A Phase II Study of IRD (Ixazomib, Lenalidomide, & Dexamethasone) for Consolidation Therapy Post Autologous Stem Cell Transplantation Followed by Maintenance Ixazomib or Lenalidomide for Multiple Myeloma
Phase: PHASE2
Conditions: Multiple Myeloma
Sponsor: Washington University School of Medicine

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Protocol Amendment 7; Version: 04/02/2018 
 
 
A Phase II Study of IRD (Ixazomib, Lenalidomide, & Dexamethasone) for Consolidation 
Therapy Post Autologous Stem Cell Transplantation followed by Maintenance Ixazomib or 
Lenalidomide for Multiple Myeloma 
 
Washington University School of Medicine, Division of Oncology 
660 South Euclid Avenue, Campus Box 8007 
St. Louis, MO  63110 
 
Protocol #:  201411060 
Millennium Protocol ID: X16063 
Version Date: 04/02/2018 
 
Principal Investigator: 
Ravi Vij, M.D. 
Phone:  (314) 454-8323 
E-mail:  rvij@wustl.edu 
 
Sub-Investigators: 
 
Institution: 
 
 
Modality 
Nitya Nathwani, M.D. 
 
City of Hope 
 
 
Medical Oncology 
Jonathan Kaufman, M.D.  
Emory Winship  
 
Medical Oncology 
Jeffrey A. Zonder, M.D. 
 
Karmanos Cancer Institute 
Medical Oncology 
Thomas Martin, M.D. 
 
University of California- SF 
Medical Oncology 
Ashley Rosko, MD 
 
Ohio State University 
 
Medical Oncology 
Jesus Berdeja, MD 
 
Sarah Cannon Research Institute 
Medical Oncology 
Tara Gregory, MD 
 
Sarah Cannon Research Institute 
Medical Oncology 
Ajai Chari, MD   
 
Mount Sinai Hospital 
 
Medical Oncology 
Francis Buadi 
 
 
Mayo Clinic 
 
 
Medical Oncology 
Camille Abboud, M.D.  
 
Washington University 
 
Medical Oncology 
 
 
John DiPersio, M.D., Ph.D. 
Washington University 
 
Medical Oncology 
  
Todd Fehniger, M.D., Ph.D. 
Washington University 
 
Medical Oncology 
 
 
Armin Ghobadi, M.D.  
 
Washington University 
 
Medical Oncology 
 
Megan Jacoby, M.D., Ph.D. 
Washington University 
 
Medical Oncology 
 
 
Jesse Keller, M.D.  
 
Washington University 
 
Medical Oncology 
Iskra Pusic, M.D.  
 
Washington University 
 
Medical Oncology 
 
Rizwan Romee, M.D. 
 
Washington University 
 
Medical Oncology 
 
 
Mark Schroeder, M.D.  
 
Washington University 
 
Medical Oncology 
Keith Stockerl-Goldstein, M.D. 
Washington University 
 
Medical Oncology 
Michael Tomasson, M.D.  
Washington University 
 
Medical Oncology 
Geoffrey Uy, M.D. 
 
Washington University 
 
Medical Oncology 
Matthew Walter, M.D. 
 
Washington University 
 
Medical Oncology 
Lukas Wartman, M.D. 
 
Washington University 
 
Medical Oncology 
John Welch, M.D., Ph.D.  
Washington University 
 
Medical Oncology 
Peter Westervelt, M.D., Ph.D. 
Washington University 
 
Medical Oncology 
Feng Gao, Ph.D.  
 
Washington University 
 
Biostatistics 
 
Study Drug(s):  
 
Ixazomib 
Lenalidomide 
Dexamethasone 
 
IND#: 
124293 
Clinical Trials.gov# 
NCT02253316 
 

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Protocol Amendment 7; Version: 04/02/2018 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 

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Protocol Amendment 7; Version: 04/02/2018 
A Phase II Study of IRD (Ixazomib, Lenalidomide, & Dexamethasone) for Consolidation 
Therapy Post Autologous Stem Cell Transplantation followed by Maintenance Ixazomib or 
Lenalidomide for Multiple Myeloma 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
11/06/2014 
Amendment 1 
 
 
 
 
 
 
 
01/13/2015 
Amendment 2 
 
 
 
 
 
 
 
06/15/2015 
Amendment 3 
 
 
 
 
 
 
 
06/01/2016 
Amendment 4 
 
 
 
 
 
 
 
11/16/2016 
Amendment 5 (Wash U Only) 
 
 
 
 
 
05/17/2017 
Amendment 6 
 
 
 
 
 
 
 
07/06/2017 
Amendment 7 
 
 
 
 
 
 
 
04/02/2018 
 
 

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Protocol Amendment 7; Version: 04/02/2018 
A Phase II Study of IRD (Ixazomib, Lenalidomide, & Dexamethasone) for Consolidation 
Therapy Post Autologous Stem Cell Transplantation followed by Maintenance Ixazomib or 
Lenalidomide for Multiple Myeloma 
 
Principal Investigator Signature Page 
 
 
Principal Investigator: 
 
 
 
 
 
 
Signature of Investigator 
 
Date 
 
 
 
Printed Name of Investigator 
 
 
 
By my signature, I agree to personally supervise the 
conduct of this study and to ensure its conduct in 
compliance with the protocol, informed consent, 
IRB/HRPO procedures, the Declaration of Helsinki, ICH 
Good Clinical Practices guidelines, and the applicable 
parts of the United States Code of Federal Regulations or 
local regulations governing the conduct of clinical 
studies. 
 
 
 
 

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Protocol Amendment 7; Version: 04/02/2018 
Contact Information 
 
Washington University School of Medicine 
 
Principal Investigator 
Sub-Investigator 
Ravi Vij, M.D.  
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8007 
St. Louis, MO  63110 
Phone: (314) 454-8323 
E-mail:  rvij@wustl.edu  
Keith Stockerl-Goldstein, M.D. 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8007 
St. Louis, MO  63110 
Phone:  (314) 454-8304 
E-mail: ksgoldstein@ wustl.edu  
 
Project/Database Manager 
Sarah Cannon Research Institute 
Mark Fiala, MSW, CCRP 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8007 
St. Louis, MO  63110 
Phone:  (314) 454-8302 
E-mail: mfiala@ wustl.edu  
Jesus Berdeja, MD 
 
Sarah Cannon Research Institute 
250 25th Avenue North, Suite 301 
Nashville, TN 37203 
Phone: (615) 329-7274 
Email: jberdeja@tnonc.com  
City of Hope 
Karmanos Cancer Institute 
Nitya Nathwani, M.D.  
 
City of Hope 
1500 East Duarte Road 
Duarte, CA, 91010   
Phone: (626) 256-4673 
Email: nnathwani@coh.org 
Jeffrey Zonder, M.D. 
Karmanos Cancer Institute  
4100 John R. HW04HO 
Detroit, MI 48201 
Phone: (313) 576-8732 or (313) 576-8730 
Email: zonderj@karmano.org 
 
Ohio State University 
 
University of California- San Francisco 
Ashley Rosko, MD 
Ohio State University 
A345 Starling Loving Hall 
320 W. 10th Ave. 
Columbus, Ohio 43210 
Phone: (614) 293-7807 
Email: Ashley.Rosko@osumc.edu 
Thomas Martin, M.D. 
University of California- San Francisco 
Box 0324, UCSF 
3333 Calif. St, Laurel Heights 
San Francisco, CA 94118 
Phone: (415) 353-9365 
Email: tmartin@medicine.ucsf.edu  
 
   Sarah Cannon Research Institute 
 
   Tara Gregory, MD 
   Sarah Cannon Research Institute    
   1721 East 19th  Avenue, Suites 200 & 300 
   Denver, Colorado 80218 
   Phone: (720) 754-4800 
   Email: Tara.Gregory@HealthONECares.com  
    
Emory Winship Cancer Institute 
Jonathan Kaufman, M.D. 
Emory Winship Cancer Institute  
5665 Peachtree Dunwoody Rd #150 
Atlanta, GA 30342 
Phone: (678) 843-6800 
Email: jonathan.kaufman@emoryhealthcare.org  

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Mount Sinai Hospital 
 
Ajai Chari, MD 
 
Mount Sinai Hospital 
One Gustave L Levy Place, Box 1185 
New York, New York 10029 
Phone: (212) 241-7873 
Email: ajai.chari@mountsinai.org   
 
 
 
Mayo Clinic 
Francis Buadi, MD  
Mayo Clinic 
 
200 First Street SW  
Rochester, MN 55905 
Phone: (507) 538-3270 
Email: Buadi.Francis@mayo.edu  
 

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Protocol Amendment 7; Version: 04/02/2018 
A Phase II Study of IRD (Ixazomib, Lenalidomide, & Dexamethasone) for Consolidation 
Therapy Post Autologous Stem Cell Transplantation followed by Maintenance Ixazomib or 
Lenalidomide for Multiple Myeloma 
 
STUDY SCHEMA 
 
 
                             
 
 
 
 
 Autologous Stem 
Cell Transplant 
 
Day 80-120: 
MRD Assessment & 
Study Enrollment 
 Consolidation with 
4 Cycles of IRD 
 
 
 
 
Randomized to 
Ixazomib 
Maintenance 
Randomized to 
Lenalidomide 
Maintenance 
 
Assess Tolerability, PFS, OS  
Restaging: 
MRD Assessment 

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Protocol Amendment 7; Version: 04/02/2018 
PROTOCOL SUMMARY  
Study Title:  A Phase II Study of IRD (Ixazomib, Lenalidomide, & Dexamethasone) for 
Consolidation Therapy Post Autologous Stem Cell Transplantation followed by Maintenance 
Ixazomib or Lenalidomide for Multiple Myeloma 
Phase:  II 
Number of Patients:  ~240 
Primary Objective 
• To determine the improvement in MRD-negative rate after 4 cycles of IRD consolidation 
Secondary/Exploratory Objectives 
• To determine the MRD-negative rate after ASCT 
• To evaluate the toxicity, response rate, PFS, and OS of IRD consolidation   
• To collect pilot data to compare toxicity, response rate, PFS, OS, and the rate of MRD-
positive to MRD-negative conversion between the two maintenance arms 
• To evaluate the association of PFS and OS with MRD-negativity and MRD-positivity prior to 
consolidation and after 4 cycles of IRD consolidation 
• To evaluate the relationship between HEVYLITE assay results with response and MRD status 
• To evaluate the effect of ixazomib maintenance on the immune system 
Overview of Study Design:  Patients will undergo standard of care ASCT with conditioning 
regimen determined by the treating physician per institutional guidelines. The ASCT is not 
considered part of this study.  Consolidation therapy will begin on between Day 80 and Day 120 
following ASCT and will consist of four 28-day cycles of IRD (ixazomib, lenalidomide, & 
dexamethasone). Barring dose modifications for toxicity, 4 mg of ixazomib and 40 mg of 
dexamethasone will be administered on Days 1, 8, and 15, and 15 mg of lenalidomide will be 
administered on daily on Days 1-21.   
 
Following completion of consolidation therapy, patients will undergo restaging and will be 
randomized on a 1:1 basis to maintenance therapy with ixazomib or lenalidomide. Patients will be 
stratified based on MRD status at restaging (MRD-positive v. MRD-negative).  
 
Barring dose modifications for toxicity, ixazomib maintenance will consist of 4 mg administered on 
Days 1, 8 and 15 of each 28-day cycle, and lenalidomide maintenance will consist of 10 mg daily on 
Days 1-28 for the first three 28-day cycles and 15 mg daily for all further cycles. Maintenance 
therapy with either ixazomib or lenalidomide will continue until the patient experiences disease 
progression or unacceptable toxicity.  
Study Population:  Patients between the ages of 18 and 70 years of age (inclusive) at time of 
enrollment with a histologically confirmed diagnosis of symptomatic multiple myeloma, who have 
received at least two cycles of any regimen as initial systemic therapy for multiple myeloma and are 
within 2-16 months of the first dose of initial therapy who provide voluntary written consent. 
Duration of Study:  Three years to complete accrual; approximately 7 year patient participation; 
therefore 10 years total.   
 
 
 

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Table of Contents 
STUDY SCHEMA.......................................................................................................................... 7 
PROTOCOL SUMMARY .............................................................................................................. 8 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS .................................................. 11 
1.0 
BACKGROUND AND RATIONALE .............................................................................. 13 
1.1 
Multiple Myeloma .......................................................................................................... 13 
1.2 
Ixazomib (MLN9708) .................................................................................................... 13 
1.3 
Value of Minimal Residual Disease Assessment ........................................................... 24 
1.4 
Study Rationale .............................................................................................................. 25 
1.5 
Correlative Studies Background..................................................................................... 26 
2.0 
OBJECTIVES .................................................................................................................... 26 
2.1 
Primary Objective .......................................................................................................... 26 
2.2 
Secondary Objectives ..................................................................................................... 26 
2.3 
Exploratory Objectives ................................................................................................... 26 
3.0 
PATIENT SELECTION .................................................................................................... 27 
3.1 
Inclusion Criteria ............................................................................................................ 27 
3.2 
Exclusion Criteria ........................................................................................................... 28 
3.3 
Inclusion of Women and Minorities............................................................................... 29 
4.0 
REGISTRATION PROCEDURES ................................................................................... 29 
4.1 
Confirmation of Patient Eligibility ................................................................................. 29 
4.2 
Patient Registration in the Siteman Cancer Center Database ........................................ 29 
4.3 
Assignment of UPN ....................................................................................................... 30 
5.0 
TREATMENT PLAN ........................................................................................................ 30 
5.1 
Overview ........................................................................................................................ 30 
5.2 
IRD Consolidation.......................................................................................................... 30 
5.3 
Maintenance Therapy ..................................................................................................... 33 
5.4 
Excluded Concomitant Medications and Procedures ..................................................... 35 
5.5 
Permitted Concomitant Medications and Procedures .................................................... 36 
5.6 
Pregnancy Risks – Precautions and Restrictions ........................................................... 36 
5.7 
Duration of Therapy ....................................................................................................... 37 
5.8 
Duration of Follow-up .................................................................................................... 38 
6.0 
DOSE MODIFICATIONS ................................................................................................ 38 
6.1 
Dose Levels .................................................................................................................... 39 
6.2 
Criteria for Beginning a New Treatment Cycle ............................................................. 40 
6.3 
Dosing Modifications for Hematologic Toxicities......................................................... 40 
6.4 
Dosing Modifications for Non-Hematologic Toxicities ................................................ 42 
6.5 
Management of Clinical Events ..................................................................................... 44 
7.0 
PHARMACEUTICAL INFORMATION .......................................................................... 47 
7.1 
Ixazomib ......................................................................................................................... 47 
7.2 
Lenalidomide .................................................................................................................. 49 
7.3 
Dexamethasone .............................................................................................................. 49 
8.0 
STUDY CALENDAR ....................................................................................................... 50 
9.0 
CENTRAL LABS .............................................................................................................. 52 
9.1 
Mayo Clinic MFC MRD Panel ...................................................................................... 52 
9.2 
Adaptive ClonoSEQ MRD Testing ................................................................................ 52 
9.3 
HEVYLITE Assay ......................................................................................................... 52 

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9.4 
Handling of Specimen(s) ................................................................................................ 53 
9.5 
Future Research .............................................................................................................. 53 
10.0 DATA SUBMISSION SCHEDULE ................................................................................. 53 
11.0 REGULATORY AND REPORTING REQUIREMENTS ............................................... 54 
11.2 Product Complaints ........................................................................................................ 57 
11.3 Medication Error ............................................................................................................ 57 
11.4 Reporting to the Human Research Protection Office (HRPO) at Washington University
 
57 
11.5 Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University .............................................................................................................. 58 
11.6 Reporting Requirements for Secondary Sites ................................................................ 58 
11.7 Reporting to Secondary Sites ......................................................................................... 58 
11.8 Reporting to the FDA ..................................................................................................... 58 
11.9 Reporting to Millennium ................................................................................................ 59 
11.10 
Timeframe for Reporting Required Events ................................................................ 60 
12.0 MEASUREMENT OF EFFECT........................................................................................ 60 
12.1 Response Criteria ........................................................................................................... 60 
12.2 Minimal Residual Disease .............................................................................................. 63 
13.0 DATA AND SAFETY MONITORING ............................................................................ 63 
14.0 AUDITING ........................................................................................................................ 64 
15.0 STATISTICAL CONSIDERATIONS............................................................................... 65 
15.1 Determination of Sample Size........................................................................................ 65 
15.2 Randomization and Stratification ................................................................................... 66 
15.3 Data Analysis ................................................................................................................. 67 
15.4 Interim Analysis ............................................................................................................. 67 
16.0 MULTICENTER REGULATORY REQUIREMENTS ................................................... 68 
17.0 REFERENCES .................................................................................................................. 70 
APPENDIX A: ECOG Performance Scale ................................................................................... 73 
APPENDIX B: Cockcroft-Gault Equation ................................................................................... 74 
APPENDIX C: New York Heart Association (NYHA) Functional Classification ...................... 75 
APPENDIX D: Administration Questionnaire: Consolidation Cycle ___________ ................... 76 
APPENDIX E: Administration Questionnaire: Maintenance Cycle ___________ ..................... 76 
APPENDIX F: Correlative Sub-study .......................................................................................... 78 
 
