment after a stem cell transplant. Out of 100 people taking ixazomib, 20 to 100 people 
may experience the following risks, some of which maybe serious: viral upper respiratory 
infections and fevers, nausea, vomiting and diarrhea, cough, and joint pains. Out of 100 
people taking ixazomib, 4 to 20 people may experience the following risks, some of which 
may be serious: flu (influenza), low platelet counts, muscle pain, infections, headache, 
fatigue, and numbness and tingling. Out of 100 people taking ixazomib, 3 or fewer people 
may experience the following rare and serious risks: neutropenia (low levels of white blood 
cells that make it hard for your body to fight infections) and thrombocytopenia (low levels of 
platelets which cause an increased risk of bleeding and bruising). The use of ixazomib as 
maintenance treatment with or without prior transplant, has resulted in longer time for 
myeloma recurrence in two randomized trials. At the current time, the final results on overall 
survival have not been reached from those trials. When those results are complete, we will 
inform you as soon as we know what they are, whether there is a detriment to survival, no 
effect on survival, or an improvement. Based on the results thus far from those trials, there is 
no evidence that ixazomib given as maintenance after transplant will improve overall 
survival. 
Additional Drug Risks 
The study drug could interact with other drugs. Share this information with your family 
members, caregivers, other health care providers, and pharmacists. 
Rarely, there are problems getting enough supplies of the study drug. If that happens, your 
doctor will talk with you about your options. 
Imaging Risks 
Procedures such as CT scans, X-rays, and/or radioactive drugs will be used during this 
research study to see how you are doing. Some of the scans are what you would normally 
undergo with your disease. The cumulative radiation exposure from these tests is considered 
small and is not likely to adversely affect you or your disease. However, the effects of 
radiation add up over a lifetime. It is possible that having several of these tests may add to 
your risk of injury or disease. When deciding to enter this study, think about your past and 
future contact with radiation. Examples of contact with radiation include x-rays taken for any 
reason or radiation therapy for cancer treatment. 


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What are my responsibilities in this study? 
If you choose to take part in this study you will need to: 
• Keep your study appointments. 
• Tell your doctor about: 
• all medications and supplements you are taking 
• any side effects 
• any doctors’ visits or hospital stays outside of this study 
• if you have been or are currently in another research study. 
• Write down in your medication diary when you take the study drug at home. 
For women: Do not get pregnant or breastfeed while taking part in this study.  
For men: Do not father a baby while taking part in this study.  
For all: Tell your study doctor right away if you think that you or your partner have become 
pregnant during the study or within 28 days after your last dose of study treatment. 
What are the costs of taking part in this study? 
You and/or your insurance plan will need to pay for the costs of medical care you get as part 
of the study, just as you would if you were getting the usual care for your MM. This includes: 
• the costs of tests, exams, procedures, and drugs that you get during the study to monitor 
your safety, and prevent and treat side effects.   
• bone marrow biopsies and aspirates. 
• imaging scans. 
• lenalidomide. 
• your insurance co-pays and deductibles. 
Talk to your insurance provider and make sure that you understand what your insurance pays 
for and what it doesn’t pay for if you take part in this clinical trial. Also, find out if you need 
approval from your plan before you can take part in the study. 
Ask your doctor or nurse for help finding the right person to talk to if you are unsure which 
costs will be billed to you or your insurance provider. 
You and/or your insurance provider will not have to pay for exams, tests, and procedures 
done for research purposes only or that are covered by the study. These include: 
• scheduled MRD testing on the bone marrow biopsy/aspirate samples. This does not 
include the costs of the biopsy/aspirate itself. 
• patient reported outcomes questionnaires 
You or your insurance provider will not have to pay for ixazomib/placebo while you take 
part in this study. 
Celgene Patient Support: Celgene has a Celgene Patient Support (CPS) team that is focused 
on providing assistance accessing lenalidomide to patients who are insured, uninsured and/or 


