Alternating the Administration of Ixazomib and Lenalidomide as Maintenance Therapy After Autologous Transplant for Treating Multiple Myeloma
Phase: PHASE2
Conditions: Plasma Cell Myeloma, Transplant-Related Carcinoma
Sponsor: Fred Hutchinson Cancer Center

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CLINICAL STUDY PROTOCOL  
FHCRC #  9266 
FRED HUTCHINSON CANCER RESEARCH CENTER 
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
Millennium Study Number:  X16064 
  
 Alternating the Administration of Ixazomib and Lenalidomide as Maintenance Therapy 
after Autologous Transplant for Treating Multiple Myeloma 
 
 
Indication: 
Maintenance therapy after autologous Tx for Multiple Myeloma 
  
 
Phase:  
II 
  
 
Protocol History 
Original 
 
02 July 2015 
Previous 
 
30 October 2015 
Previous 
 
28 December 2015 
Previous 
Current 
 
03 July 2018 
16 September 2019 
 
Investigator and Study Center: 
Principal Investigator 
Leona Holmberg, MD, PhD 
Member, FHCRC, Professor of 
Medicine, UW 
FHCRC 
1100 Fairview Avenue N. 
PO Box 19024, MS D5-390 
Seattle, WA 98109-1024  
206-667-6447 phone 
 
FHCRC Emergency (24 hours) Phone: (206) 598-8902; Fax: (206) 598-4034 
 
This is an investigator-initiated study.  The principal investigator Leona A Holmberg MD, PhD 
(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.  
IRO REC'D SEP 20 2021
FHCRC IRB Approval  
OCT 14  2021 
Document Released Date

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PROTOCOL SUMMARY  

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Study Title:  Alternating the Administration of Ixazomib and Lenalidomide as Maintenance 
Therapy after Autologous Transplant for Treating Multiple Myeloma 
Phase:  II 
Number of Patients:  30 
Study Objectives 
Primary 
• Evaluate the toxicity of the use of ixazomib and lenalidomide as maintenance therapy 
after autologous transplant  
Secondary 
• Evaluate the ability to deliver the planned therapy 
• Assess initial response to therapy 
• Evaluate the median time to disease progression 
• Assess overall survival 
 

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Overview of Study Design: 
Hypothesis of this phase II study is that ixazomib and lenalidomide as maintenance therapy 
after autologous PBSC transplant for Multiple Myeloma will be safe and tolerable and 
prolong the time to disease progression post transplant. The treatment regimen is alternating 
ixazomib with lenalidomide every two months until disease progression, intolerable toxicity 
or maximum of 24 months of therapy. The dose of ixazomib is 4.0 mg po on days 1, 8 and 15 
per each 28-day cycle given for two consecutive months, followed by then lenalidomide 10 
mg po daily for two consecutive months, then ixazomib for two months etc. Dose reduction 
for toxicity will be incorporated. If >30 days off initially planned next cycle of therapy, then 
patient will be taken off study.  Toxicity will be graded per CTCAE version 4.0.  The first 
four months of therapy will be used as the time period to evaluate end point of toxicity for 
stopping rules.  Toxicity that meets stopping rules will be determined based on the number of 
patients that are withdrawn from study for significant toxicity (grade IV, non-hematological, 
non-metabolic, non-peripheral neuropathy) and the number of patients who stop therapy for 
toxicity and are withdrawn from study as they could not recover adequately and resume 
therapy by 30 days from the initial stopping of the study drugs. We shall consider the 
withdrawal rate to be excessive, and hence the therapy to be too toxic, if the true withdrawal 
rate from the study exceeds 15% in the first four months. An interim analysis at 15 treated 
patients will be conducted. If > 50% of patients are unable to receive > 50% of planned 
therapy in first 12 months of treatment, the study will be terminated due to lack of feasibility. 
Another endpoint is time to disease progression.  Patients will be followed for initial response 
and for progression of disease, response criteria will be determined by International Myeloma 
working group criteria.  In patients with chemo-refractory disease at the time of ASCT, the 
therapy will be felt to be promising if median time to progression is >9 months. If chemo-
sensitive disease at time of ASCT, the therapy will be felt to be promising if median time to 
progression is >41 months based on CALGB 10014 lenalidomide maintenance study post 
ASCT.  Cytogenetic information will be collected and initial response rates and outcome will 
be descriptively reported. Patients will be followed for overall survival. The incidence of 
secondary cancers will also be collected. If this study regimen is deemed to be potentially 
efficacious and is not regarded as too toxic per stopping rules outlined above and observed 
EFS rate are consistent with rates that match or exceed historical benchmarks, then a phase III 
trial to show efficacy rate of this regimen over single agent therapy will be designed. 
Study Population: 
Adult Autologous Multiple Myeloma Transplant patients  
Duration of Study: 
Five  years (2-3 years to enroll patients on study) 

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SCHEDULE OF EVENTS 
 Study Flow Chart 
(Each cycle is 28 days) Cycle 
 
1-4 cycles 
 
5-24 cycles 
 
 
Day 
Screening 
(Baseline 
within 30 days) 
Predose 
Day (within 
3 days ) to 
Day 1 of 
Cycle 1-4 
Day 8 
(+/- 3 days) 
Week one 
Day 15 and 
22 
(+/- 3 days) 
Weeks 2 
and 3 
Predose 
Day (within 
3 days ) to 
Day 1 of 
Cycle 5-24 
Day 8 
(+/- 3 day) 
Week one 
Day 15 
(+/- 3 days) 
Week 2 
End of  
Study 
(Labs 
within 7 
days and 
other tests 
within 
month after 
last dose of 
drug) 
Survival 
Follow-up 
Phase 
Screening 
Pretreatment 
Treatment 
Treatment 
 
Treatment 
Treatment 
Post-
Treatment 
Post-
Treatment 
Study Procedures 
 
 
 
 
 
 
 
 
 
Obtain study informed consent  
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Review Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
Review/collect prior medications  
X 
 
 
 
 
 
 
 
 
Collect medical history 
X 
 
 
 
 
 
 
 
 
Enroll Revlimid REMS TM  program  pre cycle 3  
 
X 
 
 
 
 
 
 
 
Safety Labs/ Measurements 
 
 
 
 
 
 
 
 
 
Collect serum β-hCG pregnancy testb 
X 
Xb 
 
 
 
 
 
 
 
Collect CBC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collect blood chemistry 
X 
X 
X 
X 
X 
X 
 
X 
X 
Collect PT/INR &  aPTTa 
X 
 
 
 
 
 
 
 
 
Collect urinalysis (complete) 
X 
 
 
 
 
 
 
 
 
Collect 24-hour urine creatinine clearance 
X 
 
 
 
 
 
 
 
 
 
 

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Cycle 
------ 
1-4 
5-24 
 
 
-------- 
Day 
Screening 
(Baseline) 
Within 30  
days prior to 
first dose 
Predose 
Day ( within 
3 days 
Day 1 of 
Cycle 1-4 
Day X 
(+/- 3 days) 
Week one 
Day X 
Cycle 1-24 
Pre dose 
within 3 
days 
Day X 
(+/- 3 days 
Week one 
Day X 
(+/- 3 days) 
Week 2 
End of 
Study 
(within 
month after 
last dose of 
drug) 
Survival 
Follow-up 
Phase 
Screening 
Pretreatment 
Treatment 
Treatment 
Treatment 
Treatment 
 
Post-
treatment 
Post-
Treatment 
Review concomitant medications 
X 
X 
 
 
X 
 
 
 
 
Review adverse experiences 
 
X 
 
 
X 
 
 
X 
 
ECOG Performance Status 
X 
X 
 
 
X 
 
 
X 
X 
Perform physical examination and collect vital 
signs (including height at screening and weight at 
all visits) 
X 
X 
 
 
X 
 
 
X 
X 
Efficacy Measurements 
 
 
 
 
 
 
 
 
 
MRI Bone Marrow and osseous survey 
 
 
 
 
 
 
 
X 
X (yearly) 
BM aspirate and biopsy unilateral for pathology, 
flow, cytogenetics and myeloma FISH panel 
X 
 
 
 
 
 
 
X 
X (yearly) 
Serum free light or SPEP with IF 
X 
 
 
X (every 3 
months 
 
 
 
X 
X (every 3 
months) 
24 hour urine for UPEP with IF, total protein, 
Bence Jones quantification 
X (if abnormal 
pre TX) 
 
 
X (every 3 
months if 
abnormal 
pre Tx) 
 
 
 
X 
X (yearly) 
Drug Administration & Accountability 
 
 
 
 
 
 
 
 
 
Administer premedication/prophylactic supportive 
care medications as specified  
 
X 
 
 
X 
 
 
 
 
Dispense ixazomib only for cycles 1-2, 5-6 , 9-10, 
13-14, 17-18, 21-22 from IDS Pharmacy  
 
X 
 
 
X 
 
 
 
 
Dispense lenalidomide only for cycles, 3-4, 7-8, 
11-12, 15-16, 19-20, 23-24 (commercial source) 
 
X 
 
 
X 
 
 
 
 
Perform ixazomib pill count as indicated  
 
X 
 
 
X 
 
 
 
 
a PT/INR and aPTT should be collected at baseline and monitored throughout the study if the patient is being treated with warfarin or other anticoagulant therapy. 
b  Female patients of childbearing potential must have a negative serum pregnancy test (β-hCG pregnancy test) within 24  hours prior to receiving the first dose of 
  study drug(s). Follow Revlimid REMS TM standard plan for follow-up testing.  

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TABLE OF CONTENTS 
PROTOCOL SUMMARY ....................................................................................................... 2 
SCHEDULE OF EVENTS .................................................................................................. 5 
Study Flow Chart ................................................................................................................. 5 
1. BACKGROUND AND STUDY RATIONALE ............................................................... 14 
1.1 Scientific Background .................................................................................................. 14 
1.1.1 Disease Under Treatment ...................................................................................... 14 
1.1.2 Ixazomib (MLN9708) ........................................................................................... 14 
1.2 Preclinical Experience ................................................................................................. 14 
1.3 Clinical Experience ...................................................................................................... 14 
1.4 Pharmacokinetics and Drug Metabolism ..................................................................... 15 
1.5 Clinical Trial Experience Using the Oral Formulation of Ixazomib ........................... 16 
1.6 Relapsed and/or Refractory Multiple Myeloma .......................................................... 24 
1.7 Newly Diagnosed Multiple Myeloma (NDMM) ......................................................... 25 
1.8 Lenalidomide ............................................................................................................... 27 
1.8.1 Pharmacology and pharmacokinetics.................................................................... 27 
1.8.2 Toxicity profile ..................................................................................................... 27 
1.8.3 Special toxicity considerations.............................................................................. 27 
1.8.4 Administration ...................................................................................................... 28 
1.8.5 Clinical non TX data ............................................................................................. 28 
1.10 Study Rationale .......................................................................................................... 29 
1.10.1 Introduction/Background ........................................................................................ 29 
1.11 Potential Risks and Benefits ...................................................................................... 36 
2. STUDY OBJECTIVES ...................................................................................................... 37 
2.1 Primary Objectives ...................................................................................................... 37 
2.2 Secondary Objectives .................................................................................................. 37 
3. STUDY ENDPOINTS ....................................................................................................... 37 
3.1 Primary Endpoints ....................................................................................................... 37 
3.2 Secondary Endpoints ................................................................................................... 37 
4. STUDY DESIGN............................................................................................................... 37 
4.1 Overview of Study Design ........................................................................................... 37 
4.2 Number of Patients ...................................................................................................... 38 
4.3 Duration of Study ......................................................................................................... 38 
5. STUDY POPULATION .................................................................................................... 38 
5.1 Inclusion Criteria ......................................................................................................... 38 
5.2 Exclusion Criteria ........................................................................................................ 39 
6. STUDY DRUG .................................................................................................................. 40 
6.1 Description of Investigational Agents ......................................................................... 40 
6.1.1 Ixazomib Capsules ................................................................................................ 40 
6.2 Study Drug Administration of Ixazomib ..................................................................... 41 
6.2.1 Ixazomib Administration ...................................................................................... 41 
6.2.2 Ixazomib Destruction ............................................................................................ 42 
6.3 Lenalidomide ............................................................................................................... 42 
6.3.1 Administration of Lenalidomide ........................................................................... 42 
6.3.2 How Supplied ........................................................................................................ 42 
6.4 Dose-Modification Guidelines ..................................................................................... 42 