 
 

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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
Abbreviation 
Definition 
°C 
degrees Celsius 
ADR 
adverse drug reaction 
AE 
adverse event 
AL 
primary  amyloidosis 
ALT 
alanine aminotransferase/ serum glutamic pyruvic transaminase 
ASCT 
autologous stem cell transplant 
AST 
aspartate aminotransferase/serum glutamic oxaloacetic transaminase  
AUC 
area under the plasma concentration versus time curve 
BCRP 
Breast cancer resistant protein 
BSA 
body surface area 
CL 
clearance, IV dosing 
cm 
centimeter 
CR 
complete response 
CRF 
case report form 
CTCAE 
(NCI) Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DSMC 
Data and Safety Monitoring Committee 
FDA 
Food and Drug Administration 
GI 
Gastrointestinal 
GCP 
Good Clinical Practices 
HRPO 
Human Research Protection Office 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IRB 
institutional review board 
IRD 
ixazomib, lenalidomide, and dexamethasone 
ITT 
intent-to-treat 
IV 
intravenous 
m2 
square meters 
MFC 
multiparameter flow cytometry 
Millennium 
Millennium Pharmaceuticals, Inc., and its affiliates 
mL 
milliliter 
MM 
multiple myeloma 

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Abbreviation 
Definition 
mm3 
cubic millimeters 
MRD 
minimal residual disease 
NDMM 
newly diagnosed multiple myeloma 
NYHA 
New York Heart Association 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
Pgp 
P-glycoprotein 
PO 
per os; by mouth (orally) 
PR 
partial response 
QASMC 
Quality Assurance and Safety Monitoring Committee 
RP2D 
recommended phase 2 dose 
RRMM 
Relapsed/Refractory Multiple Myeloma 
SAE 
serious adverse event 
sCR 
stringent complete response 
SD 
stable disease 
SMA 
safety management attachment 
TEAE 
treatment emergent adverse event 
Tmax 
single-dose time to reach maximum (peak) concentration 
UPN 
unique patient number 
VGPR 
very good partial response 
VTE 
venous thromboembolism 
 
 

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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Multiple Myeloma 
 
Multiple myeloma (MM) is a multifocal plasma cell neoplasm resulting from the clonal 
expansion of terminally differentiated B-cells. The disease is characterized by a serum or 
urine monoclonal protein and skeletal destruction with osteolytic lesions, bone pain, 
pathologic fractures, and hypercalcemia. Recurrent infections from depressed normal 
immunoglobulin production, renal dysfunction from light chain production, and anemia 
from generalized marrow involvement are also common. In the United States, MM is the 
second most common hematologic malignancy behind non-Hodgkin’s lymphomas with 
an estimated 15,270 new cases and 11,070 deaths in 2004 [1].  
 
Progress in the treatment of MM has been modest since the introduction of melphalan 
more than 25 years ago. Melphalan combined with prednisone produces an objective 
response of 50-60%, although median survival remains approximately 3 years with 5-
10% of patients surviving 10 or more years [2]. With the advent of novel targeted agents, 
the majority of patients have experienced improved survival outcomes in recent years. 
The immunomodulatory agents thalidomide and lenalidomide and the proteasome 
inhibitor bortezomib are routinely used as first line therapy and have improved the 
outcomes for myeloma patients. Despite the availability of these newer therapies, the 
overall prognosis of patients with myeloma remains poor, as patients who do respond to 
therapy will almost invariably relapse.  
 
1.2 
Ixazomib (MLN9708)  
 
1.2.1    Preclinical Experience 
 
Please refer to the current ixazomib Investigator’s Brochure (IB) and Safety 
Management Attachment (SMA). 
 
1.2.2    Clinical Experience 
 
Ixazomib has been evaluated as an oral single agent in phase 1 studies that have 
included patients with advanced solid tumors, lymphoma, relapse/refractory MM 
(RRMM), and relapsed or refractory light-chain (AL) amyloidosis and 
demonstrated early signs of activity. Ongoing studies continue to investigate both 
single-agent ixazomib and ixazomib in combination with standard treatments. 
Based on encouraging preliminary data observed in patients with MM requiring 
systemic treatment, 2 phase 3 trials in newly diagnosed MM (NDMM) (C16014) 
and RRMM (C16010) patient populations are currently evaluating ixazomib in 
combination 
with 
Revlimid 
and 
Dexamethasone 
(RevDex) 
versus 
placebo/RevDex. Both trials are combining ixazomib at a weekly dose of 4.0 mg 
on Days 1, 8, and 15 in a 28-day cycle to a standard dose of lenalidomide with a 
weekly dexamethasone dose of 40 mg. In addition, ongoing clinical 
pharmacology studies include evaluation of drug-drug interactions with 

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Protocol Amendment 7; Version: 04/02/2018 
ketoconazole and rifampin, effect of food, and oral bioavailability. Studies 
evaluating the safety and pharmacokinetic (PK) of ixazomib alone (in Japanese 
patients) and in combination with lenalidomide and dexamethasone in Asian adult 
patients (including Japanese patients) with a diagnosis of NDMM are ongoing. 
 
As of 27 March 2013, preliminary clinical data is available for a total of 653 
patients across 13 studies. The emerging safety profile indicates that ixazomib is 
generally well tolerated. The adverse events (AEs) are consistent with the class-
based effects of proteasome inhibition and are similar to what has been previously 
reported with VELCADE though the severity of some, for example peripheral 
neuropathy, is less. While some of these potential toxicities may be severe, they 
can be managed by clinical monitoring and standard medical intervention, or, as 
needed, dose modification or discontinuation. 
 
Fatigue was the most common AE reported among 384 patients treated in the oral 
(PO) studies (47%). Other common AEs reported in the pooled intravenous (IV) 
and PO safety populations include nausea, thrombocytopenia, diarrhea, and 
vomiting. Rash is also a commonly reported treatment-emergent event; however, 
there is some variety in its characterization and causality resulting in different 
preferred terms to describe it. A high-level term outline of rash events includes 
rashes, eruptions and exanthems NEC; pruritus NEC; erythemas; papulosquamous 
conditions; and exfoliative conditions. The dose escalation phases of most trials 
reported in the IB have now completed enrollment, and gastrointestinal (GI) 
symptoms were the common dose-limiting toxicities (DLTs) when the use of 
prophylactic anti-emetics was not permitted per protocol. In the expansion cohorts 
or phase 2 cohorts (as per each study), the incidence and severity of GI symptoms 
was mitigated by the use of the lower maximum tolerated dose 
(MTD)/recommended phase 2 dose (RP2D) (as per each study) and standard 
clinical usage of anti-emetics and/or antidiarrheal medications as deemed 
appropriate. Prophylactic use of anti-emetics has not been required as with other 
agents but (as outlined in Section 6.7) has been used according to standard 
practice and are effective. 
 
The most frequent (at least 20%) treatment-emergent adverse events (TEAEs) 
reported with the PO formulation pooled from single-agent studies (n = 201) 
irrespective of causality to ixazomib, include nausea (53%), fatigue (51%), 
diarrhea (44%), thrombocytopenia (34%), vomiting (38%), decreased appetite 
(32%), fever (21%), and anemia (21%). The most frequent (at least 20%) TEAEs 
reported with the PO formulation pooled from combination trials (irrespective of 
the combination) (n = 173), irrespective of causality to ixazomib, include diarrhea 
(47%), fatigue (44%), nausea (38%), peripheral edema (35%), constipation 
(33%), insomnia (29%), thrombocytopenia (28%), anemia (26%), vomiting 
(26%), neutropenia (25%), back pain (24%), pyrexia (23%), peripheral edema 
(21%, each), fever (20%), cough (20%), hypokalemia (20%), neutropenia (20%), 
and upper respiratory tract infection (20%). Overall rash of all grades is reported 

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Protocol Amendment 7; Version: 04/02/2018 
in approximately 50% of patients and is more common when ixazomib is given in 
combination with lenalidomide where rash is an overlapping toxicity. 
 
Additional detailed information regarding the clinical experience of ixazomib 
may be found in the IB, including information on the IV formulation.   
 
1.2.3   Pharmacokinetics and Drug Metabolism 
 
Clinical IV and PO PK data show that ixazomib citrate (measured as the 
biologically active boronic acid form of ixazomib [MLN2238]) has multi-
exponential disposition with a rapid initial phase that is largely over by 4 hours. 
Oral ixazomib citrate is rapidly absorbed with a median single-dose first time of 
occurrence of maximum (peak) concentration (Tmax) of approximately 0.5 to 2.0 
hours and a terminal disposition half-life (t1/2) after multiple dosing of 
approximately 5 to 7 days [1]. Results of a population PK analysis (n = 137) show 
that there is no relationship between body surface area (BSA) or body weight and 
clearance (CL). Also, based on stochastic simulations for fixed dose, exposures 
are independent of the individual patient’s BSA [2]. Based on these data, a 
recommendation was made for fixed dosing in clinical trials. An absolute 
bioavailability of 67% was determined for ixazomib using the population PK 
analysis. Please refer to the current ixazomib IB and Safety Management 
Attachment (SMA) for information on the PK for IV doses of ixazomib. 
 
Metabolism appears to be the major route of elimination for ixazomib, and 
urinary excretion of the parent drug is negligible (< 5% of dose). In vitro studies 
indicate that ixazomib is metabolized by multiple cytochrome P450s (CYPs) and 
non-CYP enzymes/proteins. The rank order of relative biotransformation activity 
of the 5 major human CYP isozymes was 3A4 (34.2%) > 1A2 (30.7%) > 2D6 
(14.7%) > 2C9 (12.1%) > 2C19 (< 1%). Ixazomib is not an inhibitor of CYPs 
1A2, 2C9, 2C19, 2D6, or 3A4 nor a time-dependent inhibitor of CYP3A4/5. The 
potential for ixazomib treatment to produce drug-drug interactions (DDIs) via 
CYP inhibition is inferred to be low. However, there may be a potential for DDIs 
with a concomitant strong CYP3A4 or CYP1A2 inhibitor or inducer because of 
the potential for first-pass metabolism when ixazomib is administered via the PO 
route and because of the moderate contribution of CYP3A4- and CYP1A2-
mediated metabolism of ixazomib in human liver microsomes. Ixazomib may be a 
weak substrate of P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), 
and multidrug resistance associated protein (MRP2) efflux pump transporters. 
Ixazomib is not an inhibitor of Pgp, BCRP, and MRP2. The potential for DDIs 
with substrates or inhibitors of Pgp, BCRP, and MRP2 is, therefore, inferred to be 
low. Clinical Study C16009 (Arm 1) with ketoconazole, a strong CYP3A4 
inhibitor, showed a 2-fold increase in area under the plasma concentration versus 
time curve (AUC) in the presence of ketoconazole. This resulted in the continued 
exclusion of strong CYP3A4 inhibitors in ongoing/planned clinical studies. 
 
Further details on these studies are provided in the IB. 

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Protocol Amendment 7; Version: 04/02/2018 
 
1.2.4    Clinical Trial Experience Using the Oral Formulation of Ixazomib 
 
As of 27 March 2013, a total of 507 patients with differing malignancies (multiple 
myeloma, AL amyloidosis, nonhematologic cancers, and lymphoma) have been 
treated in studies evaluating the oral ixazomib formulation.  These patients have 
been treated with different doses of ixazomib either as a single-agent treatment (in 
201 patients) or in combination with currently clinically available treatments (in 
306 patients).  Information regarding the ongoing studies, patient populations, and 
doses investigated is included in Table 1-1. 
 

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Protocol Amendment 7; Version: 04/02/2018 
Table 1-1    
Clinical Studies of Oral Ixazomib 
Trial/ 
Population 
Description 
Doses Investigated 
C16003 
RRMM 
N = 60 
PO, TW, single agent 
0.24-2.23 mg/m2 TW 
MTD:  2.0 mg/m2 
DLT:  rash, thrombocytopenia 
Closed to enrollment 
C16004 
RRMM 
N = 60 
PO, W, single agent 
0.24-3.95 mg/m2 W 
MTD:  2.97 mg/m2 
DLT:  rash, nausea, vomiting, diarrhea 
Closed to enrollment 
C16005 
NDMM 
N = 65 
PO, W, combination with LenDex 
28-day cycle 
1.68-3.95 mg/m2 W 
MTD:  2.97 mg/m2 
DLT:  nausea, vomiting, diarrhea, syncope 
RP2Da:  4.0 mg fixed (switched to fixed dosing in 
phase 2, equivalent  to 2.23mg/m2) 
Closed to enrollment 
C16006 
NDMM 
N = 20 
PO, TW (Arm A- 42 day cycle) and 
W (Arm B- 28 day cycle), 
combination with Melphalan and 
Prednisone 
Arm Aa:  3-3.7-mg fixed dose TW 
DLT:  rash, thrombocytopenia, subileus 
Arm Ba:  3-5.5-mg fixed dose, W 
DLT:  Esophageal ulcer nausea, vomiting, 
hematemesis, thrombocytopenia, ileus, 
neurogenic bladder 
MTD = 3.0 mg 
C16007 
RRAL 
N = 27 
PO, W, single agent 
4-5.5-mg fixed dosea W 
DLT:  thrombocytopenia, diarrhea, dyspnea, acute 
rise in creatinine, cardiac arrest  
MTD:  4.0  mg W 
 
C16008 
NDMM 
N = 64 
PO, TW, combination with LenDex 
21-day cycle 
3.0-3.7-mg fixed dosea W 
MTD:  3.0 mg 
Closed to enrollment 
C16009 
Solid tumors, 
Lymphomas 
N = 54 
PO, W, single agent 
5.5-mg fixed dosea W 
C16010 
RRMM 
N = 200 
PO, W, with LenDex versus placebo-
LenDex 
4.0 mg W 
C16011 
RRAL 
N = 4 
PO, W, with Dex versus physician’s 
choice of a Dex-based regimen 
4.0 mg W 
C16013 
RRMM 
N = 9 
PO, W, with LenDex 
4.0 mg W 

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Table 1-1    
Clinical Studies of Oral Ixazomib 
Trial/ 
Population 
Description 
Doses Investigated 
C16014 
Symptomatic 
MM 
N=701 
PO, combination with LenDex 
ixazomib 4.0 mg or matching placebo on Days 1, 
8, and 15, plus Len 25 mg on Days 1-21 (10 mg if 
low creatinine clearance, with escalation to 15 mg 
if tolerated) and Dex 40 mg (or 20 mg if >75 
years old) on Days 1, 8, 15, and 22 
C16015 
Symptomatic 
MM with 
normal renal 
function or 
severe renal 
impairment 
N=28 
PO, combination with Dex 
Part A: ixazomib  3.0 mg on Day 1 
Part B: ixazomib  4.0 mg on Days 1, 8, and 15, 
plus Dex 40 mg (or 20 mg if >75 years old) on 
Days 1, 8, 15 and 22 of a 28-day cycle 
 
C16017 
RR follicular 
lymphoma 
N=58 
PO, W 
4.0, 5.3, and 7.0 mg, W 
Treatment at RP2D once determined. 
 
C16018 
Advanced 
solid tumors 
or 
hematologic 
malignancies 
with varying 
degrees of 
liver 
dysfunction 
N=45 
Part A: PO, Day 1 of 15-day cycle 
Part B: PO, W 
1.5 mg (severe hepatic impairment), 2.3 mg 
(moderate hepatic impairment), or 4.0 mg 
(normal hepatic function) 
 
TB-
MC010034 
RRMM 
N = 10 
PO, W 
4.0 mg, W 
Single agent: 4.0 mg 
Combination with Rd 
Abbreviations:  RRAL = Relapsed and/or refractory Primary systemic light chain (AL) amyloidosis; BSA = 
body surface area; Dex=dexamethasone; DLT = dose-limiting toxicity; IV = intravenously; LenDex = 
lenalidomide plus dexamethasone; MTD = maximum tolerated dose; NDMM = newly diagnosed multiple 
myeloma; PO = orally; RR= relapsed and/or refractory; RRAL= relapsed and/or refractory systemic light 
chain amyloidosis RRMM = relapsed and/or refractory multiple myeloma; TBD = to be determined; TW 
= twice weekly; W = weekly; RP2D= recommended phase 2 dose. 
Note that blinded data from pivotal Studies C16010 and C16011 are not included.   
a Approximate BSA and fixed dosing equivalence:  3 mg~ equivalent to 1.68 mg/m2 BSA dosing; 4.0 mg ~ 
equivalent to 2.23 mg/m2 BSA dosing; and 5.5 mg~ equivalent to 2.97 mg/m2 BSA dosing. 
 
