Phase II Randomized Trial of Continuation of Post-Transplant Maintenance With Single-Agent Lenalidomide vs. Consolidation/Maintenance With Ixazomib-Lenalidomide-Dexamethasone in Patients With Residual Myeloma
Phase: PHASE2
Conditions: Plasma Cell Myeloma, Residual Disease
Sponsor: University of Chicago

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CLINICAL STUDY PROTOCOL 
X16047 
UC IRB# 14-0899 
 
Phase II Randomized Trial of Continuation of Post-Transplant Maintenance with Single-Agent 
lenalidomide vs. Consolidation/Maintenance with Ixazomib-lenalidomide-Dexamethasone in 
Patients with Residual Myeloma  
 
 
Indication: 
Post-transplant maintenance  
 
Phase: 
Phase II 
 
 
 
Protocol History 
Original 
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Version 1.2 
Version 2 
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Version 2.6 
01 JUL 2014 
09 JUN 2015 
10 SEP 2015 
14 DEC 2015 
4 APR 2016 
26 OCT 2016 
19 JUN 2017 
14 JUN 2019 
17JUL2019 
25Sept2019 
 
 
Investigator and Coordinating Study Center: 
 
Andrzej Jakubowiak MD, PhD 
The University of Chicago 
5841 South Maryland Ave 
Chicago, IL 60637 
ajakubowiak@medicine.bsd.uchicago.edu 
 
 
 
 
 
This is a multi-institution investigator-initiated study. The principal investigator Dr. Andrzej 
Jakubowiak (who may also be referred to as the sponsor-investigator) is conducting the study 
and acting as the sponsor.  Therefore, the legal/ethical obligations of the principal investigator 
include both those of a sponsor and those of an investigator. 

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PROTOCOL SUMMARY  

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Study Title:  Phase II Randomized Trial of Continuation of Post-Transplant Maintenance with 
Single-Agent lenalidomide vs. Consolidation/Maintenance with Ixazomib-lenalidomide-
Dexamethasone in Patients with Residual Myeloma 
Phase:  II 
Number of Patients:   60 
Study Objectives  
Primary 
• 
To determine the rate of MRD-negative disease by multiparameter flow cytometry (MFC) for 
patients enrolled based on MFC-positivity or by next generation sequencing (NGS) for patients 
enrolled based on NGS-positivity (with MRD-negative disease by MFC at screening), at 12 
months after randomization  
Secondary 
• 
Evidence of response as demonstrated by the improvement of the depth of response by at least 
one category according to IMWG response criteria. (For example, an improvement from very 
good partial response (VGPR) to near complete response (nCR) or better than nCR including 
conversion from CR to MRD negative disease [overall response]) at 6 and 12 months. 
• 
Estimate of progression free survival 
• 
Estimate of overall survival 
• 
Estimate of duration of MRD-negative disease 
• 
Safety and tolerability of experimental arm vs. control 
Tertiary/Exploratory (if applicable) 
• 
Determination of markers of response based on pre-treatment characteristics using methods 
described in correlative research, protocol section 8. 
• 
Evaluation of MRD by gene sequencing method using the Adaptive Biotechnologies platform 
(clonoSEQ®) in parallel with multi-parameter flow cytometry (MFC) 

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Overview of Study Design:   
This is a phase 2, open-label, randomized study in which subjects are enrolled 1:1 control to 
experimental arm stratified by 1) level of response at study entry (in accordance with the IMWG 
uniform response criteria) and 2) risk factors: 
1) Level of response including transplant; response is assessed at study screening for 
this protocol: 
i. <VGPR 
ii. ≥VGPR 
2) Risk Factors at the time of diagnosis: 
i. At least one of the following poor prognostic risk factors (Yes/No): 
1. del-13 (by karyotyping) 
2. hypodiploidy (by karyotyping) 
3. t(4;14) (by FISH) 
4. t(4;16) (by FISH) 
5. t(14;20) (by FISH) 
6. del17p (by FISH) 
7. 1q21 gain (by FISH) 
Dose Schedule  
Each cycle is 28 days for both the Control arm and Experimental Arm. 
  
Cycle 
CONTROL 
EXPERIMENTAL 
Lenalidomide 
Lenalidomide 
Ixazomib 
Dexb 
Cycle 
1 - 4 
Last best tolerated dose 
of either 10 or 15 mg. If 
the 10 mg dose is 
tolerated for 3 cycles, 
either off or on 
protocol, it can be 
escalated to 15 mg per 
dose  
25 mg daily 
First cycle 3 
mg per dose; 
can be 
escalated to 4 
mg per dose 
in cycle 2  
Initially 40 
mg weekly 
(or last best 
tolerated 
dose prior to 
transplant) 
Cycle 
 5 - 12 
Best tolerated dose 
Best tolerated 
dose 
Best tolerated 
dose 
STOP* 
Treatment 
Days 
1 – 28 
1 - 21 
1, 8, 15 
1, 8, 15, 22 
1) * A total of 20 mg of dexamethasone weekly or prednisone equivalent will be permitted to 
improve/prevent  toxicities (ex. rash or GI side effects) 

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Study Population:  Post-Transplant Multiple Myeloma on Lenalidomide Maintenance 
Key Inclusion Criteria: 
1) Patients who completed induction treatment followed by autologous stem cell transplant as 
initial therapy for symptomatic myeloma as per IMWG criteria and are considered for single 
agent Lenalidomide maintenance or initiated single agent Lenalidomide maintenance  
a. Patients will be eligible for enrollment in the first 0-6 months of lenalidomide 
maintenance provided that lenalidomide maintenance has been initiated 
within 6 months after transplant as per standard of care. 
i. Patients do not have to be on Lenalidomide at the time of study 
consent. 
b. Patients already in lenalidomide must be receiving lenalidomide 10 mg or 15 
mg (as per CALGB trial, McCarthy et al., N Eng J Med, 2012) and be able to 
tolerate dose escalation to 25 mg daily. 
c. Patients receiving off protocol lenalidomide maintenance cannot exceed6 
months post-transplant 
d. A one week break from off protocol lenalidomide is suggested, prior to 
initiating treatment on the study 
i. Any delays >7 days to align treatment with the start of Cycle 1 Day 1, 
of either arm, must be discussed with the PI. 
e. Patients who completed tandem transplantation will be eligible for enrollment 
2) No evidence of progressive disease on lenalidomide 
3) Evidence of minimal residual disease at the time of screening defined as at least MRD-
positive disease  
a. A primary method of evaluation of MRD is Multi-parameter Flow Cytometry 
(MFC) performed at University of Chicago 
b. Patients who have negative MRD by Multi-Parameter Flow Cytometry (MFC) but 
have residual original monoclonal protein by serum or urine immunofixation may be 
eligible if they are found to have MRD-positive disease by Next Generation 
Sequencing (NGS). 
c. If patient is receiving lenalidomide, any delays required to align treatment with the 
start of Cycle 1 of either arm, must be discussed with the PI. 
4) Bone marrow specimen will be required at study entry; available DNA sample will be used 
for calibration step for MRD evaluation by gene sequencing 
5) Males and females ≥ 18 years of age 
6) Life expectancy of more than 3 months 
7) ECOG performance status of 0-2 
8) Adequate hepatic function, with bilirubin ≤1.5 x ULN and aspirate aminotransferase (AST) 
and alanine aminotransferase (ALT) ≤ 3 xULN 
9) ANC ≥1.0 x 109/L, hemoglobin ≥8 g/dL, platelet count ≥75 x 109/L. 
10) Calculated creatinine clearance (by Cockcroft-Gault) ≥50 ml/min or serum creatinine below 
2 g/dL (section 13.2) 
11) 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. 
12)  Female patients who: 
a. Are postmenopausal for at least 1 year before the screening visit, OR 
b. Are surgically sterile, OR 

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c. If they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing the informed consent form 
through 90 days after the last dose of study drug, OR 
d. 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, sympto-
thermal, post-ovulation methods] and withdrawal are not acceptable methods of 
contraception.) 
13) Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree to one of 
the following: 
a. Agree to practice effective barrier contraception during the entire study treatment 
period and through 90 days after the last dose of study drug, OR 
b. 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, sympto-
thermal, post-ovulation methods] and withdrawal are not acceptable methods of 
contraception.) 
Exclusion 
14) Evidence of progressive disease on lenalidomide maintenance as per IMWG criteria 
15) Patients who have already started or received multi-drug consolidation regimen post-
transplant except for patients receiving up to 6 months of single agent lenalidomide 
maintenance 
16) Longer than 12 months since the initiation of induction therapy at the  of start of 
lenalidomide maintainance 
17) Prior progression after initial therapy.  
a. Subjects, whose therapy changed due to suboptimal response, intolerance, etc., 
remain eligible, provided they do not meet criteria for progression.  
b. No more than two regimens will be allowed excluding dexamethasone alone. 
18) Diarrhea > Grade 1 in the absence of anti-diarrheals 
19) Central Nervous System involvement 
20) Female patients who are lactating or have a positive serum pregnancy test during the 
screening period.  
21) History of allergy to mannitol 
22) Major surgery within 14 days before enrollment. 
23) Radiotherapy within 14 days before randomization. If the involved field is small, 7 days will 
be considered a sufficient interval between treatment and administration of the ixazomib. 
24) Evidence of current uncontrolled cardiovascular conditions such as hypertension, cardiac 
arrhythmias, symptomatic congestive heart failure or New York Heart Association Stage III 
and IV, or unstable angina, or myocardial infarction within the past 6 months. 
25) Rate-corrected QT interval of electrocardiograph (QTc) > 470 msec on a 12-lead ECG 
during screening 
26) Uncontrolled diabetes 
27) Acute infection requiring systemic anti-infectives, antivirals, or antifungals within two 
weeks prior to first dose 
28) Systemic treatment, within 14 days before the first dose of ixazomib, with strong CYP3A 
inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use 
of Ginkgo biloba or St. John’s wort. 
29) Ongoing or active systemic infection, active hepatitis B or C virus infection, or known 
human immunodeficiency virus (HIV) positive. 
30) Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol. 
31) Known allergy to any of the study medications, their analogues, or excipients in the various 
formulations of any agent. 

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32) Known GI disease or GI procedure that could interfere with the oral absorption or tolerance 
of ixazomib including difficulty swallowing. 
33) Diagnosed or treated for another malignancy within 2 years before study enrollment or 
previously diagnosed with another malignancy and have any evidence of residual disease.  
Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if 
they have undergone complete resection. 
34) Patient has ≥ Grade 3 peripheral neuropathy or Grade 2 with pain on clinical examination 
during the screening period. 
35) Participation in other clinical trials, with other investigational agents not included in this 
trial, within 30 days of the start of this trial and throughout the duration of this trial.  
Duration of Study:  
Subjects will be treated on protocol for 12 months or until disease progression or if lenalidomide 
and/or ixazomib are permanently discontinued due to intolerance before the end of 1year. Patients 
who complete 12 months of protocol treatment will be taken off protocol with management as per PI 
discretion and standards of care but will continue to be followed for progression, if the patient did 
not progress on study treatment, and survival.  
 
 

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STUDY OVERVIEW DIAGRAM 
 

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SCHEDULE OF EVENTS    
Assessment 
Screening2 
Cycles 1-12 
EOT 
Long-
term 
follow-up 
Day 
-42 to -1 
1 
8 
15 
22 
Informed Consent+♥ 
X 
 
 
 
 
 
 
Medical History / Treatment History1 
X 
 
 
 
 
 
 
Skeletal Survey 
X 
 
 
 
 
 
 
ECG3 
X 
 
 
 
 
X 
 
Physical Exam / ECOG4, 5 
X 
X 
 
 
 
X 
 
Vital Signs6 
X 
X 
 
 
 
X 
 
Height7, Weight, BSA 
X 
X 
 
 
 
X 
 
24-hour urine8 
X 
X 
 
 
 
X 
 
Urinalysis 
X 
 
 
 
 
X 
 
C- Reactive Protein 
X 
 
 
 
 
 
 
Hematology9 
X 
X 
[X] 
[X] 
 
X 
 
Serum Chemistry10 
X 
X 
[X] 
[X] 
 
X 
 
Pregnancy Test11, 12 
X 
X 
 
 
 
X 
 
Disease Assessment 
 
 
 
 
 
 
X20 
β2-microglobulin 
X 
 
 
 
 
 
 
SPEP, UPEP13 
X 
X 
 
[X] 
 
X 
 
BM Aspirate/biopsy, cytogenetics, 
FISH14 
X 
 
 
 
 
X 
 
Quantitative Immunoglobulins 
X 
X 
 
[X] 
 
X 
 
SFLC 
X 
X 
 
[X]15 
 
X 
 

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Assessment 
Screening2 
Cycles 1-12 
EOT 
Long-
term 
follow-up 
Day 
-42 to -1 
1 
8 
15 
22 
Neurological Assessment16 
X 
X 
 
 
 
X 
 
QOL Assessment16 
X 
X 
 
 
 
X 
 
Correlative Samples17 
X 
X 
 
 
 
X 
 
Sample for MRD Analysis18, ∞ 
X 
 
 
 
 
X 
 
Adverse Events19 
X 
 
Control Arm 
 
 
 
 
 
 
 
Lenalidomide21,22, 28 
 
Continuous Days 1-28 
X26 
X26 
Experimental Arm 
 
 
 
 
 
 
 
Lenalidomide21,23, 28 
 
Continuous Days 1-21 
 
X26 
X26 
Ixazomib24 
 
X 
X 
X 
 
 
 
Dexamethasone25 
 
X 
X 
X 
X 
 
 
Survival and Evaluation of Second 
Primary malignancies 
 
 
 
 
 
 
X27 
+ 
Documented informed consent must be obtained prior to any screening procedures but can be obtained prior to the screening window of 42 days 
♥ 
Informed consent is valid for 42 days – if the patient has not been enrolled/randomized within the screening window, re-consent must be obtained 
prior to submitting the registration packet for review 
* 
Variations of ± 3 days of the scheduled visit are permitted 
∞ 
Using diagnostic bone marrow samples for the Adaptive ID (calibration) testing is preferred as these will have the highest disease burden. If the 
calibration is successful, please submit the screening bone marrow samples to determine MRD status prior to study entry. If DNA identification 
from the diagnostic sample fails, procure additional slides from the screening marrow as these can be used for both calibration and MRD tracking. 
Contact the UC Multi-Site Coordinator prior to submitting additional samples, if the initial ID test fails. 
[X] Only as clinically indicated 
2) Includes neuropathy history and documentation of the CTCAE grade if peripheral neuropathy is present at baseline.  

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Assessment 
Screening2 
Cycles 1-12 
EOT 
Long-
term 
follow-up 
Day 
-42 to -1 
1 
8 
15 
22 
3) May be within 42 days of planned treatment start.  Includes: lateral radiograph of the skull, anteroposterior and lateral views of the spine, and 
anteroposterior views of the pelvis, ribs, femora, and humeri. Skeletal surveys performed outside of the 42-day window may be considered for 
inclusion 6 or 8 weeks prior to randomization.  Please contact the Lead Principal Investigator and/or/CRA on a case-by-case basis. 
4) 12-lead ECG, including QTc interval completed on local machine. 
5) For Day 1 of cycle 1, screening results may be used if within 7 days of treatment start.   
6) Complete physical exam (including vital signs [systolic and diastolic blood pressure, respiration, pulse, and oral temperature], weight, calculation of 
body surface area [BSA] & ECOG score) required at screening & Day 1 of each cycle. 
7) Systolic and diastolic blood pressure, pulse, respiration, temperature day 1 of each cycle, EOT visit and as clinically indicated.   
8) Height required at screening only 
9) 24 hour urine total protein, urine protein electrophoresis (UPEP), and urine protein immunofixation. For subjects whose disease is being monitored 
through UPEP, additional post baseline 24-hour urine collections are required as indicated 
10) On day 1 of each cycle and EOT visit is required, and as clinically indicated at other time-points. Hemoglobin, WBC with complete differential, 
platelet count, absolute lymphocyte and absolute neutrophil counts.  Results must be reviewed before dosing. 
11) On day 1 of each cycle and EOT visit is required, and as clinically indicated at other time-points. Full serum chemistry panel at screening, day 1 of 
each cycle and at EOT visit: sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, total protein, albumin, calcium, total bilirubin, 
alkaline phosphatase, ALT, AST, LDH, and CRP.  Abbreviated serum chemistry panel should be included as necessary.  
12) Pregnancy tests for females of childbearing potential.  A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not had a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally post-menopausal for at least 24 consecutive months (i.e., menses within the 
preceding 24 months)  See Appendix F of protocol for details.    
13) Pregnancy tests must occur within 10-14 days and again within 24 hours prior to prescribing lenalidomide (prescriptions must be filled within 7 
days.  FCBP with regular or no menstruation must have a pregnancy test weekly for the first 28 days and then every 28 days while on therapy 
(including breaks in therapy); at discontinuation of lenalidomide and at Day 28 post the last dose of lenalidomide.  Females with irregular 
menstruation must have a pregnancy test weekly for the first 28 days and then every 14 days while on therapy (including breaks in therapy), at 
discontinuation of lenalidomide and at Day 14 and Day 28 post the last dose of lenalidomide (see Appendix 13.6). 
14) Serum protein electrophoresis and urine protein electrophoresis (the latter only for those whose disease is being followed by UPEP).  Subjects with 
baseline urine protein greater than 200 mg/24 hours must have a UPEP to confirm VGPR or better.  Obtain blood for M-protein levels measured by 
SPEP or quantitative immunoglobulins for those subjects in whom SPEP/UPEP are felt to be unreliable (IgA type multiple myeloma), depending 
upon which studies were positive at baseline. Response will be assessed comparing day 1 of each cycle values to the respective baseline (pre-
induction treatment) values for each subject. 