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6.4.1 Recommended Ixazomib Criteria for Beginning or Delaying a Subsequent 
Treatment Cycle & Dose Modifications for Treatment Associated Toxicity 42 
6.4.2 Recommended Dose Modifications for Lenalidomide Treatment Associated 
Toxicity .......................................................................................................... 46 
6.5 Additional medications ................................................................................................ 50 
6.6 Excluded Concomitant Medications and Procedures .................................................. 50 
6.7 Permitted Concomitant Medications and Procedures .................................................. 51 
6.8 Precautions and Restrictions ........................................................................................ 51 
6.9 Patients will also enroll in Revlimid REMS TM program for Lenalidomide use and 
followed appropriately as Revlimid is associated with birth defects. .................. 52 
6.10 Management of Ixazomib Clinical Events ................................................................. 52 
6.11 Preparation, Reconstitution, and Dispensing ............................................................. 55 
6.12 Packaging and Labeling ............................................................................................. 55 
6.13 Storage, Handling, and Accountability ...................................................................... 55 
6.14 Study Compliance ...................................................................................................... 56 
6.15 Termination of Treatment and/or Study Participation ............................................... 56 
7. STATISTICAL AND QUANTITATIVE ANALYSES .................................................... 57 
7.1 Statistical Methods ....................................................................................................... 57 
7.1.1 Determination of Sample Size .............................................................................. 57 
7.1.2 Randomization and Stratification.......................................................................... 57 
7.1.3 Populations for Analysis ....................................................................................... 57 
7.1.4 Procedures for Handling Missing, Unused, and Spurious Data ............................ 57 
7.1.5 Demographic and Baseline Characteristics........................................................... 57 
7.1.6 Efficacy Analysis .................................................................................................. 58 
7.1.7 Safety Analysis ..................................................................................................... 58 
7.1.8 Interim Analysis .................................................................................................... 58 
8. ADVERSE EVENTS ......................................................................................................... 59 
8.1 Definitions ................................................................................................................... 59 
8.1.1 Pretreatment definitions ........................................................................................ 59 
8.1.2 Adverse Event Definition...................................................................................... 59 
8.1.3 Serious Adverse Event Definition......................................................................... 59 
8.2 Procedures for Reporting Serious Adverse Events ...................................................... 60 
8.3 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events .......... 62 
9. ADMINISTRATIVE REQUIREMENTS ......................................................................... 62 
9.1 Product Complaints ...................................................................................................... 62 
10. DATA AND SAFETY MONITORING PLAN .............................................................. 64 
11. REFERENCES ................................................................................................................ 65 
12. APPENDICES ................................................................................................................. 70 
12.1 Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status ......... 70 
12.2 Cockcroft-Gault Equation .......................................................................................... 71 
12.3 Package Insert for Lenalidomide ............................................................................... 72 
12.4 Evaluation and Counseling of Patient ...................................................................... 108 
12.5 Protocol Registration ............................................................................................... 109 

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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
Common abbreviations used in oncology protocols are provided below.  Program-specific or 
protocol-specific abbreviations must be added to this list, and unnecessary abbreviations removed, 
as applicable.  Abbreviations that are retained should not be changed. 
Abbreviation 
Term 
 
 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
ASCT 
Autologous Peripheral Blood Stem Cell Transplant 
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 
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 
CFR 
Code of Federal Regulations 
CLP 
plasma clearance 
CLTotal 
total clearance 
Cmax 
single-dose maximum (peak) concentration 
CNS 
central nervous system 

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Abbreviation 
Term 
CO2 
carbon dioxide 
CR 
complete remission  
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 
ELISA 
enzyme-linked immunosorbent assay 
EOS 
End of Study (visit) 
EOT 
End of Treatment (visit) 
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 
GMP 
Good Manufacturing Practice 
Hb 
Hemoglobin 
Hct 
Hematocrit 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC50 
concentration producing 50% inhibition 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IRB 
institutional review board 
ITT 
intent-to-treat 

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Abbreviation 
Term 
IV 
intravenous; intravenously 
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 
QD 
quaque die; each day; once daily 
QOD 
quaque altera die; every other day 
RBC 
red blood cell 
SAE 
serious adverse event 
SD 
stable disease 
SmPC 
Summary of Product Characteristics 
t1/2 
terminal disposition half-life 

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Abbreviation 
Term 
TGI 
tumor growth inhibition 
Tmax 
single-dose time to reach maximum (peak) concentration 
ULN 
upper limit of the normal range 
US 
United States 
Vz 
volume of distribution in the terminal phase 
VGPR 
Very good partial response 
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 
Autologous transplants (ASCT) can cause remission in Multiple Myeloma (MM) patients, but 
relapse remains a major problem. Proteasome inhibitors and IMiDs are classes of drugs that are 
very active in treating Multiple Myeloma. Recently, at ASH 2013 Mateos et al [1] reported in a non-
transplant setting on the use of an alternating schedule of VMP and lenalidomide plus Dex in 
elderly newly diagnosed non- transplant Multiple Myeloma patients. The alternating schedule was 
superior to sequential therapy with respect 18 month TTP and overall Survival in patients, 
especially those who achieved a CR/sCR. Post ASCT, the addition of maintenance therapy (i.e. 
bortezomib, thalidomide and lenalidomide) changes the outcome of transplant patients by 
consistently and significantly prolonging the time to disease progression. But, there is no 
universally accepted standard of care for maintenance therapy post ASCT. The purpose of this 
study is to determine if alternating the IMiD lenalidomide with the proteasome inhibitor ixazomib is 
a well-tolerated all oral maintenance regimen and if it is effective therapy in terms of changing the 
time to disease progression post ASCT. It is felt that the use of an alternating schedule may 
decrease the development of resistant clones to emerge dominant. If feasible to deliver this therapy 
and the therapy appears to be effective, then a larger randomized trial would be appropriate 
comparing alternating schedule with single agent therapy. 
 
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 is a potent, reversible, and specific 20S proteasome inhibitor. 
Ixazomib is the first orally bioavailable proteasome inhibitor to enter clinical development. 
The ixazomib clinical development program includes investigation of activity in both 
hematologic and nonhematologic malignancies, 2 routes of administration (IV and PO), and 
more convenient/less frequent dosing schedules than those currently used with commercially 
available proteasome inhibitors. There are no new studies planned using the IV formulation 
at this time, as only the oral formulation is currently being developed for commercialization. 
Data are available from 637 patients who have received at least 1 dose of ixazomib across 
the clinical development program; in addition, 817 patients have enrolled in phase 3 clinical 
trials, either in placebo-controlled Studies C16010 or C16014 (and received either ixazomib 
or placebo in combination with LenDex), or in Study C16011 (and received either ixazomib 
and dexamethasone, or physician’s choice of a dexamethasone-containing regimen). 
Pharmacokinetic data demonstrate that the disposition of IV ixazomib is multi-exponential, 
with the rapid initial phase being largely over by 4 hours after the dose. The terminal halflife 

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after multiple doses ranges from 2.8 to 12.2 days. Oral ixazomib is rapidly absorbed with a median 
Tmax of 1 hour. The terminal half-life after multiple doses ranges from 2.1 to 11.3 days. Population 
PK analyses demonstrated that oral ixazomib can be administered as a fixed dose rather than BSA-
based dosing and starting dose adjustment is not required in patients with mild (60-90 mL/min) or 
moderate (30-60 mL/min) renal impairment. These findings have been incorporated into the 
summary of clinical studies with ixazomib (Table 1-1). 
 
Clinical studies are ongoing to investigate the safety and activity of ixazomib, including further 
characterization of the clinical pharmacology aspects of the drug. Preliminary efficacy data suggest 
that ixazomib has early anti-tumor activity across all clinical studies. The preliminary safety data 
indicate that ixazomib is generally well tolerated with manageable and reversible AEs. Most of the 
AEs seen in the clinical studies to date were reversible at tolerated doses or with drug 
discontinuation and can be monitored in the clinic with routine clinical observations and tests. 
Enrollment continues in the ongoing studies to further characterize safety and efficacy. 
 
Additional detailed information regarding the clinical experience of ixazomib may be found in the 
IB. 
1.4 Pharmacokinetics and Drug Metabolism 
The PK of ixazomib after IV dosing is characterized by a multi-exponential disposition profile in 
plasma with the terminal half-life after multiple doses ranging from 2.8 to 12.2 days. Plasma 
exposures increase proportionally over the dose range of 0.5 to 3.11 mg/m2 (0.8-6.8 mg actual 
administered dose range). Renal elimination appears to be a minor clearance pathway for ixazomib 
as renal clearance is less than 5% of the total body clearance estimate from the population PK 
analysis. 
 
After both once- and twice-weekly oral dosing, ixazomib is rapidly absorbed with a median Tmax of 
1 hour. The observed range for the terminal half-life after multiple doses is 2.1 to 11.3 days. Dose 
proportionality has been observed for doses between 0.48 and 3.95 mg/m2 (0.8-8.9 mg actual 
administered dose range). 
 
Pharmacokinetic parameters for ixazomib coadministered with LenDex (Studies C16005 
and C16008), or MP (Study C16006), appear to be similar to those observed when ixazomib 
is administered as a single agent. This suggests that there is no readily apparent effect of 
coadministration of LenDex, or MP, on the clinical PK of ixazomib. Likewise, no apparent 
differences in the PK of ixazomib have been noted between patients with different malignancies. 
 
After once-weekly dosing, Day 1 geometric mean dose-normalized ixazomib exposures in Japanese 
and Asian patients receiving ixazomib plus LenDex are similar to the observed values in Western 
patients (Studies C16004, C16005, and C16007). On Day 15, the geometric mean dose-normalized 
ixazomib AUC0-168 in Asian patients is approximately 45% higher than the observed values in 
Western patients. 
 
Ixazomib is neither a time-dependent nor a reversible inhibitor of CYP isozymes 1A2, 2B6, 2C8, 
2C9, 2C19, 2D6, or 3A4/5 (IC50 >30 µM). Treatment with up to 5000-ng/mL ixazomib citrate did 
not induce CYP1A2, 2B6, and 3A4/5 activity or corresponding immunoreactive protein levels in 

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cultured human hepatocytes. Therefore, the potential for CYP isozymes-mediated DDIs is low. 
However, there may be a potential for DDIs with a concomitant strong CYP3A4/5 or 1A2 inhibitor 
or inducer because CYP3A4/5 and 1A2 are the primary isozymes that contribute to the overall 
metabolism of ixazomib in HLMs. Clinical evaluation with a strong CYP3A4/5 inhibitor and a 
strong CYP3A4/5 inducer is ongoing (Study C16009). Ixazomib showed medium permeability in 
Caco-2 cells and may be a low-affinity substrate of P-gp, BCRP, and MRP2 efflux pump 
transporters. Ixazomib is not an inhibitor of P-gp, BCRP, and MRP2 (IC50 > 100 µM). Ixazomib 
citrate is not a substrate of OATPs and is not an inhibitor of OCT2, OAT1, OAT3, or OATPs. The 
contribution of efflux transporters to ixazomib transport is low (19% of total transport). 
Consequently, the potential for ixazomib to cause transporter-mediated DDIs is low. Results from 
these clinical pharmacology studies support the continued exclusion of strong CYP3A4 inhibitors in 
ongoing clinical trials [2] . A high-fat meal decreased both the rate and extent of absorption of 
ixazomib. Therefore,  ixazomib should continue to be administered on an empty stomach (no food 
for 2 hours before and 1 hour after dosing) [3]. Based on clinical experience from the phase 1 studies, 
the dose selected for phase 3 studies is 4 mg given weekly. 
 
Further details on these studies are provided in the IB. 
1.5    Clinical Trial Experience Using the Oral Formulation of Ixazomib 
As of March 2014, there are 18 ongoing clinical studies of ixazomib, 1 completed study, and 2 
studies initiating clinical sites. Information regarding these ongoing studies, patient populations, 
and ixazomib doses investigated are included in Table 1-1. 