1.2.5 Overview of the Oral Formulation of Ixazomib 
 
The emerging safety profile indicates that ixazomib is generally well tolerated.  
The adverse events (AEs) are consistent with the class-based effects of 

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proteasome inhibition and are similar to what has been previously reported with 
VELCADE though the severity of some, for example peripheral neuropathy, is 
less.  While some of these potential toxicities may be severe, they can be managed 
by clinical monitoring and standard medical intervention, or, as needed, dose 
modification or discontinuation.   
 
In the 4 ongoing studies (C16003, C16004, C16007, and C16009) investigating 
single-agent oral ixazomib in patients with differing malignancies (multiple 
myeloma, AL amyloidosis, nonhematologic cancers, and lymphoma), a total of 
201 patients have been treated as of 27 March 2013. These patients have been 
treated with different doses of ixazomib as they are all phase 1 trials. An overview 
of the most frequent (at least 10%) AEs occurring in the pooled safety population 
from single-agent oral ixazomib Studies (C16003, C16004, C16007, and C16009) 
is shown in Table 1-2. 
 
Table 1-2    
Most Common (At Least 10% of Total) Treatment-Emergent Adverse 
Events in Oral Single-Agent Studies 
Primary System Organ Class 
     Preferred Term 
Oral Single Agent 
Total 
n = 201 
n (%) 
Subjects with at Least One Adverse Event 
197 (98) 
Gastrointestinal disorders 
160 (80) 
Nausea 
106 (53) 
Diarrhoea 
88 (44) 
Vomiting 
77 (38) 
Constipation 
46 (23) 
Abdominal pain 
33 (16) 
General disorders and administration site 
conditions 
151 (75) 
Fatigue 
103 (51) 
Pyrexia 
51 (25) 
Oedema peripheral 
27 (13) 
Asthenia 
31 (15) 
Nervous system disorders 
92 (46) 
Headache 
29 (14) 
Dizziness 
26 (13) 
Neuropathy peripheral 
21 (10) 
Metabolism and nutrition disorders 
107 (53) 
Decreased appetite 
64 (32) 
Dehydration 
37 (18) 
Blood and lymphatic system disorders 
98 (49) 
Thrombocytopenia 
68 (34) 

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Table 1-2    
Most Common (At Least 10% of Total) Treatment-Emergent Adverse 
Events in Oral Single-Agent Studies 
Primary System Organ Class 
     Preferred Term 
Oral Single Agent 
Total 
n = 201 
n (%) 
Anaemia 
42 (21) 
Neutropenia 
29 (14) 
Lymphopenia 
20 (10) 
Skin and subcutaneous tissue disorders 
90 (45) 
Rash maculara 
23 (11) 
Musculoskeletal and connective tissue 
disorders 
93 (46) 
Back pain 
24 (12) 
Arthralgia 
28 (14) 
Respiratory, thoracic and mediastinal 
disorders 
78 (39) 
Cough 
28 (14) 
Dyspnoea 
30 (15) 
Infections and infestations 
89 (44) 
Upper respiratory tract infection 
31 (15) 
Source:  Ixazomib Investigator’s Brochure Edition 7 
Abbreviations:  MedDRA = Medical Dictionary for Regulatory Activities, version 15.0. 
Subject Incidence:  A subject counts once for each preferred term.  Percentages use the number of treated 
subjects as the denominator. 
a Note that rash maculopapular and rash macular represent the 2 most common terms used to describe rash. 
 
As of 27 March 2013, there are 5 studies actively enrolling patients with multiple 
myeloma to investigate oral ixazomib in combination with standard combination 
regimens.   
 
The most frequent (at least 10%) AEs occurring in the pooled safety population 
from Studies C16005, C16006, C16008, and C16013 are shown for all grades 
(Table 1-3).  Note that in combination trials, related is defined as related to any 
study drug in the combination regimen. 
 
 
 

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Table 1-3    
Most Common (At Least 10% of Total) Treatment-Emergent Adverse 
Events in Oral Combination Studies 
Primary System Organ Class 
     Preferred Term 
Total Oral Combo Agent 
(5/6/8/13) 
n = 173 
n (%) 
Subjects with at Least One Adverse Event 
163 (94) 
Gastrointestinal disorders 
139 (80) 
Nausea 
65 (38) 
Diarrhoea 
81 (47) 
Vomiting 
51 (29) 
Constipation 
57 (33) 
General disorders and administration site 
conditions 
132 (76) 
Fatigue 
76 (44) 
Pyrexia 
39 (23) 
Oedema peripheral 
61 (35) 
Asthenia 
20 (12) 
Nervous system disorders 
115 (66) 
Headache 
28 (16) 
Dizziness 
34 (20) 
Neuropathy peripheral 
45 (26) 
Metabolism and nutrition disorders 
91 (53) 
Decreased appetite 
25 (14) 
Hypokalaemia 
34 (20) 
Blood and lymphatic system disorders 
88 (51) 
Thrombocytopenia 
49 (28) 
Anaemia 
45 (26) 
Neutropenia 
43 (25) 
Lymphopenia 
20 (12) 
Skin and subcutaneous tissue disorders 
102 (59) 
Rash maculopapulara 
29 (17) 
Rash maculara 
22 (13) 
Musculoskeletal and connective tissue 
disorders 
99 (57) 
Back pain 
42 (24) 
Pain in extremity 
31 (18) 
Arthralgia 
22 (13) 
Respiratory, thoracic and mediastinal 
disorders 
80 (46) 
Cough 
36 (21) 

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Table 1-3    
Most Common (At Least 10% of Total) Treatment-Emergent Adverse 
Events in Oral Combination Studies 
Primary System Organ Class 
     Preferred Term 
Total Oral Combo Agent 
(5/6/8/13) 
n = 173 
n (%) 
Dyspnoea 
26 (15) 
Infections and infestations 
92 (53) 
Upper respiratory tract infection 
35 (20) 
Psychiatric disorders 
73 (42) 
Insomnia 
50 (29) 
Source:  Ixazomib Investigator’s Brochure Edition 7 
Abbreviations:  MedDRA = Medical Dictionary for Regulatory Activities, version 15.0. 
Subject Incidence:  A subject counts once for each preferred term.  Percentages use the number of treated 
subjects as the denominator.  
Data from ongoing blinded pivotal trials (C16010) are not included. 
a Note that rash maculopapular and rash macular represent the 2 most common terms used to describe rash..   
 
The clinical experience with ixazomib also shows early signs of antitumor activity 
as evidenced by at least a 50% reduction in disease burden in some patients and 
prolonged disease stabilization in others across all ongoing trials. The antitumor 
activity has been seen with single-agent ixazomib, when combined with 
established therapies, and across the malignancies studied (advanced solid tumors 
[3], non-Hodgkin’s disease, Hodgkin’s disease [4], relapsed and/or refractory 
multiple myeloma [RRMM; 5; 6], relapsed or refractory systemic light chain 
amyloidosis [RRAL; 7], and newly diagnosed multiple myeloma [NDMM; 8; 9; 
10]) to date. 
 
Though additional data are needed to characterize the clinical benefit of this drug, 
the emerging data supports the ongoing development of ixazomib. 
 
1.2.6    Relapsed and/or Refractory Multiple Myeloma 
 
The early development of ixazomib in patients with RRMM involves 2 studies 
(C16003 and C16004) with similar objectives, but each investigated 1 of the 2 
dosing schedules commonly used with the first-in-class proteasome inhibitor, 
VELCADE. 
 
Study C16003 is an open-label, dose escalation, phase 1 study of ixazomib dosing 
on a twice-weekly schedule on Days 1, 4, 8, and 11 of a 21-day cycle in adult 
patients with RRMM.(11, 12)  Study C16004 is an open-label, dose escalation, 
phase 1 study of ixazomib dosing on a weekly schedule on Days 1, 8, and 15 of a 
28-day cycle in adults patients with RRMM.(13, 14, 15)  Both studies have now 
completed enrollment.  The DLTs in Study C16003 were rash macular and 

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thrombocytopenia and the DLTs in C16004 were nausea, diarrhea, vomiting, and 
erythema multiforme. 
 
In the dose escalation component of both studies, patients had multiple myeloma 
that had relapsed following at least 2 lines of therapy that must have included 
bortezomib, thalidomide (or lenalidomide), and corticosteroids.  In both studies, 
when the MTD was established, cohorts of patients representing the 
heterogeneous patient population currently seen in clinical practice were to be 
enrolled into 1 of 4 expansion cohorts, including a relapsed and refractory cohort, 
a carfilzomib cohort, a proteasome inhibitor-naïve cohort, and a VELCADE-
relapsed cohort. 
 
Final study results are currently being analyzed, but preliminary data suggest that 
ixazomib has anti-tumor activity in heavily pretreated MM patients, with durable 
responses/disease control, and is generally well tolerated. Please refer to the 
ixazomib IB and SMA for further information.  
 
1.2.7    Newly Diagnosed Multiple Myeloma (NDMM) 
 
Multiple research paths are being explored in patients with NDMM with a focus 
on evaluating ixazomib in combination with agents commonly used across 
treatment settings.  The development of ixazomib in combination with 
lenalidomide with dexamethasone (LenDex) in patients with NDMM who are 
transplant eligible or ineligible involves 2 studies (C16005 and C16008) with 
similar study designs except for a few key differences, namely the schedules of 
ixazomib and dexamethasone.  Ixazomib is also being evaluated in combination 
with melphalan and prednisone (MP) for patients who are not transplant eligible 
due to age or coexisting morbidity (in Study C16006).  
 
All 3 studies are phase 1/2, with phase 1 focusing on safety and phase 2 on 
efficacy (and further characterization of safety).  Please refer to the ixazomib IB 
and SMA for further information.  
 
1.2.8 Clinical Trial Experience Using the Intravenous Formulation of 
Ixazomib 
 
See the IB for descriptions of the 2 studies that investigated IV ixazomib in 
advanced solid tumors and advanced lymphoma (Studies C16001 and C16002, 
respectively). 
 
1.2.9 FDA Approval 
 
In November 2015, the U.S. FDA approved the use of ixazomib in combination 
with lenalidomide and dexamethasone for the treatment of patients with multiple 
myeloma who have received at least one prior therapy. 

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The approval was based on an improvement in progression- free survival (PFS) in 
a multicenter, randomized, double-blind, placebo-controlled trial enrolling 722 
patients with multiple myeloma who had received 1 to 3 prior lines of 
therapy. Patients were randomized in a 1:1 ratio to either the combination of 
ixazomib, lenalidomide and dexamethasone (n=360) or the combination of 
placebo, lenalidomide and dexamethasone (n=362).  Patients continued treatment 
until disease progression or unacceptable toxicity.  
 
The trial showed a statistically significant improvement in PFS. The median PFS 
on the combination arm of ixazomib, lenalidomide and dexamethasone was 20.6 
months (95% CI: 17.0, NE) compared to a median PFS of 14.7 months (95% CI: 
12.9, 17.6) on the combination arm of placebo, lenalidomide and dexamethasone 
(PFS HR 0.74, 95% CI: 0.59, 0.94; p value=0.012).  
 
1.3 
 Value of Minimal Residual Disease Assessment 
 
Historically, the achievement of complete response (CR), defined by absence of 
monoclonal protein in the serum and urine by immunofixation, along with < 5% bone 
marrow plasma cells, has been used as the most important determinant to predict outcome 
following treatment [15-21]. However, in many patients who achieve a complete 
response, low-level bone marrow disease, so-called minimal residual disease (MRD), can 
be demonstrated. Several studies have shown that MRD-negativity is a stronger predictor 
of PFS and OS than conventional CR [29], and thus many new trials are favoring MRD-
negativity rate as the primary endpoint over conventional CR rates.  
 
To date, only 5 pubmed searchable studies have analyzed MRD-negative rates post 
ASCT and the results have varied widely, ranging from 8% to 62% of patients achieving 
MRD-negative status [22-26]. A meta-analysis of the 5 studies was performed, and of 
818 patients analyzed, 416 (51%) achieved MRD-negative status at Day 100 
(unpublished data).  
 
Currently there is no consensus way to measure MRD. There are a number of unique 
panels that utilize multiparameter flow cytometry (MFC) that are currently available or in 
various stages of testing. Mayo Clinic uses a seven-color panel of antibodies that detect 
Kappa, Lambda, CD19, CD38, CD45, CD138, and Dapi.  
 
More recently, next generation sequencing techniques have been used to measure MRD, 
such as Adaptive ClonoSEQ. Adaptive ClonoSEQ involves DNA amplification and 
sequencing of a bone marrow sample collected prior to the start of treatment. A high-
frequency myeloma clone (>5%) is identified and additional samples following the start 
of treatment are tested using IGH-VDJH and IGK or IGH-VDJH, IGH-DJH, and IGK 
assays to identify the presence of absence of the original clone. The Adaptive ClonoSEQ 
technology has been shown to be superior to MFC in predicting response [41], however, 
its applicability to each patient is dependent on the availability of a pre-treatment bone 
marrow sample and the identification of high frequency clone. 
 

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1.4 
Study Rationale 
 
Based on the further need to improve PFS and OS post-ASCT for multiple myeloma and 
the benefits seen of consolidation/maintenance treatment with immunomodulatory drugs 
thalidomide and lenalidomide and the proteasome inhibitor bortezomib, the natural next 
step is to evaluate combination regimens of immunomodulatory drugs and proteasome 
inhibitors as consolidation/maintenance post-ASCT. The regimen consisting of ixazomib, 
lenalidomide, and dexamethasone (IRD) has been shown to have low toxicity, and the 
availability of an oral formulation of ixazomib allows for easier administration when 
compared to bortezomib. 
 
In this study, following consolidation with IRD, patients will be randomized to 
maintenance therapy with lenalidomide or ixazomib in order to collect pilot data 
comparing the toxicity and efficacy of maintenance therapy with immunomodulatory 
drugs and proteasome inhibitors.  
 
The proposed study would: 
 
1) Provide data on the efficacy and tolerability of IRD as consolidation post ASCT;  
2) Provide data on the value of MRD-negativity as a surrogate for PFS and OS; 
3) Provide data on the efficacy and tolerability of single agent ixazomib as maintenance 
therapy post-ASCT;  
4) Provide pilot data that could generate hypotheses for a larger phase III study 
designed to conclusively address the value of IRD consolidation and single agent 
ixazomib maintenance. 
1.4.1 Hypotheses 
 
• Consolidation with 4 cycles of IRD will be well tolerated and will result in ≥ 
15% improvement in MRD-negative rate 
• MRD-negativity after 4 cycles of IRD consolidation will be associated with an 
improved PFS and OS  
• Maintenance therapy with ixazomib will be well tolerated and will be similar 
in response rate, PFS, OS, and MRD-positive to MRD-negative conversion 
rate to maintenance therapy with lenalidomide. 
 
1.4.2 Potential Risks and Benefits 
 
Please refer to the current ixazomib IB and SMA. 
 
The clinical benefit of ixazomib continues to be studied in a comprehensive and 
global development plan that involves studies sponsored by Millennium.  
Ixazomib appears to show early signs of anti-tumor activity as evidenced by at 
least 50% reduction in disease burden in some patients, including patients that 
have been heavily pretreated as well as those with newly diagnosed MM, and 
prolongs stabilization of the underlying disease in other patients across all 

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ongoing trials.  The preliminary findings are favorable when considering 
historical and currently available therapies for the patient populations evaluated.  
Though additional data are needed to characterize the clinical benefit of this drug, 
the emerging data supports expanded development of ixazomib for the treatment 
of patients with advanced malignancy. 
 
This study will be conducted in compliance with the protocol, good clinical 
practice (GCP), applicable regulatory requirements, and International Conference 
on Harmonisation (ICH) guidelines.  
 
1.5 
Correlative Studies Background 
 
The HEVYLITE assay by The Binding Site can identify the different light chain types of 
each immunoglobulin class ie IgGκ, IgGλ, IgAκ, IgAλ, IgMκ, IgMλ separately, therefore 
the assay has the potential to identify clonality more precisely than the current assays 
(SPEP/IF, SFLC, immunoglobulins). 
 
The effect of ixazomib maintenance on the immune system is unknown. In a correlative 
lab sub-study, we will perform lymphocyte phenotyping and functional assays on 
peripheral blood samples from 40-50 patients, approximately 20 in each maintenance 
arm, prior to and post-3 cycles of maintenance.  
 
 
2.0 
OBJECTIVES 
 
2.1 
Primary Objective 
 
To determine the improvement in MRD-negative rate after 4 cycles of IRD consolidation.   
 
2.2 
Secondary Objectives 
 
1. To determine the MRD-negative rate after ASCT 
2. To evaluate the toxicity, response rate, PFS, and OS of IRD consolidation   
3. To collect pilot data to compare toxicity, response rate, PFS, OS, and the rate of 
MRD-positive to MRD-negative conversion between the two maintenance arms 
4. To evaluate the association of PFS and OS with MRD-negativity and MRD-positivity 
prior to consolidation and after 4 cycles of IRD consolidation 
 
2.3 
Exploratory Objectives 
 
1. To evaluate the relationship between HEVYLITE assay results with response and 
MRD status. 
2. To evaluate the effect of ixazomib maintenance on the immune system.  
 