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Assessment 
Screening2 
Cycles 1-12 
EOT 
Long-
term 
follow-up 
Day 
-42 to -1 
1 
8 
15 
22 
15) Bone marrow aspirate and biopsy – quantify % myeloma cell involvement; bone marrow sample for cytogenetics and fluorescent in situ 
hybridization (FISH). Please note that cytogenetic profile at the time of diagnosis will be used for patient stratification at study entry. Bone marrow 
aspirate and biopsy should be performed at screening, end of 12 cycles/end of treatment and at any time that a bone marrow is performed as standard 
of care.  If CR is recorded between screening and EOT, a Bone Marrow Biopsy can be indicated as per standards of care to be performed at 6 
months from randomization (with acceptable window 3-9 months; for 6 months response assessment). However, if CR is suspected within 3 months 
of EOT, it is acceptable to wait for the EOT BM biopsy. Repeat bone marrow biopsy/aspirate if CR is suspected and as appropriate to confirm 
achievement of sCR, CR, or nCR (aspirate only—biopsy not required).  If institution has established flow-based multi-color study for minimal 
residual disease (MRD), this evaluation should include MRD evaluation. Bone marrow biopsy/aspirate performed outside of the 42-day window 
may be considered for inclusion.  Please contact the Lead Principal Investigator and/or the CRA on a case-by-case basis.   
16) Serum Free Light Chains repeated only to confirm response. 
17) Screening and Day 1 of every cycle. Includes neurologic exam (to detect peripheral neuropathy and/or changes in pre-existing neuropathy) and 
examination of clinical AEs indicative of neuropathy. Collect FACT/GOG neurotoxicity questionnaire and QOL assessment at each time point 
above. 
18) For patients who sign additional consent: peripheral blood and bone marrow aspirate samples collected at screening, end of treatment, and any time 
after randomization that CR or better is suspected. Buccal mucosa swab will be collected at screening only. 
19) All patients are required to have a sample for MRD collected at screening, at the End of Treatment visit, and at any other time a Bone Marrow 
biopsy/aspirate is collected as SOC. Additionally, FFPE or BMA slides from diagnosis will be required for calibration of MRD by NGS for all 
patients. If CR is recorded between screening and EOT, a Bone Marrow Biopsy can be indicated. However, if CR is suspected within 3 months of 
EOT, it is acceptable to wait for the EOT BM biopsy. It is expected that samples will be collected at a minimum of two time-points for each patient. 
Refer to lab manual for collection and shipping instructions. Central analysis includes MRD by multi-parameter flow cytometry and MRD by gene 
sequencing. 
20) AEs will be collected from the time of signing informed consent to 30 days following the last dose of treatment. Please refer to section 9 for specific 
collection requirements. 
21) Assessment for disease progression in subjects who did not progress during treatment.  At least every 3 months (+/- 30 days) for 2 years from safety 
follow-up visit (which must be 28days (+/- 3 days) post-last study treatment). 
22) lenalidomide must be prescribed through and in compliance with the lenalidomide REMS™ program of Celgene Corporation.  Prescriptions must be 
filled within 7 days.  Consideration should be given to prescribing lenalidomide 5 to 7 days in advance of Day 1 of each cycle to allow time for 
required patient and prescriber surveys, and drug shipment to patient.  Any unusedlenalidomide will be counted and documented by each site.   
23) Control Arm: Lenalidomide should continue at best tolerated dose of either 10 mg or 15 mg on days 1-28. If the 10 mg dose is tolerated for three 
cycles, it can be escalated to 15 mg per dose. 

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Assessment 
Screening2 
Cycles 1-12 
EOT 
Long-
term 
follow-up 
Day 
-42 to -1 
1 
8 
15 
22 
24) Experimental Arm: lenalidomide dosing Days 1-21. Cycle 1-4 lenalidomide will be administered at 25 mg daily. Cycles 5-12 lenalidomide will 
continue at best tolerated dose days 1-21. lenalidomide should be taken in the evening at approximately the same time each day. 
25) Cycles 1-4: Ixazomib at 3-4 mg Days 1, 8, 15. Cycles 5+ Ixazomib at best tolerated dose on Days 1, 8, 15. Ixazomib should be taken on an empty 
stomach or at least 1 hour before or 2 hours after a meal. 
26) Days 1, 8, 15 and 22, dexamethasone should be taken with a meal, and approximately 2 hours before Ixazomib on days they coincide. At Cycles 1-4, 
dexamethasone will be administered at 40 mg. Dexamethasone will be discontinued at the end of cycle 4.  
27) Single-agent lenalidomide maintenance therapy is recommended using last tolerated dose of lenalidomide for 21 days in 28 day cycles after 
completion of protocol treatment. 
28) Patients will be followed for survival and development of any new cancers, at least every 3 months for 2 years form last treatment.  Reports of any 
death should include date of death and specific cause (disease under study or specify other cause). 
29) If patient is currently receiving lenalidomide, any delays required to align treatment with the start of Cycle 1 of either arm, must be discussed with 
the PI 
 

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TABLE OF CONTENTS 
STUDY OVERVIEW DIAGRAM .......................................................................................... 8 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS............................................ 17 
1. BACKGROUND AND STUDY RATIONALE ............................................................... 21 
1.1 Scientific Background .................................................................................................. 21 
1.1.1 Disease Under Treatment ...................................................................................... 21 
1.1.2 Ixazomib (MLN9708) ........................................................................................... 21 
1.2 Preclinical Experience ................................................................................................. 21 
1.3 Clinical Experience ...................................................................................................... 21 
1.4 Pharmacokinetics and Drug Metabolism ..................................................................... 23 
1.5 Clinical Trial Experience Using the Oral Formulation of Ixazomib ........................... 24 
1.6 Relapsed and/or Refractory Multiple Myeloma .......................................................... 30 
1.7 Newly Diagnosed Multiple Myeloma (NDMM) ......................................................... 31 
1.8 Clinical Trial Experience Using the Intravenous Formulation of Ixazomib ............... 31 
1.9 Study Rationale ............................................................................................................ 31 
1.10 Potential Risks and Benefits ...................................................................................... 34 
2. STUDY OBJECTIVES ...................................................................................................... 35 
2.1 Primary Objectives ...................................................................................................... 35 
2.2 Secondary Objectives .................................................................................................. 35 
2.3 Tertiary/Exploratory Objectives (if applicable) .......................................................... 35 
3. STUDY ENDPOINTS ....................................................................................................... 35 
3.1 Primary Endpoints ....................................................................................................... 35 
3.2 Secondary Endpoints ................................................................................................... 37 
3.3 Tertiary/Exploratory Endpoints ................................................................................... 37 
4. STUDY DESIGN............................................................................................................... 37 
4.1 Overview of Study Design ........................................................................................... 37 
4.2 Study Procedures ......................................................................................................... 38 
4.2.1 Screening Procedures ............................................................................................ 38 
4.2.2 Treatment Phase Procedures ................................................................................. 40 
4.2.3 End of Treatment Procedures ................................................................................ 42 
4.3 Number of Patients ...................................................................................................... 43 
4.4 Duration of Study ......................................................................................................... 43 
4.5 Response Evaluation .................................................................................................... 44 
5. STUDY POPULATION .................................................................................................... 44 
5.1 Inclusion Criteria ......................................................................................................... 44 
5.2 Exclusion Criteria ........................................................................................................ 46 
6. REGISTRATION PROCESS ............................................................................................ 48 
7. STUDY DRUG .................................................................................................................. 49 
7.1 Description of Investigational Agents ......................................................................... 49 
7.2 Study Drug Administration .......................................................................................... 50 
7.2.1 Experimental Arm ................................................................................................. 50 
7.2.2 Control Arm .......................................................................................................... 52 
7.3 Dose-Modification Guidelines ..................................................................................... 53 
7.3.1 Recommended Criteria for Beginning or Delaying a Subsequent Treatment Cycle 
& Dose Modifications for Treatment Associated Toxicity ............................ 54 

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7.4 Mandatory Concomitant Medications ......................................................................... 62 
7.4.1 Recommended Concomitant Medications ............................................................ 62 
7.4.2 Excluded Concomitant Medications ..................................................................... 62 
7.4.3 Permitted Concomitant Medications and Procedures ........................................... 63 
7.5 Precautions and Restrictions ........................................................................................ 64 
7.6 Management of Clinical Events ................................................................................... 65 
7.7 Investigational Product ................................................................................................ 68 
7.7.1 Ixazomib Preparation, Reconstitution, and Dispensing ........................................ 68 
7.7.2 Lenalidomide ........................................................................................................ 70 
7.7.3 Dexamethasone ..................................................................................................... 70 
7.8 Study Compliance ........................................................................................................ 71 
7.9 Treatment Assignment ................................................................................................. 71 
7.10 Termination of Treatment and/or Study Participation ............................................... 72 
8. STATISTICAL AND QUANTITATIVE ANALYSES .................................................... 73 
8.1 Statistical Methods ....................................................................................................... 73 
8.1.1 Determination of Sample Size .............................................................................. 74 
8.1.2 Randomization and Stratification ......................................................................... 74 
8.1.3 MRD Evaluations .................................................................................................. 75 
8.1.4 Populations for Analysis ....................................................................................... 75 
8.1.5 Demographic and Baseline Characteristics........................................................... 76 
8.1.6 Efficacy Analysis .................................................................................................. 76 
8.1.7 Safety Analysis ..................................................................................................... 77 
9. CORRELATIVE SAMPLES ............................................................................................. 78 
10. ADVERSE EVENTS ....................................................................................................... 78 
10.1 Adverse Event Definition .......................................................................................... 78 
10.2 Causality .................................................................................................................... 79 
10.3 Adverse Event Reporting Procedures ........................................................................ 79 
10.4 Serious Adverse Event ............................................................................................... 81 
10.4.1 Serious Adverse Event Definition ...................................................................... 81 
10.4.2 Serious and Unexpected Suspected Adverse Reaction (SUSAR) ...................... 82 
10.4.3 Procedures for Reporting Serious Adverse Events ............................................. 83 
10.5 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ........ 87 
10.6 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ........ 87 
11. ADMINISTRATIVE REQUIREMENTS ....................................................................... 88 
11.1 Product Complaints .................................................................................................... 88 
12. REGULATORY OBLIGATIONS................................................................................... 88 
12.1 Informed Consent ...................................................................................................... 88 
12.2 Compliance with Laws and Regulations ................................................................... 89 
12.3 Pre-Study Documentation Requirements ................................................................... 90 
12.4 Annual IRB Renewals, Continuing Review and Final Reports ................................. 90 
12.5 Subject Confidentiality .............................................................................................. 90 
12.6 Protocol Amendments and Study Termination .......................................................... 91 
12.7 Study Documentation and Archive ............................................................................ 91 
12.7.1 Source Documentation ........................................................................................ 91 
12.7.2 Record Retention ................................................................................................ 92 
12.7.3 Case Report Form Completion ........................................................................... 92 

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12.7.4 Archival of Records ............................................................................................ 92 
12.7.5 Clinical Monitoring Procedures .......................................................................... 93 
12.7.6 Obligations of Study Site Investigators .............................................................. 94 
12.7.7 Protocol Deviations ............................................................................................. 94 
12.7.8 Data Safety and Monitoring ................................................................................ 94 
12.7.9 Quality Assurance & Auditing ............................................................................ 95 
13. REFERENCES ................................................................................................................ 96 
14. APPENDICES ................................................................................................................. 98 
14.1 Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status ......... 98 
14.2 Cockcroft-Gault Equation .......................................................................................... 99 
14.3 Response Criteria for Multiple Myeloma ................................................................ 100 
14.4 FACT/GOG-Neurotoxicity Questionnaire, Version 4.0 .......................................... 103 
14.5 Quality of Life Assessment Tool ............................................................................. 104 
14.6 Lenalidomide Risk Evaluation and Mitigation Strategy (REMS)™ Program ........ 105 
14.7Lenalidomide Prescribing Information 2013 ............................................................ 106 
 

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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
Abbreviation 
Term 
5-HT3 
5-hydroxytryptamine 3 serotonin receptor 
AE 
adverse event 
ALL 
acute lymphoblastic leukemia 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myelogenous leukemia 
ANC 
absolute neutrophil count 
API 
active pharmaceutical ingredient 
aPTT 
activated partial thromboplastin time 
Ara-C 
Cytarabine 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
AUC24 hr 
area under the plasma concentration versus time curve from zero to 24 hours 
AUCinf 
area under the plasma concentration versus time curve from zero to infinity 
AUCτ 
area under the plasma concentration versus time curve from zero to next dose 
BCRP 
breast cancer resistance protein 
βhCG 
beta-human chorionic gonadotropin 
BID 
bis in die; twice a day 
BM 
bone marrow 
BSA 
body surface area 
BUN 
blood urea nitrogen 
BZD 
Benzodiazepines 
CBC 
complete blood count 
CCTO 
Cancer Clinical Trials Office (University of Chicago) 
CFR 
Code of Federal Regulations 
CL 
clearance, IV dosing 
CLP 
plasma clearance 
CLTotal 
total clearance 
Cmax 
single-dose maximum (peak) concentration   
CNS 
central nervous system 
CO2 
carbon dioxide 
CR 
complete response   

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Abbreviation 
Term 
CRM 
continual reassessment method 
CRP 
C-reactive protein 
CSF-1R 
colony-stimulating factor 1 receptor 
CT 
computed tomography 
Ctrough 
single-dose end of dosing interval (trough) concentration 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DLT 
dose-limiting toxicity 
DME 
drug metabolizing enzymes 
DNA 
deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ELISA 
enzyme-linked immunosorbent assay 
EOS 
End of Study (visit) 
EOT 
End of Treatment (visit) 
EU 
European Union 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony stimulating factor 
GGT 
gamma glutamyl transferase 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practices 
GM-CSF 
granulocyte macrophage-colony stimulating factor 
GMP 
Good Manufacturing Practice 
Hb 
Hemoglobin 
Hct 
Hematocrit 
HDPE 
high-density polyethylene 
hERG 
human ether-à-go-go related gene 
HIV 
human immunodeficiency virus 
HNSTD 
highest nonseverely toxic dose 
IB 
Investigator’s Brochure 
IC50 
concentration producing 50% inhibition 

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Abbreviation 
Term 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IRB 
institutional review board 
ITT 
intent-to-treat 
IV 
intravenous; intravenously 
IVRS 
interactive voice response system 
Ki 
inhibition constant 
KPS 
Karnofsky Performance Status 
LDH 
lactate dehydrogenase 
LFT 
liver function test(s) 
MedDRA 
Medical Dictionary for Regulatory Activities 
Millennium 
Millennium Pharmaceuticals, Inc., and its affiliates 
MRI 
magnetic resonance imaging 
MRU 
medical resource utilization 
MTD 
maximum tolerated dose 
MUGA 
multiple gated acquisition (scan) 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NPO 
nothing by mouth 
NYHA 
New York Heart Association 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD 
progressive disease (disease progression) 
Pgp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PO 
per os; by mouth (orally) 
PR 
partial response  
PRO 
patient-reported outcome 
PSA 
prostate-specific antigen 
QD 
quaque die; each day; once daily 
QID 
quater in die; 4 times a day 
QOD 
quaque altera die; every other day 
QOL 
quality of life 

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Abbreviation 
Term 
QTc 
rate-corrected QT interval (millisec) of electrocardiograph 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SC 
Subcutaneous 
SD 
stable disease 
SmPC 
Summary of Product Characteristics 
t1/2 
terminal disposition half-life 
TGI 
tumor growth inhibition 
Tmax 
single-dose time to reach maximum (peak) concentration 
UK 
United Kingdom 
ULN 
upper limit of the normal range 
US 
United States 
Vz 
volume of distribution in the terminal phase 
WBC 
white blood cell 
WHO 
World Health Organization 
 

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1.    
BACKGROUND AND STUDY RATIONALE 
1.1    Scientific Background 
1.1.1    Disease under Treatment 
Multiple myeloma is a clonal neoplastic proliferation of plasma cells affecting 19,900 US 
patients each year [1]. Multiple myeloma is characterized by anemia, bone destruction, 
monoclonal gammopathy, renal failure, hypercalcemia and increased susceptibility to infections. 
The disease is systemic, and chemotherapy is indicated for management of symptomatic 
myeloma. Current front-line treatments include combination chemotherapy with regimens using 
melphalan (Alkeran®), bortezomib (Velcade®), thalidomide (Thalomid®), and lenalidomide 
and their combinations with and without corticosteroids. In addition, two agents, pomalidomide 
(Pomalyst®) and carfilzomib (Kyprolis®), have been recently approved in the treatment of 
relapsed disease. Younger patients are consolidated with high-dose therapy (ablative 
chemotherapy or radiation) with autologous stem cell transplantation (ASCT). Although 
improvements in progression free survival and overall survival have occurred in the past 5 years, 
even with the best available approved agents, 10-30% of patients fail to respond to the primary 
therapy, and almost all subjects eventually relapse, with a median overall survival of 44.8 
months. [2] 
1.1.2         Ixazomib (MLN9708)  
1.2    Preclinical Experience 
Please refer to the current ixazomib Investigator’s Brochure (IB) and Safety Management 
Attachment (SMA). 
1.3    Clinical Experience 
Ixazomib has been evaluated as an oral single agent in Phase 1 studies that have included 
patients with advanced solid tumors, lymphoma, relapsed/refractory MM (RRMM), and relapsed 
or refractory light-chain (AL) amyloidosis, with 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 III trials in newly diagnosed MM (NDMM) (C16014) and 
RRMM (C16010) patient populations are currently evaluating ixazomib in combination with 
lenalidomide and Dexamethasone (Rd) versus placebo/R/d. Both trials compare 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 

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include evaluation of drug-drug interactions with ketoconazole and rifampin, effect of food, and 
oral bioavailability. Studies evaluating the safety and pharmacokinetics (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 exanthemas 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%), 

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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 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.   
1.4   Pharmacokinetics and Drug Metabolism 
Clinical IV and PO PK data shows 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 [3]. 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 [4]. 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. 

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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. 
 
1.5    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, non-hematologic cancers, and lymphoma) have been treated in studies evaluating 
the oral ixazomib formulation.  These patients have been treated with differing doses of 
ixazomib either as a single-agent treatment (in 201 patients) or in combination with 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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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 Rd 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 Rd 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 Rd versus placebo-Rd 
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 Rd 
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 Rd 
ixazomib 4.0 mg or matching placebo on Days 1, 
8, and 15, plus Rev 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; Rd = 
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. 
 