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Table 1-1 
Clinical Studies of Oral Ixazomib 

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Trial/ 
Population 
Description 
Doses Investigated 
C16003 
RRMM 
N = 60 
PO, TW, single agent 
21-day cycle 
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 
28-day cycle 
0.24-3.95 mg/m2 W 
MTD:  2.97 mg/m2 
DLT:  rash, nausea, vomiting, diarrhea 
Closed to enrollment 
C16005 
NDMM 
N = 65 
PO, W, combination with LenDex 
28-day cycle 
1.68-3.95 mg/m2 W 
MTD:  2.97 mg/m2 
DLT:  nausea, vomiting, diarrhea, syncope 
RP2Da:  4.0 mg fixed (switched to fixed dosing in 
phase 2, equivalent  to 2.23 mg/m2) 
Closed to enrollment 
C16006 
NDMM 
N = 55 
PO, TW (Arm A- 42 day cycle),  W 
(Arm B- 28 day cycle), W (Arm C- 42 
day cycle), and W (Arm D-42 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 
Arm C: 3-4–mg fixed dose, W 
Arm D: 4-mg, W 
MTD = 3.0 mg 
C16007 
RRAL 
N = 27 
PO, W, single agent 
28-day cycle 
4-5.5-mg fixed dosea W 
DLT:  thrombocytopenia, diarrhea, dyspnea, acute 
rise in creatinine, cardiac arrest  
MTD:  4.0  mg W 
C16008 
NDMM 
N = 64 
PO, TW, combination with LenDex 
21-day cycle 
3.0-3.7-mg fixed dosea TW 
MTD:  3.0 mg 
Closed to enrollment 
C16009 
Solid tumors, 
Lymphomas 
N = 74 
PO, W, 5-Arm sequentially enrolling 
trial, combination with ketoconazole, 
rifampin, or clarithromycin 
2.5-5.5-mg fixed dosea W 
C16010 
RRMM 
N = 683 
PO, W, with LenDex versus placebo-
LenDex 
28-day cycle 
4.0 mg W 
C16011 
RRAL 
N = 42 
PO, W, with Dex versus physician’s 
choice of a Dex-based regimen 
28-day cycle 
4.0 mg W 
C16013 
RRMM 
N = 36 
PO, W, with LenDex 
28-day cycle 
4.0 mg W 

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Trial/ 
Population 
Description 
Doses Investigated 
C16014 
Symptomatic 
MM 
N=92 
PO, combination with LenDex 
Ixazomib 4.0 mg or matching placebo on Days 1, 
8, and 15, plus Len 25 mg on Days 1-21 (10 mg if 
low creatinine clearance, with escalation to 15 mg 
if tolerated) and Dex 40 mg (or 20 mg if >75 
years old) on Days 1, 8, 15, and 22 
C16015 
Symptomatic 
MM with 
normal renal 
function or 
severe renal 
impairment 
N=6 
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 
 

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Trial/ 
Population 
Description 
Doses Investigated 
C16017 
RR follicular 
lymphoma 
N=6 
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=24 
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) 
 
C16019 
Adult patients 
with NDMM 
following 
standard-of-care 
specific 
induction 
therapy 
followed by 
HDT and ASCT 
N=652 planned, 
site initiation in 
progress 
PO, W, single agent 
28-day cycle 
3.0-mg W (increased to 4.0mg at Cycle 5, if 
tolerated) 
 
C16020 
Treatment 
naiive adult 
patients with 
NDMM who 
are ineligible 
for high-dose 
therapy 
followed by 
ASCT due to 
age (≥65 years) 
or comorbidies 
N=2 
Arm-A: PO, W with cyclo 300 mg/m2 
and dex 40 mg (or 20 mg if (≥75 years 
old) 
Arm-B: PO, W with cyclo 400 mg/m2 
and dex 40 mg (or 20 mg if (≥75 years 
old) 
28-day cycle 
4.0 mg fixed dose, W 
TB-MC010034 
RRMM 
N = 14 
PO, W 
4.0 mg, W 
Single agent: 4.0 mg 
Combination with Rd 
Source: Clinical study protocols for all studies listed, and \biostatistics\MLNM9708\DSUR\2014\Tables\T14.1.1.1-
Disposition; data cutoff 27 March 2014. 
Abbreviations: ASCT = autologous stem cell transplant; BA = bioavailability; CSR = clinical study report; cyclo = 
cyclophosphamide; DDI = drug-drug interaction; dex = dexamethasone; HDT = high-dose therapy; IV = intravenous; 
keto = ketoconazole; len = lenalidominde; MTD = maximum tolerated dose; mel = melphalan; NDMM = newly 
diagnosed multiple myeloma; NSCLC = non-small cell lung cancer; ORR = overall response rate; PD = progressive 
disease; PFS = progression-free survival; PK = pharmacokinetics; pred = prednisone; RP2D = recommended phase 2 
dose; RP3D = recommended phase 3 dose; RRAL = relapsed and/or refractory systemic light-chain amyloidosis; 

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RRMM = relapsed and/or refractory multiple myeloma; SCT = stem cell transplant; SD = stable disease; TBD = to be 
determined; thal = thalidomide; TW = twice weekly; US = United States; UK = United Kingdom.  
Unless otherwise noted, patients may continue study treatment per protocol until disease progression or unacceptable 
toxicity. Study protocols C16001, C16002, C16003, C16004, C16007, C16009, C16015, C16017, C16018, and TB-
MC010034 specify a maximum of 12 cycles unless it is determined that a patient would derive clinical benefit from 
continued therapy beyond 12 cycles. c Within this table, number of patients enrolled is defined as the safety population, 
ie, patients who received at least 1 dose of study drug. 
aApproximate 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. 
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. An overview of the most frequent (at least 10%) AEs occurring in the pooled 
safety population from single-agent ixazomib and ixazomib in combination with standard regimen  
oral ixazomib studies is shown in Tables 1-2 and 1-3. 
Table 1-2    
Overall Safety Population Oral Ixazomib: Most Common Treatment-Emergent 
Events (>20%) by MedDRA System Organ Class and Preferred Term 
MedDRA SOC 
Preferred Term 
Total Oral Studies 
(n = 491)a 
Preferred Term 
Single-Agent Ixazomib 
(n = 153)b 
Preferred Term 
Ixazomib in 
Combination with 
Standard Regimen 
(n = 220)c 
Gastrointestinal disorders 
Nausea (47%), diarrhea 
(47%), vomiting (37%), 
constipation (27%) 
Nausea (48%), diarrhea 
(44%), vomiting (33%), 
constipation (19%) 
Diarrhea (53%), nausea 
(42%), constipation 
(35%), vomiting (33%) 
General disorders and 
administration site 
conditions 
Fatigue (45%), pyrexia 
(23%), peripheral edema 
(25%) 
Fatigue (51%), pyrexia 
(25%), peripheral 
edema (12%) 
Fatigue (45%), 
peripheral edema 
(37%), pyrexia (22%) 
Skin and subcutaneous 
tissue disorders 
Rash (all terms; 40%)d 
Rash (all terms; 36%)d Rash (all terms; 53%)d 
Blood and lymphatic 
system disorders 
Thrombocytopenia 
(33%), anemia (23%), 
neutropenia (21%) 
Thrombocytopenia 
(41%), anemia (21%), 
neutropenia (18%) 
Thrombocytopenia 
(35%), neutropenia 
(29%), anemia (26%) 
Metabolism and 
nutrition disorder 
Decreased appetite (24%) 
Decreased appetite 
(29%) 
Decreased appetite 
(19%) 
Nervous system 
Dizziness (17%), 
Peripheral neuropathy 
(16%) 
Dizziness (15%), 
peripheral neuropathy 
(13%) 
Peripheral neuropathy 
(26%), dizziness (25%) 
Infections and 
infestations 
Upper respiratory tract 
infection (19%) 
Upper respiratory tract 
infection (18%) 
Upper respiratory tract 
infection (28%) 

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Table 1-2    
Overall Safety Population Oral Ixazomib: Most Common Treatment-Emergent 
Events (>20%) by MedDRA System Organ Class and Preferred Term 
MedDRA SOC 
Preferred Term 
Total Oral Studies 
(n = 491)a 
Preferred Term 
Single-Agent Ixazomib 
(n = 153)b 
Preferred Term 
Ixazomib in 
Combination with 
Standard Regimen 
(n = 220)c 
Musculoskeletal and 
connective tissue 
disorders 
Back pain (15%), pain in 
extremity (13%) 
Back pain (12%) 
Back pain (27%), 
pain in extremity (21%) 
Psychiatric disorders 
Insomnia (18%) 
 
Insomnia (29%) 
Source: \biostatistics\MLNM9708\IB\2014\Tables\T14.1.3-TEAE_Pct10_Pooled, 
\biostatistics\MLNM9708\IB\2014\Tables\T14.1.4-TEAE_Pct10_OralSingle, and 
\biostatistics\MLNM9708\IB\2014\Tables\T14.1.5-TEAE_Pct10_OralComb; data cutoff 27 March 2014. 
a Studies with oral formulation C16003/4/5/6/7/8/9/13/15/17/18/TB_MC010034) excluding ongoing phase 
3 trials. 
b Studies C16003, C16004, C16007, and C16017. 
c Studies C16005 (w/ LenDex), C16006 (w/ MP), C16008 (w/ LenDex), and C16013 (w/ LenDex) 
(n = 220). 
d Represents aggregate frequency as no individual preferred term reported at ≥ 20% frequency. 
 
Table 1-3    
Most Common (>10% of Total) Treatment-Emergent Adverse Events in Oral  
Studies 
Primary System Organ Class 
     Preferred Term 
Oral Studies 
Total 
n = 491 
n (%) 
Subjects with at Least One Adverse 
Event 
482 (98) 
Gastrointestinal disorders 
400 (81) 
Nausea 
230 (47) 
Diarrhoea 
230 (47) 
Vomiting 
181 (37) 
Constipation 
134 (27) 
Abdominal pain 
60 (12) 
General disorders and 
administration site conditions 
363 (74) 
Fatigue 
223 (45) 
Pyrexia 
112 (23) 
Oedema peripheral 
122 (25) 
Asthenia 
74 (15) 
Nervous system disorders 
272 (55) 

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Table 1-3    
Most Common (>10% of Total) Treatment-Emergent Adverse Events in Oral  
Studies 
Primary System Organ Class 
     Preferred Term 
Oral Studies 
Total 
n = 491 
n (%) 
Dizziness 
85 (17) 
Headache 
74 (15) 
Neuropathy peripheral 
81 (16) 
Metabolism and nutrition disorders 
267 (54) 
Decreased appetite 
120 (24) 
Dehydration 
61 (12) 
Hypokalaemia 
57 (12) 
Blood and lymphatic system 
disorders 
256 (52) 
Thrombocytopenia 
161 (33) 
Anaemia 
114 (23) 
Neutropenia 
103 (21) 
Lymphopenia 
61 (12) 
Skin and subcutaneous tissue 
disorders 
255 (52) 
Rash (all terms) 
197 (40) 
Rash maculo-papulara 
60 (12) 
Rash maculara 
56 (11) 
Musculoskeletal and connective 
tissue disorders 
249 (51) 
Back pain 
88 (18) 
Arthralgia 
72 (15) 
Pain in extremity 
66 (13) 
Respiratory, thoracic and 
mediastinal disorders 
228 (46) 
Cough 
94 (19) 
Dyspnoea 
80 (16) 
Infections and infestations 
244 (50) 
Upper respiratory tract infection 
94 (19) 
Psychiatric disorders 
151 (31) 
Insomnia 
89 (18) 

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Table 1-3    
Most Common (>10% of Total) Treatment-Emergent Adverse Events in Oral  
Studies 
Primary System Organ Class 
     Preferred Term 
Oral Studies 
Total 
n = 491 
n (%) 
Source:  Ixazomib Investigator’s Brochure Edition 8 
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. 
aNote that rash maculopapular and rash macular represent the 2 most common terms used to describe rash. 
 
Modest transient increases in creatinine and infrequent (<8%) cases of reversible renal failure have 
also been reported. 
 
As of 27 March 2014, there are 16 studies actively enrolling patients with Multiple Myeloma to 
investigate oral ixazomib in combination with standard combination regimens. 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 
[4], non-Hodgkin’s disease, Hodgkin’s disease[5], relapsed and/or refractory Multiple Myeloma 
RRMM[6][7], relapsed or refractory systemic light chain amyloidosis RRAL[8], and newly diagnosed 
Multiple Myeloma NDMM[9][10][11] 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 development of ixazomib in patients with RRMM includes 2 phase 1 dose escalation single-
agent studies (Studies C16003 and C16004) (see study details in IB). Across these studies, 120 
patients were treated, 60 in each study (Study C16003 with the twice-weekly schedule and Study 
C16004 with the weekly schedule). The MTD in Study C16003 was 2 mg/m2 twice-weekly dosing 
based on DLTs of macular rash and thrombocytopenia (platelet count = 10 x 109/L). The MTD in 
Study C16004 was 2.97 mg/m2 given weekly based on DLTs of diarrhea, nausea, vomiting, and 
erythema multiforme. 
 