 
 

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3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
Each patient must meet all of the following inclusion criteria to begin IRD Consolidation 
 
1. 
Between the ages of 18 and 70 years of age (inclusive) at time of enrollment 
2. 
Voluntary written consent must be given before performance of any study-related 
procedure not part of standard medical care, with the understanding that consent 
may be withdrawn by the patient at any time without prejudice to future medical 
care. 
3. 
Histologically confirmed diagnosis of symptomatic multiple myeloma. (Patients 
with multiple myeloma with secondary amyloidosis are eligible.) 
4. 
Received at least two cycles of any regimen as initial systemic therapy for 
multiple myeloma and are within 2-16 months of the first dose of initial therapy  
5. 
Eastern Cooperative Oncology Group (ECOG) performance status and/or other 
performance status 0, 1, or 2 (see Appendix A).  
6. 
Adequate organ function as defined below: 
• 
Absolute neutrophil count (ANC) ≥ 1,000/mm3. 
• 
Platelet count ≥ 75,000/mm3; platelet transfusions to help patients meet 
eligibility criteria are not allowed within 7 days before study enrollment. 
• 
Total bilirubin ≤ 1.5 × the upper limit of the normal range (ULN). 
• 
Alanine 
aminotransferase 
(ALT) 
and 
aspartate 
aminotransferase 
(AST) ≤ 3 × ULN. 
• 
Calculated creatinine clearance ≥ 30 mL/min (see Appendix B). 
7. 
Women of childbearing potential (as defined in Section 5.6) must follow 
pregnancy testing requirements as outlined in the Revlimid REMS® program 
material. This is defined as either committing to continued abstinence from 
heterosexual intercourse or beginning TWO acceptable methods of contraception 
(one highly effective method and one additional effective method (as defined in 
Section 5.6) AT THE SAME TIME) at least 28 days prior to the start of 
lenalidomide, for the duration of study participation, and for 28 days following 
the last dose of lenalidomide.  Women of childbearing potential must also agree to 
ongoing pregnancy testing.   
8. 
Men must agree to use a latex condom during sexual contact with a woman of 
childbearing potential even if they have had a successful vasectomy.  All patients 
must be counseled at a minimum of every 28 days about pregnancy precautions 
and risks of fetal exposure.  Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she must inform her treating physician 
immediately. 

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9. 
All study participants must be registered into the mandatory Revlimid REMS® 
program and be willing to comply with its requirements. Per standard Revlimid 
REMS® program requirements, all physicians who prescribe lenalidomide for 
research subjects enrolled into this trial, must be registered in, and must comply 
with, all requirements of the Revlimid REMS® program. 
 
 
3.2 
Exclusion Criteria 
 
Patients meeting any of the following exclusion criteria are not to be enrolled in the 
study: 
 
1. Female patients who are lactating or have a positive serum pregnancy test during the 
screening period.  
2. Evidence of MM disease progression any time prior to enrollment. Progression from 
smoldering/asymptomatic MM to symptomatic MM is not exclusionary.  
3. Tandem autologous transplantation 
4. History of plasma cell leukemia or MM CNS involvement. 
5. Administration or planned administration of any other concomitant chemotherapy, 
immunotherapy, radiotherapy, or any ancillary therapy which would be considered a 
treatment of multiple myeloma until Day +28 post-transplant through discontinuation 
from study. Patients may be on corticosteroids if they are being given for disorders 
other than multiple myeloma (e.g., adrenal insufficiency, rheumatoid arthritis, etc.). 
6. Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol. 
7. Prior organ transplant requiring immunosuppressive therapy. 
8. Active hepatitis A, B or C virus infection, or known human immunodeficiency virus 
(HIV) positive. 
9. Known allergy to any of the study medications, their analogues, or excipients in the 
various formulations of any agent. 
10. Known GI disease or GI procedure that could interfere with the oral absorption or 
tolerance of ixazomib. 
11. Concurrent hematologic or non-hematologic malignancy requiring treatment (other 
than multiple myeloma and secondary amyloidosis).  
12. Cardiac syncope, uncompensated NYHA Class 3 or 4 congestive heart failure 
(Appendix C), myocardial infarction within the previous 6 months, unstable angina 
pectoris, 
clinically 
significant 
repetitive 
ventricular 
arrhythmias 
despite 
antiarrhythmic treatment, severe orthostatic hypotension, or clinically important 
autonomic disease. 
13. Grade > 3 peripheral neuropathy, or Grade 2 with pain on clinical examination during 
the screening period. 
14. Major surgery within 14 days prior to start of study treatment. 
15. Infection requiring systemic antibiotic therapy or other serious infection within 
14 days prior to start of study treatment. 

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16. Participation in other clinical trials, including those with other investigational agents 
not included in this trial, within 30 days prior to start of study treatment and 
throughout the duration of this trial.  
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this 
trial.  
 
 
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN) 
 
Once the patient has been entered in the Siteman Cancer Center database, the WUSM 
coordinator will forward verification of enrollment and the UPN via email. 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below and scanning and 
emailing it to the research coordinator listed in the Siteman Cancer Center Clinical Trials 
Core Protocol Procedures for Secondary Sites packet at least one business day prior to 
registering patient: 
 
1. Copy of signed consent form (patient name may be blacked out) 
2. Planned date of enrollment 
3. Completed eligibility checklist, signed and dated by a member of the study team 
 
4.2 
Patient Registration in the Siteman Cancer Center Database 
 
Registrations may be submitted Monday through Friday between 8am and 5pm CT. 
Urgent late afternoon or early morning enrollments should be planned in advance and 
coordinated with the Washington University research coordinator.  Registration will be 
confirmed by the research coordinator or his/her delegate by email within one business 
day. Verification of eligibility and registration should be kept in the patient chart. 
 

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All patients at all sites must be registered through the Siteman Cancer Center database at 
Washington University. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  
Patients will also be identified by first, middle, and last initials.  If the patient has no 
middle initial, a dash will be used on the case report forms (CRFs).  All data will be 
recorded with this identification number on the appropriate CRFs. 
 
 
 
5.0 
TREATMENT PLAN 
 
5.1 
Overview 
 
In general, patients will provide informed consent prior to ASCT. However, patients may 
be allowed to provide informed consent following ASCT, determined on a case-by-case 
basis by the PI. In this event, any of the assessments required prior to ASCT not 
performed for SOC will not be required.   
 
Patients will undergo standard of care ASCT with conditioning regimen determined by 
the treating physician per institutional guidelines. The ASCT is not considered part of this 
study.  Consolidation therapy will begin on between Day 80 and Day 120 following 
ASCT and will consist of four 28-day cycles of IRD (ixazomib, lenalidomide, & 
dexamethasone). Barring dose modifications for toxicity, 4 mg of ixazomib and 40 mg of 
dexamethasone will be administered on Days 1, 8, and 15, and 15 mg of lenalidomide 
will be administered on daily on Days 1-21.   
 
Following completion of consolidation therapy, patients will undergo restaging and will 
be randomized on a 1:1 basis to maintenance therapy with ixazomib or lenalidomide. 
Patients will be stratified based on MRD status at restaging (MRD-positive v. MRD-
negative). Patients who discontinue either ixazomib or lenalidomide during the 
consolidation phase due to toxicity will not be randomized. They will be preferentially 
enrolled on the opposing arm.   
 
Barring dose modifications for toxicity, ixazomib maintenance will consist of 4 mg 
administered on Days 1, 8 and 15 of each 28-day cycle, and lenalidomide maintenance 
will consist of 10 mg daily on Days 1-28 for the first three 28-day cycles and 15 mg daily 
for all further cycles. Maintenance therapy with either ixazomib or lenalidomide will 
continue until the patient experiences disease progression or unacceptable toxicity.  
 
5.2 
IRD Consolidation 
 

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5.2.1 Ixazomib Administration 
 
Ixazomib will be prescribed only to eligible patients under the supervision of the 
investigator or identified sub-investigator(s). Ixazomib will be administered on 
Days 1, 8, and 15 of a 28-day cycle at a starting dose of 4 mg. Sufficient quantity 
of drug for one cycle of therapy will be prescribed to the patient at a time.   
 
Patients should be monitored for toxicity as necessary, and doses of ixazomib 
should be modified as needed to accommodate patient tolerance to treatment; this 
may include symptomatic treatment, dose interruptions, and adjustments of 
ixazomib dose (see Section 6.0). Once ixazomib is reduced for toxicity, no dose 
re-escalation is permitted. 
 
Ixazomib should be taken on an empty stomach (no food or drink), at least 1 hour 
before or 2 hours after a meal. Patients should be instructed to swallow ixazomib 
capsules whole and not to break, chew, or open the capsules. Each capsule should 
be swallowed separately with a sip of water. A total of approximately 8 ounces 
(240 mL) of water should be taken with the capsules.  
 
Ixazomib should be taken at the same time each day. Missed doses can be taken 
as soon as the patient remembers if the next scheduled dose is 72 hours or more 
away. A double dose should not be taken to make up for a missed dose. Patients 
who vomit a dose after ingestion will not receive an additional dose, but should 
resume dosing at the time of the next scheduled dose. 
 
5.2.2 Lenalidomide Administration 
 
Lenalidomide will be prescribed only to eligible patients under the supervision of 
the investigator or identified sub-investigator(s). Lenalidomide will be 
administered daily on Days 1-21 of a 28-day cycle at a starting dose of 15 mg. 
Sufficient quantity of drug for one cycle of therapy will be prescribed to the 
patient at a time.  Lenalidomide will be provided in accordance with the Celgene 
Corporation’s Revlimid REMS® program. 
 
As per standard lenalidomide treatment guidelines, VTE prophylaxis with aspirin 
81mg daily should be administered unless the patient is being treated with 
alternate prophylaxis (Coumadin, low molecular weight heparin, etc) or VTE 
prophylaxis is contraindicated.  
 
Patients should be monitored for toxicity, as necessary, and doses of lenalidomide 
should be modified as needed to accommodate patient tolerance to treatment; this 
may include symptomatic treatment, dose interruptions, and adjustments of 
lenalidomide dose (see Section 6.0). Once lenalidomide is reduced for toxicity, no 
dose re-escalation is permitted. 
 

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Lenalidomide can be taken without regards to food or drink. Patients should be 
instructed to swallow lenalidomide capsules whole and not to break, chew, or 
open the capsules. Each capsule should be swallowed separately with a sip of 
water.  
 
Lenalidomide should be taken at the same time each day. Missed doses can be 
taken as soon as the patient remembers if the next scheduled dose is 8 hours or 
more away. A double dose should not be taken to make up for a missed dose. 
Patients who vomit a dose after ingestion will not receive an additional dose, but 
should resume dosing at the time of the next scheduled dose.  
 
 

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5.2.3 Dexamethasone Administration 
 
Dexamethasone will be prescribed only to eligible patients under the supervision 
of the investigator or identified sub-investigator(s). Dexamethasone will be 
administered on Days 1, 8, and 15 of a 28-day cycle at a starting dose of 40 mg. 
Sufficient quantity of drug for one cycle of therapy will be prescribed to the 
patient at a time.   
 
Patients should be monitored for toxicity, as necessary, and doses of 
dexamethasone should be modified as needed to accommodate patient tolerance 
to treatment; this may include symptomatic treatment, dose interruptions, and 
adjustments of dexamethasone dose (see Section 6.0). Once dexamethasone is 
reduced for toxicity, no dose re-escalation is permitted. 
 
Dexamethasone should be taken with food or milk. Patients should be instructed 
to swallow dexamethasone capsules whole and not to break, chew, or open the 
capsules. Each capsule should be swallowed separately with a sip of water.  
 
Dexamethasone should be taken at the same time each day. Dexamethasone 
should be taken approximately 1 hour after ixazomib on days when both drugs are 
being administered. 
 
Missed doses can be taken as soon as the patient remembers if the next scheduled 
dose is 72 hours or more away. A double dose should not be taken to make up for 
a missed dose. Patients who vomit a dose after ingestion will not receive an 
additional dose, but should resume dosing at the time of the next scheduled dose. 
 
5.3 
Maintenance Therapy 
 
5.3.1 Randomization 
 
Following completion of consolidation therapy, patients will undergo restaging 
and will be randomized on a 1:1 basis to maintenance therapy with ixazomib 
(Arm1) or lenalidomide (Arm2). Patients will be stratified based on MRD status 
at restaging (MRD-positive vs. MRD-negative). To better ensure the balance of 
patient characteristics across two arms, treatment assignment will be implemented 
in small blocks of 4 to 6 patients. The randomization table will be uploaded in our 
REDCap system.  Randomization will occur via an online form with entry of the 
patient ID number and stratum information.  Once all information is entered, 
randomization is carried out via a submit button through REDCap.  The 
randomization scheme will be created using a formal probability model 
implemented in SAS (version 9.3 or higher).  
 
 
 
 

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5.3.2 Ixazomib Administration 
 
Ixazomib will be prescribed only to eligible patients under the supervision of the 
investigator or identified sub-investigator(s). Ixazomib will be administered on 
Days 1, 8, and 15 of a 28-day cycle at a starting dose of 4 mg. Sufficient quantity 
of drug for one cycle of therapy will be prescribed to the patient in Cycles 1-3 of 
maintenance therapy, and for three cycles of therapy in Cycles 4+.    
 
Patients should be monitored for toxicity, as necessary, and doses of ixazomib 
should be modified as needed to accommodate patient tolerance to treatment; this 
may include symptomatic treatment, dose interruptions, and adjustments of 
ixazomib dose (see Section 6.0). Once ixazomib is reduced for toxicity, no dose 
re-escalation is permitted. 
 
Ixazomib should be taken on an empty stomach (no food or drink), at least 1 hour 
before or 2 hours after a meal. Patients should be instructed to swallow ixazomib 
capsules whole and not to break, chew, or open the capsules. Each capsule should 
be swallowed separately with a sip of water. A total of approximately 8 ounces 
(240 mL) of water should be taken with the capsules.  
 
Ixazomib should be taken at the same time each day. Missed doses can be taken 
as soon as the patient remembers if the next scheduled dose is 72 hours or more 
away. A double dose should not be taken to make up for a missed dose. Patients 
who vomit a dose after ingestion will not receive an additional dose, but should 
resume dosing at the time of the next scheduled dose. 
 
If ixazomib maintenance is discontinued, crossover to the lenalidomide 
maintenance arm can occur if permission is granted by the Principal Investigator. 
Patients who crossover will continue to be followed per all protocol guidelines.  
 
5.3.3 Lenalidomide Administration 
 
Lenalidomide will be prescribed only to eligible patients under the supervision of 
the investigator or identified sub-investigator(s). Lenalidomide will be 
administered daily continuously for a 28-day cycle at a starting dose of 10 mg. If 
lenalidomide is tolerated well (i.e. no dose modification required) during the first 
three cycles, lenalidomide dose will be increased to 15 mg daily. Sufficient 
quantity of drug for one cycle of therapy will be prescribed to the patient in 
Cycles 1-3, and for three cycles of therapy in Cycles 4+.   Lenalidomide will be 
provided in accordance with the Celgene Corporation’s Revlimid REMS® 
program. 
 
VTE prophylaxis is not required during single-agent lenalidomide maintenance 
but is permissible at the discretion of the treating physician.  
 

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Patients should be monitored for toxicity, as necessary, and doses of lenalidomide 
should be modified as needed to accommodate patient tolerance to treatment; this 
may include symptomatic treatment, dose interruptions, and adjustments of 
lenalidomide dose (see Section 6.0).  
 
If a lenalidomide dose reduction has occurred for hematologic toxicity and ANC 
>1000/µL and platelet count is >75,000/µL, lenalidomide drug dose may be re-
escalated one dose level per cycle to a maximum of 15 mg daily. If lenalidomide 
was reduced due to non-hematologic toxicity, no dose re-escalation is permitted.  
 
Lenalidomide can be taken without regards to food or drink. Patients should be 
instructed to swallow lenalidomide capsules whole and not to break, chew, or 
open the capsules. Each capsule should be swallowed separately with a sip of 
water.  
 
Lenalidomide should be taken at the same time each day. Missed doses can be 
taken as soon as the patient remembers if the next scheduled dose is 8 hours or 
more away. A double dose should not be taken to make up for a missed dose. 
Patients who vomit a dose after ingestion will not receive an additional dose, but 
should resume dosing at the time of the next scheduled dose. 
 
If lenalidomide maintenance is discontinued, crossover to the ixazomib 
maintenance arm can occur if permission is granted by the Principal Investigator. 
Patients who crossover will continue to be followed per all protocol guidelines. 
 