 
 

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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 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, non-
hematologic 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), 
are 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) 
Diarrhea 
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) 
Edema peripheral 
27 (13) 
Asthenia 
31 (15) 
Nervous system disorders 
92 (46) 
Headache 
29 (14) 
Dizziness 
26 (13) 

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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 (%) 
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) 
Anemia 
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) 
Dyspnea 
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) 
Diarrhea 
81 (47) 
Vomiting 
51 (29) 
Constipation 
57 (33) 
General disorders and administration site 
conditions 
132 (76) 
Fatigue 
76 (44) 
Pyrexia 
39 (23) 
Edema 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) 
Hypokalemia 
34 (20) 
Blood and lymphatic system disorders 
88 (51) 
Thrombocytopenia 
49 (28) 
Anemia 
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) 
Dyspnea 
26 (15) 

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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 (%) 
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 [5], non-Hodgkin’s disease, Hodgkin’s disease [6], relapsed and/or 
refractory multiple myeloma [RRMM; 7; 8], relapsed or refractory systemic light chain 
amyloidosis [RRAL; 9], and newly diagnosed multiple myeloma [NDMM; 10; 11; 12]) to date. 
Though additional data are needed to characterize the clinical benefit of this drug, the emerging 
data supports the ongoing development of ixazomib. 
1.6    Relapsed and/or Refractory Multiple Myeloma 
The early development of ixazomib in patients with RRMM involved 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.[13, 14]  
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.[15, 16,17]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 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 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.  
1.7    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 (Rd) 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.  
1.8      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). 
1.9 
Study Rationale 
In the recent years, emerging evidence demonstrates that increased control of multiple myeloma, 
and possibly a functional cure in some patients, may be achieved if we deliver extended 
treatment to patients with newly diagnosed disease. In addition, as more sensitive methods for 
the assessment of minimal residual disease (MRD) have been developed, including allele-
specific oligonucleotide polymerase chain reaction (ASO-PCR), multiparameter flow cytometry 

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(MFC), and more recently gene sequencing, MRD negativity is evolving as the new goal of 
therapy and possibly a new surrogate marker for progression free survival (PFS) and overall 
survival (OS). For example, in a multivariate analysis of 295 newly diagnosed MM patients, 
MRD negativity at 100 days post-transplant was the most important, independent prognostic 
factor for PFS and OS. [19] 
In addition, there is vast data demonstrating that post-transplant maintenance improves 
outcomes. Most recently, two studies have shown that post-transplant maintenance with single-
agent lenalidomide improves PFS and in one of these two studies OS. [20,21] Based on these 
results, post-transplant maintenance with lenalidomide has now been incorporated into the MM 
treatment algorithm in the United States. Improved outcomes in the maintenance phase have 
been also shown with single agent thalidomide and bortezomib. [22, 23, 24] Furthermore, there 
is also emerging evidence that two- or three-drug regimens are active in post-transplant setting. 
For example, bortezomib, thalidomide, dexamethasone (VTD) when given every 3 months, was 
reported to prolong PFS when compared to thalidomide alone, with surprisingly significant 
benefit for standard risk but not poor risk patients. [25] In addition, there is also mounting 
evidence that post-transplant consolidation, given in addition to or prior to maintenance, deepens 
the response and likely contributes to improved PFS, particularly with 3-drug regimens including 
proteasome inhibitor (PI) and immunomodulatory drug (IMiD). [26, 27] 
Extended treatment with bortezomib, lenalidomide, dexamethasone (RVD) and carfilzomib, 
lenalidomide, dexamethasone (CRd) resulted in deeper responses over time and likely 
contributed to the excellent results with CR+nCR rate of 57% and 67%, respectively (phase II) 
and an estimated 18-month and 24-month PFS of 75% and 92%, respectively. In a recently 
presented follow-up of the CRd study, the rate of MRD negativity improved by about 20% 
between 8 and 16 months of CRd maintenance. [28] Furthermore, it was demonstrated that 
extended, 2-year treatment with three drug combinations (CRd and RVd), which included low-
dose dexamethasone is well tolerated, with limited and mostly mild toxicity, including limited 
dexamethasone-related toxicity. [28] 
Taken together, these studies shows that combinations of a PI and IMiD may be superior 
compared to single agents in the consolidation/maintenance phase and results in improved depth 
of response and prolonged PFS and OS. The advent of active oral PIs, and, in particular, the 
proven efficacy of ixazomib (MLN9708) in combination with lenalidomide and low dose 
dexamethasone [10, 11]), yields the possibility of exploring this strategy without the limitations 
that chemotherapy infusions pose over extended treatment both in convenience and increased 
toxicity. 

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Lenalidomide maintenance is most commonly used in the post-transplant setting and considered 
standard of care in the United States. Approximately 30% of patients who initiate lenalidomide 
maintenance are in CR post-transplant (McCarthy et al, N Eng J Med, 2012). Of these patients, 
approximately 70% would be expected to have MRD negative status. [19] However, a significant 
proportion of patients are not in CR, and consequently with residual MRD and therefore at 
higher risk for earlier relapse and shorter survival. [19] Based on this observation, we propose to 
evaluate the impact of consolidation and extended maintenance with an all oral combination of 
ixazomib, lenalidomide, and low dose dexamethasone (IRD) in patients who are already on 
single agent lenalidomide maintenance but who have persistent residual disease, a population 
that is in need of further improvement in their disease outcome. [19] The aim of this proposal is 
to provide preliminary evidence that IRD will statistically improve the rate of MRD-negative 
disease and the depth of response in the post-transplant setting compared to the rate observed in 
patients who continue single agent lenalidomide. Since there is vast evidence that the rate of CR 
and in particular the rate of MRD-negative disease translates into longer PFS, the study is 
anticipated to generate preliminary information for further, more definite exploration of this 
strategy. 
The rationale for adding a PI (ixazomib) to lenalidomide in this subset of patients is discussed 
above. The rationale for adding low dose dexamethasone is three-fold: (1) 3-drug combinations 
of PI, IMiD, and low dose dexamethasone, and in particular IRD have a proven track record of 
efficacy, while only limited information is available for combination of lenalidomide with PI, 
with evidence that it could have inferior efficacy without dexamethasone [29]; (2) low dose 
dexamethasone has previously been shown to be well tolerated with long term use [30]; (3) 
dexamethasone appears to improve the tolerability of ixazomib, particularly by reducing the 
incidence of rash and gastrointestinal symptoms that are associated with this agent [10, 16]. 
Subjects are randomized in a 1:1 ratio between IRd vs. R with both arms undergoing 12 months 
of treatment to balance the study objectives and risk of toxicities. This duration of treatment is 
supported by prior observations that the median time to the achievement sCR and MRD-negative 
status is approximately12-13 months of treatment and that the plateau of sCR and MRD is 
reached at about 16-18 months from the start of the treatment. [28] All subjects enrolled into the 
trial will already be on a post-transplant lenalidomide maintenance regimen such that the 
protocol period of 12 months will prove to be sufficient for determination of the primary 
objective and for the duration that limits increased risks of toxicities. 
An extended treatment with lenalidomide in post-transplant setting may raise concerns for 
increased risk of second primary malignancies (SPM). While the risk of SPM has been reported 
with lenalidomide maintenance, in a recent large meta-analysis by Palumbo et al, the risk of 

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SPM was greatest in patients in the context of recent melphalan, particularly in patients who 
received oral melphalan in addition to lenalidomide. Moreover, in the post-transplant setting, 
mostly initial exposure to lenalidomide accounted for SMPs, and there is no evidence to date that 
an extended treatment with lenalidomide beyond an initial period of 1 year increases this rate. 
[21] In addition, the overall cumulative risk of death due to myeloma was much greater 
compared to risk of death from SPM, suggesting a positive benefit/risk profile in patients 
receiving lenalidomide [31], supporting further the proposed duration of treatment on this 
protocol. 
Because of the emergence of a correlation between minimal residual disease (MRD) and 
PFS/OS, the rate of MRD negativity will be used as a surrogate marker for PFS and exploration 
of the  primary objective. MRD-negative status will be determined by multiparameter flow 
cytometry (MCF) and next generation sequencing (NGS). We hypothesize that the IRD 
combination will increase the rate of MRD-negative disease by 20% in the experimental versus 
control arm within 12 months from the date of randomization as specified in the statistical 
section. If the results meet statistical endpoints for a promising outcome, future phase III clinical 
trials will be warranted to expand on this hypothesis. 
1.10    
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 
ongoing trials.  The preliminary findings are favorable when considering historical and 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. 
Clinical benefit and safety of ixazomib in combination with lenalidomide and dexamethasone 
has been established, based on the results of studies listed in Table 1-1 above. Two ongoing 
randomized trials with Ixazomib and lenalidomide and dexamethasone reflect the confidence of 
safety of the combination and dexamethasone in newly diagnosed and relapsed myeloma. In 
addition, the combination of Ixazomib and lenalidomide was well tolerated as maintenance in 
post-transplant setting (Shah et al, ASH 2013, Abstract 1983) and is providing rationale for 
randomized trial in cooperative groups. 

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This study will be conducted in compliance with the protocol, good clinical practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines. 
2.    
STUDY OBJECTIVES 
2.1    Primary Objectives 
• To determine the rate of MRD-negative disease by multiparameter-flow cytometry 
(MFC) for patients enrolled based on MFC-positivity or by next generation sequencing 
(NGS) in patients enrolled based on NGS-positivity (patients with MRD-negative disease 
by MFC at screening), at 12 months after randomization 
2.2    Secondary Objectives 
• Evidence of response as demonstrated by the improvement in the depth of response by at 
least one category according to IMWG response criteria. (For example, an improvement 
from very good partial response (VGPR) to near complete response (nCR) or better than 
nCR including conversion from CR to MRD negative disease [overall response]) at 6 and 
12 months 
• Progression free survival (PFS) 
• Overall survival (OS) 
• Duration of MRD-negative disease 
• Safety and tolerability of experimental arm (IRd) vs. control arm (R) 
2.3    Tertiary/Exploratory Objectives (if applicable) 
• Determination of markers of response based on pre-treatment characteristics using methods 
described in correlative research, protocol section 8. 
• Evaluation of MRD by gene sequencing method using the  Adaptive Biotechnologies platform 
(clonoSEQ® assay) in parallel with multi-parameter flow cytometry (MFC) 
3.    
STUDY ENDPOINTS 
3.1    Primary Endpoints  
Rate of MRD negativity after 12 months of treatment with Ixazomib in combination with 
lenalidomide and dexamethasone compared to MRD negativity rate after 12 months of 
lenalidomide alone. For the majority of patients, where MRD positivity at screening will be 
determined by Multi-parameter Flow Cytometry (MFC), an improvement will be defined as a 

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conversion from MRD-positive to MRD-negative disease by MFC. Additionally, in the fraction 
of patients with MRD-negative disease by MFC at screening, who were MRD-positive by Next 

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Generation Sequencing (NGS), an improvement will be defined as a conversion from MRD-
positive to MRD-negative disease by NGS  
3.2    Secondary Endpoints 
• The assessment of other measures of response including rate of VGPR, CR, sCR 
• The assessment of duration of MRD-negative disease 
• Estimates of PFS and OS 
• Estimate of correlation between MRD status and PFS 
• The assessment of safety and tolerability of IRd arm compared to R arm 
3.3    Tertiary/Exploratory Endpoints  
• Correlation of MRD results obtained by MCF with MRD results by gene sequencing method 
• Feasibility of MRD evaluations in the multi-site setting 
• Identification of biologic markers that may predict which patients are likely to benefit from to 
IRd maintenance 
4.    
STUDY DESIGN  
4.1    Overview of Study Design 
This is a phase 2, open-label, randomized study in which subjects are enrolled 1:1 control to 
experimental arm stratified by 1) level of response at study entry and 2) risk factors: 
1. Level of response to first line therapy including transplant; response is assessed at study 
screening  
a. <VGPR 
b. ≥VGPR 
2. Risk Factors at the time of diagnosis 
a. At least one of the following poor prognostic risk factors: 
i. 
del-13 (by karyotyping) 
ii. 
hypodiploidy (by karyotyping) 
iii. 
(4;14) ( by FISH) 
iv. 
t(14;16) (by FISH) 

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v. 
t(14;20) (by FISH) 
vi. 
del17p (by FISH) 
vii. 
1q21 gain (by FISH) 
b. No risk factors 
4.2    Study Procedures 
Refer to the Study Schedule of Events for an overview. After screening, eligibility determination, 
enrollment & randomization, subjects will receive treatment in either control or experimental 
arm in 28-day cycles for 12 cycles or until progression, unacceptable toxicity or subject 
withdraws consent. 
A subject is considered to be off-treatment following a 30-day safety follow-up period after the 
last treatment. Long-term follow-up for survival will be 2 years from End of Treatment visit. 
4.2.1    Screening Procedures 
The screening period is 42 days in length. Screening can only start after the patient has signed the 
Informed Consent Form. 
Signed written informed consent 
Obtained prior to performing any study specific 
assessments 
Demographics and medical 
history 
• Age, gender, ethnic background 
• Details on myeloma diagnosis prior cancer 
therapy, including start and stop dates, transplant 
regimen, lenalidomide maintenance regimen 
• Previous and concurrent relevant diseases 
• Current symptoms and/ or residual toxicities  
Pregnancy test (if applicable) 
(Day - 7 to -1) 
A serum pregnancy test will be performed in pre-
menopausal women and women who are post-
menopausal for < 2 years. In case the sampling date 
for the serum pregnancy test exceeds 7 days before 
treatment start, a urine test is required for 
confirmation 
Physical examination and vital 
signs  
• Body height and weight 
• BSA 
• ECOG Performance Status 
• Blood pressure, pulse, temperature 
• Physical examination 

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Cardiac evaluation  
12-lead ECG required at screening (local machine) 
Urinalysis  
Urine bilirubin, glucose, hemoglobin, ketones, pH, 
protein.  
Hematology (CBC)  
Hemoglobin, hematocrit, mean corpuscular volume, 
mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration, white blood cell (WBC) 
count, WBC differential, red blood cell count, 
lymphocytes, monocytes, neutrophils, band 
neutrophils, eosinophils, basophils, platelets.  WBC 
differential may be automated or manual as per 
institutional standards. Reticulocytes may be done 
only when clinically indicated 
Clinical chemistry  
Sodium, potassium, chloride, bicarbonate, BUN, 
creatinine, glucose, calcium, phosphate, magnesium, 
ALT, AST, alkaline phosphatase, total bilirubin, 
total protein, albumin,  uric acid, LDH, and CRP 
CRP & β2 microglobulin 
Required at screening only 
Myeloma Disease Assessment -
laboratory 
M-protein determination: 
• Serum Protein Electrophoresis (SPEP) and 
immunofixation 
• Urine Protein Electrophoresis (UPEP) and 
immunofixation 
• Serum Free Light Chains (SFLC) 
• Serum quantitative immunoglobulins (Igs) 
All of the above assessments are required at 
screening regardless of the disease classification.  
Bone Marrow Biopsy 
Quantify percent myeloma cell involvement, and 
obtain bone marrow aspirate for conventional 
cytogenetics and fluorescent in situ hybridization. 
Required specimen for calibration step for MRD 
evaluation by gene sequencing. For subjects who 
sign consent for correlative samples, an additional 
aspirate sample should be collected at screening 
(Section 8). Bone marrow biopsy/aspirate performed 
outside of the 42 day window may be considered for 
inclusion.  Please contact the Lead Principal 
Investigator and/or the CRA on a case-by-case basis.   
Plasmacytoma Evaluation 
May be performed by physical exam or imaging, 
whichever is clinically indicated and at the treating 
investigator’s discretion. 

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Skeletal Survey 
May be within 42 days of planned treatment start 
(does not need to be repeated if within 42 days). 
Includes: lateral radiograph of the skull, 
anteroposterior and lateral views of the spine, and 
anteroposterior views of the pelvis, ribs, femora, and 
humeri.  
Neurotoxicity Assessment 
Includes Neurotoxicity Questionnaire (Appendix 
13.4) 
QOL Assessment 
Patient reported survey (Appendix 14.5) 
Adverse Events  
Only SAEs considered related to study procedure 
need to be reported.  
Correlative Samples 
Peripheral blood and bone marrow aspirate samples 
collected at screening. Buccal mucosa swab will be 
collected at screening only 
 
4.2.2    Treatment Phase Procedures 
Following randomization, these assessments should be performed on Day 1 of each cycle unless 
otherwise noted. 
Complete Physical examination 
and vital signs 
• Body weight 
• BSA 
• ECOG Performance Status 
• Blood pressure, pulse, temperature 
• Pulse oximetry  
Hematology 
(Day 1 of every cycle and when 
clinically indicated) 
Hemoglobin, hematocrit, mean corpuscular volume, 
mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration, white blood cell (WBC) 
count, WBC differential, red blood cell count, 
lymphocytes, monocytes, neutrophils, band 
neutrophils, eosinophils, basophils, platelets.  WBC 
differential may be automated or manual as per 
institutional standards. Reticulocytes may be done 
only when clinically indicated 

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Complete clinical chemistry 
(Day 1 of every cycle and when 
clinically indicated) 
Sodium, potassium, chloride, bicarbonate, BUN, 
creatinine, glucose, calcium, phosphate, magnesium, 
ALT, AST, alkaline phosphatase, total bilirubin, 
total protein, albumin, uric acid, LDH, CRP.  
Pregnancy Test 
Day 1 of every cycle in accordance with the 
lenalidomide REMS™ program for FCBP 
(Appendix 13.6) 
Myeloma Disease Assessment –
laboratory 
(Day 1 of every cycle) 
M-protein determination: 
• Serum Protein Electrophoresis (SPEP) and 
immunofixation 
• Urine Protein Electrophoresis (UPEP) and 
immunofixation 
• Serum Free Light Chains  
• Serum quantitative immunoglobulins (Igs) 
Only those assessments used to follow the myeloma 
disease are required past screening. All assessments 
are required for confirmation of response. 
Neurotoxicity Assessment 
Including Neurotoxicity Questionnaire (Appendix 
13.4) 
QOL Assessment 
Patient reported survey (Appendix 14.5) 
Adverse events  
Assessed on an ongoing basis 

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Study Treatment – Experimental 
Arm 
Ixazomib on Days 1, 8, 15. lenalidomide on Days 1-
21. Dexamethasone 1, 8, 15, 22 (Cycle 1-4). Refer 
to Schedule of Events Table and Section 7.2.1 
Study Treatment – Control Arm 
lenalidomide on Days 1-28. Refer to Schedule of 
Events Table and Section 7.2.2 
Correlative Samples 
For patients who give consent, peripheral blood and 
bone marrow aspirate samples collected at any time 
after randomization that CR or better is suspected. 
4.2.3    End of Treatment Procedures 
Patients who discontinue therapy for any reason must have and end of treatment (EOT) visit 
completed 30 days (± 7 days) after the last application of study drug. Following the end of 
treatment, subjects will be followed for survival for 2 years. 
Physical examination and vital 
signs 
• Body weight 
• Blood pressure, pulse, temperature 
• Physical examination 
• Pulse oximetry 
Cardiac evaluation  
12-lead ECG 
Urinalysis  
Urine bilirubin, glucose, hemoglobin, ketones, pH, 
protein 
Hematology  
Hemoglobin, hematocrit, mean corpuscular volume, 
mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration, white blood cell (WBC) 
count, WBC differential, red blood cell count, 
lymphocytes, monocytes, neutrophils, band 
neutrophils, eosinophils, basophils, platelets. WBC 
differential may be automated or manual as per 
institutional standards. Reticulocytes may be done 
only when clinically indicated 
Clinical chemistry  
Sodium, potassium, chloride, bicarbonate, BUN, 
creatinine, glucose, calcium, phosphate, magnesium, 
ALT, AST, alkaline phosphatase, total bilirubin, 
total protein, albumin, uric acid, LDH, CRP 

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Pregnancy test (if applicable) 
A serum pregnancy test will be performed in pre-
menopausal women and women who are post-
menopausal for < 2 years to exclude that a 
pregnancy occurred under treatment and in 
accordance with lenalidomide REMS™ (Appendix 
13.6) 
Myeloma Disease Assessment–
laboratory 
M-protein determination: 
• Serum Protein Electrophoresis (SPEP) and 
immunofixation 
• Urine Protein Electrophoresis (UPEP) and 
immunofixation 
• Serum Free Light Chains  
• Serum quantitative immunoglobulins (Igs) 
Bone Marrow Biopsy 
Quantify percent myeloma cell involvement, and 
obtain bone marrow aspirate for conventional 
cytogenetics and fluorescent in situ hybridization. A 
sample for MRD evaluation is required to be 
collected. For subjects who sign consent for 
correlative samples, an additional aspirate sample 
should be collected at screening (Section 8) 
Correlative Samples 
For patients who give consent, peripheral blood and 
bone marrow aspirate samples collected at End of 
Treatment 
Neurotoxicity Assessment 
Including Neurotoxicity Questionnaire (Appendix 5) 
QOL Assessment 
Patient reported survey 
Adverse events  
Record through 30-days after last treatment. All 
SAEs considered related to treatment must be 
followed until resolution. 
4.3   Number of Patients 
A total of  60 patients will be enrolled in a 1:1 ratio into one of two arms: IRd or lenalidomide 
alone. Enrollment is defined as the time of randomization. Protocol treatment must start 
within 2 days of randomization. 
4.4    Duration of Study 
The study is planned to start in Q3 2014 with respect to first patient in (FPI). The enrollment 
period is expected to be 12-14 months across 8 centers for a total enrollment of  60 subjects. The 
maximum length of treatment period will be 12 months not accounting for dose delays or 

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interruptions. Subjects will be followed after the end of treatment visit for up to 2 years. The 
accrual end date will be by 3/31/2020.  
 