At the data cutoff, with 3 patients remaining on study, the median number of cycles administered in 
Study C16003 was 4 (range 1-61) with 33 (55%) patients treated for ≥ 4 cycles, 17 (28%) for ≥ 8 
cycles, and 11 (18%) for ≥ 12 cycles. Across all patients treated, including above and below the 
MTD, dose reductions were needed once in 57% of patients, with ≥ 2 reductions needed in 20% of 
patients. 
 

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At the data cutoff, all patients in Study C16004 have discontinued treatment. The median number of 
cycles administered was 2 (range 1-24) with 19 (32%) patients treated for ≥ 4 cycles, 12 (20%) for 
≥ 8 cycles, and 2 (3%) for ≥ 12 cycles. Across all patients treated including above and below the 
MTD, dose reductions were needed once in 33% of patients, with ≥ 2 reductions needed in 13% of 
patients.  
 
The development of ixazomib in patients with RRMM includes combinational studies (Studies 
C16010, C16013, and TB-MC010034). Study C16013 is a phase 1 study to characterize the PK and 
tolerability of 4 mg of PO ixazomib when administered in combination with LenDex in adult Asian 
patients with RRMM (see Table 1-1 for details). Two non-DLT evaluable patients reported AEs 
that, although they did not meet the protocol definition of DLT, were considered dose limiting by 
the investigator: ALT increase (Grade 3) with increased alkaline phosphatase and GGT (Grade 2) in 
one patient and diarrhea (Grade 3) in a second patient. At the data cutoff, the median number of 
cycles administered was 4.5 (range 1-15), with 20 (56%) patients treated for ≥ 4 cycles, 12 (33%) 
for ≥ 8 cycles, and 4 (11%) for ≥ 12 cycles. Across all patients treated including above and below 
the MTD, dose reductions were needed once in 28% of patients and no patient needed more than 1 
reduction. Study TB-MC010034 is a phase 1/1b study in Japanese patients with RRMM. The study 
is designed to assess the tolerability, safety, and PK of oral ixazomib both as a single agent and in 
combination with LenDex in a Japanese patient population (see Table 1-1 for details). Ixazomib at 4 
mg as a single agent and in combination with LenDex was considered tolerable because DLTs 
occurred in 1 of 6 DLT-evaluable patients in either cohort. Doselimiting toxicities included 
diarrhea, nausea, hypokalaemia, hypertension, thrombocytopenia, and hyponatraemia in the single-
agent cohort and thrombocytopenia and neutropenia in combination with LenDex. At the data 
cutoff across both cohorts, the median number of cycles administered was 7 (range 1-23) with 9 
(64%) treated for ≥ 4 cycles, 6 (43%) for ≥ 8 cycles, and 5 (36%) for ≥12 cycles. Across all patients 
treated, dose reductions were needed once in 14% of patients and 1 patient needed more than 1 
reduction. 
 
No dose adjustment is required for Asian patients based on PK and safety data. 
 
Study C16010 is an ongoing, randomized, double-blind, multicenter, phase 3 study evaluating 
ixazomib or placebo once weekly for 3 weeks in 28-day cycles, in combination with LenDex in 
patients with RRMM. At the data cutoff, a total of 683 patients were randomized in a 1:1 ratio (see 
Table 1-1 for details). Because this study is ongoing, nonserious safety or efficacy data are not 
available. Serious safety data and deaths (blinded) are summarized. 
 
1.7    Newly Diagnosed Multiple Myeloma (NDMM) 
Three phase 1/ 2 studies are being conducted with ixazomib in combination with standard anti-
myeloma regimens; 2 in combination with LenDex (Studies C16005 and C16008) and 1 in 
combination with MP (Study C16006). Study C16014 is a randomized, placebo controlled phase 3 
study of ixazomib or placebo in combination with LenDex. (See Table 1-1 for details). Throughout 
this section, Studies C16005 and C16008 are presented first, followed by Study C16014 (SAEs and 
deaths only), and then Study C16006. 
 
Study C16005 is a phase 1/2 study of weekly ixazomib in combination with LenDex in a 28- 

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day cycle during the induction phase followed by single-agent ixazomib during the maintenance 
phase [10] [12] [13][14]. The MTD was 2.97 mg/m2 given weekly with LenDex based on DLTs of 
urticaria rash, dizziness, nausea, orthostatic hypotension, vomiting, peripheral neuropathy, and 
syncope. The recommended phase 2 dose (RP2D) is 2.23 mg/m2 determined after evaluation of the 
available data from the phase 1 portion of the trial, which included but was not limited to analyses 
of both efficacy results and safety results. This RP2D has been translated into a fixed dose of 4.0 
mg on the basis of the results of the population PK analysis (IB Section 5.4) [15] [16]. 
 
At the data cutoff, in Study C16005, 15 patients remained on study receiving ixazomib in the 
maintenance phase. The median number of cycles administered was 7 (range 1-39) with 59 (91%) 
patients treated for ≥ 4 cycles, 32 (49%) for ≥ 8 cycles, 26 (40%) for ≥12 cycles, and 14 (22%) for 
≥ 25 cycles, including 1 patient who received 39 cycles. Across all patients treated including above 
and below the MTD, dose reductions of any drug in the combination were needed once in 20% of 
patients, with ≥ 2 reductions needed in 8% of patients. 
 
Study C16008 is a phase 1/2 study of twice-weekly ixazomib in combination with LenDex in a 21-
day cycle during the induction phase followed by single-agent ixazomib during the maintenance 
phase [13]. While there were no DLTs reported in this study, 3.0 mg was determined to be the RP2D 
following evaluation of the available data from the phase 1 portion of this trial including, but not 
limited to, analyses of efficacy results and toxicity characterization [17]. At the data cutoff, in Study 
C16008, 12 patients remained on study receiving ixazomib in the maintenance phase. The median 
number of cycles administered was 9 (range 1-39) with 59 (92%) patients treated for ≥ 4 cycles, 49 
(77%) for ≥ 8 cycles, 24 (38%) for ≥12 cycles, and 5 (8%) for ≥ 25 cycles, including 1 patient who 
received 38 cycles. Across all patients treated including above and below the MTD, dose reductions 
were needed once in 30% of patients, with ≥ 2 reductions needed in 11% of patients. Study C16014 
is an ongoing, randomized, double-blind, multicenter, phase 3 study conducted at more than 150 
sites worldwide. As of 27 March 2014, a total of 92 patients were randomized in a 1:1 ratio (see 
Table 1-1 for details). Because this study is ongoing, nonserious safety or efficacy data are not 
available. Serious safety data and deaths (blinded) are summarized. 
 
Study C16006 is a phase 1 study of ixazomib in combination with MP [11]. Multiple dosing 
schedules are being explored in this study as outlined in Table 1-1 and the IB. Arm A, twice-weekly 
ixazomib plus MP, was terminated due to nonhematologic toxicity findings. The MTD for Arm A is 
3 mg twice weekly with MP in a 6-week cycle based on DLTs of rash, neutropenia, and 
thrombocytopenia. Although the MTD was established, Arm A, twice weekly ixazomib plus MP, 
was terminated due to nonhematologic toxicity findings in subsequent cycles. The MTD for Arm B, 
weekly ixazomib plus MP in a 28-day cycle, is 4 mg based on DLTs of ileus, neurogeneic bladder, 
diarrhea, hematoemesis, esophageal ulcer hemorrhage, thrombocytopenia, and vomiting. One 
patient has reported DLTs (thrombocytopenia and neutropenia) in Arm D, ixazomib 2 weeks on/1 
week off × 2 plus MP in a 6-week cycle. Study C16006 is still enrolling patients. At the data cutoff, 
the median number of cycles administered was 8 (range 1-28) with 43 (78%) patients treated for ≥ 4 
cycles, 29 (53%) for ≥ 8 cycles, 21 (38%) for ≥ 12 cycles, and 3 (5%) for ≥ 25 cycles, including 1 
patient who has received 28 cycles. Across all patients treated including above and below the MTD, 
dose reductions were needed once in 35% of patients, with ≥ 2 reductions needed in 20% of 
patients.  
 

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Please refer to the ixazomib IB and SMA for further information. 
1.8   Lenalidomide 
1.8.1  Pharmacology and pharmacokinetics 
Clinical pharmacokinetics studies have shown that lenalidomide when administered as a single 200-
mg dose has a half-life of elimination that ranged from 3.2 hours to 8.7 hours. Initially, there is a 
rapid decrease in plasma levels, then there is a less rapid decline. Peak plasma levels occur between 
0.6-1.5 hours post dose being given. Co-administration with food delays absorption but does not 
alter the extent of absorption. With multiple doses, steady state plasma concentrations were 
obtained within four days. Sixty-eight percent of the orally administered lenalidomide is excreted 
by the kidneys. No pharmacokinetic or pharmocodynamic interactions between lenalidomide and 
warfarin have been observed. The interaction with digoxin if any is small and digoxin levels should 
thus be followed based on clinical judgment in patients receiving both digoxin and lenalidomide. 
   
1.8.2 Toxicity profile 
Below are listed the side effects which occurred in patients treated with lenalidomide in other 
clinical trials. 
 
Frequent (chance of 10-50% that this will happen) side effects include: fatigue, nausea, rash, 
diarrhea, constipation, vomiting, pyrexia, cough, insomnia, pruritis, peripheral edema, dyspnea, 
back pain, anorexia, abdominal pain and dizziness, headache. 
 
In addition, the following severe adverse events have been reported in patients treated with 
lenalidomide in previous research studies. 
 
Occasional (chance of 1-10% that this will happen) side effects include: thrombosis or pulmonary 
emboli, leucopenia, thrombocytopenia, neutropenia, dyspnea, pneumonia, anemia, dehydration, 
vomiting, asthenia, increased pain and kidney failure. 
 
Rare (chance of less than 1% that this will happen) side effects include: pancytopenia, 
hyperuricemia, sinusitis, fatigue, arthritis, diffuse gastritis, diverticulitis, abnormal liver function 
test, blood transfusion reaction, thyroid disorders, myositis, myocarditis with congestive heart 
failure, respiratory failure, pulmonary edema, pulmonary hypertension, interstitial lung disease, 
ischemic colitis, hepatitis, arrhythmia, increased pressure in the eye, retinal hemorrhage, fainting, 
condition characterized by weight loss and malnutrition, encephalopathy, development of new 
cancer and anaphylaxis. 
 
Recent data suggests that Multiple Myeloma patients receiving the combination of lenalidomide 
and Dexamethasone are at an increased risk for developing deep vein thrombosis.  
 
1.8.3  Special toxicity considerations 
Both men and women will enroll in the Revlimid REMS TM program and will follow appropriate 
precautions to avoid pregnancy. 

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1.8.4  Administration 
Oral Route 
  
Lenalidomide is FDA approved for treating Multiple Myeloma and  is commercially available. 
Patients, prescribers and dispensing pharmacies must be registered in the FDA-mandated Revlimid 
REMS TM program. 
 