5.4 
Excluded Concomitant Medications and Procedures 
 
Systemic treatment with any of the following metabolizing enzyme inducers should be 
avoided in this study (14 days before the 1st dose of ixazomib until the final dose of 
ixazomib), unless there is no appropriate alternative medication for the patient’s use. 
(Rationale:  Unlike with inhibitors, if there were to be a DDI with an inducer, ixazomib 
exposure would be less; therefore, there would be a reduced chance of an AE.  However, 
there may be less chance for an antitumor effect, but that is not an absolute reason to be 
taken off ixazomib.) 
• Strong CYP3A inducers:  rifampin, rifapentine, rifabutin, carbamazepine, 
phenytoin, and phenobarbital 
• Excluded foods and dietary supplements include St. John’s wort and Ginkgo 
biloba 
 
The following procedures are prohibited during the study. 
• Any antineoplastic treatment with activity against MM, other than study drugs 
• Radiation therapy (note that, in general, the requirement for local radiation 
therapy indicates disease progression) 
• Platelet transfusions to help patients meet eligibility criteria are not allowed 
within 3 days prior to study drug dosing for any dosing day 
 

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5.5 
Permitted Concomitant Medications and Procedures  
 
The following medications and procedures are permitted during the study: 
• Antiemetics, including 5-HT3 serotonin receptor antagonists, may be used at the 
discretion of the investigator. 
• Loperamide or other antidiarrheal should be used for symptomatic diarrhea at 
discretion of the investigator. The dose and regimen will be according to 
institutional guidelines. IVF should be given to prevent volume depletion. 
• Growth factors (e.g., granulocyte colony stimulating factor [G-CSF], granulocyte 
macrophage-colony stimulating factor [GM-CSF], recombinant erythropoietin) 
are permitted, but should not be given prophylactically. Their use should follow 
published guidelines and/or institutional practice; however, alternative usage may 
be reviewed with the principal investigator.  
• Patients should be transfused with red cells and platelets as clinically indicated 
and according to institutional guidelines. 
• Antiviral therapy such as acyclovir may be administered if medically appropriate. 
• Concomitant treatment with bisphosphonates will be permitted, as appropriate. 
• Patients who experience worsening neuropathy from baseline may be observed 
for recovery, have dose reductions/delays as indicated in the protocol, and any 
supportive therapy or intervention may be initiated as appropriate at the discretion 
of the investigator. 
• Supportive measures consistent with optimal patient care may be given 
throughout the study. 
 
5.6     Pregnancy Risks – Precautions and Restrictions  
 
It is not known what effects ixazomib has on human pregnancy or development of the 
embryo or fetus.  Therefore, female patients participating in this study should avoid 
becoming pregnant, and male patients should avoid impregnating a female partner.  Non-
sterilized female patients of reproductive age group and male patients should use 
effective methods of contraception through defined periods during and after study 
treatment as specified below. 
 
Female patients must meet 1 of the following:  
 
• Postmenopausal for at least 1 year before the screening visit, or 
• Surgically sterile, or 
• If they are of childbearing potential, agree to practice 2 effective methods of 
contraception from the time of signing of the informed consent form through 90 
days after the last dose of study drug, or  
• Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [e.g., calendar, ovulation, 

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symptothermal, post-ovulation methods] and withdrawal are not acceptable 
methods of contraception.) 
 
Male patients, even if surgically sterilized (i.e., status postvasectomy) must agree to 1 of 
the following: 
 
• Practice effective barrier contraception during the entire study treatment period 
and through 90 days after the last dose of study drug, or 
• Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [e.g., calendar, ovulation, 
symptothermal, post-ovulation methods for the female partner] and withdrawal 
are not acceptable methods of contraception.) 
 
The use of lenalidomide in pregnant females and nursing mothers has not been studied 
nor has the effect of the lenalidomide on human eggs and sperm. Lenalidomide is 
structurally related to thalidomide. Thalidomide is a known human teratogenic active 
substance that causes severe life-threatening birth defects. An embryofetal development 
study in animals indicates that lenalidomide produced malformations in the offspring of 
female monkeys who received the drug during pregnancy. The teratogenic effect of 
lenalidomide in humans cannot be ruled out. Therefore, a risk minimization plan to 
prevent pregnancy must be observed.  
 
A woman of childbearing potential is defined as a sexually mature woman who: 1) has 
not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally 
postmenopausal for at least 24 consecutive months.  Women of childbearing potential are 
required to have a negative serum or urine pregnancy test within 10-14 days prior to and 
again no more than 24 hours before the first dose of lenalidomide.  Women of 
childbearing potential are required to use two forms of contraception at the same time, 
including one highly effective method (i.e., intrauterine device, hormonal (birth control 
pills, injections, or implants), tubal ligation, partner’s vasectomy) and one additional 
effective (barrier) method (i.e., latex condom, diaphragm, cervical cap), from the time of 
signing of the informed consent form through 90 days after the last dose of study drug. 
Male patients engaged in a sexual relationship with a woman of childbearing potential 
must agree to use a latex condom during sexual contact, even if he has had a successful 
vasectomy. 
 
If a patient is suspected to be pregnant, both study drugs should be immediately 
discontinued.  In addition a positive urine test must be confirmed by a serum pregnancy 
test.  If it is confirmed that the patient is not pregnant, the patient may resume dosing.  
 
5.7 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation 
documented in the case report forms. 

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Protocol Amendment 7; Version: 04/02/2018 
 
 
 
 
Patients will be removed from the study for any of the following reasons: 
 
• Disease progression or relapse 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
• General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious noncompliance with the study protocol 
• Lost to follow-up 
• Patient withdraws consent 
• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 
 
5.8 
Duration of Follow-up 
 
Participants will be followed for 18 months after removal from study or until death, 
whichever occurs first.  
 
 
6.0 
DOSE MODIFICATIONS 
 
Toxicities should be attributed to a specific study drug if possible so that dose modifications can 
be made rationally. If multiple toxicities are noted, the dose adjustments and or/delays should 
made once per cycle according to the guidelines for the most severe toxicity. The maximum 
delay before treatment should be discontinued will be 3 weeks unless permission to resume 
treatment is granted by the Principal Investigator. Alternative dose modifications than those 
listed below may be recommended in order to maximize exposure of study treatment while 
protecting patient safety.   
 
 

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6.1 
Dose Levels 
      
 
 
         Ixazomib Dose Levels 
 
Dose Level 
Dose (mg) 
 Starting Dose 
4.0 mg 
-1 
3.0 mg 
-2 
2.3 mg 
-3 
Discontinue 
 
 
 
         Lenalidomide Dose Levels for Consolidation Therapy 
 
Dose Level 
Dose (mg) 
Starting Dose 
15 mg 
-1 
10 mg 
-2 
5 mg 
-3 
Discontinue 
 
                                 Lenalidomide Dose Levels for Maintenance Therapy 
 
Dose Level 
Dose (mg) 
+1 
15 mg 
Starting Dose 
10 mg  
-1 
5 mg 
-2 
5 mg daily for 21 days 
every 8 
-3 
Discontinue 
                     
 
 
    Dexamethasone Dose Levels 
 
Dose Level 
Dose (mg) 
Starting Dose 
40 mg 
-1 
20 mg  
-2 
8 mg 
-3 
Discontinue 
 
 
 

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6.2 
Criteria for Beginning a New Treatment Cycle  
 
For a new cycle of treatment to begin, the patient must meet the following criteria: 
 
• ANC must be ≥ 1,000/mm3. 
• Platelet count must be ≥ 75,000/mm3. 
• All other treatment related non-hematologic toxicity (except for alopecia) 
must have resolved to ≤ Grade 1 or to the patient’s baseline condition 
 
If the patient fails to meet the above-cited criteria for initiation of the next cycle of 
treatment, dosing should be delayed for 1 week. At the end of that time, the patient 
should be re-evaluated to determine whether the criteria have been met. If the criteria 
have been met, resume at previous dose levels. 
 
If the patient continues to fail to meet the above-cited criteria, delay therapy and continue 
to re-evaluate weekly. If a delay of > 2 weeks is required, reduce the suspected drug(s) by 
one dose level when treatment is resumed. Dosing adjustments should not occur in both 
ixazomib and lenalidomide simultaneously. 
 
6.3 
Dosing Modifications for Hematologic Toxicities 
 
6.3.1 Thrombocytopenia 
 
Only thrombocytopenia determined to be related to one or more study drugs 
require dose reductions or adjustments as described in this section. Platelet 
transfusion support is permissible at the discretion of the treating physician.  
Participants who have treatment delayed for greater than 3 weeks should 
discontinue protocol therapy.   
 
Dose modifications for thrombocytopenia during IRD Consolidation should be 
instituted as follows: 
Grade  Platelet 
           Modification 
3*   
< 50,000/mm3 
First episode: Hold all drugs until platelets resolve to 
grade < 1, then reduce lenalidomide by one dose level 
Second episode: Hold all drugs until platelets resolve 
to grade < 1, then reduce ixazomib by one dose level  
Third episode: Hold all drugs until platelets resolve 
to grade < 1, then reduce lenalidomide by one dose 
level 
Fourth episode: Hold all drugs until platelets resolve 
to grade < 1, then reduce ixazomib by one dose level 
Fifth episode: Discontinue protocol therapy. 
 
 
 
 
 
 

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Dose modifications for thrombocytopenia during ixazomib or lenalidomide 
maintenance should be instituted as follows: 
Grade  Platelet 
           Modification 
3 
< 50,000/mm3 
First episode: Hold ixazomib/lenalidomide until 
platelets resolve to grade < 1, then reduce 
ixazomib/lenalidomide by one dose level 
Second episode: Hold ixazomib/lenalidomide until 
platelets resolve to grade < 1, then reduce 
ixazomib/lenalidomide by one dose level  
Third episode: Hold ixazomib/lenalidomide until 
platelets resolve to grade < 1, then reduce 
ixazomib/lenalidomide by one dose level 
Fourth episode: Discontinue protocol therapy. 
 
 
 
 
6.3.2 Neutropenia or Febrile Neutropenia 
 
Only neutropenia/febrile neutropenia determined to be related to one or more 
study drugs require dose reductions or adjustments as described in this section. 
Colony-stimulating factor support (such as G-CSF or GM-CSF) for neutropenia is 
permissible at the discretion of the treating physician, but should not be given 
prophylactically. Participants who have treatment delayed for greater than 3 
weeks should discontinue protocol therapy.  
 
Dose modifications for neutropenia during IRD Consolidation should be instituted 
as follows: 
Grade  ANC 
           Modification 
3 
< 1000 /mm3 
First episode: Hold all drugs until ANC resolves to 
grade < 1, then reduce lenalidomide by one dose level 
Second episode: Hold all drugs until ANC resolves 
to grade < 1, then reduce lenalidomide by one more 
dose level 
Third episode: Hold all drugs until ANC resolves to 
grade < 1, then reduce lenalidomide by one more 
dose level 
Fourth episode: Hold all drugs until ANC resolves 
to grade < 1, then reduce lenalidomide by one more 
dose level 
Fifth episode:  Discontinue protocol therapy. 
 
 
 

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Dose modifications for neutropenia during ixazomib or lenalidomide maintenance 
should be instituted as follows: 
 
 
 
6.4 
D
o
s
i
n
g
 
M
o
difications for Non-Hematologic Toxicities 
 
Dose modification guidelines for treatment related non-hematologic toxicities are as 
follows: 
Toxicity 
Grade             Modification 
Tumor Lysis Syndrome 
Any 
First episode: Hold all drugs until symptoms 
resolve to baseline, then restart at previous dose 
levels with appropriate TLS prophylaxis  
 
Second episode: Discontinue protocol treatment.  
Confusion or Mood 
Alteration 
2 
First episode: Hold dexamethasone until symptoms 
resolve to baseline, then reduce dexamethasone by 
one dose level.   
 
Second episode: Discontinue dexamethasone 
Dyspepsia, Gastric or 
duodenal ulcer, or 
Gastritis 
2 
Each episode: Treat with histamine-2 blockers, 
sucralfate, or omeprazole as needed. If symptoms 
persist despite these measures, decrease 
dexamethasone by 1 dose level. 
Pancreatitis 
2 
First episode: Discontinue dexamethasone.  
Peripheral Neuropathy 
with pain 
2 
Each episode: Hold suspected study drug(s) until 
toxicity resolves to < grade 1 or baseline, then 
reduce suspected drug(s) by one dose level. 
Muscle Weakness  
2 
First episode: Decrease dexamethasone by one dose 
level.  
 
Second episode: If weakness persists, decrease 
dexamethasone by one more dose level.  
 
Third episode: Discontinue dexamethasone  
Grade  ANC 
           Modification 
3 
< 1000/mm3 
First episode: Hold  ixazomib/lenalidomide until 
ANC resolves to grade < 1,  then reduce 
ixazomib/lenalidomide by one dose level 
Second episode: Hold  ixazomib/lenalidomide until 
ANC resolves to grade < 1,  then reduce 
ixazomib/lenalidomide by one dose level 
Third episode: Hold  ixazomib/lenalidomide until 
ANC resolves to grade < 1,  then reduce 
ixazomib/lenalidomide by one dose level 
Fourth episode:    Discontinue protocol therapy. 

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Toxicity 
Grade             Modification 
Rash 
 
 
2 
Each episode: Hold suspected study drug(s) until 
toxicity resolves to < grade 1 or baseline, then restart 
at previous dose level once at the investigator’s 
discretion. 
Thrombosis or 
Embolism 
2 
Each episode: Hold lenalidomide and commence 
anticoagulation therapy, then restart at previous dose 
level at the investigator’s discretion. 
Diarrhea 
3 
Each episode: Only if the event occurred despite 
optimal supportive therapy, Hold suspected study 
drug(s) until toxicity resolves to < grade 1 or 
baseline, then reduce suspected drug(s) by one dose 
level. 
Dyspepsia, Gastric or 
duodenal ulcer, or 
Gastritis 
3 
First episode: Hold dexamethasone until toxicity 
resolve to < grade 1 or baseline, then decrease 
dexamethasone by 1 dose level. Prophylactically 
treat with histamine-2 blockers, sucralfate, or 
omeprazole as needed.  
 
Second episode: If symptoms persist despite these 
measures, discontinue dexamethasone.  
Edema 
3 
First episode: Treat with diuretics as needed. 
Decrease dexamethasone by one dose level.  
 
Second episode: If edema persists, decrease 
dexamethasone by one more dose level.  
 
Third episode: Discontinue dexamethasone 
Fatigue 
3 
Each episode: No modification required. 
Hyperglycemia 
3 
Each episode: Treat with insulin or hypoglycemic 
as needed. If uncontrolled despite these measures, 
decrease dexamethasone by 1 dose level.  
Nausea/Vomiting 
 
3 
Each episode: Only if the event occurred despite 
optimal anti-emetic prophylaxis, Hold suspected 
study drug(s) until toxicity resolves to < grade 1 or 
baseline, then reduce suspected drug(s) by one dose 
level. 
Rash  
Exfoliative or bollus 
rash; Stevens-Johnson 
Synrome, toxic 
epidermal necrolysis or 
Angioedema suspected 
3 
First episode: Discontinue suspected study drug(s).  
Other non-hematologic 
toxicity  
3 
Each episode: Hold suspected study drug(s) until 
toxicity resolves to < grade 1 or baseline, then 
reduce suspected drug(s) by one dose level. 

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Toxicity 
Grade             Modification 
Other non-hematologic 
toxicity 
4 
Each episode: Discontinue protocol therapy unless 
principal investigator grants permission to continue  
 
6.5 
Management of Clinical Events 
 
Adverse drug reactions such as thrombocytopenia, diarrhea, fatigue, nausea, vomiting, 
and rash have been associated with ixazomib treatment.  Management guidelines 
regarding these events are outlined below.  Further details of management of 
ixazomib AEs are described in Section 6 of the ixazomib IB.   
 
6.5.1 Prophylaxis against Risk of Reactivation of Herpes Infection 
 
Patients may be at an increased risk of infection including reactivation of herpes 
zoster and herpes simplex viruses.  Antiviral therapy such as acyclovir, 
valacyclovir, or other antivirals may be initiated as clinically indicated.  Other 
antivirals are also acceptable. 
 
6.5.2 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. 
 
6.5.3 Diarrhea 
 
Prophylactic antidiarrheals will not be used in this protocol. However, diarrhea 
should be managed according to clinical practice, including the administration of 
antidiarrheals 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. 
 
 

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6.5.4 Erythematous Rash With or Without Pruritus 
 
As with bortezomib, 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 macular.  To date, when it does occur, rash is most commonly 
reported within the first 3 cycles of therapy.  The rash is often transient, self-
limiting, and is typically Grade 1 to 2 in severity.  
 
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 (eg, prednisone ≤ 10 
mg per day or equivalent) is permitted.  Management of a Grade 3 rash may 
require intravenous antihistamines or corticosteroids.  Administration of ixazomib 
(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 (eg, using a thick, 
alcohol-free emollient cream on dry areas of the body or oral or topical 
antihistamines).  A rare risk is Stevens-Johnson Syndrome, a severe and 
potentially life-threatening rash with 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. 
 
6.5.5 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 administration 
should be modified as noted as per dose modification recommendations in the 
protocol when thrombocytopenia occurs (see Table 6-2). 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. 
 