4.5    Response Evaluation 
Response will be evaluated based on IMWG criteria (Appendix 13.3). The first evaluation will 
be completed at the end of Cycle 1 and the M-spike value will be compared to baseline (pre-
induction treatment) M-spike to determine response. If M-spike is not available, the respective 
pre-treatment immunoglobulin level and for light-chain-disease-only subjects, involved free light 
chain level or 24-hr total protein level, will be used to assess response. 
If at any time throughout the treatment a complete  response or better is suspected, a complete 
disease assessment should be performed to confirm response according to IMWG criteria 
(Appendix 13.3). 
5.    
STUDY POPULATION 
5.1    Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
1. Patients who completed induction treatment followed by autologous stem cell transplant 
as initial therapy for symptomatic myeloma as per IMWG criteria and are considered for 
single agent lenalidomide maintenance or initiated single agent lenalidomide 
maintenance.  
a) Patients will be eligible for enrollment in the first 0-6 months of lenalidomide 
maintenance provided that lenalidomide maintenance has been initiated within 6 
months post transplant as per standard of care. 
i. Patients do not have to be on Lenalidomide at the time of study consent. 
b) Patients already in lenalidomide maintenance must be received lenalidomide 10 
mg or 15 mg and be able to tolerate dose escalation to 25 mg daily. 
c) Patients receiving off protocol lenalidomide maintenance cannot exceed 6 months 
post-transplant 
d) A one week break from off protocol lenalidomide is suggested, prior to initiating 
treatment on the study 
i. Any delays >7 days to align treatment with the start of Cycle 1 Day 1, of 
either arm, must be discussed with the PI. 

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e) Patients who completed tandem transplantation will be eligible for enrollment 
2. No evidence of progressive disease on lenalidomide 
3. Evidence of minimal residual disease at the time of screening defined as at least MRD-
positive disease.  
 
a) The primary method of evaluation of MRD is Multi-parameter Flow Cytometry 
(MFC) performed at the University of Chicago. 
b) Patients who have negative MRD by Multi-Parameter Flow Cytometry (MFC) but 
have residual original monoclonal protein by serum or urine immunofixation may 
be eligible if they are found to have MRD-positive disease by Next Generation 
Sequencing (NGS)  
c) If patient is receiving lenalidomide, any delays required to align treatment with 
the start of Cycle 1 of either arm, must be discussed with the PI. 
4. Bone marrow specimen from diagnosis (or pre-induction) will be required at study entry; 
available DNA sample will be used for calibration step for MRD evaluation by gene 
sequencing 
5. Males and females ≥ 18 years of age 
6. Life expectancy of more than 3 months 
7. ECOG performance status of 0-2 
8. Adequate hepatic function, with bilirubin ≤1.5 x ULN and aspirate aminotransferase 
(AST) and alanine aminotransferase (ALT) ≤ 3 xULN 
9. ANC ≥1.0 x 109/L, hemoglobin ≥8 g/dL, platelet count ≥75 x 109/L. 
10. Calculated creatinine clearance (by Cockcroft-Gault) ≥50 ml/min or serum creatinine 
below 2 g/dL (section 13.2) 
11. 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. 
12.  Female patients who: 
• Are postmenopausal for at least 1 year before the screening visit, OR 
• Are surgically sterile, OR 

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• If they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing 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, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable methods 
of contraception.) 
13. Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree to one 
of the following: 
• Agree to 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] and withdrawal are not acceptable methods 
of contraception.)  
5.2    Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
1. Evidence of progressive disease on lenalidomide maintenance as per IMWG criteria 
2. Patients who have already started or received multi-drug consolidation regimen post-
transplant except for patients receiving up to 6 months of single agent lenalidomide 
maintenance. 
3. Longer than 12 months since the initiation of induction therapy at the time of start 
lenalidomide maintainance  
4. Prior progression after initial therapy.  
a) Subjects, whose therapy changed due to suboptimal response, intolerance, etc., 
remain eligible, provided they do not meet criteria for progression.  
b) No more than two regimens will be allowed excluding dexamethasone alone. 
5. Diarrhea > Grade 1 in the absence of anti-diarrheals 
6. Central Nervous System involvement of the disease under study. 
7. Female patients who are lactating or have a positive serum pregnancy test during the 
screening period.  

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8. History of allergy to mannitol 
9. Major surgery within 14 days before enrollment. 
10. Radiotherapy within 14 days before randomization. If the involved field is small, 7 days 
will be considered a sufficient interval between treatment and administration of the 
ixazomib. 
11. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled 
cardiac conditions such as hypertension, or cardiac arrhythmias, or New York Heart 
Association Stage III and IV congestive heart failure, or unstable angina or myocardial 
infarction within the past 6 months. 
12. Rate-corrected QT interval of electrocardiograph (QTc) > 470 msec on a 12-lead ECG 
during screening 
13. Uncontrolled diabetes 
14. Acute infection requiring systemic anti-infectives, antivirals, or antifungals within two 
weeks prior to first dose 
15. Systemic treatment, within 14 days before the first dose of ixazomib, with strong CYP3A 
inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or 
use of Ginkgo biloba or St. John’s wort. 
16. Ongoing or active systemic infection, active hepatitis B or C virus infection, or known 
human immunodeficiency virus (HIV) positive. 
17. Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol. 
18. Known allergy to any of the study medications, their analogues, or excipients in the 
various formulations of any agent. 
19. Known GI disease or GI procedure that could interfere with the oral absorption or 
tolerance of ixazomib including difficulty swallowing. 
20. Diagnosed or treated for another malignancy within 2 years before study enrollment or 
previously diagnosed with another malignancy and have any evidence of residual disease.  
Patients with non-melanoma skin cancer or carcinoma in situ of any type are not 
excluded if they have undergone complete resection. 
21. Patient has ≥ Grade 3 peripheral neuropathy or Grade 2 with pain on clinical examination 
during the screening period. 

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22. Participation in other clinical trials with other investigational agents not included in this 
trial, within 30 days of the start of this trial and throughout the duration of this trial.  
6.   REGISTRATION PROCESS 
When a potential patient has been identified, notify the CRA via phone or email to ensure a 
reservation on the study (contact information listed on enrollment form). Reservations for 
potential subjects will only be held for subjects who have signed consent for that particular 
study. 
When registering a subject, the following must occur:  
• 
Confirm that the institution has a current IRB approval letter for the correct version of 
protocol/consent and has an annual update on file, if appropriate.  
• 
Submit all required materials (Eligibility Checklist, Source documentation, & signed 
consent form) to confirm eligibility and required pre-study procedures to the CRA a 
minimum of 48 hours prior to the subject’s scheduled therapy start date.  
• 
Source documentation includes copies of all original documents that support each 
inclusion/exclusion criteria.  The eligibility checklist does not serve as source 
documentation but rather as a checklist that original source documentation exists for each 
criterion. 
• 
Communicate with the CRA to ensure all necessary supporting source documents are 
received and the potential subject is eligible to start treatment on schedule. If there are 
questions about eligibility, the CRA will discuss it with the PI. PI may clarify, but not 
overturn, eligibility criteria.  
• 
Affiliate sites must confirm registration of subjects by obtaining a subject study ID 
number from the CRA via phone, fax or email.  
• 
If a subject does not start on the scheduled day 1 treatment date, promptly inform the 
CRA as the delay in start may deem the subject ineligible and/or require further or repeat 
testing to ensure eligibility.  
• The date the patient is randomized if randomization is involved or receives treatment for 
the first time will be considered the patient’s “On Study Date.” The patient’s subject ID 
will be assigned and a confirmation of registration will be issued by the CRA on this 
date. Subjects that sign consent and do not go “On Study” will be recorded in the 
database with the date they signed consent and the reason for not going “On Study” (e.g., 
Ineligible, Screen Failure or Withdrawn Consent).  

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7.STUDY DRUG 
7.1 Description of Investigational Agents 
Ixazomib Capsules 
The ixazomib drug product is provided in strengths of 4.0-, 3.0-, and 2.3-mg and 2.0-, 0.5-, and 
0.2 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 
2.0 mg 
Size 2 
Swedish orange 
0.5 mg 
Size 3 
Dark green 
0.2 mg 
Size 4 
White opaque 
For additional details, please see the ixazomib IB. 
Lenalidomide 
Lenalidomide, a thalidomide analogue, is an immunomodulatory agent with anti-angiogenic and 
anti-neoplastic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-
yl) piperidine-2,6-dione. The empirical formula for lenalidomide is C13H13N3O3, and the gram 
molecular weight is 259.3. 
Lenalidomide is off-white to pale-yellow solid powder.  It is soluble in organic solvent/ water 
mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic solvents and 
low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 
0.4 to 0.5 mg/mL.  Lenalidomide has an asymmetric carbon atom and can exist as the optically 
active forms S(-) and R(+), and is produced as a racemic mixture with a net optical rotation of 
zero.  Lenalidomide is available in 5mg, 10mg, 15mg and 25mg capsules for PO administration.  
Each capsule contains lenalidomide as the active ingredient and the following inactive 
ingredients: lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and 
magnesium stearate.  The 5 mg and 25 mg capsule shell contains gelatin, titanium dioxide and 
black ink.  The 10 mg capsule shell contains gelatin, FD&C blue #2, yellow iron oxide, titanium 
dioxide and black ink.  The 15 mg capsule shell contains gelatin, FD&C blue #2, titanium 
dioxide and black ink. 

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Dexamethasone 
Dexamethasone is a commercially available PO drug, supplied as 2 and 4 mg tablets. It is a 
synthetic adrenocortical steroid and occurs as a white to off-white,  odorless, crystalline powder.  
It is stable in air and practically insoluble in water. 
7.2    Study Drug Administration 
All protocol-specific criteria for administration of study drug must be met and documented 
before drug administration.  Study drug will be administered or dispensed only to eligible 
patients under the supervision of the investigator or identified sub-investigator(s).  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 7.3). 
7.2.1    Experimental Arm 
All Cycles are 28 days long. 
Ixazomib Administration 
Capsules of ixazomib will also be referred to as study drug.  Study drug will be supplied by 
Millennium as capsules of 0.2-, 0.5-, and 2.0 mg, or as capsules of 2.3-, 3.0- and 4.0 mg 
ixazomib.  
Subjects randomized to the experimental arm will receive Ixazomib as follows: 
• Cycles 1-4: Ixazomib will be administered on Days 1, 8, and 15.  
o Cycle 1 will started at 3 mg. If 3 mg Ixazomib is well tolerated, the dose may be 
increased to 4 mg at the start of Cycle 2 
• Cycles 5-12: Ixazomib will be administered on Days 1, 8, and 15 at the best tolerated 
dose established for the individual patient during Cycles 1-4. 
Patients should be instructed to swallow ixazomib capsules whole, with water, and not to break, 
chew, or open the capsules.  Ixazomib should be taken on an empty stomach (no food or drink) at 
least 1 hour before or 2 hours after a meal or any other medication.  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.   

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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.  If the 
patient vomits after taking a dose, the patient should not repeat the dose but should resume 
dosing at the time of the next scheduled dose. 
Site staff will oversee the study subject taking day 1 doses of every cycle of all medications (IRd 
or R) during the visits to ensure proper administration. Site staff should not provide any study 
drug until dosing is to begin. Additionally, site staff will ensure that the study subject is 
adequately informed and understands dosing instructions for all medications. The site staff might 
consider asking the subject to repeat the dosing instructions to ensure his/her understanding, and 
allow the opportunity to ask questions. Dosing instructions should be repeated before a new dose 
of study drug is provided to the study subject. 
Finally, dosing diaries will be completed by the site personnel including dates of doses to be 
taken, # of capsules to be taken/dosing day. In addition, where applicable, the site staff will cross 
out non-dosing days on the study subject’s dosing diary at each dispensation visit.   
Ixazomib 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. 
Lenalidomide Administration 
Lenalidomide will be provided in accordance with the lenalidomide REMS® program of 
Celgene Corporation.  Per standard lenalidomide REMS® requirements, all physicians who 
prescribe lenalidomide for research subjects enrolled into this trial must be registered in must 
comply with all requirements of the lenalidomide REMS® program.  Prescriptions must be filled 
within 7 days.  Only enough lenalidomide for one cycle of therapy will be supplied to the patient 
each cycle.  Unused lenalidomide will be counted and documented by each site.   
Subjects randomized to the experimental arm will receive lenalidomide as follows: 
• Cycles 1-4: Lenalidomide will be administered on Days 1-21 at a dose of 25 mg.  
• Cycles 5-12: Lenalidomide will be administered on Days 1-21 at the best tolerated dose. 
Lenalidomide should be taken in the evening at approximately the same time each day.  
Lenalidomide is taken with water on a full or empty stomach.  Subjects should not break, chew 

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or open capsules. Missed doses can be taken as soon as the patient remembers as long as it is less 
than 12 hours since the scheduled time. If it has been more than 12 hours, the dose should be 
skipped. Vomited doses will not be made up. Subjects should be instructed to never take 
lenalidomide past Day 21 of each cycle. 
Dexamethasone Administration 
Dexamethasone will ideally be best administered in the morning with a meal 2 hours before 
Ixazomib. If this is not possible, dexamethasone will be administered with a meal and at least 1 
hour after ixazomib dose on days that they coincide (Days 1, 8, 15), as follows:  
• Cycles 1-4: 40 mg PO per dose Days 1, 8, 15 and 22 
o Dexamethasone may administered as a split schedule of 20 mg PO or IV (pre-
ixazomib during weeks 1-3 when ixazomib is administered) on Days 1, 2, 8, 9, 
15, 16, 22, and 23 after discussion with the Lead Principal Investigator. 
• Cycles 5-12: Dexamethasone discontinuation  
o Low dose of dexamethasone up to 20 mg per dose weekly on days 1, 8, 15, and 22 
is allowed based on investigator determination of best tolerability of regimen.  
Dexamethasone given on days without ixazomib and lenalidomide (Days 22) may be self-
administered by the subject on an outpatient basis. Missed doses of dexamethasone will not be 
made up.  
7.2.2    Control Arm 
Lenalidomide Administration 
Lenalidomide will be provided in accordance with the Lenalidomide REMS® program of 
Celgene Corporation.  Per standard lenalidomide REMS® requirements, all physicians who 
prescribe lenalidomide for research subjects enrolled into this trial must be registered in must 
comply with all requirements of the lenalidomide REMS® program.  Prescriptions must be filled 
within 7 days.  Only enough lenalidomide for one cycle of therapy will be supplied to the patient 
each cycle.  Unused lenalidomide will be counted and documented by each site.  
Subjects randomized to the control arm will receive lenalidomide as follows: 
• Cycles 1-12: Lenalidomide will be continuously administered on Days 1-28 at a dose of 
either 10 mg or 15 mg.  

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o Lenalidomide administration may be given at 5 mg only if it is documented that 
this was the best last tolerated dose. 5 mg dosing requires Lead Principal 
Investigator approval.  
o If the 10 mg dose is tolerated for 3 cycles – off or on protocol – the dose can be 
escalated to 15 mg. 
Lenalidomide should be taken at approximately the same time each day. Lenalidomide is taken 
with water on a full or empty stomach.  Subjects should not break, chew or open capsules.  Late 
doses of lenalidomide should if possible be taken on the assigned day but should not be made up 
the next day. Vomited doses will not be made up.  
7.3    Dose-Modification Guidelines  
The following sections summarize dosing modifications for ixazomib, lenalidomide, and 
dexamethasone.  Dose modifications different from those stated in the protocol must be 
discussed with the Lead Principal Investigator.  Administration of ixazomib and/or lenalidomide 
will be discontinued in the event of any toxicity that, in the opinion of the Lead or Treating 
Investigator, warrants discontinuation.   
In addition to dose reductions, administration of ixazomib and/or lenalidomide will be held 
temporarily in the event of a treatment-related toxicity, at the Treating Investigator's discretion.  
Study treatment may be re-introduced, if the event resolves back to the patient’s baseline value 
or to ≤ Grade 1 within 21 days; otherwise, study drug will be permanently discontinued. Any 
deviations from this plan must be approved by the Lead Principal Investigator.  
Experimental Arm: 
Table 7-1 Ixazomib Dose Adjustments 
Nominal 
Ixazomib Dose 
Dose -1 
Dose -2 
Dose -3 
4 mg Days 1, 8, 15 
(if escalated after 
Cycle 1) 
3 mg 
2.3 mg 
Discontinue 
3 mg Days 1,8,15 
2.3mg 
Discontinue 
N/A 
Table 7-2 Lenalidomide Dose Adjustments 
Nominal 
Lenalidomide 
Dose 
Dose -1 
Dose -2 
Dose -3 
Dose -4 
Dose -5 
25 mg Days 1-21 
20mg 
15 mg 
10 mg 
5 mg 
5 mg every 
other day 

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15 mg Days 1-21 
10 mg 
5 mg 
5 mg every 
other day 
Discontinue 
N/A 
1 mg Days 1-21 
5 mg 
5 mg every 
other day 
Discontinue 
N/A 
N/A 
 
Table 7-3 Dexamethasone Dose Adjustments* 
Nominal 
Dexamethasone Dose 
Dose -1 
Dose -2 
Dose -3 
Dose -4 
40 mg 
20 mg 
12 mg 
8 mg 
4 mg 
*Split dosing of dexamethasone on days 1, 2, 8, 9, 15, 16, 22, and 23 may be implemented to 
control toxicities that do not require a dose reduction. Split dosing requires Lead Principal 
Investigator approval before implementing 
 
Control Arm 
Table 7-4 Lenalidomide Dose Adjustments 
Nominal 
Lenalidomide 
Dose 
Dose -1 
Dose -2 
Dose -3 
Dose -4 
15 mg Days 1-28 
10 mg 
5 mg 
5 mg Days 
1-21 
5 mg every 
other day 
Days 1-21 
10 mg Days 1-28 
5 mg 
5 mg Days 
1-21 
5 mg every 
other day 
Days 1-21 
Discontinue 
 
 
7.3.1 
Recommended Criteria for Beginning or Delaying a Subsequent Treatment Cycle 
& Dose Modifications for Treatment Associated Toxicity 
All treatment cycles are 28 days. 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 non-hematologic toxicity (except for alopecia) must have resolved to ≤ Grade 1 
or to the patient’s baseline condition 
 

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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 patient continues to fail to meet the 
above-cited criteria, delay therapy and continue to reevaluate. The maximum delay before 
treatment should be discontinued will be 3 weeks or at the discretion of the Principal 
Investigator. Any delay greater than 21 days must be reviewed with the Lead Principal 
Investigator if the treating investigator believes that continued treatment is in the subject’s best 
interest and confirmation of clinical benefit (absence of disease progression).  
 