1.8.5 Clinical non TX data  
Two multicenter randomized studies evaluated the efficacy and safety of lenalidomide. The analysis 
showed superior outcome with lenalidomide arm, over the placebo arm.  For both studies, extended 
follow-up and crossover were also analyzed.    
Table 1.4.  
TTP, Response and Survival results  
 
Study 1 
 
Study 2 
 
 
Len/Dex 
(n=177) 
Placebo/Dex 
(n-176) 
Len/Dex 
(n=176) 
Placebo/Dex 
(n=175) 
TTP 
 
 
 
 
Median TTP in months 
(95% CI)  
13.9 (9.5, 18.5) 
4.7 ( 3.7, 4.9) 
12.1 (9.5, NE) 
4.7 (38, 4.8) 
Hazard ratio (95% CI) 
0.285 (.21,.386) 
 
0.324 (.24,.438) 
 
Log rank Test, p value  <.001 
 
<.001 
 
Response 
 
 
 
 
CR n (%) 
23 (13) 
1 (1) 
27 (15)  
7 (4) 
PR  n (%) 
84 (48) 
33 (19) 
77 ( 44)  
34 (19) 
Overall response n (5)  
107 (61) 
34 (19) 
104 ( 59)  
41 (23) 
p-value 
<.001 
 
<.001 
 

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Odds ratio  
6.38 (3.95, 
10.32) 
 
4.72 (2.98, 
7.49)  
 
Survival  
 
 
 
 
Median months (95% 
CI) 
39.4 (32.9, 
47.4) 
31.6   (24.1, 
40.9)  
37.5 (29.9, 
46.6) 
30.8 (23.5, 40.3) 
Hazard ratio  (95% CI) 
0.79 ( .61-1.03) 
 
1.86 (.65-1.14)  
 
1.10  Study Rationale 
1.10.1 Introduction/Background 
Single agent high dose Melphalan combined with autologous stem cell rescue is well established as 
the standard of care for treating chemoresponsive and chemorefractory Multiple Myeloma. 
However, relapse continues to remain a major problem after a standard autologous transplant. 
Moreau, et al,[18] compared, in a prospective and randomized trial, the two most widely used 
autologous transplant conditioning regiments at that time for treatment of Multiple Myeloma. A 
total of 282 evaluable, newly-diagnosed, chemotherapy-responsive patients under the age of 65 
years old were randomized. 142 patients received Melphalan 200mg/m2 
alone. The rest were treated 
with Melphalan 140 mg/m2, Cytoxan, and total body radiation (TBI). The median duration of EFS 
was similar 21 vs. 20.5 months respectively, p=.6. The 45-month survival, though, was superior for 
Melphalan alone therapy, 65.8% vs. 45.5% (p=. 05). Vesole, et al,[19] reported on the SWOG 
experience in treating patients with chemorefractory Multiple Myeloma using high-dose Melphalan 
followed by autologous stem cell transplantation. Patients up to the age of 70 years were enrolled if 
they were refractory to VAD or other alkylating agents. All patients were given Cytoxan and GM-
GSF for collection of peripheral blood stem cells. Upon recovery from autologous transplant, 
patients were treated with maintenance interferon alfa-2b until disease progression. Of 66 
assessable patients, 56 patients went to transplant. The overall response rate to Melphalan of 
transplanted patients was 35% CR, 20% VGPR, and 39% PR. There were 4 deaths (7.1%) from 
regimen-related transplant toxicity. Overall, the median survival was 19 months based on intent to 
treat. Three-year actuarial PFS and S was 25% and 31%, respectively. Recently tandem autologous 
transplants are being offered to treat patients with Multiple Myeloma, yet, even tandem autologous 
transplants result in high relapse rates. Attal, et al,[20]showed at 4 years the EFS rate was still only 
20%. Overall, Cavo, et al, [21] have shown that tandem autologous transplants prolong the EFS rate 
by 12 months (p=.001) and time to progression by 17 months (p=.0001).  But, tandem autologous 
transplants work best in patients who do not achieve CR, near CR or VGPR with first autologous 
transplants.   
 
Thus, strategies to prevent relapse after stem cell transplant have focused on adding  novel 
treatment strategies as maintenance or consolidation therapy post ASCT.  
 
They have fallen into different approaches of consolidation without or with maintenance therapy or 
maintenance therapy alone.  Consolidation therapy regimens originally were more commonly used 

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in Europe and maintenance therapy alone in USA.  Consolidation therapy has been defined as 
improving on response and accepting more toxicity and maintenance therapy has been defined as 
maintaining response with less toxicity. But, these are really artificial definitions for if one looks at 
other disease like ALL  where maintenance therapy is also given to improve response and is given 
to patients in CR to prevent future relapses. 
  
In the era before IMiDs and bortezomib, alpha interferon and glucosteroids were all studied post 
ASCT.  The use of these drugs was limited by the question of efficacy and toxicity.  Shustik C et 
al[22] questioned the benefit of steroid therapy.  Meta-analysis of interferon showed a benefit but 
with a lot of toxicity[23] with interferon. 
 
 
 

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Thalidomide  
As the first available novel agents, thalidomide was first studied as additional therapy post ASCT. 
See tables 1.5 and 1.6 for summary of response rates and summary of outcome of studies. 
 
Table 1.5 
Initial Disease Response Rates for Thalidomide Post ASCT 
TRIAL 
CR+VGPR (%) 
Thal vs control arm 
Barlogie et al TT II[24] 
62 vs. 43, p<.01  
Attal et al[25] 
76 vs. 55, p=.03  
Spencer et al[26] 
63 vs. 40, p=.001  
Lokhorst et al[27] 
66 vs. 54, p=.005 
 
 
 

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Table 1.6 
Summary of Studies giving Thalidomide after ASCT 
Study 
Comparison 
Duration 
Thal 
PFS/EFS 
OS(yrs) 
Attal et al[25] 
T vs. none 
Prog  
+ 
+ (4 yr) 
 
Barlogie  et al[24]  
T vs. none 
Prog 
+ 
+ (8 yr) 
Lokhorst et al[27] 
T vs. inf 
Prog 
+ 
ND 
Morgan et al[28] 
T vs. none 
Prog 
+ 
ND (3 yr) 
Spencer et al[26] 
T/P vs. P 
1 yr or Prog 
+ 
+ (3 yr) 
Maiolino et al[29] 
T/D vs. D 
1 yr or Prog 
+ 
ND ( 2 yr)  
Stewart et al[30] 
T/P vs. none 
Prog 
+ 
ND (4 yr) 
+ Statistical difference in favor thalidomide-containing therapy, ND not detected difference 
statistically  
 
Differences in results may be due to differences in design of study, dose of thalidomide given, 
number of patients treated, use with steroids and type of steroid, comparison group, prior use of 
thalidomide in induction, duration of therapy and follow-up interval. In general, all have statically 
shown better event free survival (efs)/progressive free survival (pfs) in thalidomide arms of study, 
four reported increase in response rates, three studies had increase in OS.  Thalidomide seems 
though to do best in standard risk disease. Peripheral neuropathy was an issue though in the studies 
and did result in discontinuation of drug.  Little data about CR after ASCT and if those patients 
benefited by addition of thalidomide though was presented.  IFM study 99-02 reported most benefit 
of thalidomide was in patients less than VGPR after ASCT[23] but MRC My IX study did not sees 
difference in benefit based on response to ASCT[27]. Recently, Rawstron AC et al[31] showed in 
clinical trial setting MRD can be used to track efficacy of maintenance therapy as 8 out of 29 
patients with MRD positive after ASCT randomly assigned to thalidomide maintenance became 
MRD negative vs. only one out of 29 not receive maintenance therapy.  
 
Combination therapy with thalidomide has also been studied as consolidation after ASCT.  Cavo et 
al[32] reported that after tandem ASCT the PFS for VTD was superior to TD. The beneficial effect 
was most evident in patient not achieving at least near CR after ASCT in the initial report. 
 
Lenalidomide 
 
Lenalidomide was the next drug studied to be given after ASCT.  The largest randomized studies 
has been CALGB[33] and the IFM study[34]  that used maintenance or consolidation/maintenance 
approaches.  See tables 1.7 and 1.8 for summary of design of studies, comparisons of studies and 
outcomes. 

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Table 1.7 
CALGB  vs. IFM Lenalidomide Studies 
Study 
# pts 
Therapy 
EFS 
OS 
Duration 
Therapy 
CALGB 10014 [33] 
462 
Induction pre 
TX: Thal and 
Len 74%, and 
no 
progression 
during 
induction 
allowed 
All got single 
ASCT 
Cons: No 
Maint: 10 mg 
Len vs. 
Placebo 
3 yr 
EFS  
43 vs. 27 
mos 
(p<.001) 
85 vs. 77%, 
p=.028 
Med fu 34 
mos 
Superior S 
even with 
crossover 
Crossover 
Range  Len 
exposure 
30-72 mos  
All continue 
on therapy 
IFM 05-02[34] 
605 
Induction pre 
TX :  VAD 
52% and VD 
44%, pre 
ASCT  also 
25% got 
DCEP    
One ASCT 
(79%) , 2 
ASCT (21%)  
Cons: Len 2 
mos  pre day 
100 
Maint: Len 10 
mg vs. 
placebo 
4 yr 
EFS 40 vs. 
23 mos 
P<.001) 
74 vs. 75% 
(p=.7) 
Median fu 
45 mos 
 
No 
crossover 
Range  Len 
exposure 
32-59 mos 
All stopped 
therapy on 
Jan 2011 
(concern 
about 
secondary 
cancers) 
Median 32 
months 
therapy  
 
 
 

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Table 1.8  
Comparisons of CALGB and IFM studies 
Comparisons 
CALGB[33] 
IFM[34] 
Stratification  
 
 
 
 
 
Planned doses  
 
 
Median follow-up unblinded  
 
 
Response to Therapy 
Age < 71 years, Normal or 
elevated,  beta 2 microglobulin 
Prior use of Thalid, Prior use 
of Len  
 
 
Not reported  
 
 
18 months  
 
 
Cytogenetic not reported but 
analysis is ongoing 
 
 
 
CR post TX  about  29-34% 
 
Did increase time to 
progression in patients not in 
CR.  
 
 
 
 
 
No statistical difference in 
benefit between CR and not in 
CR at randomization in TTP 
and OS 
 
Induction and  maintenance 
with Len  and  OS better 
(p=.03) even with cross over 
benefit from Len in TTP  and 
OS  
Age < 65 years, CR/VGPR vs. 
PR or stable  
 
Beta 2 microglobulin < 3 or > 
3 
 
83% before stopped study  
 
 
33 months  
 
 
Len arm had more t4,14 and 
17p del (p=.006)  
Del 13  EFS 53% vs. 24%, 
(p<.001)   
 
CR post TX was 5-8% 
 
Tandem ASCT not show 
different outcome then single 
ASCT. Conversion to 
CR/VGPR 58% - 69% in two 
groups with consolidation 
therapy  
 
 
Conversion with Maintenance 
84 vs. 76 % (p= .009)  
 
VGPR benefit 64 vs. 49%, 
p=.006 
 
Less than VGPR 51 vs. 18%, 
p<.001 
 
Del 13 53% vs. 24%, p<.001 
 
 
 

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Both studies reported secondary cancer risks about 3 X increased in CALGB and 2.6 X increased in 
IFM study in lenalidomide arms vs. placebo with increased AML/MDS in CALGB and increased 
ALL and HL in IFM. 
 
A recent update at ASH 2013 Attal et al[35] showed in IFM study no OS advantage benefit for 
maintenance therapy at  68 vs. 67% for placebo (HR=1), at 5 years.  In the update, 5 year PFS was 
42% with lenalidomide vs. 18% with control arm, p, .0001.  Median survival after first progression 
after ASCT was 10 months in lenalidomide  arm vs. 19 months in placebo arm (p<.0001).  Note it is 
important though to know how patients were treated when they  relapsed as if bulk got lenalidomide 
again one would question how much benefit they would get as result.  If one looked at alternative 
drugs then one might see better survival based on how treat at relapse for example if used 
carfilzomib salvage. Another major difference in the IFM and CALGB STUDY is the stopping of 
lenalidomide in the IFM study and this may mean that lenalidomide drug if only drug given is 
better used to maximize response if ones stay on it as long as tolerated or to disease progression.  
Since CALGB has not reported seeing increased secondary malignances after long term use of 
lenalidomide with longer follow-up, it argues all risk is early in use of drug and not with long term 
use for secondary cancers. 
 
Recently, Gay et al[36], reported in a landmark analysis on the use of lenalidomide maintenance in 
patients that were < 65 years old (n=402).  They found that lenalidomide therapy increased both 
PFS and OS rates.  The 4 year OS rate from start of maintenance therapy was 80% for lenalidomide 
maintenance vs. 62% without maintenance therapy, p=.01. 
 
Bortezomib 
Bortezomib was the next novel agent studied post ASCT. Sonneveld P et al [37] looked at treating 
with PAD vs. VAD followed by auto TXs followed by thalidomide therapy in VAD group vs. 
bortezomib maintenance in PAD group.  If adjust in multivariate analysis, the OS at 3 years was 
improved in all PAD arms.  Patients with poor risk cytogenetic benefited especially del 17p13 with 
statistically significant differences in PFS (p=.0020 adj).  But although patients presenting with 
higher beta 2 microglobulin levels at diagnosis benefited from PAD they did have less benefit then 
patients with lower risk beta 2 microglobulin.  Also patients in renal failure at diagnosis had most 
benefit with bortezomib.  Bortezomib therapy was reported to improve the CR/near CR rates after 
ASCT.  Recently, Mellqvist et al[38] reported on single agent bortezomib vs. placebo after ASCT in 
bortezomib naïve patients.  The TTP was 27 months vs. 20 months for placebo p=.05.  
Improvement in response was statistically different <p=.007. Most benefit was in patients in less 
than VGPR state. But, no difference in OS was reported. 
 