 

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6.5.6 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 
administration should be modified as noted as per dose modification 
recommendations in the protocol when neutropenia occurs (see Table 6-2).  
Therapy can be reinitiated at a reduced level upon recovery of ANCs. 
 
6.5.7 Fluid Deficit 
 
Dehydration should be avoided since ixazomib may cause vomiting, diarrhea, and 
dehydration.  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. 
 
6.5.8 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. 
 
6.5.9 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. 
 
 

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6.5.10 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. 
 
 
7.0 
PHARMACEUTICAL INFORMATION 
 
7.1 
Ixazomib 
 
7.1.1 Description 
 
Ixazomib will be provided by the study in strengths of 4.0, 3.0, and 2.3 mg 
capsules as the active boronic acid. The different dose strengths are differentiated 
by both capsule size and color as described below: 
 
 
Dose Strength 
Capsule Size 
Capsule Color 
4.0 mg 
Size 4 
Ivory 
3.0 mg 
Size 3 
Light gray 
2.3 mg 
Size 2 
Light pink 
 
 
For additional details, please see Section 1.2 or refer to the ixazomib IB. 
 
7.1.2 Storage, Handling, and Accountability 
 
Upon receipt at the investigative site, ixazomib should remain in the blister and 
carton provided until use or until drug is dispensed. Ensure that the drug is used 
before the retest expiry date provided by Millennium. Expiry extensions will be 
communicated accordingly with updated documentation to support the extended 
shelf life. 
 
In countries where local regulations permit, ixazomib capsules dispensed to the 
patient for take-home dosing should remain in the blister packaging until the point 
of use. The investigative site is responsible for providing the medication to the 
patient in the correct daily dose configurations. Comprehensive instructions 
should be provided to the patient in order to ensure compliance with dosing 
procedures. Patients should be instructed to return their empty blister packs to the 
investigative site, rather than discarding them. Reconciliation will occur 
accordingly when the patient returns for their next cycle of take-home medication.  
 
 

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The ixazomib capsules should be stored according to the label. When applicable, 
the container should be stored at the investigative site refrigerated (36°F to 46°F, 
2°C to 8°C) and patients should be instructed to store the medication refrigerated 
(36°F to 46°F, 2°C to 8°C) for the duration of each cycle. Any extreme in 
temperature should be reported as an excursion and should be dealt with on a 
case-by-case basis. 
 
Because ixazomib is an investigational agent, it should be handled with due care. 
Patients should be instructed not to chew, break, or open capsules. In case of 
contact with broken capsules, raising dust should be avoided during the clean-up 
operation. The product may be harmful by inhalation, ingestion, or skin 
absorption. Gloves and protective clothing should be worn during cleanup and 
return of broken capsules and powder to minimize skin contact. 
 
The area should be ventilated and the site washed with soap and water after 
material pick-up is complete. The material should be disposed of as hazardous 
medical waste in compliance with federal, state, and local regulations. 
 
In case of contact with the powder (eg, from a broken capsule), skin should be 
washed immediately with soap and copious amounts of water for at least 15 
minutes. In case of contact with the eyes, copious amounts of water should be 
used to flush the eyes for at least 15 minutes. Medical personnel should be 
notified. Patients are to be instructed on proper storage, accountability, and 
administration of ixazomib, including that ixazomib is to be taken as intact 
capsules. 
 
7.1.3 Packaging and Labeling 
 
Ixazomib will be labeled and handled as open-label material, and packaging labels 
will fulfill all requirements specified by governing regulations.  
  
The capsules are individually packaged using cold-form foil-foil blisters that are 
in a child-resistant carton.  There are 3 capsules in each wallet/carton.  
 
7.1.4 Destruction 
 
Investigational ixazomib (expired or end of study) should be destroyed on site 
according to the institution’s standard operating procedure.  Be sure to document 
removal and destruction on drug accountability logs. 
 
7.1.5 Compliance 
 
Study drug will be administered or dispensed only to eligible patients under the 
supervision of the investigator or identified sub-investigator(s).  The appropriate 
study personnel will maintain records of study drug receipt and dispensing. 
 

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7.2 
Lenalidomide 
 
7.2.1 Lenalidomide Description 
 
Lenalidomide will not be provided by the study. It will be sourced from each 
patient’s commercial pharmacy of choice in accordance with the Celgene 
Corporation’s Revlimid REMS® program. 
 
7.3 
Dexamethasone 
 
7.3.1 Description 
 
Dexamethasone will not be provided by the study. It will be sourced from each 
patient’s commercial pharmacy of choice. 
 
 

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8.0 
STUDY CALENDAR 
Please note that all assessments allow a window of +/-3 days for scheduling issues. 
 
Screening 
Consolidation3 
Restaging4 
Maintenance5 
EOS7 
F/U8 
Prior to 
ASCT1 
Prior to 
beginning 
consolidation2 
D1 
D8 
D15 
D1 
D8 
D15 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
H&P, ECOG PS, plasmacytoma assessment 
X 
X 
X13 
 
 
X 
X13,14 
 
 
X 
X15 
CBC & CMP 
X 
 
X13 
 
X6 
X 
X13,14 
 
 
X 
 
SPEP and immunofixation 
X 
X 
X13 
 
 
X 
X13,14 
 
 
X 
 
24h urine for total protein, UPEP, and 
immunofixation9 
X 
X 
X13 
 
 
X 
X13,14 
 
 
X 
 
Serum-free light chains & β2 microglobulin 
X 
X 
X13 
 
 
X 
X13,14 
 
 
X 
 
Quantitative immunoglobulins (IgA, IgG, IgM) 
X 
X 
X13 
 
 
X 
X13,14 
 
 
X 
 
Serum βhCG10 
X 
X 
X 
 
 
 
X 
 
 
X 
 
Bone marrow biopsy and aspirate11 
X 
X 
 
 
 
X 
X16 
 
 
 
 
Central labs12 (MRD Analysis) 
 
X 
 
 
 
X 
X16 
 
 
 
 
Central labs12 (Hevylite) 
X 
 
X13 
 
 
X 
X13,14 
 
 
X 
 
Central labs18 (Sub-study) 
 
X18 
 
 
 
 
X18 
 
 
 
 
Ixazomib 
 
X 
X 
X 
 
X 
X 
X 
 
 
Lenalidomide 
 
Days 1-21 
 
Days 1-28 
 
 
Dexamethasone 
 
X 
X 
X 
 
 
 
 
 
 
Administration Questionnaire17 
 
X 
 
 
 
X 
 
 
 
 
Adverse events assessment 
 
X ------------------------------------------------------------------- X 
 
1. Day -60 to Day -2 
2. Day +80 to Day +120; to occur within 28 days prior to C1D1 of consolidation 
3. 4 28-day cycles 
4. Prior to beginning maintenance (approx. Day +192 to Day +232); to occur within 28 days after completing C4 of consolidation and within 28 days prior to C1D1 of maintenance 
5.  28-day cycles; continued until progression or unacceptable toxicity 
6. Cycles 1-2 only 
7. Within 30 days of last dose of study drug(s) 
8. Every 3 months for 18 months 
9. Repeat 24h urine only required for patients with ≥ 200 mg/24h of M-protein at screening 
10. Women of childbearing potential only; 2 negative tests are required within 14 days before study drug dosing on C1D1 of consolidation 
11. Bone marrow aspirate and core biopsy – differential required; Cytogenetics, and fluorescent in situ hybridization (FISH) studies performed per institutional guidelines. 
12. See Section 9.0 
13. Not required on C1D1 if screening/restaging visit occurred within 28 days prior 
14. C1-C4 then every 3 cycles thereafter (i.e., C7, C10, C13 …) 
15. A telephone call to assess OS and PFS can be made in lieu of a physical exam 
16. Cycle 13 for all patients. Cycle 25 and 37 also required for patients in suspected  or confirmed CR/sCR at that time. 

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17. See Appendix D. Patient to complete following each cycle of study treatment (consolidation and maintenance).  
18. Only performed on selected patients at Washington University or Ohio State University. See Appendix F.  
 

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9.0 
CENTRAL LABS 
 
9.1 
Mayo Clinic MFC MRD Panel   
 
Approximately 5 ml of bone marrow aspirate in EDTA (pink top) tube(s) will be 
collected at the following time points: 
 
• Prior to beginning consolidation therapy 
• Prior to beginning maintenance therapy 
• Cycle 13 Day 1 of maintenance therapy 
• Cycle 25 Day 1 of maintenance therapy* 
• Cycle 37 Day 1 of maintenance therapy* 
 
*- Only required for patients in suspected or confirmed CR/sCR at that time 
 
9.2 
Adaptive ClonoSEQ MRD Testing 
 
If archived bone marrow aspirate or core slides or sections are available from the time of 
diagnosis or any time prior to study entry, they will be requested. 
 
Additionally, approximately 5 ml of bone marrow aspirate in EDTA (pink top) tube(s) 
will be collected at the following time points: 
 
• Prior to beginning consolidation therapy 
• Prior to beginning maintenance therapy 
• Cycle 13 Day 1 of maintenance therapy 
• Cycle 25 Day 1 of maintenance therapy* 
• Cycle 37 Day 1 of maintenance therapy* 
 
*- Only required for patients in suspected or confirmed CR/sCR at that time 
 
9.3 
HEVYLITE Assay 
 
Approximately 10 ml of peripheral blood in serum (red top) tube(s) will be collected at 
the following time points: 
 
• Prior to ASCT 
• Prior to beginning consolidation therapy 
• Day 1 of each cycle of consolidation therapy 
• Prior to beginning maintenance therapy 
• Day 1 C1-C4 of maintenance and then every 3 cycles thereafter 
• End of Study 
 
 

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9.4 
Handling of Specimen(s) 
 
Instructions for handling and shipment of central labs will be provided in the study lab 
binder.  
 
9.5 
Future Research 
 
Any remaining specimens from blood or marrow after the required correlative studies are 
completed will be stored for future research including, but not limited to, genetic studies.  
 
10.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. Electronic data management systems will be used in this trial in 
collaboration with the Division of Biostatistics at Washington University.   
 
REDCap is a web-based clinical studies data management system that will be used for capture of 
clinical data from this trial.  The case report forms developed for this trial will be transformed to 
electronic format. An electronic study calendar will drive the study’s data collection workflow. 
 
Each participating center has access only to data from its own participants.  Washington 
University, as the data coordinating center, has access to data from all sites. Training in entering 
data in REDCap is required before a participating center will be given access to the database. In 
addition, a participating center must have IRB approval of this protocol prior to initiation of 
REDCap data entry training, which must be completed prior to site study activation. 
 
 

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Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
Registration Form 
Eligibility Form 
Medical History Form 
Treatment History Form 
Safety Labs Form 
MM labs Form 
Stem Cell Transplant Form 
At Baseline 
Study Drug Dosing Form 
Safety Labs Form 
MM Labs Form 
Response Form 
Each Cycle of Treatment 
Bone Marrow Form 
Response Form 
As Per Protocol Requirements 
Correlative Studies Form 
As Per Protocol Requirements 
Adverse Events 
Continuous from baseline through safety follow-up 
visit  
MedWatch Form 
See Section 8.0 for reporting requirements 
 
Any queries generated by Washington University must be responded to within 28 days of receipt 
by the participating site.  The Washington University research team will conduct a regular 
review of data status at all secondary sites, with appropriate corrective action to be requested as 
needed. 
 
 
11.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outlined below. 
 
The Washington University Human Research Protection Office (HRPO) requires that all events 
meeting the definition of unanticipated problem or serious noncompliance be reported as 
outlined in Section 11.4.  
 
The FDA requires that all serious and unexpected adverse events be reported as outlined in 
Section 11.7. In addition, any fatal or life-threatening adverse experiences where there is a 
reasonable possibility of relationship to study intervention must be reported. 
 
 

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11.1 Definitions 
 
11.1.1 Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease. 
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized 
for all toxicity reporting.  A copy of the CTCAE version 4.0 can be downloaded 
from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for 
the terms listed that should be used are those provided by the Department of 
Health and Human Services’ Office for Human Research Protections (OHRP).  A 
copy of this guidance can be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
11.1.2 Serious Adverse Event (SAE) 
 
Definition:  any adverse drug experience occurring at any dose that results in any 
of the following outcomes: 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial 
disruption of a person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above 
 
All unexpected SAEs must be reported to the FDA. 
 
11.1.3 Unexpected Adverse Experience 
 
Definition: any adverse drug experience, the specificity or severity of which is 
not consistent with the current investigator brochure (or risk information, if an IB 
is not required or available). 
 
Events that are both serious AND unexpected must be reported to the FDA.  
 
 

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11.1.4 Life-Threatening Adverse Experience  
 
Definition: any adverse drug experience that places the subject (in the view of the 
investigator) at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that, had it occurred in a more severe form, might have 
caused death. 
 
Life-threatening adverse experiences must be reported to the FDA. 
 
11.1.5 Unanticipated Problems 
 
Definition: 
 
• unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
• related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research); 
and 
• suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
11.1.6 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that 
govern human subjects research or failure to follow the determinations of the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate 
choice to ignore regulations, institutional policies, or determinations of the IRB. 
11.1.7 Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in 
substantial harm to subjects or others, or that materially compromises the rights or 
welfare of participants. 
 
11.1.8 Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the 
research team’s control. Exceptions apply only to a single participant or a singular 
situation. 
 
 

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Local IRB Pre-approval of all protocol exceptions must be obtained prior to the 
event.  For secondary sites, the Washington University PI will issue approval of 
the exception, but it must also be submitted to the local IRB with documentation 
of approval forwarded to Washington University.  Washington University IRB 
approval is not required for protocol exceptions occurring at secondary sites. 
 
11.2 
Product Complaints 
 
Definition: A product complaint is a verbal, written, or electronic expression that implies 
dissatisfaction regarding the identity, strength, purity, quality, or stability of a drug 
product.  Individuals who identify a potential product complaint situation should 
immediately contact MedComm Solutions (see below) and report the event.  Whenever 
possible, the associated product should be maintained in accordance with the label 
instructions pending further guidance from a Millennium Quality representative. 
 
Product complaints in and of themselves are not AEs.  If a product complaint results in an 
SAE, an SAE form should be completed (refer to Section 8.10).    
 
11.3 
Medication Error 
 
A medication error is a preventable event that involves an identifiable patient and that 
leads to inappropriate medication use, which may result in patient harm.  While 
overdoses and underdoses constitute medication errors, doses missed inadvertently by a 
patient do not.  Individuals who identify a potential medication error situation should 
immediately contact Millennium (see below) and report the event 
 
11.4 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 
• Any unanticipated problems involving risks to participants or others which occur 
at WU, any BJH or SLCH institution, or that impacts participants or the conduct 
of the study. 
• Noncompliance with federal regulations or the requirements or determinations of 
the IRB. 
• Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of 
the event or notification to the PI of the event.  The death of a research participant that 
qualifies as a reportable event should be reported within 1 working day of the occurrence 
of the event or notification to the PI of the event. 
 
 
 

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11.5 
Reporting to the Quality Assurance and Safety Monitoring Committee 
(QASMC) at Washington University 
 
The PI is required to notify the QASMC of any unanticipated problem occurring at WU 
or any BJH or SLCH institution that has been reported to and acknowledged by HRPO as 
reportable.  (Unanticipated problems reported to HRPO and withdrawn during the review 
process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email to 
a QASMC auditor. 
 
11.6 
Reporting Requirements for Secondary Sites 
 
The research team at each secondary site is required to promptly notify the Washington 
University PI and research coordinator of all reportable events (as described in Section 
11.7) within 1 working day of the occurrence of the event or notification of the 
secondary site’s PI of the event.  This notification may take place via email if there is not 
yet enough information for a formal written report (using either an FDA MedWatch form 
if required or an institutional SAE reporting form if not).  A formal written report must be 
sent to the Washington University PI and research coordinator within 10 working days 
of the occurrence of the event or notification of the secondary site’s PI of the event.  The 
death of a research participant that qualifies as a reportable event should be reported 
within 1 working day of the occurrence of the event or notification of the secondary 
site’s PI of the event. 
 
The research team at a secondary site is responsible for following its site’s guidelines for 
reporting applicable events to its site’s IRB according to its own institutional guidelines. 
The research team at Washington University is responsible for reporting all applicable 
events to the FDA.  
 
11.7 
Reporting to Secondary Sites 
 
The Washington University PI (or designee) will notify the research team at each 
secondary site of all reportable events that have occurred at other sites within 10 working 
days of the occurrence of the event or notification of the PI of the event.  This includes 
events that take place both at Washington University and at other secondary sites, if 
applicable. 
 
11.8 
Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  
PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA DIFFER 
FROM REPORTING REQUIREMENTS FOR HRPO/QASMC.  It is the 
responsibility of the Washington University principal investigator to report any 
unanticipated problem to the FDA as follows: 
 

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• Report any unexpected fatal or life-threatening adverse experiences (Section 
11.1.4) associated with use of the drug by telephone or fax no later than 7 
calendar days after initial receipt of the information.   
• Report any serious, unexpected adverse experiences (Section11.1.2), as well as 
results from animal studies that suggest significant clinical risk within 15 
calendar days after initial receipt of this information.   
 