The following tables outline dosing recommendations for Ixazomib, lenalidomide and 
Dexamethasone. 

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Dosage adjustments for hematologic toxicity are outlined in Table 6-5  
Table 7-5    
Ixazomib and Lenalidomide Dose Adjustments for Hematologic 
Toxicitiesa, b 
Criteria 
Action 
If platelet count decreased to Grade 3 with clinically 
significant bleeding or Grade 4 < 25 × 109/L on any 
dosing day (other than Day 1) 
 
Within-Cycle Dose Modifications 
• 
Ixazomib dose and lenalidomide should be 
withheld.   
• 
Complete blood count (CBC) with differential 
should be repeated at least twice weekly until the 
platelet counts have exceeded the pre-specified 
values (see Section 6.3.1) on at least 2 occasions.   
• 
Once resolved to Grade ≤1:  
o 
1st occurrence – decrease lenalidomide 
by 1 dose level; ixazomib may be 
reinitiated without dose reduction on the 
first occurrence. 
o 
2nd occurrence -  decrease ixazomib 1 
dose level and resume len at its most 
recent dose 
o 
3rd occurrence – decrease len 1 dose 
level from previous dose 
o 
4th occurrence – decrease ixazomib 1 
dose level from previous dose  
 
Day 1 of Cycle Dose Modifications 
 
• 
1st occurrence – decrease lenalidomide 1 dose 
level 
• 
2nd occurrence – decrease ixazomib 1 dose level 
• 
3rd occurrence – decrease lenalidomide by 1 
additional dose level 
• 
4th occurrence – decrease ixazomib by 1 
additional dose level 
 
Neutrophil count (ANC) decreased Grade 3 (ANC 
500-1000/mm3) or > Grade 3 with fever (temperature 
>38.5°C) 
 

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Dosage adjustments for hematologic toxicity are outlined in Table 6-5  
Table 7-5    
Ixazomib and Lenalidomide Dose Adjustments for Hematologic 
Toxicitiesa, b 
Criteria 
Action 
Within-Cycle Dose Modifications 
• 
Ixazomib dose and lenalidomide should be 
withheld.   
• 
Complete blood count (CBC) with differential 
should be repeated at least twice weekly until 
the ANC has exceeded the pre-specified values 
(see Section 6.3.1) on at least 2 occasions.   
• 
If neutropenia resolved to <Grade 2: 
o 
Lenalidomide decrease 1 dose level 
o 
Ixazomib – resume at its most recent 
dose if ANC recovered prior to next 
planned dose and resume planned 
treatment cycle 
 
Day 1 of Cycle Dose Modifications 
• 
If neutropenia is the only toxicity for which a 
dose reduction is required, G-CSF may be used 
prophylactically, as per ASCO guidelines, for 
the subsequent cycle and dose maintained 
• 
For each subsequent occurrence of the same 
level of neutrophil count decrease, hold 
lenalidomide treatment and upon recovery of 
ANC to >1,000/mm3 resume as follows: 
o 
1st occurrence – decrease lenalidomide 
1 dose level 
o 
2nd occurrence – decrease ixazomib 1 
dose level 
o 
3rd occurrence – decrease lenalidomide 
by 1 additional dose level; do not dose 
below 5mg daily 
Grade 4 neutropenia (<500/mm3) 
 
Within Cycle Dose Modifications 
• 
Ixazomib dose and lenalidomide should be 
withheld.   
• 
Complete blood count (CBC) with differential 
should be repeated at least twice weekly  
• 
If neutropenia resolved to <Grade 2 within the 
cycle:  
o 
Lenalidomide decrease 1 dose level 
below current dose level  
o 
Ixazomib if prior to next planned dose, 
decrease 1 dose level 
 

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Dosage adjustments for hematologic toxicity are outlined in Table 6-5  
Table 7-5    
Ixazomib and Lenalidomide Dose Adjustments for Hematologic 
Toxicitiesa, b 
Criteria 
Action 
Day 1 of Cycle Dose Modifications 
• 
Use of G-CSF as above 
• 
For each subsequent drop <1,000/mm3 and 
recovery to >1,000/mm3, decrease lenalidomide 
one dose level less than the previous dose, but 
do not dose below 5 mg daily 
a) Both drugs may be reduced at the same time at the investigator’s discretion 
b) Doses held during a treatment cycle are not to be replaced 
 
 
 
Treatment modifications due to ixazomib-related AEs are outlined in Table 6-6. 
Table 7-6    
Ixazomib Treatment Modification (Delays, Reductions, and 
Discontinuations) Due to Adverse Events (Non-Hematologic Toxicities) 
Adverse Event (Severity) 
Action on ixazomib 
Further Considerations 
Peripheral Neuropathy: 
Grade 1 peripheral neuropathy 
without pain 
 
• No action 
 
Grade 1 signs and symptoms:  
asymptomatic; without pain or loss 
of function; clinical or diagnostic 
observations only [14] 
 
New or worsening Grade 1 
peripheral neuropathy with pain or 
Grade 2 
• Hold ixazomib until resolution 
to Grade ≤ 1 without pain or 
baseline 
• Reduce ixazomib 1 dose level 
Grade 2 signs and symptoms:  
Moderate symptoms; limiting 
instrumental activities of daily 
living (ADL) [14] 
 
 
New or worsening Grade 2 
peripheral neuropathy with pain or 
Grade 3 
• Hold ixazomib until resolution 
to Grade ≤ 1 without pain or 
baseline 
• Reduce ixazomib to next lower 
dose upon recovery 
 
Grade 3 signs and symptoms:  
severe symptoms; limiting self-
care ADL; assistive device 
indicated [14] 
New or worsening Grade 4 
peripheral neuropathy 
• Discontinue ixazomib 
 
 
 

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Table 7-6    
Ixazomib Treatment Modification (Delays, Reductions, and 
Discontinuations) Due to Adverse Events (Non-Hematologic Toxicities) 
Adverse Event (Severity) 
Action on ixazomib 
Further Considerations 
Grade 2 Rash 
• 
Follow at least weekly 
• 
Symptomatic 
recommendations as per 
section 6.6 
The investigator and project 
clinician may discuss 
considerations for dose 
modifications and symptom 
management. 
 
Grade 3 non-hematologic toxicity 
judged to be related to ixazomib 
except for the following toxicity: 
• 
> Grade 3 nausea and/or 
emesis in the absence of 
optimal anti-emetic 
prophylaxis (section 6.7) 
• 
> Grade 3 diarrhea that 
occurs in the absence of 
optimal supportive 
therapy (section 6.7) 
• 
Grade 3 fatigue 
 
• Hold ixazomib until resolution 
to Grade < 1 or baseline 
 
Subsequent recurrence Grade 3 
that does not recover to < Grade 1 
reduce ixazomib 1 dose level 
 
Symptomatic recommendations 
noted in Section 6.7 
Monitor closely, take appropriate 
medical precautions, and provide 
appropriate symptomatic care 
 
 
 
Grade 4 non-hematologic toxicities 
judged to be related to ixazomib 
• Consider permanently 
discontinuing ixazomib 
Exceptions are cases in which the 
investigator determines the patient 
is obtaining a clinical benefit  
Delay of >2 weeks in the start of a 
subsequent cycle due to lack of 
toxicity recovery related to 
ixazomib 
Hold ixazomib until resolution  
 
Reduce ixazomib 1 dose level 
The maximum delay before 
treatment should be discontinued 
will be 3 weeks. If the maximum 
delay has been exceeded, resuming 
treatment can be considered after 
discussion with overall PI if 
clinical benefit is determined 
 
Once ixazomib, lenalidomide, and/or dexamethasone are reduced for any toxicity, the dose may 
not be re-escalated. 
Lenalidomide dose adjustments are allowed based on clinical and laboratory findings. Sequential 
lenalidomide dose reductions to 15 mg daily, 10 mg daily, and 5 mg daily are recommended for 
toxicity as indicated in Table 6-7. 

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Table 7-7    
Lenalidomide Lenalidomide Dose Modifications Due to Non-Hematologic 
Toxicities 
Adverse Event (Severity) 
Action 
Other Grade 3/4 toxicities 
• 
Hold lenalidomide treatment until toxicity has resolved to ≤ 
Grade 1 or patient’s baseline; restart at the next lower dose 
level (5mg less than the previous dose) 
o 
Do not dose below 5 mg daily 
Rash 
 
• 
Non-blistering Rash, Grade 3 
 
• 
Hold lenalidomide and follow weekly. If the toxicity resolves 
to ≤ Grade 1 prior to Day 21 of the current cycle, restart at 1 
dose decrement and continue the cycle until Day 21 of the 
current cycle. 
• 
Non-blistering Rash, Grade 4 
• 
Discontinue lenalidomide treatment 
• 
Desquamating (blistering 
rash) – Any grade 
• 
Discontinue Lenalidomide treatment 
Erythema multiforme ≥ Grade 3 
• 
Discontinue lenalidomide treatment 
Sinus Bradycardia / other new onset 
cardiac arrhythmia not present at 
baseline or deterioration of pre-existing 
cardiac arrhythmia 
 
• 
≤ Grade 2 
• 
Hold lenalidomide, follow at least weekly. If the toxicity 
resolves to ≤ Grade 1 prior to Day 21, restart at 1 dose 
decrement and continue the cycle until Day 21. 
• 
≥ Grade 3 
• 
Discontinue lenalidomide treatment 
Allergic Reaction / Hypersensitivity 
 
• 
Grade 2-3 
• 
Hold Lenalidomide, follow at least weekly. If the toxicity 
resolves to ≤ Grade 1 prior to Day 21, restart at 1 dose 
decrement and continue the cycle until Day 21. 
• 
Grade 4 
• 
Discontinue lenalidomide treatment 
Infection Grade 3-4 
Hold lenalidomide, ixazomib, and dexamethasone until systemic 
treatment for infection is completed. If no neutropenia, restart all three 
drugs at same dose.  If neutropenic, follow neutropenic instructions. 
Herpes Zoster or simplex of any grade 
Hold Lenalidomide, ixazomib , and dexamethasone until lesions are 
dry. Resume at same doses. 
Renal Dysfunction 
Dose reduce per lenalidomide package insert for impaired renal 
function; monitor renal function regularly 
Venous Thrombosis/Embolism ≥ Grade 
3 
Hold lenalidomide dose and adjust anticoagulation regimen; re-start at 
Treating Investigator’s discretion at same dose 
Hyperthyroidism or hypothyroidism 
Omit lenalidomide for remainder of cycle, evaluate, and initiate 
appropriate therapy. Restart lenalidomide next cycle at 1 dose 
decrement 
Congestive heart failure (CHF) 
Any subject with NYHA stage III or IV CHF, whether or not 
lenalidomide related, must have the dose held until resolution or return 
to baseline.  If CHF was felt to be lenalidomide related, reinstate by 
one dose decrement after return to baseline. If no resolution of CHF 
after 2 weeks, the subject will be withdrawn from the study. 

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Table 7-8    
Treatment Guidelines for Toxicity Related to Dexamethasone 
Body System 
Symptom 
Recommended Action 
Gastrointestinal 
Dyspepsia, gastric or duodenal ulcer, 
gastritis Grade 1-2 (requiring medical 
management) 
Treat with H2 blockers, sucralfate, or 
omeprazole.  If symptoms persist despite 
above measures, decrease dexamethasone 
dose by  
1 dose level. 
Gastrointestinal 
≥ Grade 3 (requiring hospitalization or 
surgery) 
Hold dexamethasone until symptoms 
adequately controlled.  Restart at 1 dose 
decrement along with concurrent therapy 
with H2 blockers, sucralfate, or 
omeprazole.  If symptoms persist despite 
above measures, discontinue 
dexamethasone permanently. 
Gastrointestinal 
Acute pancreatitis 
Discontinue dexamethasone permanently.   
Cardiovascular 
Edema ≥ Grade 3 (limiting function 
and unresponsive to therapy or 
anasarca) 
Diuretics as needed, and restart 
dexamethasone at  1 dose decrement; if 
edema persists despite above measures, 
decrease dose another level.  Discontinue 
dexamethasone permanently if symptoms 
persist despite second reduction 
Neurology 
Confusion or mood alteration  
> Grade 2 (interfering with function +/- 
interfering with activities of daily 
living) 
Hold dexamethasone until symptoms 
resolve.  Restart at 1 dose decrement.  If 
symptoms persist despite above measures, 
discontinue dexamethasone permanently. 
Musculoskeletal 
Muscle weakness > Grade 2 
(symptomatic and interfering with 
function +/- interfering with activities 
of daily living) 
Decrease dexamethasone by 1 dose level.  
If weakness persists, decrease dose by 1 
more dose level.  Discontinue 
dexamethasone permanently if symptoms 
persist. 
Metabolic 
Hyperglycemia ≥ Grade 3 
Treatment with insulin or PO 
hypoglycemic agents as needed.  If 
uncontrolled despite above measures, 
decrease dose by 1 dose level until levels 
are satisfactory. 
 
7.3.1.1    Conditions Not Requiring Dose Reduction 
The following conditions are exceptions to the above guidelines. 
• Grade 3 nausea, vomiting, or diarrhea (unless persisting more than 3 days with adequate 
treatment of antiemetics or antidiarrheal agents) 
• Grade 3 dexamethasone-related hyperglycemia (see Table 6-8 for guidelines and 
treatment) 

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• Grade 1-2 lenalidomide and/or ixazomib-induced rash 
• Grade 3 fatigue (unless persisting for > 14 days) 
• Alopecia 
 
7.4    Mandatory Concomitant Medications      
7.4.1    Recommended Concomitant Medications 
• Aspirin for VTE prophylaxis. 
o Note:  If a subject is allergic to aspirin, low-molecular-weight heparin or 
clopidogrel may be used.  In subjects with a prior history of venous thrombosis, 
low-molecular-weight heparin or therapeutic doses of warfarin (target INR 2-3) are 
required (or follow most current guidelines for DVT prophylaxis). 
• Acyclovir 400 mg orally twice a day for HZV prophylaxis (or equivalent)    
 
7.4.2    Excluded Concomitant Medications 
Concurrent therapy with a marketed or investigational anticancer therapeutic is not allowed. 
Corticosteroids for non-malignant conditions (e.g., asthma, inflammatory bowel disease) 
equivalent to a dexamethasone dose ≥ 4 mg/day or prednisone ≥ 20 mg/day are not permitted.   
Other investigational agents are not to be used during the study.   
The following medications and procedures are prohibited during the study. 
Systemic treatment with any of the following metabolizing enzyme inducers should be avoided, 
unless there is no appropriate alternative medication for the patient’s use (Rationale:   If there 
were to be a 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. 

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• 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 
7.4.3    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. Their use should follow published guidelines and/or institutional practice. 
Erythropoietin will be allowed in this study. Their use should follow published guidelines 
and/or institutional practice. 
• Patients should be transfused with red cells and platelets as clinically indicated and 
according to institutional guidelines however screening platelet count must be 
independent of platelet transfusions for at least 2 weeks. 
• 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 and 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. 

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• Radiation therapy to a localized mass is acceptable with prior approval of the Lead 
Principal Investigator.  
• Prophylactic proton pump inhibitor or an H2 antagonist are recommended but NOT 
required and considered optional medications. 
• Vaccines that are required post-transplant. 
7.5    Precautions and Restrictions  
• Fluid deficit should be corrected before initiation of treatment and during treatment. 
• Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided with impaired renal 
function given reported NSAID-induced renal failure in patients with decreased renal 
function. 
Pregnancy 
It is not known what effects ixazomib has on human pregnancy or development of the embryo or 
fetus.  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 embryo/fetal 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. 
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 

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• 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, symptothermal, 
post-ovulation methods] and withdrawal are not acceptable methods of contraception.) 
Male patients, even if surgically sterilized (i.e., status post-vasectomy) 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.) 
All study participants must be registered into the mandatory lenalidomide REMS® program and 
be willing and able to comply with the requirements of lenalidomide REMS®. Before starting 
lenalidomide, FCBP must have 2 negative pregnancy tests (sensitivity of at least 50 mIU/mL) 
prior to initiating lenalidomide.  The first pregnancy test must be performed within 10-14 days 
before, and the second pregnancy test must be performed within 24 hours before prescribing 
lenalidomide (prescriptions must be filled within 7 days). The subject may not receive 
lenalidomide until the investigator has verified that the results of these pregnancy tests are 
negative. 
7.6  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.   
Prophylaxis Against Risk of Reactivation of Herpes Infection 

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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 will 
be mandatory (see section 7.4.1).  Other antivirals are also acceptable. 
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. 
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. 
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 (e.g., prednisone ≤ 10 mg per day or equivalent) is permitted.  
Management of a Grade 3 rash may require intravenous antihistamines or corticosteroids.  
Administration of ixazomib (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 

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patient has previously developed a rash (e.g., using a thick, alcohol-free emollient cream on dry 
areas of the body or oral or topical antihistamines).  A rare 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. 
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. 
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. 
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. 
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 

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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. 
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. 
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. 
7.7 Investigational Product 
7.7.1  
Ixazomib Preparation, Reconstitution, and Dispensing 
Ixazomib is an anticancer drug and as with other potentially toxic compounds caution should be 
exercised when handling ixazomib capsules. 
7.7.1.1  Ixazomib Packaging and Labeling 
The study drug ixazomib capsules will be provided by Millennium.  The study drug 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.  
7.7.1.2  Ixazomib 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. The container should be stored at the investigative site 
refrigerated (36°F to 46°F, 2°C to 8°C). Ensure that the drug is used before the retest expiry date 

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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 and refrigerated as noted above 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 who are receiving take-
home medication should be given only 1 cycle of medication at a time. 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. 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. 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 (e.g., 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. 
After cycle 1 and with approval of the treating investigator, subjects may take ixazomib at home. 
Research center personnel will review the dosing instructions with subjects.  Subjects will be 
asked to maintain a diary to record drug administration.  Subjects will be asked to bring any 
unused drug and empty drug containers to the research center at their next visit.  Research 
personnel will count and record the number of used and unused drug at each visit and reconcile 
with the patient diary. 