Sahebi F et al[39] looked at the use of sequential therapy with bortezomib, dexamethasone for six 
cycles followed by thalidomide and dexamethasone for six cycles then thalidomide alone until 
progression as maintenance therapy after ASCT.  Thirty-three percent of the patients upgrade their 
response after ASCT to CR after the addition of maintenance therapy. 
 
As result of all these post ASCT studies NCCN guidelines recommend with category 1 evidence as 
standard of care after ASCT to treat with thalidomide or lenalidomide and bortezomib as category 
2B.   
 

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Novel agents have increased the initial CR rates, and also it is known that getting into CR appears 
to increase survival post ASCT. But, it is also important not only to get into CR but also important 
to maintain the CR.  Patients with sustained CR after ASCT > 3 years had longer median overall 
survival then those not in sustained CR (82 vs. 42 months), p<.001.   
 
ASCT is a platform to build on in which you can amplify the disease response in the setting of 
reduced tumor burden and changed immune system and thus prolong the duration of responses. 
Long term disease control remains an important part of Multiple Myeloma treatment currently in 
the absence of curative potential.  In the era of novel agents we have seen improved outcomes after 
ASCT.  Prolong therapy with induction, ASCT, consolidation therapy/maintenance therapy appear 
to be the standard approach to induce remission status that improve outcomes. The data to date 
from prospective studies show that to achieve the higher CR rates and prolong duration of their 
duration is induction with novel agents, followed by ASCT then consolidation/maintenance 
therapy.  This sequential approach seems the appropriate stage to upgrade responses.  Overall 
effective induction therapy, consolidation and/or maintenance therapy have increased the efficacy 
of ASCT with CR/near CR of 36 to 70% and 5 year OS from 61 to 72% reported.  But, there are 
many unanswered questions about how to optimize maintenance therapy post ASCT.     
 
We are thus proposing a study of ixazomib and lenalidomide as maintenance therapy after 
autologous transplant for Multiple Myeloma with the proposed modified dosing schedule based on 
overlapping toxicity of the individual drugs and decreased marrow reserve early after autologous 
transplant. Since we do not know the best way to deliver maintenance therapy after ASCT, and the 
best regimen, it is possible this alternating schedule can decrease the duration of therapy and  thus 
making it a more practical regimen for patients as well as overcome the development of cross 
resistance.   
 
In summary, autologous transplants can cause remission in Multiple Myeloma patients, but relapse 
remains a major problem.  Post-transplant maintenance therapy seems to change the outcome of 
transplant patients; however, the optimal regimen for maintenance therapy is not known. Ixazomib 
and lenalidomide are active drugs to treat Multiple Myeloma.  Thus, it is reasonable to study the 
combination of lenalidomide and ixazomib as maintenance therapy after autologous transplants. 
1.11    Potential Risks and Benefits 
Please refer to the current ixazomib IB and SMA and FDA package insert for lenalidomide (See 
Section 12.3). 
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 
Multiple Myeloma, and prolongs stabilization of the underlying disease in other patients across all 
ongoing trials.  The preliminary findings are favorable when considering historical and currently 
available therapies for the patient populations evaluated.  Though additional data are needed to 
characterize the clinical benefit of this drug, the emerging data supports expanded development of 
ixazomib for the treatment of patients with advanced malignancy. 

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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 Harmonization (ICH) 
guidelines 
 
2.    
STUDY OBJECTIVES 
2.1    Primary Objectives 
• Evaluate the toxicity of the use of ixazomib and lenalidomide as maintenance therapy after 
autologous transplant  
2.2    Secondary Objectives 
• Evaluate the ability to deliver the planned therapy  
• Assess initial response to therapy 
• Evaluate the median time to disease progression 
• Assess overall survival   
 
 
3.    
STUDY ENDPOINTS 
3.1    Primary Endpoints  
Toxicity  
3.2    Secondary Endpoints 
 Time to progression of disease  
  
4.    
STUDY DESIGN  
4.1    Overview of Study Design  
  Treatment regimen  
 
Alternating ixazomib 4.0 mg po on days 1, 8 and 15 per each 28- day cycle for two consecutive 
cycles, followed by then lenalidomide 10 mg po daily for two consecutive cycles until disease 
progression, intolerable toxicity or maximum of 24 cycles of therapy. Dose reduction for toxicity 
will be incorporated. If >30 days off initially planned next cycle of therapy, then patient will be 
taken off study. Toxicity will be graded per CTCAE version 4.0.  
 
Therapy will start 30-120 days post autologous transplant when the patient is recovered from acute 
toxicity. See study flow chart on page 4 for scheduling of events for study.  

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4.2    Number of Patients 
   Thirty patients. First day of treatment will define enrolled on study therapy.  
 
4.3    Duration of Study 
Enroll 30 patients over 2-3 years with then two year follow-up of last patient who started treatment 
on the study.   
 
5.    
STUDY POPULATION 
5.1    Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
1. Male or female patients 18 years or older.   
a. Eastern Cooperative Oncology Group (ECOG) performance status and/or other 
performance status 0, 1, or 2.  
b. Any autologous patient who underwent high dose Melphalan (>140 mg/m2) 
therapy/PBSC rescue for any stage of Multiple Myeloma and did not participate in 
another clinical transplant trial whose primary endpoint is also evaluating long-term, 
disease-free survival or survival. Consenting for study between 30 days to 120 days 
after transplant. Earliest can start therapy is 30 days post transplant after recovered 
from acute toxicity of ASCT.  
2. Voluntary written consent must be given before performance of any study related procedure 
not part of standard medical care, with the understanding that consent may be withdrawn by 
the patient at any time without prejudice to future medical care. 
3. Female patients who: 
a. Are postmenopausal for at least 1 year before the screening visit, OR 
b. Are surgically sterile, OR 
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, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable methods 
of contraception.) 

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4. 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, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable methods 
of contraception.)  
5. Patients must meet the following clinical laboratory criteria: 
a. Absolute neutrophil count (ANC) ≥ 1,000/mm3 and platelet count (transfusion 
independent)  ≥ 75,000/mm3. 
b. Total bilirubin ≤ 1.5 × the upper limit of the normal range (ULN). 
c. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN. 
d. Calculated creatinine clearance ≥ 30 mL/min (see appendix). 
 
5.2    Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
1. 
Female patients who are lactating or have a positive serum pregnancy test during the 
screening period.  
2. 
Failure to have fully recovered (i.e., ≤ Grade 1 toxicity) from the reversible effects of prior 
ASCT chemotherapy. 
3. 
Major surgery within 14 days before enrollment. 
4. 
Radiotherapy within 14 days before enrollment. If the involved field is small, 7 days will 
be considered a sufficient interval between treatment and administration of the ixazomib. 
5. 
History of central nervous system multiple myeloma involvement. 
6. 
Infection requiring systemic antibiotic therapy or other serious infection within 14 days 
before study enrollment. 
7. 
Evidence of current uncontrolled cardiovascular conditions, including uncontrolled 
hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, 
unstable angina, or myocardial infarction within the past 6 months. 

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8. 
Systemic treatment, within 14 days before the first dose of ixazomib, with strong inhibitors 
of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A 
(clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, 
posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, 
phenytoin, phenobarbital), or use of Ginkgo biloba or St. John’s wort. 
9. 
Ongoing or active systemic infection, active hepatitis B or C virus infection, or known 
human immunodeficiency virus (HIV) positive. 
10. Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol. 
11. Known allergy to any of the study medications, their analogues, or excipients in the various 
formulations of any agent. Patient cannot be allergic to boron. 
12. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance 
of ixazomib including difficulty swallowing. 
13. 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 nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if 
they have undergone complete resection. 
14. Patient has ≥ Grade 2 peripheral neuropathy, or Grade 1 with pain on clinical examination 
during the screening period. 
15. Participation in other clinical trials, including those 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.  
16. Patients with history prior to transplant of progression on lenalidomide therapy.   
 
6.      STUDY DRUG 
6.1  Description of Investigational Agents 
Treatment regimen consists of alternating ixazomib 4.0 mg po on days 1, 8 and 15 per each 28- day 
cycle for two consecutive months, followed by then lenalidomide 10 mg po daily for two 
consecutive months until disease progression, intolerable toxicity or maximum of 24 months of 
therapy.  Dose reduction for toxicity will be incorporated. If >30 days off initially planned next 
cycle of therapy, then the patient will be taken off study. Toxicity graded per CTCAE version 4.  
Patients will start therapy 30-120 days post autologous transplant. 
6.1.1 Ixazomib Capsules 
The ixazomib drug product is provided in strengths of 4.0-, 3.0-, and 2.3-mg capsules as the 
active boronic acid. The different dose strengths are differentiated by both capsule size and color 

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as described below: 
 
Dose 
Strength 
Capsule Size 
Capsule Color 
4.0 mg 
Size 4 
Ivory 
3.0 mg 
Size 3 
Light gray 
2.3 mg 
Size 2 
Light pink 
 
 
 
 
 
 
 
 
 
 
For additional details, please see the ixazomib IB. 
 
6.2    Study Drug Administration of Ixazomib 
Ixazomib is stored in the IDS Pharmacy according to storage conditions detailed in the 
Investigator’s Brochure and is dispensed by IDS Pharmacy for each cycle. Patients will keep diary 
to show took drugs. Patients should be instructed to swallow ixazomib capsules whole, with water, 
and not to break, chew, or open the capsules.  Study drug should be taken on an empty stomach (no 
food for 2 hours before and 1 hour after dosing).  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.   
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. 
6.2.1 Ixazomib 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 subinvestigator(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 9.3). 
Capsules of ixazomib will also be referred to as study drug.  Study drug will be supplied by 
Millennium as capsules of 2.3-, 3.0- and 4.0 mg ixazomib.  This is dependent on available ixazomib 
formulation.  
The prescribed administration of ixazomib doses in this study is 4 mg ixazomib on days 1, 8 and 15 
of each 28 day cycle for two cycles in a row followed then by lenalidomide therapy for two 28 day 
cycles for a total of 24 months of therapy. 

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6.2.2 Ixazomib Destruction 
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. 
6.3 Lenalidomide  
6.3.1 Administration of Lenalidomide 
After first two 28 day cycles of ixazomib, the starting dose of lenalidomide will be 10 mg po daily 
on days 1-28, every 28 day cycles for two cycles alternating with ixazomib. Lenalidomide should 
be taken orally about the same time every day, either with or without food. The capsules should not 
be opened, broken or chewed. 
 
6.3.2 How Supplied 
Lenalidomide is commercially available. Patients, prescribers and dispensing pharmacies must be 
registered in the FDA-mandated Revlimid REMS TM program. 
 
6.4 Dose-Modification Guidelines 
6.4.1 Recommended Ixazomib Criteria for Beginning or Delaying a Subsequent 
Treatment Cycle & Dose Modifications for Treatment Associated Toxicity 
Treatment with ixazomib will use a cycle length of 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 nonhematologic toxicity (except for alopecia) and peripheral neuropathy must 
have resolved to ≤ Grade 1 or to the patient’s baseline condition. 
 
If the patient fails to meet the above-cited criteria for initiation of the next cycle of treatment, 
dosing should be delayed for 1 week. At the end of that time, the patient should be re-evaluated to 
determine whether the criteria have been met. If the 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 30 days or at the discretion of the Principal Investigator. 
 
For dosing recommendations upon recovery, refer to Table 6-1, Table 6-2, and Table 6-3. 
 
 
 

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Table 6-1 
Ixazomib Dose Adjustments 
Dose Level 
Dose (mg) 
Starting Dose 
4.0 mg 
-1 
3.0 mg 
-2 
2.3 mg 
-3 
Discontinue 
 
Dosing adjustments for hematologic toxicity are outlined in Table 6-2. 
 