All MedWatch forms will be sent by the investigator or investigator’s team to the FDA at 
the following address or by fax: 
 
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Oncology Drug Products 
5901-B Ammendale Rd. 
Beltsville, MD 20705-1266 
FAX: 1-800-FDA-0178 
 
Secondary sites must submit a completed MedWatch form to the Washington University 
PI and research coordinator within 4 calendar days (for fatal or life-threatening adverse 
experiences) or 11 calendar days (for serious, unexpected adverse experiences).  The 
Washington University PI will be responsible for submitting all MedWatch forms from 
secondary sites to the FDA within the timeframes specified above. 
 
11.9 
Reporting to Millennium 
 
AEs may be spontaneously reported by the patient and/or in response to an open question 
from study personnel or revealed by observation, physical examination, or other 
diagnostic procedures.  Any clinically relevant deterioration in laboratory assessments or 
other clinical finding is considered an AE.  When possible, signs and symptoms 
indicating a common underlying pathology should be noted as one comprehensive event.  
For serious AEs, the investigator must determine both the intensity of the event and the 
relationship of the event to study drug administration.  
 
AEs which are serious must be reported to Millennium Pharmacovigilance (or designee) 
from the first dose of study drug through 30 days after administration of the last dose of 
ixazomib. Any SAE that occurs at any time after completion of ixazomib treatment or 
after the designated follow-up period that the sponsor-investigator and/or sub-investigator 
considers to be related to any study drug must be reported to Millennium 
Pharmacovigilance (or designee).  In addition, new primary malignancies that occur 
during the follow-up periods must be reported, regardless of causality to study regimen, 
for a minimum of three years after the last dose of the investigational product, starting 
from the first dose of study drug. All new cases of primary malignancy must be reported 
to Millennium Pharmacovigilance (or designee).    
 
Regardless of expectedness or causality, all SAEs (including serious pretreatment events) 
must also be reported in English to Millennium Pharmacovigilance (or designee).  Fatal 

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and life threatening SAEs must be reported within 24 hours of the sponsor-investigator’s 
observation or awareness of the event, and all other serious (non-fatal/non life 
threatening) events must be reported within 4 calendar days of the sponsor-investigator’s 
observation or awareness of the event. 
 
US and Canada 
Toll-Free Fax #: 1-800-963-6290 
E-mail: takedaoncocases@cognizant.com 
 
If a woman becomes pregnant or suspects that she is pregnant while participating in this 
study, she must inform the investigator immediately and must permanently discontinue 
bortezomib.  A Pregnancy Form must be requested, completed, and faxed to Millennium 
Pharmacovigilance.  The pregnancy must be followed for the final pregnancy outcome. 
 
If a female partner of a male patient becomes pregnant during the male patient’s 
participation in this study, this must be reported to Millennium Pharmacovigilance 
immediately using the Pregnancy Form.  Every effort should be made to follow the 
pregnancy for the final pregnancy outcome. 
 
11.10 Timeframe for Reporting Required Events  
 
Adverse events will be collected from first dose of study treatment through the end of 
study visit.  
 
 
12.0 
MEASUREMENT OF EFFECT 
 
12.1 
Response Criteria  
 
Response will be determined by the International Myeloma Working Group (IMWG) 
Uniform Response Criteria.36  
 
12.1.1 Stringent Complete Response  
 
Stringent complete response (sCR) requires all of the following:  
• CR as defined below 
• Normal free light chain ratio (0.26-1.65) 
• Absence of clonal cells in the bone marrow by immunohistochemistry or 
immunofluorescence  
 
 

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12.1.2 Complete Response  
 
Complete response (CR) requires all of the following:  
• Disappearance of monoclonal protein by both protein electrophoresis and 
immunofixation studies from the blood and urine 
• If serum and urine monoclonal protein are unmeasurable, Normal free 
light chain ratio (0.26-1.65) 
• <5% plasma cells in the bone marrow  
• Disappearance of soft tissue plasmacytoma 
 
12.1.3 Very Good Partial Response  
 
Very good partial response (VGPR) requires all of the following:  
• Serum and urine monoclonal protein detectable by immunofixation but not 
on electrophoresis  
OR  
≥ 90% reduction in serum monoclonal protein with urine monoclonal 
protein < 100 mg per 24 hours  
• If serum and urine monoclonal protein are unmeasurable, a > 90% 
decrease in difference between the involved and uninvolved free light 
chain levels is required in place of monoclonal protein criteria (The 
absolute decrease must be > 10 mg/dl) 
• If present, > 50% reduction in the size of soft tissue plasmacytomas (by 
clinical or radiographic examinations) 
 
12.1.4 Partial Response  
 
Partial response (PR) requires all of the following:  
• > 50% reduction in the level of the serum monoclonal protein  
• Reduction in urine monoclonal protein by either > 90% or to < 200 mg  
• If serum and urine monoclonal protein are unmeasurable, a >50% decrease 
in difference between the involved and uninvolved free light chain levels 
is required in place of monoclonal protein criteria (The absolute decrease 
must be > 10 mg/dl)  
• If serum and urine monoclonal protein are unmeasurable and serum free 
light chain is unmeasurable, a > 50% reduction in plasma cells is required 
in place of monoclonal protein, provided that baseline bone marrow 
plasma cell percentage was > 30%  
• If present, > 50% reduction in the size of soft tissue plasmacytomas (by 
clinical or radiographic examinations). 
 
 

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12.1.5 Stable Disease  
 
Stable disease (SD) is defined as not meeting criteria for any other response as 
defined in this section. 
 
12.1.6 Progressive Disease or Clinical Relapse 
 
Progressive disease (PD) requires one or more of the following:  
• > 25% increase in the level of serum monoclonal protein, which must also 
be an absolute increase of at least 0.5 g/dL and confirmed on a repeat 
investigation 
• > 25% increase in 24-hour urine monoclonal protein, which must also be 
an absolute increase of at least 200 mg/24hr and confirmed on a repeat 
investigation.  
• If serum and urine monoclonal protein are unmeasurable, > 25% increase 
in the difference between involved and uninvolved free light chain levels, 
which must also be an absolute increase of at least 10 mg/dL and 
confirmed on a repeat investigation 
• > 25% increase in plasma cells in a bone marrow aspirate or on trephine 
biopsy, which must also be an absolute increase of at least 10%.  
• Definite increase in the size of existing lytic bone lesions or soft tissue 
plasmacytomas. A definite increase is defined as at least 50% (and at least 
1 cm) increase as measured serially as the sum of the products of the 
cross-diameters of the lesions.  
• Development of new bone lesions or soft tissue plasmacytomas (not 
including compression fracture).  
• Development of hypercalcaemia (corrected serum calcium > 11.5 mg/dL 
or 2.8 mmol/L not attributable to any cause other than progressive 
multiple myeloma).  
• Decrease in hemoglobin > 2 g/dl not attributable to any cause other than 
progressive multiple myeloma  
• Increase in creatinine by > 2 mg/dl not attributable to any cause other than 
progressive multiple myeloma  
• Other worsening laboratory result, or clinical condition that the treating 
physician determines is not attributable to any cause other than 
progressive multiple myeloma  
 
Note: A response of progressive disease/clinical relapse nullifies any other 
concurrent response. For example, at a given time point a participant meets 
criteria for VGPR but has development of new bone lesions the response is PD 
not VGPR. 
 
 
 

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12.1.7  Relapse from Complete Response  
 
Relapse from a complete response requires a prior CR or sCR as described above 
and subsequently developing one or more of the following:  
• Reappearance of serum or urinary paraprotein on immunofixation or 
routine electrophoresis excluding oligoclonal immune reconstitution, and 
confirmed on a repeat investigation 
• Development of > 5% plasma cells in the bone marrow aspirate or biopsy. 
• Appearance of any sign of progressive disease or clinical relapse as stated 
above.  
 
12.2 
Minimal Residual Disease 
 
For the purposes of this study, a patient will be considered as having minimal residual 
diseases if a positive result is obtained using the Adaptive Clonoseq  MRD testing. In the 
event that Adaptive Clonoseq cannot be performed, a patient will be considered as having 
minimal residual diseases if a positive result is obtained using the Mayo MFC MRD 
Panel.  
 
 
13.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, 
the Data and Safety Monitoring Committee (DSMC) will meet to review toxicity data at least 
every 6 months following the activation of the first secondary site.  The report will be prepared 
by the statistician with assistance from the study team and will be submitted to the Quality 
Assurance and Safety Monitoring Committee (QASMC).  This report will include: 
 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of 
study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol 
exceptions, error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual including numbers from 
participating sites 
• Protocol activation date at each participating site 
• Average rate of accrual observed in year 1, year 2, and subsequent years at each 
participating site 
• Expected accrual end date, accrual by site, and accrual by cohort 
• Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
• Measures of efficacy 

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• Early stopping rules with supporting data and list the number of participants who 
have met the early stopping rules 
• Summary of toxicities at all participating sites and separated by cohorts with the 
number of dose-limiting toxicities indicated 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study 
 
Until such a time as the first secondary site activates this protocol, a semi-annual DSM report to 
be prepared by the study team will be submitted to the QASM Committee beginning 6 months 
after study activation at Washington University. 
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC 
according to institutional guidelines. 
 
A DSMC will consist of no fewer than 3 members including 2 clinical investigators and a 
biostatistician.  Like investigators, DSMC members are subject to the Washington University 
School of Medicine policies regarding standards of conduct. Individuals invited to serve on the 
DSMC will disclose any potential conflicts of interest to the trial principal investigator and/or 
appropriate university officials, in accordance with institution policies. Potential conflicts that 
develop during a trial or a member’s tenure on a DSMC must also be disclosed.  
 
Refer to the Washington University Quality Assurance and Data Safety Monitoring Committee 
Policies and Procedures for full details on the responsibilities of the DSMC at 
https://siteman.wustl.edu/wp-content/uploads/2015/10/QASMC-Policies-and-Procedures-
03.31.2015.pdf 
 
 
14.0 
AUDITING 
 
Since Washington University is the coordinating center, each site will be audited annually by 
Siteman Cancer Center personnel (QASMC) unless the outside institution has an auditing 
mechanism in place and can provide a report. The outside sites will be asked to send copies of all 
audit materials, including source documentation.  The audit notification will be sent to the 
Washington University Research Patient Coordinator, who will obtain the audit materials from 
the participating institution. 
 
Notification of an upcoming audit will be sent to the research team one month ahead of the audit. 
Once accrual numbers are confirmed, and approximately 30 days prior to the audit, a list of the 
cases selected for review (up to 10 for each site) will be sent to the research team. However, if 
during the audit the need arises to review cases not initially selected, the research team will be 
asked to provide the additional charts within two working days. 
 

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Additional details regarding the Auditing Policies and procedures can be found at 
http://www.siteman.wustl.edu/uploadedFiles/Research_Programs/Clinical_Research_Resources/
Protocol_Review_and_Monitoring_Committee/QASMCQualityAssurcance.pdf  
 
15.0 
STATISTICAL CONSIDERATIONS 
 
This is an open-label, randomized phase II study that will accrue at 4-6 centers within the United 
States. The total accrual goal is 220 patients evaluable for the primary objective. We estimate the 
percentage of patients treated that will be evaluable for the primary objective to be > 90%, thus a 
total accrual of up to ~~240 patients may be needed. The estimated accrual is 10-12 patients per 
month, with a projected enrollment time frame of 24 months.  
 
15.1 
Determination of Sample Size 
 
A power analysis was performed for the primary objective. The smallest increase in 
MRD-negative rate after four cycles of IRD that would warrant further investigation is 
10%, with a result of < 9% being considered ineffective. Based on a meta-analysis of five 
prior studies in this population, the expected MRD-negative rate at Day 100 post-
transplant is ~50%. If the true rate of MRD-negative is 40-60% at the Day 100 post-
transplant visit, 220 evaluable patients will detect a 10% improvement in MRD-negative 
rate with 90% power at 1-sided 0.05 alpha. Due to highly varied data of baseline MRD 
(i.e., 5 published studies showed MRD-negative rates ranged from 8% to 62%) as well as 
the lack of pilot information for the association over time, we currently choose a rather 
conservative estimation and the sample size is estimated using non-paired design instead. 
However, an interim analysis will be performed when ~50 patients are randomized to 
maintenance arms, and sample size adjustment will then be made if needed (see details 
below for interim analysis).        
 
The randomized maintenance portion of the study will provide pilot data that will be used 
to design future studies. Although the study was not powered to show non-inferiority or 
superiority of either of the two maintenance arms, the designed sample size (n=110 
evaluable patients/arm) will provide us a reasonable power for our hypothesis that 
"Maintenance therapy with ixazomib will be well tolerated and will be similar in 
response rate, PFS, OS, and MRD-positive to MRD-negative conversion rate to 
maintenance therapy with lenalidomide". Taking PFS  as an example, the recent meta-
analysis of lenalidomide versus placebo/observation showed that the 5-year cumulative 
incidence of events (PD or 2nd-line treatment) was ~54%. [29] The figure below 
illustrates the statistical power to show non-inferiority given the “true” difference of 
event rates (e.g., death or recurrence or treatment failure) between the ixazomib arm 
(experimental group) and lenalidomide arm (control group). With a non-inferiority 
margin of 10% in 5-year PFS (or equivalently a hazard ratio (HR) of 1.3), for example, 
the designed sample size would allow 80% power to claim non-inferiority when a slightly 
better PFS is observed in the ixazomib arm.   
 
 

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This power analysis was based on 
a simulation study where 
• the true rate in the 
experimental treatment 
(ixazomib) varied from 45% 
to 65%; 
• the true recurrence rate in the 
control (lenalidomide) varied 
from 52% to 56%; 
• a total of 10,000 replicates are 
generated under each 
scenario, and each replicate 
includes N=110 ixazomib 
patients and N=110 
lenalidomide patients; 
• events in each arm were 
generated following binomial 
distributions; 
• 1-sided 90% confidence interval (CI) for the difference between event rates was 
calculated and non-inferiority will be declared if the upper boundary of CI is below 
10% [30]. That is, the non-inferiority margin was set as 10% absolute difference, or 
equivalently a hazard ratio (HR) of 1.3 when assuming the time following an 
exponential distribution; 
• The figure shows average power as a function of the true difference of event rates 
between experimental and control groups; 
• Note that the current simulation was based on binary data for simplicity. We expect 
that more power could be achieved in the actual time-to-event analysis due to the 
availability of richer information (i.e., not only the status of event, but also the exact 
time when it happens).     
 
The accrual rate over six participating centers will be roughly 6 patients per month, with 
a total accrual timeframe of about 3 years following study activation. 
 
15.2 
Randomization and Stratification 
 
Following initial treatment with IRD consolidation therapy, patients will be randomized 
to a pilot portion of the study evaluating ixazomib or lenalidomide as maintenance 
therapy. 
 
Patients will be restaged following completion of consolidation treatment and will be 
randomized on a 1:1 basis to maintenance therapy with ixazomib or lenalidomide.  
Patients will be stratified based on MRD status at restaging (MRD-negative v. MRD-
positive). For the purposes of randomization, if there are discrepant results from the 
Mayo Clinic MFC and the Adaptive ClonoSEQ MRD tests, the Adaptive ClonoSEQ 
results will be used for stratification. In the event that the Adaptive ClonoSEQ results are 
not available, the Mayo Clinic MFC results will be used for stratification, and vice versa.  

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15.3 
Data Analysis 
 
For the analysis of consolidation therapy, the data for safety analysis will include these 
patients who have at least 1 dose of IRD consolidation therapy, while the data for 
efficacy analysis will include patients who complete 4 cycles therapy. Demographic and 
clinical characteristics of the sample, as well as adverse events, complications and loss to 
follow-up will be summarized using descriptive statistics. The change of MRD-negative 
rates for pre- and post-consolidation therapy will be described using contingency table 
and compared by McNemar test. The incidences of mortality, progression, relapse, as 
well as tumor response (complete response and overall) and their 95% confidence 
intervals following consolidation therapy will also be calculated.  
 
Data analysis for maintenance portion will be performed following the intent-to-treat 
(ITT) principle. The balance of demographic and baseline clinical characteristics between 
two arms will be compared using t-test, Mann-Whitney rank-sum test, or Chi-square test 
as appropriate. The distributions of responses and adverse events across two arms will be 
summarized using contingency tables and compared by 2-sample Chi-square test or 
Fisher’s exact test. Contingency table and Fisher's exact test will also be used to assess 
the between-arms difference for the rates of conversion from MRD-positive to MRD-
negative. Chi-square test will be used to compare the distribution of responses, and 
Kaplan-Meier curves with log rank tests will be used to compare PFS and OS.  
 