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7.7.2  
Lenalidomide 
7.7.2.1  Lenalidomide Dispensing 
Commercially available (lenalidomide) capsules are supplied through the lenalidomide REMS® 
program as the drug is approved for indications in this study. Lenalidomide is for PO (oral) 
administration only. 
Lenalidomide will be provided in accordance with the lenalidomide REMS® program of 
Celgene Corporation.  Per standard lenalidomide REMS® requirements, all physicians who 
prescribe lenalidomide for research subjects enrolled into this trial must be registered in must 
comply with all requirements of the lenalidomide REMS® program.  Prescriptions must be filled 
within 7 days.  Only enough lenalidomide for one cycle of therapy will be supplied to the patient 
each cycle.  Unused lenalidomide will be counted and documented by each site. See appendix 
14.7 for lenalidomide Prescribing Information. 
7.7.2.2  Lenalidomide Storage, Handling and Accountability 
Store lenalidomide at 25°C (77 °F) away from direct sunlight; excursions permitted to 15-30°C 
(59-86 °F). Bottles of lenalidomide will contain a sufficient number of capsules to last for one 
cycle of dosing.  Sites will be required to record and document subject compliance regarding 
lenalidomide dosing. 
Research center personnel will review the dosing instructions with subjects.  Subjects will be 
asked to maintain a diary to record drug administration.  Subjects will be asked to bring any 
unused drug and empty drug containers to the research center at their next visit.  Research 
personnel will count and record the number of used and unused drug at each visit and reconcile 
with the patient diary. 
7.7.3  
Dexamethasone 
Dexamethasone, a synthetic adrenocortical steroid, is a white to practically white, odorless, 
crystalline powder.  It is stable in air.  It is practically insoluble in water. 
7.7.3.1  Dexamethasone Dispensing 
Dexamethasone is a commercially available PO drug, supplied as 2 and 4 mg tablets. 

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7.7.3.2  Dexamethasone Storage, Handling and Accountability 
Store dexamethasone at controlled room temperature 20ºC to 25ºC (68ºF to 77ºF). Sites will be 
required to record and document subject compliance regarding dexamethasone dosing. Subjects 
may take oral dexamethasone at home. Research center personnel will review the dosing 
instructions with subjects.  Subjects will be asked to maintain a diary to record drug 
administration.  
7.8      Study 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. 
7.9   Treatment Assignment 
Subjects who are deemed eligible for enrollment into the trial will be randomized to the 
experimental arm (IRd) vs. the control arm (single-agent lenalidomide) in a 1:1 ratio. Two 
factors will be considered during randomization:  
 
a. Level of overall response including transplant from the pre-induction level of 
disease; response is assessed at study screening 3 months following initiation of 
lenalidomide maintenance at the time of screening for this protocol: 
ii. <VGPR 
iii. ≥VGPR 
2) Risk Factors at the time of diagnosis 
iv. At least one of the following poor prognostic risk factors: 
1. del-13 (by karyotyping) 
2. hypodiploidy (by karyotyping) 
3. (4;14) ( by FISH) 
4. t(14;16) (by FISH) 
5. t(14;20) (by FISH) 
6. del17p (by FISH) 
7. 1q21 gain (by FISH) 
v. No risk factors 
 

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7.10   
Termination of Treatment and/or Study Participation 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care.  The investigator also has the right to withdraw 
patients from the study for any of the following reasons: 
• Adverse event 
• Protocol violation / subject non-compliance 
• Lost to follow-up 
• Progressive disease 
• Study terminated  
• Subject no longer consents to participate in the study 
• Pregnancy or suspected pregnancy 
• Delay in treatment >21 days due to unrecovered toxicity unless treating investigator 
considers continued therapy to be in the subject’s best interest and approval is granted by 
the Lead Principle Investigator 
• Other 
The Lead Principal Investigator must be contacted to discuss any impending discontinuation of a 
study subject/patient prior to withdrawal from the study.  If withdrawal occurs prior to discussion 
with the Lead Principal Investigator, they must be notified within 24 hours via email with a copy 
to the University of Chicago CRA.  
If the reason for withdrawal is the occurrence of an AE, the subject will be followed until such 
events resolve, stabilize, and, according to the Treating Investigator’s judgment, there is no need 
of further follow-up.  The reason for withdrawal from the study will be documented in the case 
report form. 
At the time of withdrawal, all study procedures outlined for the End of Study visit should be 
completed. The primary reason for patient’s withdrawal from the study should be recorded in the 
source documents and CRF. 

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8.    
STATISTICAL AND QUANTITATIVE ANALYSES 
8.1    Statistical Methods 
A total of  60 patients will be enrolled in a 1:1 ratio stratified according to level of response 
(<VGPR vs ≥ VGPR) and presence or absence of at least one poor prognostic risk factor (Yes to 
at least one cytogenetic risk factor including del-13 or hypodiploidy by karyotyping, or any of 
t(4;14), t(14;16), t(14;2), del17p, 1q21 gain by FISH. The primary objective of this study is to 
compare the rate of MRD at 12 months between the two arms. Because this is a proof of concept 
trial rather than a confirmatory trial, the comparison will be made using one--sided test at  80%  
power and at most 10% type I error. The outcome will be considered promising and warrant 
evaluation with phase III trial if MRD negative disease is 20% higher in the experimental arm vs. 
the control arm. This assumption is based on the following data: 
1) While it is well established that CR rate may increase over time post-transplant, even 
without any maintenance (in the IFM study, at randomization to lenalidomide 
maintenance or placebo 5% and 8% of patients were in CR, but ultimately 29% and 27%, 
respectively achieved CR; Attal et al, N Eng J Med, 2012), the conversion to CR on 
lenalidomide maintenance in patients with established persistent measurable disease is 
expected to be less than 5% 
2) CR rate to lenalidomide alone is estimated < 5% in newly diagnosed myeloma (Rajkumar 
et al, Blood 2005). 
3) While there is not published data on the rate of conversion from less than MRD-negative 
to MRD-negative disease while on lenalidomide maintenance, it is estimated that only a 
small proportion of patients on lenalidomide arm (which we estimate to be < 5% and/or 
not to be clinically significant) will convert to MRD-negative status because of delayed 
effect of transplant and/or lenalidomide treatment. 
4) Based on experience from the CRd trial (Jakubowiak et al, ASCO 2013), approximately 
20% of patients have a potential to convert from less than MRD-negative to MRD-
negative disease between 8 and 20 months (1-year) of the CRd treatment. 
Together, these observations provided rationale for 12 months of duration of treatment and 
statistical design: an increase of the rate of MRD-negative disease by 20% - 28% in the 
experimental arm versus control arm was used for calculation of sample size (as for example  
26.7 % rate in the experimental arm and 5% in control arm). 

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In addition, Kaplan-Meier analysis of PFS will be conducted at time points with 95% confidence 
intervals with Cox proportional hazard regression models (exploratory). For these secondary 
analyses, conventional, p-values from statistical tests at or below 5% (two-sided) will be 
considered significant. 
8.1.1     Determination of Sample Size 
A total of  60 patients (30 per arm) is based on the assumption that the rate of MRD negative 
disease that is approximately 20% higher in the experimental arm vs. the control arm will be 
considered promising for further evaluation. Because this is a proof of concept phase II 
randomized trial rather than a confirmatory trial, the comparison will be made using a one-sided 
test at  80 % power and at most 10% type I error. Table  8.1 below shows the detectable 
difference depending on the control rate.  Boldfaced figures are values assumed most likely 
based on the literature and previous studies.  Calculations are based on a Cochran-Mantel-
Haenszel test with continuity correction. 
Table 8-1 Detectable increases in the rate of MRD with  80 %power (one-sided α=0.10) 
Control Arm 
Experimental Arm 
Difference 
2.5% 
 21.8 % 
19.3 % 
5.0% 
26.7 % 
21.7 % 
10.0% 
35.5 % 
25.5% 
15.0% 
42.4% 
27.4% 
20.0% 
48.1 % 
28.1 % 
 
 
8.1.2    Randomization and Stratification 
Patients will be randomized 1:1 and stratified based on criteria outlined in section 6.9 (VGPR 
status and risk factors vs. no risk factors). Randomization will occur between Day +70 and +120 
post-transplantation. Initiation of maintenance therapy with study drug will begin between day 
+80 and +130. Prior to randomization, subjects must undergo disease re-staging, must have 
adequate organ function (ANC ≥1000µL, platelet count ≥75,000µL, creatinine clearance ≥ 
30mL/min, bilirubin ≤2mg/dL, AST ≤3 x ULN, and Alk. Phos.≤ 3 x ULN), and must have no 
evidence of progressive disease. 

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8.1.3    MRD Evaluations   
8.1.3.1 MRD Evaluations by MCF 
The primary end-point analysis will be performed by the Department of Pathology at the 
University of Chicago. Bone marrow aspirate for MRD analysis by 10-color multiparameter flow 
cytometry will be collected for all patients at the time of enrollment and during all subsequent 
bone marrow biopsies, including at the end of treatment (a minimum of two samples per patient). 
All samples collected at participating sites will be shipped and processed at the University of 
Chicago laboratories. Instructions detailing the collection method, processing, and shipment of 
these samples will be provided in a separate manual.   
8.1.3.2  MRD Evaluations by gene sequencing 
8.1.4As part of an additional MRD evaluation, all bone marrow aspirates collected for 
MRD analysis will also be analyzed using the. Clono SEQ® platform.  The 
collection time points will be as described above: at the time of enrollment, at 
any time during a suspected CR or better, and at 12 months/end of treatment. 
The samples will be part of the same aspirate collected for multiparameter flow 
cytometry and the details of this collection will be described in a separate 
manual. All samples will be sent to the University of Chicago Multiple Myeloma 
Program Coordinator. Processing of samples including DNA isolation, storage, 
and shipment to Adaptive Biotechnologies will be performed by the University 
of Chicago laboratory. Samples processing at the University of Chicago will be 
supported by separate grants and funds from the University of Chicago 
investigators. Adaptive Biotechnologies will provide funding for  Clono SEQ® 
analysis.    
Populations for Analysis 
The Intent-to Treat (ITT) population of patients will be defined as all patients who receive at 
least one dose of treatment in either of the arms (ixazomib or lenalidomide or dexamethasone in 
the experimental arm or lenalidomide in the control arm). “A secondary, evaluable population 
will also be analyzed that will include all patients in the ITT population with the following 
exceptions:   
(1) Patients who discontinued the trial for reasons other than toxicity or 
progressive disease, and  
(2) Patients who met eligibility for MRD positive disease but the MRD testing at 
the 12-month timepoint is either not successful (by NGS) or the sample is not 
available (pt withdraws consent, sample is a dry tap, etc).  
 
Patients in categories (1) or (2) will be rendered “non-evaluable.” Additionally, in the situation 
that a patient is rendered non-evaluable, a new patient will be randomized into the trial to 
preserve the sample size for primary endpoint analysis. Additionally, in the situation that a 

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patient is rendered non-evaluable, a new patient will be randomized into the trial to preserve the 
sample size for primary endpoint analysis.  Patients enrolled in this trial will be patients who 
completed initial induction followed by autologous stem cell transplant for symptomatic 
myeloma (per IMWG criteria) and in the first 0-6 months of Lenalidomide maintenance provided 
that was initiated  within 6 months after transplant as per standard of care and with at least MRD-
positive residual myeloma. The study’s primary endpoint, attainment of MRD-negative disease 
by MFC will be assessed at the completion of the 12 cycle of protocol treatment (both arms). In 
patients that were enrolled based on their MRD-positivity by MFC, an improvement will be 
counted when these patients switch to MRD-negative disease by MFC at the 12-month time-
point. Patients that were enrolled per their MRD-positivity by NGS will require NGS analysis to 
determine their MRD status at 12 months of treatment. In this patient population, only a switch 
from MRD-positivity to negativity by NGS will be counted as an improvement. We anticipate 
that no more than 10% of patients will be enrolled who are MFC negative but NGS positive.  If 
there is an imbalance between the two treatment arms in this variable we will adjust by post-hoc 
stratification or covariate analysis. All patients enrolled and receiving any IRD or R treatment 
will be evaluable for this endpoint, with the exception of patients that decline to receive 
treatment for reasons unrelated to toxicity and/or efficacy.  Patients in that category will be 
replaced.  All other patients who discontinue treatment before receiving 12 cycles of protocol 
treatment will be considered treatment failures for assessment of the study’s primary endpoint.  
The proportion of MRD-negative patients will be reported along with 95% confidence intervals. 
8.1.5    Demographic and Baseline Characteristics 
Baseline characteristics will be summarized in Baseline Characteristic summary table for two 
treatment arms 
8.1.6    Efficacy Analysis 
The primary objective of this study is to compare the rate of MRD at 12 months between the two 
arms. Because this is a proof of concept trial rather than a confirmatory trial, the comparison will 
be made using a one sided test at the 10% significance level.  This comparison will be performed 
using (i) a chi-square or Fisher’s exact test comparing the two treatment arms, and (ii) a Cochran 
Mantel-Haenszel (CMH) test stratified by VGPR status and risk factors vs. no risk factors. We 
anticipate 20-30% of pts will be high risk and 20-40% will be in less than a VGPR at study entry.  
Therefore, in the event of small stratum sizes (<5 per stratum in either treatment arm), we will 
conduct an exact logistic regression analysis in place of the CMH test (Hirji, Mehta, and Patel, et 
al., 1987).   
Secondary objectives include the overall response rate, defined as at least a partial response to 
therapy (>PR), at least VGPR (>VGPR) and at least nCR rate (>nCR), CR, and sCR rates, time 
to progression, duration of response, and progression-free and overall survival.  The rate of 
overall response will be reported along with its exact 95% binomial confidence interval.  Time to 
event endpoints will be estimated using the product-limit method of Kaplan and Meier.  Follow-

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up time for these endpoints will be calculated from the date of randomization.  For time to 
progression, patients that do not experience progression during follow-up will be censored on the 
date of their last clinical examination.  Duration of response will be assessed conditional upon 
achieving at least a partial response.  Follow-up time for this endpoint will be calculated from the 
date of the clinical examination, which confirmed the response, until the date of disease 
progression, or censoring at the date of last clinical follow-up.  For progression-free survival, 
follow-up time will continue from the date of randomization until the date of documented disease 
progression or death.  Patients who do not reach either milestone during follow-up will be 
censored on their date of last clinical assessment. 
Correlative biomarkers will be assessed for association with response in the experimental arm 
using nonparametric tests given the relatively small number of responders anticipated (20%).  A 
Wilcoxon rank-sum test will be used to compare baseline (pre-treatment) biomarker levels in the 
responders vs. non-responders.   
8.1.7 Safety Analysis 
Safety analysis will be based on the incidence, intensity, and type of adverse events, and 
clinically significant changes in the patient’s physical examination, vital signs, and clinical 
laboratory results.  Safety variables will be tabulated and presented for all patients in the study.  
Exposure to study drug and reasons for discontinuation of study treatment will be tabulated. 
Group comparisons will be performed using chi-square or Fisher’s exact test. 
All adverse events occurring on study will be listed in by-patient data listings.  Treatment 
emergent events will be tabulated, where treatment emergent is defined as any adverse event that 
occurs after administration of the first dose of study drug and through the End of Study visit or 
up through 30 days after the last dose of study drug, any event that is considered drug-related 
regardless of the start date of the event, or any event that is present at baseline but worsens in 
intensity or is subsequently considered drug-related by the Treating investigator and/or Lead 
Principal Investigator.  Events that are considered related to treatment (possibly, probably or 
definitely drug-related) will also be tabulated.  Deaths, serious adverse events and events 
resulting in study discontinuation will be tabulated. 
Change from baseline in clinical laboratory parameters will be summarized across time on study, 
and the frequency of clinically significant abnormal laboratory values will be tabulated.  
Similarly, changes in vital sign parameters will be summarized over time, and any abnormal 
values will be tabulated. 

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9.    
CORRELATIVE SAMPLES 
In addition to the required bone marrow aspirate sample for MRD analysis collected at screening 
and time of response, for patients who consent, we will collect samples including bone marrow 
core biopsy and aspirate, peripheral blood, and buccal swabsPeripheral blood and bone marrow 
samples will also be collected at the time of achievement of at least CR, or better, at 1 year after 
randomization (providing that the patient is at least in CR and no recent bone marrow evaluation 
within 1-2 months). Correlative samples should be collected at any time that bone marrow is 
performed as SOC outside of these time points. Additional evaluations may include proteomics, 
gene expression profiling, microRNA, SNP analysis, analysis of genetic variants  
 
Table 8-1 
Correlative Sample Schema 
Visit 
Bone 
Marrow 
Aspirate 
Peripheral 
Blood 
Plasma 
Serum 
Buccal Mouth 
Swab 
Screening 
X 
X 
X 
X 
X 
At any time 
after 
randomization 
after 
achievement of 
CR or better* 
X 
X 
X 
X 
 
End of 
Treatment 
X 
X 
X 
X 
 
Refer to the laboratory manual for collection procedures, processing, and shipments 
10.    ADVERSE EVENTS   
10.1    
Adverse Event Definition 
Adverse event (AE) means any untoward medical occurrence in a patient or subject administered 
a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product whether or not it is related to the medicinal product.  
This includes any newly occurring event, or a previous condition that has increased in severity or 
frequency since the administration of study drug. 