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underinsured. CPS can work with patients, caregivers, and/or physicians’ offices who opt in 
for support. Please discuss with your doctor if you would like to use this support team. 
Taking part in this study may mean that you need to make more visits to the clinic or hospital 
than if you were getting the usual approach to treat your cancer. You may: 
• Have more travel costs. 
• Need to take more time off work. 
• Have other additional personal costs. 
You will not be paid for taking part in this study. The research may lead to new tests, drugs, 
or other products for sale. If it does, you will not get any payment.  
What happens if I am injured because I took part in this study? 
If you are injured as a result of taking part in this study and need medical treatment, please 
talk with your study doctor right away about your treatment options. The study sponsors will 
not pay for medical treatment for injury. Your insurance company may not be willing to pay 
for a study-related injury. Ask them if they will pay. If you do not have insurance, then you 
would need to pay for these medical costs. 
If you feel this injury was caused by medical error on the part of the study doctors or others 
involved in the study, you have the legal right to seek payment, even though you are in a 
study. Agreeing to take part in this study does not mean you give up these rights. 
Who will see my medical information? 
Your privacy is very important to us. The study doctors will make every effort to protect it. 
The study doctors have a privacy permit to help protect your records if there is a court case. 
However, some of your medical information may be given out if required by law. If this 
should happen, the study doctors will do their best to make sure that any information that 
goes out to others will not identify who you are. 
Some of your health information, such as your response to cancer treatment, results of study 
tests, and medicines you took, will be kept by the study sponsor in a central research 
database. However, your name and contact information will not be put in the database. If 
information from this study is published or presented at scientific meetings, your name and 
other personal information will not be used. 
The ECOG-ACRIN Cancer Research Group is conducting this study. ECOG-ACRIN is a 
cancer research group that conducts studies for the National Cancer Institute. Your doctor is 
a member of ECOG-ACRIN or another group that is participating in this study. 
There are organizations that may look at your study records. Your health information in the 
research database also may be shared with these organizations. They must keep your 
information private, unless required by law to give it to another group.   
Some of these organizations are: 
• The study sponsor and any drug company supporting the study now or in the future.  


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• The NCI Central IRB, which is a group of people who review the research with the goal 
of protecting the people who take part in the study. 
• The FDA and the groups it works with to review research.  
• The NCI and the groups it works with to review research. 
• The NCI’s National Clinical Trials Network and the groups it works with to conduct 
research including the Imaging and Radiation Oncology Core (IROC). 
In addition to storing data in the study database, data from studies that are publicly funded 
may also be shared broadly for future research with protections for your privacy. The goal of 
this data sharing is to make more research possible that may improve people’s health. Your 
study records may be stored for future use in public databases. However, your name and 
other personal information will not be used. 
Some types of future research may include looking at your information and information from 
other patients to see who had side effects across many studies or comparing new study data 
with older study data. However, right now we don’t know what research may be done in the 
future using your information. This means that: 
• You will not be asked if you agree to take part in the specific future research studies 
using your health information. 
• You and your study doctor will not be told when or what type of research will be done. 
• You will not get reports or other information about any research that is done using your 
information. 
Where can I get more information? 
You may visit the NCI web site at http://cancer.gov/ for more information about studies or 
general information about cancer. You may also call the NCI Cancer Information Service to 
get the same information at: 1-800-4-CANCER (1-800-422-6237). 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site at any 
time. 
You can talk to the study doctor about any questions or concerns you have about this study or 
to report side effects or injuries. Contact the study doctor ____________________ [name(s)] 
at ____________________ [telephone number and email address if appropriate]. 
For questions about your rights while in this study, call the ____________________ [name 
of organization or center] Institutional Review Board at ____________________ [telephone 
number]. 
Optional studies that you can choose to take part in. 
This part of the consent form is about optional studies that you can choose to take part in. 
They are separate from the main study described above. These optional studies will not 
benefit your health. The researchers leading these optional studies hope the results will help 
other people with cancer in the future. The results will not be added to your medical records 


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and you or your study doctor will not know the results. 
Taking part in these optional studies is your choice. You can still take part in the main study 
even if you say “no” to any or all of these studies. There is no penalty for saying “no.” You 
and your insurance company will not be billed for these optional studies. If you sign up for, 
but cannot complete any of these studies for any reason, you can still take part in the main 
study. 
Optional sample collections for storage for possible future studies 
Researchers are trying to learn more about cancer and other health problems using blood and 
tissue samples from people who take part in clinical trials. By studying these samples, 
researchers hope to find new ways to prevent, detect, treat, or cure diseases. 
Some of these studies may be about how genes affect health and disease. Other studies may 
look at how genes affect a person’s response to treatment. Genes carry information about 
traits that are found in you and your family. Examples of traits are the color of your eyes, 
having curly or straight hair, and certain health conditions that are passed down in families. 
Some of the studies may lead to new products, such as drugs or tests for diseases. 
Unknown future studies 
If you choose to take part in this optional study, leftover bone marrow from the laboratory 
research studies will be stored. Storing samples for future studies is called “bio-banking.” 
The biobank is being run by ECOG-ACRIN and is supported by the NCI. This is a publicly 
funded study. Samples from publicly funded studies are required to be shared as broadly as 
possible. However, we will protect your privacy. The goal of this is to make more research 
possible that may improve people’s health. 
The biobank is a public research resource. It has controlled access. This means that 
researchers who want to get samples and data from it must submit a specific research request. 
The request identifies who they are and what their planned research project is. Before getting 
the samples and data, the researchers must agree to keep the data private, only use it for their 
planned research project, and never use it to try to identify you. Also, any health-related 
information, such as your response to cancer treatment, results of study tests, and medicines 
you took, will be stored for future use. 
Right now, we don’t know what research may be done in the future using your bone marrow 
samples. This means that: 
• You will not be asked if you agree to take part in the future research studies. 
• You and your study doctor will not be told when or what type of research will be done. 
• You will not get reports or other information about any research that is done using your 
samples. 
Unknown future research studies may include sequencing of all or part of your DNA. This is 
called genomic sequencing. Sequencing allows researchers to identify your genetic code. 
Changes in your genetic code may just be in your tumor tissue. These are called somatic 
changes. Changes may also be in your normal tissue and passed down through your family. 
For example, these genetic changes may be passed down to your children in the same way 
that eye and hair color are passed down. These are called germline changes.   