Overall survival (OS) will be defined as time from ASCT to death due to any causes, and 
survivors will be censored at withdrawal or study closeout. Progression-free survival 
(PFS) will be defined as time from ASCT to progression, relapse, or death, whichever 
occurs first, and those event-free survivors will be censored at withdrawal or study 
closeout. The between-arm differences in OS and PFS will be described using Kaplan-
Meier product limit estimator and compared by log-rank tests. Kaplan-Meier curves will 
also be used to describe the association between MRD status (both prior to and after 
consolidation therapy) and OS or PFS, and proportional hazards Cox models will be used 
to control the potential confounding effects of other patient and clinical characteristics. 
 
15.4 
Interim Analysis 
 
 
Two interim analyses will be performed during the consolidation phase of the trial. The 
first will occur when ~50 patients complete the consolidation therapy and are randomized 
to maintenance portion. The second will occur in Year-3, after approximately 150 
evaluable patients complete the consolidation therapy and are randomized to maintenance 
portion. 
 
The data analysis will be descriptive in nature.  The change of MRD-negative rates for 
pre- and post-consolidation therapy will be estimated using contingency table. Sample 
size will be re-estimated and conditional power will also be calculated based on the 
accumulated data. Conditional power is defined as the projected power to reject the null 
hypothesis at the end of study given the data accrued up to a specific interim analysis. 

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Therefore, a high value of conditional power indicates a highly likely, if not inevitable, 
conclusion to reject the null hypothesis given the available information. Similarly, a small 
value suggests a high possibility of negative finding given the current data. This interim 
analysis will assist investigators on the decision whether the sample size (220 evaluable, 
~240 total) needs to be adjusted.  
 
Two additional interim analyses will also be scheduled to monitor the futility of 
maintenance portion and thus to reduce the exposure of patients to inferior treatment. The 
first will occur in Year-4 (i.e., near the end of accrual period) and the other at Year-6 
(i.e., when all patients have at least 2-year follow-up of maintenance therapy). Each 
interim analysis will be descriptive in nature. The rates of conversion from MRD-positive 
to MRD-negative across different arms will be summarized using contingency tables and 
compared by Fisher's exact test. The differences in PFS or OS between arms will be 
described using hazard ratios (HR). Kaplan-Meier product limit method will also be used 
to estimate survival curves and the corresponding confidence intervals. The stopping rule 
for an early termination due to futility will follow the guidelines for non-inferiority trials. 
[31] That is, the study will be recommended for an early termination whenever the 
observed HR is equal or worse than 1.3 (the non-inferiority margin) and the outcome is in 
favor of lenalidomide (control arm).  For PFS, for example, the recent meta-analysis 
showed that the 1-year and 2-year event rates in the lenalidomide cohort are 13% and 
25%, respectively, and HR=1.3 corresponds to an increase of ~3% and ~6% for 1-year 
and 2-year event rates.  
 
 
16.0 
MULTICENTER REGULATORY REQUIREMENTS 
 
Washington University requires that each participating site sends its informed consent document 
to be reviewed and approved by the Washington University Regulatory Coordinator (or 
designee) prior to IRB/IEC submission.    
 
Each participating institution must have the following documents on file at Washington 
University prior to first subject enrollment: 
• Documentation of IRB approval of the study in the form of a letter or other official 
document from the participating institution’s IRB.  This documentation must show 
which version of the protocol was approved by the IRB. 
• Documentation of IRB approval of an informed consent form. The consent must 
include a statement that data will be shared with Washington University, including 
the Quality Assurance and Safety Monitoring Committee (QASMC), the DSMC (if 
applicable), and the Washington University study team. 
• Documentation of FWA, signed FDA Form 1572, and signed and dated CVs of all 
participating investigators. 
• Documentation of training in protection of human subjects by all participating 
investigators. 
• Protocol signature page signed and dated by the investigator at each participating site. 
 

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The Principal Investigator is responsible for disseminating to the participating sites all study 
updates, amendments, reportable adverse events, etc.  There will be one current version of the 
protocol document at any given time and each participating institution will utilize that document.  
Protocol/consent modifications and IB updates will be forwarded electronically to the secondary 
sites within 2 weeks of obtaining Washington University IRB approval with acknowledgement 
of receipt requested.  Secondary sites are to submit protocol/consent/IB modifications to their 
local IRBs within 4 weeks of receipt, and confirmation of submission must be forwarded to the 
appropriate contact person on the Washington University study team at the time of submission.  
Upon the secondary sites obtaining local IRB approval, documentation of such shall be sent to 
the Washington University study team within 2 weeks of receipt of approval. 
 
Documentation of participating sites’ IRB approval of annual continuing reviews, protocol 
amendments or revisions, all SAE reports, and all protocol violations/deviations/exceptions must 
be kept on file at Washington University. 
 
The investigator or a designee from each institution must participate in a regular conference call 
to update and inform regarding the progress of the trial. 

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17.0 
REFERENCES 
 
1. 
Gupta, N., et al., Clinical Pharmacokinetics of Intravenous and Oral MLN9708, An 
Investigational Proteasome Inhibitor: An Analysis of Data From Four Phase 1 
Monotherapy Studies. in 52nd ASH Annual Meeting and Exposition, 2010. 116(21): p. 
abstr 1813. 
2. 
Gupta, N., M. Saleh, and K. Venkatakrishnan. Flat-Dosing Versus BSA-Based Dosing 
for MLN9708, An Investigational Proteasome Inhibitor: Population Pharmacokinetic 
(PK) Analysis of Pooled Data From 4 Phase-1 Studies in 53rd ASH Annual Meeting and 
Exposition. 2011. San Diego, CA; p. abstr 1433 
3. 
Chow, L.Q., et al. MLN9708, an investigational proteasome inhibitor, in patients with 
solid tumors; Updated phase 1 results in Head and Neck Symposium. 2012. Phoenix, AZ 
4. 
Assouline, S., et al. Once-weekly MLN9708, an investigational proteasome inhibitor, in 
patients with relapsed/refractory lymphoma: results of a phase 1 dose-escalation study in 
17th EHA Annual Congress. 2012. Amsterdam, the Netherlands. 
5. 
Lonial, S., et al. Phase I study of twice-weekly dosing of the investigational oral 
proteasome inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiple 
myeloma (MM) in ASCO Annual Meeting. 2012. Chicago, Illinois. 
6. 
Kumar S, et al. Weekly Dosing of the Investigational Oral Proteasome Inhibitor 
MLN9708 in Patients with Relapsed and/or Refractory Multiple Myeloma: Results From 
a Phase 1 Dose- Escalation Study In 53rd ASH Annual Meeting and Exposition; 2011 10-
13 Dec; San Diego, CA; p. abstr 816.. 
7. 
Merlini, G., et al. MLN9708, a Novel, Investigational Oral Proteasome Inhibitor, in 
Patients with Relapsed or Refractory Light-Chain Amyloidosis (AL): Results of a Phase 
1 Study in 54th ASH Annual Meeting and Exposition. 2012. Atlanta, Georgia. 
8. 
Kumar, S. et al. A Phase 1/2 Study of Weekly MLN9708, an Investigational Oral 
Proteasome Inhibitor, in Combination with Lenalidomide and Dexamethasone in Patients 
with Previously Untreated Multiple Myeloma (MM) in 54th ASH Annual Meeting and 
Exposition. 2012. Atlanta, Georgia. 
9. 
Richardson, P.G., et al. MLN9708, an investigational proteasome inhibitor, in 
combination with lenalidomide and dexamethasone in previously untreated multiple 
myeloma 
patients 
(pts): 
Evaluation of weekly and twice-weekly dosing in 17th EHA Annual Congress. 2012. 
Amsterdam, the Netherlands. 
10. 
San Miguel, J., et al. Oral MLN9708, an an investigational proteasome inhibitor, in 
combination with melphalan and prednisone in patients with previously untreated 
multiple myeloma: a phase 1 study in 17th EHA Annual Congress. 2012. Amsterdam, the 
Netherlands. 
11. 
Richardson P, Baz R, Wang L, Jakubowiak A, Berg D, Liu G, et al. Investigational Agent 
MLN9708, An Oral Proteasome Inhibitor, in Patients (Pts) with Relapsed and/or 
Refractory Multiple Myeloma (MM): Results From the Expansion Cohorts of a Phase 1 
Dose-Escalation Study In: 53rd ASH Annual Meeting and Exposition; 2011 10-13 Dec; 
San Diego, CA; p. abstr 301. 
12. 
Lonial S, Baz R, Wang M, Talpaz M, Liu G, Berg D, et al. Phase I study of twice weekly 
dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) with 

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relapsed and/or refractory multiple myeloma (MM). J Clin Oncol (ASCO Meeting 
Abstracts) 2012;30(15 suppl):abstr 8017. 
13. 
Kumar S, Bensinger W, Reeder C, Zimmerman T, Berenson J, Berg D, et al. Weekly 
Dosing of the Investigational Oral Proteasome Inhibitor MLN9708 in Patients with 
Relapsed and/or Refractory Multiple Myeloma: Results From a Phase 1 Dose- Escalation 
Study In: 53rd ASH Annual Meeting and Exposition; 2011 10-13 Dec; San Diego, CA; p. 
abstr 816. 
14. 
Kumar S, Bensinger W, Reeder C, Zimmerman T, Berenson J, Liu G, et al. Weekly 
dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) with 
relapsed/refractory multiple myeloma (MM): A phase I study. Journal of Clinical 
Oncology 2012 ASCO Annual Meeting Proceedings 2012:Abstract 8034. 
15. 
Kumar S, Niesvizky R, Berdeja J, Bensinger W, Zimmerman T, Berenson J, et al. Safety 
and Pharmacokinetics of Weekly MLN9708, an Investigational Oral Proteasome 
Inhibitor, Alone and in Combination. Clinical Lymphoma Myeloma and Leukemia 
2013;13(Supplement 1):S154; abstr P-230 
16. 
Common Terminology Criteria for Adverse Events (CTCAE). 2010. 
17.  
Attal M, et al., (1996). A prospective, randomized trial of autologous bone marrow 
transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du 
Myelome. N Engl J Med, 335(2): p. 91-97. 
18. 
Peest D, et al., (1990). Melphalan and prednisone (MP) versus vincristine, BCNU, 
adriamycin, melphalan and dexamethasone (VBAM Dex) induction chemotherapy and 
interferon maintenance treatment in multiple myeloma. Current results of a multicenter 
trial. The German Myeloma Treatment Group. Onkologie, 13(6): p. 458-460.  
19. 
Salmon SE, et al., (1994). Combination chemotherapy, glucocorticoids, and interferon 
alfa in the treatment of multiple myeloma: a Southwest Oncology Group study. J Clin 
Oncol, 12(11): p. 2405-2414.  
20. 
Westin J, et al., (1995). Interferon alfa-2b versus no maintenance therapy during the 
plateau phase in multiple myeloma: a randomized study. Cooperative Study Group. Br J 
Haematol, 89(3): p. 561-568.  
21.  
Browman GP, et al., (1995). Randomized trial of interferon maintenance in multiple 
myeloma: a study of the National Cancer Institute of Canada Clinical Trials Group. J Clin 
Oncol, 13(9): p. 2354-2360.  
22.  
Ludwig H, et al., (1995). Interferon-alpha for induction and maintenance in multiple 
myeloma: results of two multicenter randomized trials and summary of other studies. 
Ann Oncol, 6(5): p. 467-476. 
23.  
Kagoya Y, et al., (2012). Thalidomide Maintenance Therapy for Patients with Multiple 
 
Myeloma: Meta-analysis. Leuk Res, 36(8): p. 1016-1021. 
24.  
Mellqvist UH, et al., (2013). Bortezomib consolidation after autologous stem cell 
transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 
3 trial. Blood, 121(23): p. 4647-4654.  
25.  
McCarthy PL, et al., (2012). Lenalidomide after stem-cell transplantation for multiple 
myeloma. N Engl J. Med, 366(19): p. 1770–1781. 
26.  
Attal M, et al., (2012). Lenalidomide maintenance after stem-cell transplantation for 
multiple myeloma. N Engl J Med, 366(19): p. 1782–1791. 

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27. 
Attal M, et al., (1996). A prospective, randomized trial of autologous bone marrow 
transplantation and chemotherapy in multiple myeloma: Intergroupe Français du 
Myélome. N Engl J Med, 335(2): p. 91–97. 
28. 
Martinez-Lopez J, et al. (2011) Long-term prognostic significance of response in multiple 
myeloma after stem cell transplantation. Blood, 118(3): p. 529–534. 
29. 
McCarthy, PL, et al. (2017). Lenalidomide Maintenance After Autologous Stem-Cell 
Transplantation in Newly Diagnosed Multiple Myeloma: A Meta-Analysis. Journal of 
Clinical Oncology, 35(29): p. 3279-3289. 
30. 
Newcombe RG. (1998). Interval estimation for the difference between independent 
proportions. Comparison of eleven methods. Statistics in Medicine. 17:873-890 
31.  
Korn EL , and Freidlin B. (in press). Interim monitoring for non-inferiority trials: minimizing 
patient exposure to inferior therapies. Annals of Oncology, doi:10.1093/annonc/mdx788 
 
We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of 
Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Clinical Trials 
Core which provided protocol development and study coordination services. The Siteman Cancer 
Center is supported in part by an NCI Cancer Center Support Grant #P30 CA91842. 

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APPENDIX A: ECOG Performance Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% 
of waking hours. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead. 
 
 
 
 

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APPENDIX B: Cockcroft-Gault Equation 
 
For males: 
Creatinine Clearance = (140-age[years] × weight [kg]) 
OR 
(140–age[years] × weight [kg]) 
72 × (serum creatinine[mg/dL])  
0.81 × (serum creatinine[µmol/L]) 
 
For females: 
Creatinine Clearance = 0.85 (140-age[years] × weight [kg]) OR  0.85 (140-age[years] × weight [kg]) 
72 × (serum creatinine[mg/dL])  
0.81 × (serum creatinine[µmol/L]) 
 
Source:  Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41. 
 
 

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APPENDIX C: New York Heart Association (NYHA) Functional Classification 
 
NYHA Class 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary physical 
activity, e.g., shortness of breath when walking, climbing stairs, etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation 
during ordinary activity 
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary 
activity, e.g., walking short distances (20-100 m).  Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest.  Mostly bedbound 
patients. 
 
 
 

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APPENDIX D: Administration Questionnaire: Consolidation Cycle ___________ 
 
What dose of ixazomib were you prescribed for this cycle of treatment?  
(check all that apply) 
 
4.0 mg on Days 1, 8, & 15 
 
3.0 mg on Days 1, 8, & 15 
 
2.3 mg on Days 1, 8, & 15 
 
None 
 
What dose of lenalidomide were you prescribed for this cycle of treatment?  
(check all that apply) 
 
 
15 mg on Days 1-21 
 
10 mg on Days 1-21 
 
5 mg on Days 1-21 
 
None 
 
What dose of dexamethasone were you prescribed for this cycle of treatment?  
(check all that apply) 
 
 
40 mg on Days 1, 8, & 15 
 
20 mg on Days 1, 8, & 15   
 
8 mg on Days 1, 8, & 15 
 
None 
 
 
Did you take all of the prescribed doses?  (circle one)   
Yes 
 
No 
 
If No, please explain: 
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Patient Initials ______________________________________ Date______________________ 
 
APPENDIX E: Administration Questionnaire: Maintenance Cycle ___________ 

Page 77 of 78 
Protocol Amendment 7; Version: 04/02/2018 
 
What dose of ixazomib were you prescribed for this cycle of treatment?  
(check all that apply) 
 
4.0 mg on Days 1, 8, & 15 
 
3.0 mg on Days 1, 8, & 15 
 
2.3 mg on Days 1, 8, & 15 
 
None 
 
What dose of lenalidomide were you prescribed for this cycle of treatment?  
(check all that apply) 
 
 
15 mg on Days 1-28 
 
10 mg on Days 1-28 
 
5 mg on Days 1-28 
 
5 mg on Days 1-21 
 
None 
 
 
Did you take all of the prescribed doses?  (circle one)   
Yes 
 
No 
 
If No, please explain: 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________ 
 
 
Patient Initials ______________________________________ Date______________________ 
 
 
          
                                 
 
 

Page 78 of 78 
Protocol Amendment 7; Version: 04/02/2018 
APPENDIX F: Correlative Sub-study 
 
Up to 50 patients (approximately 20 in each maintenance arm) will provide informed consent to 
the optional correlative sub-study to study the effect of ixazomib maintenance on the immune 
system.  
 
Approximately 20 ml of peripheral blood in EDTA (pink top) tube(s) will be collected at the 
following time points: 
 
• Prior to beginning consolidation therapy 
• Cycle 1 Day 1 of maintenance (pre-drug) 
• Cycle 4 Day 1 of maintenance (pre-drug) 
 
Instructions for handling and shipment of samples will be provided in the study lab binder. 
Lymphocyte phenotyping and functional assays will be performed at the conclusion of the 
correlative sub-study.