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Table 6-2 
Ixazomib Dose Adjustments for Toxicities 
Criteria 
Action 
Within-Cycle Dose Modifications 
 
• If platelet count ≤ 30 × 109/L or 
ANC ≤ 0.50 × 109/L on a 
ixazomib dosing day (other than 
Day 1) 
• Ixazomib dose should be withheld.   
• Complete blood count (CBC) with 
differential should be repeated at least 
every other day until the ANC and/or 
platelet counts have exceeded the 
prespecified values (see Section 6.4.1) 
on at least 2 occasions. 
• Upon recovery, ixazomib may be 
reinitiated with 1 dose level reduction. 
Dose Modifications for Subsequent 
Treatment Cycles 
 
• Delay of up to 4 weeks in the 
start of a subsequent cycle due 
to lack of toxicity recovery as 
defined in Section 6.4.1. 
• ANC < 1.0 × 109/L, platelet 
count < 75 × 109/L, or other 
nonperipheral neuropathy, 
nonhematologic toxicities 
(except for alopecia) > Grade 1 
or not to the patient’s baseline 
condition 
• Hold ixazomib until resolution as per 
criteria Section 6.4.1. 
• Upon recovery, reduce ixazomib 1 
dose level. 
• The maximum delay before treatment 
should be discontinued will be 30 days 
or at the discretion of the PI. 
Dose Modifications for Subsequent 
Treatment Cycles 
 

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Table 6-2 
Ixazomib Dose Adjustments for Toxicities 
Criteria 
Action 
• All hematologic toxicities 
• For hematologic toxicity that occurs 
during a cycle but recover in time for 
the start of the next cycle: 
o If dose was reduced within the 
cycle, start the next cycle at that 
same dose. 
o If due to toxicity timing, i.e., after 
Day 15 dosing thus a dose 
reduction was not required at that 
point in the cycle, reduce 
ixazomib by 1 dose level at the 
start of that cycle. 
o Do not reduce the dose both 
within a cycle and at the start of 
the cycle for the same most severe 
toxicity. 
Treatment modifications due to ixazomib-related AEs are outlined in Table 6-3. 
 
Table 6-3 
Ixazomib Treatment Modification (Delays, Reductions, and 
Discontinuations) Due to Adverse Events (Non-Hematologic Toxicities) 
Adverse Event (Severity) 
Action on Study Drug 
Further Considerations 
Peripheral Neuropathy: 
Grade 1 peripheral 
neuropathy 
 
No action 
 
Grade 1 signs and 
symptoms:  asymptomatic; 
without pain or loss of 
function; clinical or 
diagnostic observations 
only[7] 
 
New or worsening Grade 1 
peripheral neuropathy with 
pain or Grade 2 
Hold ixazomib until 
resolution to Grade ≤ 1 
without pain or baseline 
Grade 2 signs and 
symptoms:  Moderate 
symptoms; limiting 
instrumental activities of 
daily living (ADL)[7] 
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[7] 

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Table 6-3 
Ixazomib Treatment Modification (Delays, Reductions, and 
Discontinuations) Due to Adverse Events (Non-Hematologic Toxicities) 
Adverse Event (Severity) 
Action on Study Drug 
Further Considerations 
New or worsening Grade 4 
peripheral neuropathy 
Discontinue ixazomib 
 
Grade 2 Rash 
Symptomatic 
recommendations as per 
section 6.10 
At the discretion of the 
investigator, may require 
dose modification. 
Grade 3 Nonhematologic, 
nonperipheral neuropathy 
toxicity judged to be related 
to ixazomib 
Hold ixazomib until 
resolution to Grade < 1 or 
baseline 
Symptomatic 
recommendations noted in 
Section 6.10 
If not recovered to < Grade 1 
or baseline within 30 days 
Reduce ixazomib to next 
lower dose upon return to < 
Grade 1 or baseline 
 
Subsequent recurrence Grade 
3 that does not recover to < 
Grade 1 or baseline within 
30 days  
Hold ixazomib until 
resolution to Grade < 1 or 
baseline 
 
Grade 4 Nonhematologic  
nonperipheral neuropathy 
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  
 
Once ixazomib is reduced for any toxicity, the dose may not be re-escalated. 
6.4.2 Recommended Dose Modifications for Lenalidomide Treatment Associated 
Toxicity 
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 nonhematologic toxicity (except for alopecia) or peripheral neuropathy must have 
resolved to ≤ Grade 1 or to the patient’s baseline condition. 
The maximum delay before treatment should be discontinued will be 30 days post original planned 
start of the cycle or at the discretion of the Principal Investigator. 
 
Dose reduction schemas for Lenalidomide 
 

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Table 6.4: Dose reduction schema for Lenalidomide cycles 
  Due to Adverse Events (Hematologic Toxicities) 
 
 
ANC < 500 
and/or 
platelets< 30,000 cells/mm3  (Other than Day 1) 
Hold to ANC 
> 1000  
and  
platelets > 
75,000 
cells/mm3, 
then dose 
reduce 
1stdose 
reduction(DR): 
21 days instead of 
28 days 
 
2nd DR: 5 mg po 21 
days on, 7 days off  
 
 
3rd DR 5 mg po qod  
 

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Table 6.5: 
Dose reduction schema for Lenalidomide cycles, by Grade 
Due to Adverse Events 
(Non-Hematologic Toxicities) 
Adverse Event (Severity) 
Action on Study Drug 
Further Considerations 
Dose De-Escalation 
Schedule 
Peripheral Neuropathy: 
 
Grade 1 peripheral neuropathy 
 
 
 
 
New or worsening  
Grade 1 peripheral neuropathy 
with pain or Grade 2 
 
 
New or worsening Grade 2 
peripheral neuropathy with pain 
or Grade 3 
 
 
 
 
New or worsening Grade 4 
peripheral neuropathy 
 
 
 
No action 
 
 
 
 
Hold study drug until 
resolution to Grade ≤ 1 
without pain or baseline 
 
 
Hold study drug until 
resolution to Grade ≤ 
1without pain or baseline 
 
Reduce study drug to next 
lower dose upon recovery 
 
Discontinue study drug 
 
 
 
Grade 1 signs and symptoms:  
asymptomatic; without pain or loss 
of function; clinical or diagnostic 
observations only [7] 
 
Grade 2 signs and symptoms:  
Moderate symptoms; limiting 
instrumental activities of daily 
living (ADL) [7] 
 
Grade 3 signs and symptoms:  
severe symptoms; limiting self-
care ADL; assistive device 
indicated [7] 
 
 
 
1st dose 
reduction(DR): 
21 days instead of 28 
days 
 
 
2nd DR: 5 mg po 21 
days on, 7 days off  
 
 
3rd DR 5 mg po qod 
Rash Grade 2 
Symptomatic 
recommendations as per 
Section 6.10 
At the discretion of the 
investigator, may require dose 
modification. 
 
Grade 3 nonhematologic, 
nonperipheral neuropathy 
toxicity judged to be related to 
lenalidomide 
 
If not recovered to < Grade 1 
or baseline within 30 days 
 
Subsequent recurrence Grade 
3 that does not recover to < 
Grade 1 or baseline within 30 
days 
Hold study drug until 
resolution to Grade < 1 or 
baseline 
 
Reduce study drug 1 to 
next lower dose upon 
return to < Grade 1 or 
baseline 
 
Hold study drug until 
resolution to Grade < 1 or 
baseline 
Reduce study drug to next 
lower dose 
 
Symptomatic recommendations 
noted in Section 6.7 
 
 
 
 
 
 
 
Monitor closely, take appropriate 
medical precautions, and provide 
appropriate symptomatic care 
 
Grade 4 nonhematologic, 
nonperipheral neuropathy 
toxicities judged to be related to 
lenalidomide 
Consider permanently 
discontinuing  
lenalidomide 
Exceptions are cases in which the 
investigator determines the patient 
is obtaining a clinical benefit 
 
 

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Once lenalidomide is reduced for any toxicity, the dose may not be re-escalated. 
6.5 Additional medications 
Supportive care 
• IV Bisphosphonates therapy as clinically indicated per Standard Practice guidelines. VZV and 
PCP prophylaxis to continue for 2 additional months post stopping therapy. 
6.6 Excluded Concomitant Medications and Procedures 
The following medications and procedures are prohibited during the study. 
Systemic treatment with any of the following metabolizing enzyme inhibitors is not permitted in 
this study. (A drug-drug interaction [DDI] with a strong inhibitor would increase the ixazomib 
exposure and could lead to a higher probability of an AE): 
• Strong inhibitors of CYP1A2:  fluvoxamine, enoxacin, ciprofloxacin 
• Strong inhibitors of CYP3A:  clarithromycin, telithromycin, itraconazole, voriconazole, 
ketoconazole, nefazodone, and posaconazole 
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: Unlike with 
inhibitors, if there were to be a DDI with an inducer, ixazomib exposure would be less; therefore, 
there would be a reduced chance of an AE. However, there may be less chance for an antitumor 
effect, but that is not an absolute reason to be taken off ixazomib): 
• Strong CYP3A inducers:  rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, and 
phenobarbital 
• Excluded foods and dietary supplements include St. John’s wort and Ginkgo biloba 
The following procedures are prohibited during the study. 
• Any antineoplastic treatment with activity against Multiple Myeloma, 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 or prior to any dosing day are 
not allowed within 3 days prior to treatment administration  (refer to eligibility criteria and 
criteria required prior to initiating next cycle of treatment or within cycle dose 
modifications). 

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6.7 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.  
• Patients should be transfused with red cells and platelets as clinically indicated and 
according to institutional guidelines. 
• 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. 
6.8 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. Therefore, female patients participating in this study should avoid becoming pregnant, and 
male patients should avoid impregnating a female partner. Nonsterilized 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.) 
6.9 Patients will also enroll in Revlimid REMS TM program for Lenalidomide use and 
followed appropriately as Revlimid is associated with birth defects. 
 
Patients should not breastfeed on this study. 
 
6.10 Management of Ixazomib 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 
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 are to be given 
as clinically indicated in Section 6.5., i.e. acyclovir 800 mg po BID or valacyclovir 500 mg po BID. 
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. 

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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 lenalidomide and also 
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 or lenolidamide should be modified per protocol and re-initiated at a 
reduced level from where rash was noted (also, per protocol). 
In line with clinical practice, dermatology consult and biopsy of Grade 3 or higher rash or any SAE 
involving rash is recommended. Prophylactic measures should also be considered if a patient has 
previously developed a rash (e.g., using a thick, alcohol-free emollient cream on dry areas of the 
body or oral or topical antihistamines). A rare 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 and 
lenalidomide 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 

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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 and lenolidomide 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 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. 
Elevated Creatinine 
Metabolism appears to be a major route of elimination for ixazomib. Urinary excretion of the parent 
compound is negligible. Modest transient increases in creatinine and infrequent (< 8%) cases of 
reversible renal failure have been reported. Two patients have required temporary dialysis for acute 
renal failure. One patient was treated above the MTD in Study C16001, where IV ixazomib was 
administered to patients with advanced solid tumors. The second patient required temporary 
dialysis due to ESRD related to progression of myeloma. Confounding factors include GI toxicities 
such as nausea, vomiting, and diarrhea, and concomitant dehydration and disease progression. As a 

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result of these events, all ongoing ixazomib clinical studies were amended to increase creatinine 
monitoring to include clinical chemistry during the week off therapy and patient management 
suggestions were enhanced. Dehydration should be avoided. Appropriate supportive care that 
includes IV fluids to prevent fluid deficits according to standard medical practice is recommended. 
Non-steroidal anti-inflammatory drugs (NSAIDs) are not recommended given they may, in and of 
themselves, have an association to renal dysfunction. 
Cough, Dyspnea, and Headache 
Cases of cough, dyspnea, and headache have been reported in the clinical studies; however, the 
relationship of onset to ixazomib is not yet completely established in humans. Standard medical 
care and additional monitoring should be performed as clinically indicated. 
Peripheral Edema 
Cases of peripheral edema have been reported in the clinical studies, primarily in the oral 
combination studies. Standard medical care and additional monitoring should be performed as 
clinically indicated. 
6.11 Preparation, Reconstitution, and Dispensing 
Ixazomib and lenalidomide are anticancer drugs and as with other potentially toxic compounds 
caution should be exercised when handling ixazomib or lenalidomide capsules. 
6.12 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. 
Lenalidomide will be supplied as commercial product.  Standard recommendations from package 
insert will be followed (See appendix 12.3). 
6.13 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 
according to storage conditions detailed in the Investigator’s Brochure. Ensure that the drug is used 
before the retest expiry date provided by Millennium. Expiry extensions will be communicated 
accordingly with updated documentation to support the extended shelf life. 
In countries where local regulations permit, ixazomib capsules dispensed to the patient for take-
home dosing should remain in the blister packaging 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 

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should be given only 1 cycle of medication at a time. Patients should be instructed to store the 
medication according to storage conditions detailed in the Investigator’s Brochure 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. 
Lenalidomide will be handled per package insert (see Section 12.3) 
6.14 Study Compliance 
Ixazomib 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. 
6.15 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 
• Lost to follow-up 
• Progressive disease 
• Study terminated 
• The treatment appears detrimental in the judgment of primary physician 

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• They develop non-hematological, non-metabolic, non-peripheral neuropathy grade IV 
toxicity 
• They are unable to resume therapy more than 30 days after initial stopping of therapy for 
toxicity or cannot tolerate lowest dose reduction level 
• Repeated noncompliance to protocol in view of principal investigator 
Patients who are withdrawn from the study will not be replaced. 
At the time of withdrawal, all study procedures outlined for the End of Study visit should be 
completed per study calendar (See Study Flow Chart). The primary reason for patient’s withdrawal 
from the study should be recorded in the source documents and CRF. 
7. STATISTICAL AND QUANTITATIVE ANALYSES 
7.1 Statistical Methods 
Research Description To see if alternating ixazomib with oral lenalidomide is well tolerated with 
acceptable toxicity profile post ASCT and if it provides equivalent or superior outcomes in terms of 
time to disease progression over lenalidomide alone. 
 