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An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline. 
An unexpected AE is any adverse drug event, the specificity or severity of which is not 
consistent with the current IB or prescribing information for a marketed compound.  Also, 
reports which add significant information on specificity or severity of a known, already 
documented AE constitute unexpected AEs.  For example, an event more specific or more severe 
than described in the IB would be considered “unexpected”. 
10.2    
Causality 
Using the following criteria, the relationship of the AE to the study drug should be assessed as 
follows: Definite, Probably, Possible, Unlikely, Unrelated. 
10.3    
Adverse Event Reporting Procedures 
Information about all AEs, whether volunteered by the subject, discovered by investigator 
questioning, or detected through physical examination, laboratory tests or other means, will be 
collected and recorded and followed as appropriate.  
All AEs (e.g., any new event or worsening in severity or frequency of a pre-existing condition or 
laboratory finding) with an onset date on or after the first dose of treatment through 30-days after 
the last treatment dose must be promptly documented on the appropriate CRF in eVelos. Any 
SAE (Section 10.4) which is considered related to study procedures and occurs after informed 
consent but before Cycle 1 Day 1 must be reported. Details of the event must include severity, 
relationship to study drug, duration, action taken, and outcome. All AEs must be followed to 
resolution or stabilization regardless of relationship to study drug. 
All AEs that are considered related to study drug must be followed to resolution or stabilization 
if improvement is not expected.  
AEs must be reported from the date of the first dose of treatment through 30 days post-last dose 
of study treatment or initiation of a new anti-cancer therapy, whichever occurs first. If a subject 
is enrolled but discontinues study prior to receiving any study drug, only SAEs that are 
considered related to study procedures must be reported through the end-of-study visit. AEs 
which completely resolve and then recur should be recorded as a new AE. For subjects who 
complete the end of study visit less than 30 days following their last dose of study drug, a follow 
up of ongoing AEs should be attempted by telephone, and documented in the subject’s source. 

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AEs continuing at 30 days post-last dose should have a comment in the source by the Treating 
Investigator that the event has stabilized or is not expected to improve. SAEs continuing at 30 
days post-last dose should be followed until resolution or stabilization. 
Whenever possible, the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
should be used to describe the event and for assessing the severity of AEs.  Any events 
representing a change in the CTCAE Grade need to be reported on the AE case report form.  
This includes any change in laboratory values.   
For AEs not adequately addressed in the CTCAE, the severity table below may be used: 
Severity 
Description 
GRADE 1 – Mild 
Transient or mild discomfort; no limitation in activity; no 
medical intervention/therapy required. 
GRADE 2 – Moderate 
Mild to moderate limitation in activity—some assistance 
may be needed; no or minimal medical 
intervention/therapy required. 
GRADE 3 – Severe 
Marked limitation in activity, some assistance usually 
required; medical intervention/therapy required, 
hospitalizations possible. 
GRADE 4 – Life-threatening 
Extreme limitation in activity, significant assistance 
required; life-threatening (immediate risk of death); 
significant medical intervention/therapy required, 
hospitalization or hospice care probable. 
GRADE 5 – Fatal 
Death 
Any condition, laboratory abnormality, or physical finding with an onset date prior to the subject 
signing consent for study participation is considered to be pre-existing in nature and part of the 
subject’s medical history. 
The Treating Investigator is responsible for evaluating all AEs for relationship to study drug and 
for seriousness, obtaining supporting documents, and determining that documentation of the 
event is adequate. The Site or Lead Principal Investigator may delegate these duties to Sub-
investigators and must ensure that these Sub-investigators are qualified to perform these duties 
under the supervision of the Principal Investigator and that they are listed on the FDA Form 1572 
and delegation log. 

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10.4    
Serious Adverse Event 
10.4.1    Serious Adverse Event Definition 
Serious AE (SAE) means any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening (refers to an AE in which the patient was at risk of death at the time of 
the event.  It does not refer to an event which hypothetically might have caused death if it 
were more severe). 
• Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph below on planned hospitalizations). 
• Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect. 
• Is a medically important event.  This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious 
when, based on appropriate medical judgment, may jeopardize the patient, require 
medical or surgical intervention to prevent 1 of the outcomes listed above, or involves 
suspected transmission via a medicinal product of an infectious agent.   Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse; any 
organism, virus, or infectious particle (e.g., prion protein transmitting Transmissible 
Spongiform Encephalopathy), pathogenic or nonpathogenic, is considered an infectious 
agent.   
Any death occurring within 30 days of the subject receiving study drug, regardless of the subject 
having discontinued from the study must be reported to the Lead Principal Investigator as an 
SAE. 
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. 

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Planned hospital admissions or surgical procedures for an illness or disease that existed before 
the patient was enrolled in the trial are not to be considered AEs unless the condition deteriorated 
in an unexpected manner during the trial (e.g., surgery was performed earlier or later than 
planned). 
Clarification should be made between a serious AE (SAE) and an AE that is considered severe in 
intensity (Grade 3 or 4), because the terms serious and severe are NOT synonymous.  The 
general term severe is often used to describe the intensity (severity) of a specific event; the event 
itself, however, may be of relatively minor medical significance (such as a Grade 3 headache).  
This is NOT the same as serious, which is based on patient/event outcomes or action criteria 
described above, and are usually associated with events that pose a threat to a patient’s life or 
ability to function.  A severe AE ((Grade 3 or 4) does not necessarily need to be considered 
serious.  For example, a white blood cell count of 1000/mm3 to less than 2000 is considered a 
Grade 3 (severe) but may not be considered serious.  Seriousness (not intensity) serves as a guide 
for defining regulatory reporting obligations. 
10.4.2    Serious and Unexpected Suspected Adverse Reaction (SUSAR) 
A serious adverse event is considered to be a suspected adverse reaction if there is evidence to 
suggest a causal relationship to the study agent. This may include a single occurrence of an event 
strongly associated with drug exposure (e.g. Stevens Johnson Syndrome), one or more 
occurrence of an event otherwise uncommon in the study population, or an aggregate analysis of 
specific events occurring at greater frequency than expected from historical controls.  
Unexpected events are those not listed at the observed specificity or severity in the protocol, 
consent, investigator brochure, FDA approved package insert, or elsewhere in the current IND 
application. This includes adverse events listed in the protocol, consent or IND as occurring 
within the class of drugs or otherwise expected from the drug’s pharmacological properties but 
which have not been previously observed with this investigational agent. ALL serious and 
unexpected suspected adverse reactions (SUSARs) occurring on this clinical trial must be 
reported to the FDA. Refer to section 10.4.3 for reporting guidelines.  
The lead institution (University of Chicago) is responsible for notifying the appropriate 
Regulatory Agencies, when required, and in accordance with applicable laws and regulations of 
any Expedited Safety Reports.  
ALL Serious Adverse Events, whether or not they are considered related to the study agent 
MUST be reported to the Lead Principal Investigator and to the University of Chicago 

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Comprehensive Cancer Center (via paper submission via fax or email). Refer to Section 
10.4.3 for reporting guidelines. 
10.4.3    Procedures for Reporting Serious Adverse Events 
Use the UC CCC protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
Information about all serious adverse events  (SAE) from the start of treatment through 30 days 
after the last dose of study drug will be collected and recorded on the appropriate SAE form.  
The responsible Research Nurse or other designated individual at the treating site should report 
the SAE to the Study Lead Investigator, the University of Chicago CRA and the CCTO by the 
end of the business day when s/he becomes aware of the event.  Events occurring after business 
hours should be reported to the CCTO by 12 pm (noon) the next business day.  Reports should 
be made using the ‘Serious Event Report’ Form.  Please scan and send via email (preferred) or 
fax to the following: 
University of Chicago Phase II CRA General: 
PhaseIICRA@medicine.bsd.uchicago.edu 
Phone: 773-834-3095 
Fax: 773-702-4889 
UC CCC Cancer Clinical Trials Office Quality Assurance: 
qaccto@bsd.uchicago.edu 
All unexpected adverse reactions must be reported to the IND holder so the University of 
Chicago CCTO can inform the FDA.  The responsible Research Nurse or other designated 
individual at the treating site should provide a complete written report using the FDA MedWatch 
3500A form. The completed form should be sent to the CCTO (qaccto@bsd.uchicago.edu) and 
the Phase II CRA (PhaseIICRA@medicine.bsd.uchicago.edu) within the specified timelines 
below regardless of whether all information regarding the event is available.  If applicable, a 
follow-up report should be provided to the CCTO when additional information on the event 
becomes available.   
Participating sites should not forward any adverse event reports directly to the FDA.  The CCTO 
will report all events to the FDA as per the current FDA guidelines.   
Fatal or Life-threatening Events: within 4 calendar days from treating investigator knowledge 
of the event. 

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All Other Reportable Events: within 10 calendar days of treating investigator knowledge of the 
event. 
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 SAEs, the investigator 
must determine both the intensity of the event and the relationship of the event to study drug 
administration. For serious pretreatment events, the investigator must determine both the 
intensity of the event and the relationship of the event to study procedures. If a subject is 
permanently withdrawn from the study because of a SAE, this information must be included in 
the initial or follow-up SAE report as well as the appropriate form for Study Discontinuation. 
The Treating Investigator is responsible for notifying their respective Institutional Review Board 
(IRB) or Independent Ethics Committee (IEC) in accordance with local regulations of all SAEs. 
Events occurring at a participating site may be reported to the University of Chicago IRB if they 
meet current reporting criteria. 
The University of Chicago will be responsible for notifying the Regulatory Agencies where 
required as described in section 10.4.3.2. 
10.4.3.1    Expedited Reporting by the University of Chicago to Millennium 
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).    
Reporting to Millennium will be done exclusively by the University of Chicago using MedWatch 
Form 3500A and submit by facsimile or email according to the following timelines: 
Fatal and Life Threatening SAEs within 24 hours but no later than 4 calendar days of the 
sponsor-investigator’s observation or awareness of the event 

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All other serious (non-fatal/non-life threatening) events within 4 calendar days of the 
sponsor-investigator’s observation or awareness of the event 
The MedWatch Form 3500A used for SAE reporting must include at minimum: 
• Event term(s) 
• Serious criteria 
• Intensity of the event(s): Sponsor-investigator’s or sub-investigator’s 
determination.  Intensity for each SAE, including any lab abnormalities, will be determined 
by using the NCI CTCAE version specified in the protocol, as a guideline, whenever 
possible.  The criteria are available online at http://ctep.cancer.gov/reporting/ctc.html. 
• Causality of the event(s): Sponsor-investigator’s or sub-investigator’s determination of the 
relationship of the event(s) to study drug administration.  
Follow-up information on the SAE may be requested by Millennium.   
SAE grades and relationship to all study drugs will be determined by the investigator or sub-
investigator according to sections 10.2 and 10.3. 
Sponsor-investigator must also provide Millennium Pharmacovigilance with a copy of all SAE 
communications with applicable regulatory authorities related to the study product(s), as soon as 
possible but no later than 4 calendar days of such communication. 
 
SAE and Pregnancy Reporting Contact Information 
Fax Number: 1-800-963-6290 
Email: TakedaOncoCases@cognizant.com 
10.4.3.2    Expedited Reporting By the University of Chicago to the FDA 
It is the responsibility of the University of Chicago coordinator on behalf of the Lead Principal 
Investigator to notify all participating sites of all serious unexpected suspected adverse reactions 
that occur on this clinical trial and which are reported to the FDA as an IND Safety Report (21 
CFR 312.32). A copy of the completed Form 3500A (MedWatch) will be provided to the 
responsible Regulatory Manager by the IND coordinator for distribution to all participating sites. 

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This study will be conducted under an IND held by Andrzej Jakubowiak at the University of 
Chicago. The University of Chicago CCTO will be responsible for facilitating all 
communications with the FDA on behalf of the IND holder.   Participating sites should not 
communicate directly with the FDA.   
Current FDA regulations require that all SUSARs (see definition in section 10.4.2 occurring on 
this trial, other findings that suggest a significant risk to humans exposed to the investigational 
drug (e.g. information from pooled analysis of multiple studies), and any clinically significant 
increase in the rate of an expected serious adverse reaction be reported as an IND Safety Report.  
In order to meet these requirements, the lead principal investigator will review all reported 
serious adverse events as they occur to determine if FDA reporting is required and will conduct a 
literature search to seek new safety information and review and analyze all safety information 
from this clinical trial at least annually and more frequently as appropriate.  
Individual Event Reports: FDA Form 3500A (MedWatch) will be completed for all SAEs that 
require FDA reporting. Serious Adverse Event Reports for fatal or life-threatening events must 
be returned to the Lead Investigator/ University of Chicago CRA within 4 calendar days. The 
University of Chicago is responsible for completing the MedWatch Form 3500A and reporting to 
the FDA. All other events must be received within 10 calendar days.  
Other findings that suggest significant risks to the subject: A narrative description summarizing 
all relevant findings will be provided by the lead principal investigator along with a copy of any 
relevant publications (if applicable).  
Clinically Significant Increase in Frequency of Events: A narrative description summarizing all 
relevant findings will be provided by the lead principal investigator along with details of 
individual cases (if applicable).  
All MedWatch reports are due to the designated University of Chicago CRA (and will be 
forwarded to the University of Chicago Clinical Trials Office IND coordinator) according to the 
specified timeline regardless of whether or not all information regarding this event is available. If 
applicable, a follow-up report should be provided to the University of Chicago CRA/ IND 
coordinator once additional information on the event is available. 
The completed MedWatch 3500A form will be forwarded to the FDA as appropriate by the 
University of Chicago Comprehensive Cancer Center – Cancer Clinical Trials Office (CCTO) on 
behalf of the IND Holder within the appropriate timeframes as designated in 21 CRF 312.32. 

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10.5    Procedures for Reporting Drug Exposure during Pregnancy and Birth Events 
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, 
she must inform the investigator immediately and permanently discontinue study drug.  The 
sponsor-investigator must immediately fax a completed Pregnancy Form provided by 
Millennium to the Millennium Department of Pharmacovigilance or designee (see Section 
10.4.3.1).  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, the sponsor-investigator must also immediately fax a completed Pregnancy Form to 
the Millennium Department of Pharmacovigilance or designee (see Section 10.4.3.1).  Every 
effort should be made to follow the pregnancy for the final pregnancy outcome. 
If the outcome of the pregnancy meets a criterion for immediate classification as an SAE—
spontaneous abortion (any congenital anomaly detected in an aborted fetus is to be documented), 
stillbirth, neonatal death, or congenital anomaly—the Investigator should repeat the procedures 
for expedited reporting of SAEs as outlined above. 
10.6    Procedures for Reporting Drug Exposure during Pregnancy and Birth Events 
Millennium shall notify the Treating Investigator via an IND Safety Report of the following 
information:  
• Any AE associated with the use of the drug in this study or other studies that is both 
serious and unexpected  
• Any findings from tests in laboratory animals that suggest a significant risk for human 
subjects including reports of mutagenicity, teratogenicity or carcinogenicity.  
The Treating Investigator shall notify his/her IRB/IEC promptly of these new serious and 
unexpected AEs or significant risks to subjects in accordance with their policies.  
The Lead Principal Investigator must keep copies of all AE information, including 
correspondence with Millennium and the IRB/IEC on file (see Section 11.7 for records retention 
information). 

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11.    ADMINISTRATIVE REQUIREMENTS  
11.1    
Product Complaints   
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. 
For Product Complaints Call: 
MedComm Solutions at 
877-674-3784 (877 MPI DRUG)  
(US and International) 
 
Product complaints in and of themselves are not AEs.  If a product complaint results in an SAE, 
an SAE form should be completed and sent to Millennium Pharmacovigilance (refer to Section 
10.4.3.1).   
 
12.    REGULATORY OBLIGATIONS 
12.1    
Informed Consent 
No Investigator may involve a human being as a subject in research unless the Investigator has 
obtained the legally effective informed consent of the subject or the subject’s legally authorized 
representative. An Investigator shall seek such consent only under circumstances that provide the 
prospective subject or the subject’s legally authorized representative sufficient opportunity to 
consider whether or not to participate, and that minimize the possibility of coercion or undue 
influence. The information that is given to the subject or the representative shall be in a language 
understandable to the subject or representative.  
The University of Chicago will provide the Site Principal Investigator with a sample consent 
form developed by the University of Chicago. Local and/or institutional requirements may 
require disclosure of additional information in the informed consent. Any changes to the consent 
form must be submitted to the University of Chicago for approval, prior to submission to the 
participating site IRB/IEC. The participating site IRB/IEC will review the consent form for 
approval. A copy of the IRB/IEC approval form must be submitted to the University of Chicago 
prior to initiation of the study at the participating site.  

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Before implementing any study procedure, informed consent shall be documented by the use of a 
written consent form approved by the IRB/IEC and signed and dated by the subject or the 
subject’s legally authorized representative at the time of consent. A copy of the signed informed 
consent will be given to the subject or subject’s legally authorized representative. The original 
signed consent must be maintained by the Site Principal Investigator and available for inspection 
at any time. 
The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study.  
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive care 
for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time.  
12.2    
Compliance with Laws and Regulations 
The study will be conducted in accordance with U.S. Food and Drug Administration (FDA) and 
International Conference on Harmonization (ICH) Guidelines for Good Clinical Practice (GCP), 
the Declaration of Helsinki, Health Canada, any applicable local health authority, and 
Institutional Review Board (IRB) or Ethics Committee requirements.  
This study must have the approval of a properly constituted IRB or Ethics Committee. Before the 
investigational drug is shipped to the Lead or Site Principal Investigator, the Lead Investigator or 
designee will provide Millennium with a copy of the IRB or Ethics Committee approval letter 
stating that the study protocol and any subsequent amendments and informed consent form have 
been reviewed and approved.  
The Lead and Site Principal Investigator or designee will be responsible for obtaining annual 
IRB or Ethics Committee re-approval throughout the duration of the study. Copies of the 
Investigator’s annual report to the IRB or Ethics Committee and copies of the IRB or Ethics 
Committee continuance of approval must be provided to Millennium. 

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12.3    
Pre-Study Documentation Requirements 
Before study can be initiated at a given site, the following documents must be on file with the 
University of Chicago for that site:  
• A U.S. Form FDA 1572 signed by the Site Principal Investigator  
• Current Curriculum Vitae (CV) for the Site Principal Investigator and all Sub-
Investigators  
• Current IRB/IEC membership list  
• IRB/IEC approved informed consent and approval letter  
• IRB/IEC approval of any advertising materials to be used for study recruitment, if 
applicable (also to be approved by the University of Chicago)  
• CAP and CLIA Laboratory certification numbers and institution lab normal values  
• Investigational drug accountability standard operating procedures  
• Additionally, before the study can be initiated at a site, the required executed research 
contract/subcontract must be on file with the University of Chicago. 
12.4    
Annual IRB Renewals, Continuing Review and Final Reports 
A continuing review of the protocol will be completed by the University of Chicago IRB and the 
participating institutions’ IRBs at least once a year for the duration of the study. The annual IRB 
renewal approvals for participating institutions should be forwarded promptly to the UCCCC 
Regulatory Manager. If the institution’s IRB requires a new version of the consent form with the 
annual renewal, the consent form should be included with the renewal letter. 
12.5    
Subject Confidentiality 
Subject medical information obtained as part of this study is confidential, and must not be 
disclosed to third parties, except as noted below. The subject may request in writing that medical 
information be given to his/her personal physician.  
The Investigator/Institution will permit direct access to source data and documents by the 
University of Chicago, Millennium, and its designee, the FDA and/or other applicable regulatory 
authority. The access may consist of trial-related monitoring, audits, IRB or Ethics Committee 
reviews, and FDA inspections.  