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If only tumor tissue is sequenced, we will not know if a genetic change in your tumor is also 
in your normal tissue. This is why sometimes both normal tissue and tumor tissue are 
sequenced. This helps researchers understand if a genetic change happened only in your 
cancer tissue, or in your normal tissue as well. 
What is involved in this optional sample collection? 
If you agree to take part, here is what will happen next: 
1. Your leftover bone marrow from the laboratory research studies will be stored in the 
biobank. There is no limit on the length of time we will keep your samples and research 
information. The samples will be kept until they are used for research or destroyed. 
2. Researchers can only get samples from the biobank after their research has been 
approved by experts. Researchers will not be given your name or contact information. 
3. Some of your genetic and health information may be placed in central databases for 
researchers to use. The databases will not include your name or contact information. 
What are the risks in this optional sample collection? 
Your medical and genetic information is unique to you. There is a risk that someone outside 
of the research study could get access to your study records or trace information in a database 
back to you. They could use that information in a way that could harm you. Researchers 
believe the chance that someone could access and misuse your information is very small. 
However, the risk may increase in the future as people find new ways of tracing information. 
In some cases, this information could be used to make it harder for you to get or keep a job 
and get or keep health insurance. There are laws against the misuse of genetic information, 
but they may not give full protection. For more information about the laws that protect you, 
ask your study doctor or visit: https://www.genome.gov/10002328/ 
How will information about me be kept private? 
Your privacy is very important to the study researchers and biobank. They will make every 
effort to protect it. Here are just a few of the steps they will take: 
1. They will remove identifiers, such as your initials, from your samples and information. 
They will replace them with a code number. There will be a master list linking the code 
numbers to names, but they will keep it separate from the samples and information. 
2. Researchers who study your samples and information will not know who you are. They 
also must agree that they will not try to find out who you are. 
3. Your personal information will not be given to anyone unless it is required by law. 
4. If research results are published, your name and other personal information will not be 
used. 
What are the benefits to taking part in this optional sample collection? 
You will not benefit from taking part. The researchers, using the samples from you and 
others, might make discoveries that could help people in the future. 


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Are there any costs or payments to this optional sample collection? 
There are no costs to you or your insurance. You will not be paid for taking part in this study. 
The research may lead to new tests, drugs, or other products for sale. If it does, you will not 
get any payment. 
What if I change my mind about this optional sample collection? 
If you decide you no longer want your samples to be used, you can call the study doctor, 
____________________ [name(s)], at ____________________ [telephone number], who 
will let the biobank know. Then, any samples that remain in the biobank will be destroyed or 
returned to your study doctor. This will not apply to any samples or related health 
information that have already been given to or used by researchers. 
What if I have questions about this optional sample collection? 
If you have questions about the use of your samples for research, contact the study doctor, 
____________________ [name(s)], at ____________________ [telephone number]. 
 
Please circle your answer below to show if you would or would not like to take part in each 
optional study: 
Samples for unknown future studies: 
May we keep any bone marrow samples leftover after the laboratory research studies for 
future research? 
My samples and related information may be kept in a Biobank for use in future health 
research. 
YES 
NO 
This is the end of the section about optional studies. 
My signature agreeing to take part in the study 
I have read this consent form or had it read to me. I have discussed it with the study doctor 
and my questions have been answered. I will be given a signed and dated copy of this form. I 
agree to take part in the main study. I also agree to take part in any additional studies where I 
circled “yes”. 
 
Participant’s signature ________________________________ 
 
Date of signature _____________________________________ 
 
Signature of person(s) conducting the informed consent discussion ___________________ 


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Date of signature _____________________________________