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Release of research results should preserve the privacy of medical information and must be 
carried out in accordance with Department of Health and Human Services Standards for Privacy 
of Individually Identifiable Health Information, 45 CFR 164.508. 
12.6    
Protocol Amendments and Study Termination 
All protocol amendments will be implemented by the University of Chicago and must receive 
IRB/IEC approval before implementation, except where necessary to eliminate an immediate 
hazard to subjects. Amendments should only be submitted to the IRB/IEC after consideration by 
Millennium. Only the Lead Investigator can authorize any modifications, amendments, or 
termination of the protocol. Once a protocol amendment has been approved by the University of 
Chicago IRB, the Regulatory Manager will send the amended protocol and consent form to the 
affiliate institutions electronically for submission to the affiliate institution’s IRB. The Site 
Principal Investigator or designee must send a copy of the approval letter from the IRB for the 
amendment, along with the revised Informed Consent form (as applicable), to the University of 
Chicago. The University of Chicago version date and/or amendment number must appear on the 
affiliate consent form and on the affiliate IRB approval letter (the version date can be found on 
the footer of every page of the protocol and consent form, and the amendment number can be 
found on the University of Chicago IRB amendment approval letter sent with the amendment).  
The University of Chicago jointly with the study supporters and the Lead Principal Investigator 
reserves the right to terminate the study according to the study contract. The Site and Lead 
Principal Investigator or designee should notify jointly the IRB/IEC in writing of the study’s 
completion or early termination and send a copy of the notification to the regulatory affairs 
manager at the University of Chicago Cancer Clinical Trials Office. 
12.7    
Study Documentation and Archive 
12.7.1    Source Documentation 
Source records are original documents, data, and records (e.g., medical records, raw data 
collection forms, pharmacy dispensing records, recorded data from automated instruments, 
laboratory data) that are relevant to the clinical trial. The Site and Lead Principal Investigators 
will prepare and maintain adequate and accurate source documents. These documents are 
designed to record all observations and other pertinent data for each subject enrolled in this 
clinical trial. Source records must be adequate to reconstruct all data transcribed onto the case 
report forms. 

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12.7.2    Record Retention 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
Government agency regulations and directives require that all study documentation pertaining to 
the conduct of a clinical trial must be retained by the study investigator.  In the case of a study 
with a drug seeking regulatory approval and marketing, these documents shall be retained for at 
least two years after the last approval of marketing application in an International Conference on 
Harmonization (ICH) region.  In all other cases, study documents should be kept on file until 
three years after the completion and final study report of this investigational study. 
12.7.3    Case Report Form Completion 
The data collected for this study will be entered into a secure database Velos eResearch. The 
University of Chicago will provide you with the applicable user registration information. Source 
documentation must be available to support the computerized patient record. Source records are 
original documents, data, and records (e.g., medical records, raw data collection forms, 
pharmacy dispensing records, recorded data from automated instruments, laboratory data) that 
are relevant to the clinical trial. Each site will prepare and maintain adequate and accurate source 
documents. These documents are designed to record all observations and other pertinent data for 
each subject enrolled in this clinical trial. Source records must be adequate to reconstruct all data 
transcribed onto the case report form. Upon registration, source documentation including 
demographics, screening labs, subject demographics, physician’s notes for confirmation of 
concurrent conditions, and confirmation of disease status and treatment history. Additional 
information may be requested on a case-by case basis. 
AEs are to be entered in real time. SAEs are to be reported to the University of Chicago within 
24 hours of the site’s knowledge of the event. All other data is to be entered within 30 days of 
source acquisition. 
12.7.4    Archival of Records 
According to 21 CFR 312.62I, the Site and Lead Principal Investigators shall retain records 
required to be maintained under this part for a period of 2 years following the date a marketing 

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application is approved for the drug for the indication for which it is being investigated. If no 
application is to be filed or if the application is not approved for such indication, the Site and 
Lead Principal Investigator shall retain these records until 3 years after the investigation is 
discontinued and the FDA or applicable regulatory authorities are notified.  
The Site and Lead Principal Investigator must retain protocols, amendments, IRB/IEC approvals, 
copies of the Form FDA, signed and dated consent forms, medical records, case report forms, 
drug accountability records, all correspondence, and any other documents pertaining to the 
conduct of the study. 
12.7.5    Clinical Monitoring Procedures 
Clinical studies coordinated by The University of Chicago must be conducted in accordance with 
the ethical principles that are consistent with Good Clinical Practices (GCP) and in compliance 
with other applicable regulatory requirements.  
This study will be remotely monitored by the designated University of Chicago Medicine 
Clinical Research Associate (CRA). Monitoring will be conducted to verify the following: 
• Adherence to the protocol 
• Completeness and accuracy of study data and samples collected 
• Compliance with regulations 
• Submission of required source documents 
Sites will be required to submit source documentation via fax or email to the University of 
Chicago. Source documentation required at screening includes but is not limited to medical 
history, treatment history, screening note for eligibility, and screening lab assessments. The 
University of Chicago will alert the sites to schedule a remote monitoring visit and to request 
source documentation.  
Prior to subject recruitment, a participating site will undergo site initiation teleconference to be 
conducted by the designated University of Chicago Medicine CRA and Lead Principal 
Investigator. The site’s principal investigator and his or her study staff should make every effort 
in attending the site initiation meeting. Study-related questions or issues identified during the site 
initiation meeting will be followed-up by the appropriate UCM personnel until they have been 
answered and resolved. 

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Participating sites will also undergo a site close-out teleconference upon completion, termination 
or cancellation of a study to ensure fulfillment of study obligations during the conduct of the 
study, and that the Site Principal Investigator is aware of his/her ongoing responsibilities.   
12.7.6    Obligations of Study Site Investigators 
The Study Site Principal Investigator is responsible for the conduct of the clinical trial at the site 
in accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki.  The Study Site Principal Investigator is responsible for personally overseeing the 
treatment of all study patients.  He/she must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
The Study Site Principal Investigator at each institution or site will be responsible for assuring 
that all the required data will be collected and entered into the CRFs. Periodically, monitoring 
visits or audits will be conducted and he/she must provide access to original records to permit 
verification of proper entry of data.  
12.7.7    Protocol Deviations 
Protocol deviations must be recorded using the Protocol Deviation Form and sent via email to 
PhaseIICRA@medicine.bsd.uchicago.edu. Deviations that are considered major because they 
impact subject safety or alter the risk/benefit ratio, compromise the integrity of the study data, 
and/or affect subjects’ willingness to participate in the study must be reported into the Velos 
system within 7. Please contact the University of Chicago CRA 
(PhaseIICRA@medicine.bsd.uchicago.edu) if you have questions about how to report deviations.  
Major protocol deviations should be reported to the local IRB according to the treating site’s 
regulations. 
12.7.8    Data Safety and Monitoring 
The University of Chicago Medical Center is responsible for data and safety monitoring for this 
study, including reviewing and monitoring the study’s scientific progress, accrual rate and any 
serious adverse events. This protocol will undergo weekly review at the University of Chicago 
multi-institutional data and safety monitoring teleconference as per procedures specified by the 
UCCCC NCI-approved Data and Safety Monitoring Plan.  
The study will conduct teleconferences at a rate determined by the Lead Principal Investigator to 
review the following: 

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12.7.9    Quality Assurance & Auditing 
In addition to the clinical monitoring procedures, the University of Chicago Cancer Clinical 
Trials Office (CCTO) will perform routine Quality Assurance Audits of investigator-initiated 
clinical trials as described in the NCI-approved UC CCC DSM Plan. Audits provide assurance 
that trials are conducted and study data are collected, documented and reported in compliance 
with the protocol. Further, they ensure that study data are collected, documented and reported in 
compliance with Good Clinical Practices (GCP) Guidelines and regulatory requirements by 
performing annual quality assurance audits. The CCTO will review subjects enrolled at the 
University of Chicago in accordance with audit procedures specified in the Data and Safety 
Monitoring plan.  
Auditing procedures for participating sites must be specified and approved by the UC CCC 
Clinical Research Advisory Committee.  In general, auditing responsibility will be delegated to 
the participating center, with the annual audit report forwarded to the University of Chicago for 
review.   
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during its 
conduct or even after its completion. If an inspection has been requested by a regulatory 
authority, the site investigator must immediately inform the University of Chicago Cancer 
Clinical Trials Office and Regulatory Manager that such a request has been made. 
• 
Enrollment rate relative to expectations, characteristics of participants  
• 
Safety of study participants (Serious Adverse Event & Adverse Event reporting)  
• 
Adherence to protocol (protocol deviations)  
• 
Completeness, validity and integrity of study data 
• 
Retention of study subjects 

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13.    REFERENCES    
 
1. 
Etchin J, Sun Q, Kentisis A, Farmer A, Zhang ZC, Sanda T, Mansour MR< Barcelo C, 
McCauley D, Kauffman M, Shacham S, Christie AL, Kung AL, Rodig SJ, Chook YM, 
Look AT. Antileukemia activity of nuclear export inhibitors that spare normal 
hematopoietic cells. Leukema 2013 Jan;27(1):66-74 
2. 
Ranganathan P, Yu X, Na C, Santhanam R, Shacham S, Kauffman M, Walker A, 
Klisovic R, Blum W, Caligiuri M, Croce CM, Marucci G, Garzon R. Preclinical activity 
of a novel CRM1 inhibitor in acute myeloma leukemia. Blood. 2012 Aug 
30;120(9):1765-73. 
3. 
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. 
4. 
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 
5. 
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 
6. 
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. 
7. 
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. 
8. 
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.. 
9. 
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. 
10. 
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. 

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11. 
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. 
12. 
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. 
13. 
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. 
14. 
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 
relapsed and/or refractory multiple myeloma (MM). J Clin Oncol (ASCO Meeting 
Abstracts) 2012;30(15 suppl):abstr 8017. 
15. 
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; 
16.  
McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell 
transplantation for multiple myeloma. N Engl J Med 2012;366:1770-1781 

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14.    APPENDICES 
14.1    
Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status 
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 
Source:  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5 (6):649-55.  
 
 
 

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14.2   
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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14.3   
Response Criteria for Multiple Myeloma 
IMWG Criteria 
Response 
IMWG criteria1,2 
sCR 
Stringent 
Complete 
Response 
CR as defined below plus:  
• normal FLC ratio and  
• absence of clonal cells in bone marrow by immunohistochemistry or 
2 – 4 color flow cytometry 
CR 
Complete 
Response 
• Negative immunofixation on the serum and urine and  
• disappearance of any soft tissue plasmacytomas and  
• < 5% plasma cells in bone marrow.   
• In patients with only FLC disease, a normal FLC ratio of 0.26–1.65 
is required. 
VGPR 
Very Good 
Partial 
Response 
• Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis or 
• > 90% reduction in serum M-protein plus urine M-protein level < 
100 mg/24 h.   
• In patients with only FLC disease, >90% decrease in the difference 
between involved and uninvolved FLC levels is required. 
PR 
Partial 
Response 
• 50% reduction of serum M-protein and reduction in 24 hours urinary 
M-protein by >90% or to < 200 mg/24 h 
• If the serum and urine M-protein are unmeasurable,3 a > 50% 
decrease in the difference between involved and uninvolved FLC 
levels is required in place of the M-protein criteria 
• If serum and urine M-protein are not measurable, and serum free 
light assay is also not measureable, > 50% reduction in plasma cells 
is required in place of M-protein, provided baseline bone marrow 
plasma cell percentage was > 30% 
• In addition to the above listed criteria, if present at baseline, a > 50% 
reduction in the size of soft tissue plasmacytomas is also required 
Stable 
Disease 
• Not meeting criteria for CR, VGPR, PR or progressive disease 

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All relapse categories (CR, sCR, VGPR, and PD) require two consecutive assessments made at 
any time before the institution of any new therapy; complete response and PR and SD categories 
also require no known evidence of progressive or new bone lesions if radiographic studies were 
performed.  VGPR and CR categories require serum and urine studies regardless of whether 
disease at baseline was measurable in serum, urine both or either.  Radiographic studies are not 
required to satisfy these response requirements. Bone marrow assessments need not be confirmed.  
For progressive disease, serum M-component increases of ≥ I gm/dl are sufficient to define 
response if starting M-component is ≥ 5 g/dl.    
 
IMWG clarification for coding PD:   
• Clarified that bone marrow criteria for PD are to be used only in patients without measurable 
disease by M protein and by FLC levels.   
• Clarified that 25% increase refers to M protein, FLC, and bone marrow results and does not 
refer to bone lesions, soft tissue plasmacytomas or hypercalcemia.  Note the lowest response 
value does not need to be a confirmed value. 
 
Additional response criteria for specific disease states1,2,3,4 
Minor response in patients with relapsed and 
refractory myeloma adapted from the EMBT 
criteria3 
≥ 25% but < 49% reduction of serum M protein 
and reduction in 24 hour urine M protein by 50 – 
89%, which still exceeds 200 mg/24hrs. 
 
In addition to above; if present at baseline, 25-
49% reduction in the size of soft tissue 
plasmacytomas is also required 
 
No increase in size or number of lytic bone 
lesions (development of compression fractures 
does not exclude response) 
Near Complete Response nCR 
The 
absence 
of 
myeloma 
protein 
on 
Progressive 
disease 
Increase of > 25% from lowest response value in any one of the following: 
• 
Serum M-component (the absolute increase must be > 0.5 g/dL)4 and/or  
• 
Urine M-component (the absolute increase must be > 200 mg/24 
h)and/or  
• 
Only in patients without measurable serum and urine M-protein, the 
difference between involved and uninvolved FLC levels. The absolute 
increase must be > 10 mg/dL 
• 
Only in patients without measurable serum and urine M-protein and without 
measurable disease by FLC levels, bone marrow plasma cell percentage (absolute % 
must be ≥ 10%)  
• 
Definite development of new bone lesions or soft tissue plasmacytomas or definite 
increase in the size of existing bone lesions or soft tissue plasmacytomas 
• 
Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be 
attributed solely to the plasma cell proliferative disorder 

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electrophoresis, with positive immunofixation, 
stable bone disease, and a normal serum calcium 
concentration 
Immunophenotypic CR 
Stringent CR plus 
Absence of phenotypic aberrant PC (clonal) in 
bone marrow with a minimum of one million of 
total BM cells analyzed by multiparametric flow 
cytometry (with ≥4 colors) 
Molecular CR 
Stringent CR plus negative ASO-PCR (sensitivity 
10-5) 
 
 
1. Durie et al. International uniform response criteria for multiple myeloma. Leukemia 2006;20:1467-73 
2. S. Vincent Rajkumar, Jean-Luc Harousseau, Brian Durie, Kenneth C. Anderson, Meletios Dimopoulos, 
Robert Kyle, Joan Blade, Paul Richardson, Robert Orlowski, David Siegel, Sundar Jagannath, Thierry 
Facon, Hervé Avet-Loiseau, Sagar Lonial, Antonio Palumbo, Jeffrey Zonder, Heinz Ludwig, David Vesole, 
Orhan Sezer, Nikhil C. Munshi, and Jesus San Miguel. Consensus recommendations for the uniform 
reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1 . Blood First 
Edition Paper, prepublished online February 3, 2011;DOI 10.1182/blood-2010-10-299487 
3. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, 
Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, Hideshima T, Esseltine 
DL, Kauffman M, Adams J, Schenkein DP, Anderson KC. A Phase 2 study of bortezomib in relapsed, 
refractory myeloma. N Engl J Med 348:2609, June 2, 2003. 
4. Richardson et al. Bortezomib or High-Dose Dexamethasone for Relapsed Multiple Myeloma. N Eng J 
Med. 352:2487-98, 2005 

University of Chicago 
                                                                 Version 2.6 
    IISR X16047 
Confidential                                                   103                                                          v25SEP2019 
14.4   
FACT/GOG-Neurotoxicity Questionnaire, Version 4.0 
By circling one (1) number per line, please indicate how true each statement has been for you 
during the past 7 days. 
ADDITIONAL CONCERNS 
Not 
at all 
A little 
bit 
Some- 
what 
Quite 
a bit 
Very 
much 
I have numbness or tingling in my hands……… 
0 
1 
2 
3 
4 
I have numbness or tingling in my feet………… 
0 
1 
2 
3 
4 
I feel discomfort in my hands…………………. 
0 
1 
2 
3 
4 
I feel discomfort in my feet…………………… 
0 
1 
2 
3 
4 
I have joint pain or muscle cramps…………… 
0 
1 
2 
3 
4 
I feel weak all over…………………………… 
0 
1 
2 
3 
4 
I have trouble hearing………………………… 
0 
1 
2 
3 
4 
I get a ringing or buzzing in my ears………… 
0 
1 
2 
3 
4 
I have trouble buttoning buttons……………… 
0 
1 
2 
3 
4 
I have trouble feeling the shape of small objects 
when they are in my hand……………………… 
0 
1 
2 
3 
4 
I have trouble walking………………………… 
0 
1 
2 
3 
4 
 
 
________________________________ 
Sources: Cella DF, Tulsky DS, Gray G, Sarafian B, Lloyd S, Linn E, et al.  The functional 
assessment of cancer therapy (FACT) scale:  development and validation of the general measure.  
J ClinOncol 1993; 11(3):570-79. 
 
 

University of Chicago 
                                                                 Version 2.6 
    IISR X16047 
Confidential                                                   104                                                          v25SEP2019 
14.5   
Quality of Life Assessment Tool 
EORTC QLQ – C30 (version 3.0) 
EORTC QLQ – MY20 
 
 

University of Chicago 
                                                                 Version 2.6 
    IISR X16047 
Confidential                                                   105                                                          v25SEP2019 
14.6  
Lenalidomide Risk Evaluation and Mitigation Strategy (REMS)™ Program 
http://www.revlimidrems.com/pdf/REV_Prescriber_Guide.pdf 
 
 

University of Chicago 
                                                                 Version 2.6 
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14.7  
Lenalidomide Prescribing Information 2013 
http://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=5fa97bf5-28a2-48f1-8955-
f56012d296be&type=pdf&name=5fa97bf5-28a2-48f1-8955-f56012d296be