7.1.1 Determination of Sample Size  
Thirty Multiple Myeloma patients post ASCT are to be enrolled over 2-3 years.  Expect to enroll 1-
1.5 patients per month. 
7.1.2 Randomization and Stratification 
There is no randomization or stratification of patients on this study. 
7.1.3 Populations for Analysis  
Multiple Myeloma patients post ASCT. 
7.1.4 Procedures for Handling Missing, Unused, and Spurious Data 
Data collection will be evaluated quarterly for record completeness. Any missing data will be 
abstracted from primary source files. Study-specific case report forms (CRFs) will specifiy required 
data to be collected to ensure that patient safety and study objectives are accurately and completely 
captured.  Primary source documents will be stored with all CRFs to provide validity for the 
abstracted data.  
7.1.5 Demographic and Baseline Characteristics 
Patients will be characterized as to whether they are chemo-sensitive or chemo-refractory disease at 
time of autologous transplant. All patients with PR or better response to last standard chemotherapy 
will be considered to have chemosensitive disease. Cytogenetic information will be collected. 

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7.1.6 Efficacy Analysis 
An endpoint of the study is time to disease progression. Patients will be followed for initial 
response and for progression of disease. Response criteria will be determined by International 
Myeloma Working Group Criteria. In patients with chemo-refractory disease at the time of ASCT, 
the therapy will be felt to be promising if median time to progression is >9 months. If chemo-
sensitive disease at time of ASCT the therapy will be felt to be promising if median time to 
progression is > 41 months based on CALGB 10014 lenalidomide maintenance study post ASCT. 
Initial response rates and outcome will be descriptively reported. Patients will be followed for 
overall survival. 
7.1.7 Safety Analysis 
The first endpoint is to evaluate the toxicity of the proposed therapy. The first four months of 
therapy will be used as the time period in which toxicity will be evaluated and stopping rules for 
unacceptable toxicity will be implemented. Rules for stopping therapy will be based on rate of 
withdrawal due to significant toxicity (grade IV, non-hematological, non-metabolic and non- 
peripheral neuropathy). A true withdrawal rate within first 4 months of 15% will be considered 
excessive. Withdrawal rate will be assessed after every ten patients are treated. Enrollment will not 
be held though until the 10th patient enrolled becomes evaluable. Sufficient evidence will be taken 
for a lower limit to the corresponding one sided 80% confidence interval that exceeds 15%. 
Operationally observed rates that say regimen is too toxic would be 2/5, 3/10, 4/15, 5/20, 6/25 and 
7/30. If the true probability of withdrawal from the study is 5%, the probability of deeming this 
regimen as too toxic after 15 or 30 patients have been treated is approximately .03 and .03, 
respectively. If the true probability of withdrawal is 10%, these probabilities are approximately .13 
and .15, respectively. On the other hand, if the true probability of withdrawal is .30, then the 
probability of judging this regimen as too toxic after 15 or 30 patients is approximately .78 and .91, 
respectively. 
 
With the semi-continuous monitoring of the withdrawal rate, the estimate of this rate, should the 
study run to completion, will be biased slightly downward. Without consideration of this bias, 30 
patients will allow us 80% confidence that the estimated withdrawal rate will be within 
approximately .094 of the true rate under the assumption that the true rate is 20%. The incidence of 
second cancers will also be collected. 
7.1.8 Interim Analysis 
An interim analysis at 15 treated patients will be conducted to assess feasibility for maintenanance 
therapy. If > 50% of patients are unable to receive > 50% of planned therapy in first 12 months of 
treatment, the study will be terminated due to lack of feasibility. 
 
If this study regimen is deemed to be potentially efficacious and is not regarded as too toxic per 
stopping rules outlined above and observed EFS rate are consistent with rates that match or exceed 
historical benchmarks, then a phase III trial to show efficacy rate of this regimen over single agent 
therapy will be designed. 
 

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8. ADVERSE EVENTS 
8.1 Definitions 
8.1.1 Pretreatment definitions 
Patients will only be evaluable for adverse event reporting after received first dose of study drug. 
8.1.2 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. 
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. 
8.1.3 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 

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particle (e.g., prion protein transmitting Transmissible Spongiform Encephalopathy), 
pathogenic or nonpathogenic, is considered an infectious agent. 
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 outcome or action criteria described 
above, and is 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 Grade 3 (severe) but 
may not be considered serious. Seriousness (not intensity) serves as a guide for defining regulatory 
reporting obligations. 
8.2 Procedures for Reporting Serious Adverse Events 
AEs may be spontaneously reported by the patient and/or in response to an open question from 
study personnel or revealed by observation, physical examination, or other diagnostic procedures. 
Any clinically relevant deterioration in laboratory assessments or other clinical finding is 
considered an AE. When possible, signs and symptoms indicating a common underlying pathology 
should be noted as one comprehensive event. For serious AEs, the investigator must determine both 
the intensity of the event and the relationship of the event to study drug administration. For serious 
pretreatment events, the investigator must determine both the intensity of the event and the 
relationship of the event to study procedures. 
 
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). 
 
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). All 
SAEs should be monitored until they are resolved or are clearly determined to be due to a patient’s 
stable or chronic condition or intercurrent illness(es). 
 
Since this is an investigator-initiated study, the principal investigator Leona Holmberg MD, PhD 
also referred to as the sponsor-investigator, is responsible for reporting serious adverse events 
(SAEs) to any regulatory agency and to the sponsor- investigator’s EC or IRB. 
 

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Regardless of expectedness or causality, all SAEs (including serious pretreatment events) must also 
be reported in English to Millennium Pharmacovigilance (or designee) within the timelines outlined 
below: 
 
Fatal and Life Threatening SAEs within 24 hours of the sponsor-investigator’s observation or 
awareness of the event 
 
All other serious (non-fatal/non-life threatening) events within 4 calendar days of the sponsor-
investigator’s observation or awareness of the event 
 
See below for contact information for the reporting of SAEs to Millennium Pharmacovigilance. 
The sponsor-investigator must fax or email the SAE Form per the timelines above. A sample of an 
SAE Form will be provided. 
The SAE report 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. 
Intensity for each SAE, including any lab abnormalities, will be determined by using the NCI 
CTCAE version used at your institution, as a guideline, whenever possible. The criteria are 
available online at http://ctep.cancer.gov/reporting/ctc.html. 
In the event that this is a multisite study, the sponsor-investigator is responsible to ensure that the 
SAE reports are sent to Millennium Pharmacovigilance (or designee) from all sites participating in 
the study. Sub-investigators must report all SAEs to the sponsor-investigator so that the sponsor-
investigator can meet his/her foregoing reporting obligations to the required regulatory agencies and 
to Millennium Pharmacovigilance, unless otherwise agreed between the sponsor-investigator and 
sub-investigator(s). 
Relationship to all study drugs for each SAE will be determined by the investigator or sub-
investigator by responding yes or no to the question: Is there a reasonable possibility that the AE is 
associated with the study drug(s)? 

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Sponsor-investigator must also provide Millennium Pharmacovigilance with a copy of all 
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 
Suggested Reporting Form: 
• SAE Report Form (provided by Millennium) 
• US FDA MedWatch 3500A: 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
• Any other form deemed appropriate by the sponsor-investigator 
 
8.3 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 or 
within 90 days after the last dose, she must inform the investigator immediately and permanently 
discontinue study drug.  The sponsor-investigator must immediately fax a completed Pregnancy 
Form to the Millennium Department of Pharmacovigilance or designee (see Section 8.2).  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 8.2). Every effort should be 
made to follow the pregnancy for the final pregnancy outcome. 
Suggested Pregnancy Reporting Form: 
• Pregnancy Report Form (provided by Millennium) 
 
In addition, reporting of lenalidomide toxicity will be per Revlimid REMS TM program. 
 
9. ADMINISTRATIVE REQUIREMENTS  
9.1 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 

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in accordance with the label instructions pending further guidance from a Millennium Quality 
representative. 
For Product Complaints, 
• 
Phone: 1-877-TAKEDA7 (1-877-825-3327) 
• 
E-mail: medicalinformation@tpna.com 
• 
FAX: 1-800-247-8860 
• 
Hours: Mon-Fri, 8 a.m. – 6 p.m. ET 
 
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 8.2). 
 

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10. DATA AND SAFETY MONITORING PLAN 
The study will be independently monitored in accordance with the Institutional Data and Safety 
Monitoring Plan of the Fred Hutchinson/University of Washington Cancer Consortium as outlined 
in: http://www.cancerconsortium.org/content/dam/consortium/Resource-Documents/Data-Safety-
Monitoring/13013S_Data_Safety_Monitoring_Plan.pdf. 
 

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11. REFERENCES 
1.  Mateos MV, Martínez-López J, Hernandez MT, Martinez R, Rosiñol L, Ocio EM, et al.  
Comparison of sequential vs alternating administration of bortezomib, melphalan and 
prednisone (VMP) and lenalidomide plus dexamethasone (Rd) in elderly patients with 
newly diagnosed multiple myeloma (MM) patients: GEM2010MAS65 trial. [Abstract] 
Blood 122(21): Abstract #403,2013 
2.  Gupta NK, Venkatakrishnan K, Noe D, Hanley M, Yu J, Bessudo A, et al. A drug-drug 
interaction study between the strong CYP3A4 inhibitor ketoconazole and ixazomib citrate 
(MLN9708), an investigational, orally active proteasome inhibitor, in patients with 
advanced solid tumors or lymphoma. [Abstract] Annual Meeting of the American Society 
of Clinical Oncology (ASCO). Chicago, IL: Abstract #2555,2013 
3.  Gupta N, H. M. (2014). A phase 1 study of the effects of a high-fat meal on the 
pharmacokinetics of ixazomib, an investigational oral proteasome inhibitor, in patients 
with advanced solid tumors or lymphoma. 19th Congress of the European Hematology 
Association (EHA). Milan, Italy: Abstract P989,2014 
4.  Chow L, Infante JR, Siu LL, Sullivan D, Kauh JS, DiBacco A, et al.  MLN9708, an 
investigational proteasome inhibitor, in patients with solid tumors: Updated phase 1 
results. [Abstract] The 2012 Multidisciplinary Head and Neck Cancer Symposium 
Phoeniz, AZ(January 26-28): Abstract #203,2012 
5.  Assouline S, Chang J, Rifkin R, Hui AM, Yu J, Di Bacco A, et al.  Once-weekly MLN9708, an 
investigational proteasome inhibitor, in patients with relapsed/refractory lymphoma: 
Results of a phase 1 dose-escalation study. [Abstract] 17th Congress of the European 
Hematology Association Amsterdam, The Netherlands(June 14-17, 2012): Abstract 
#203,2012 
6.  Lonial S, Baz RC, 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). [Abstract] J.Clin.Oncol. 30: 2012 
ASCO Annual Meeting-Abstract #8017,2012 
7.  Kumar S, Bensinger WI, Reeder CB, Zimmerman TM, Berenson JR, 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. 
[Abstract] Blood 118(21): Abstract #816,2011 
8.  Merlini G, Sanchorawala V, Zonder JA, Kukreti V, Schonland SO, Jaccard A, et al.  MLN9708, 
a novel, investigational oral proteosome inhibitor, in patients with relapsed or refractory 
ligh-chain amyloidosis (AL): Results of a phase 1 study. [Abstract] Blood 120(21): 
Abstract #731,2011 
9.  Kumar SK, Berdeja JG, Niesvizky R, Lonial S, Hamadani M, Stewart AK, et al.  A phase 1/2 
study of weekly MLN9708, an investigational oral proteosome inhibitor, in combination 
with lenalidomide and dexamethasone in patients with previously untreated multiple 

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myeloma (MM). [Abstract] Blood 120(21): Abstract #332,2011 
10.  Richardson P, Berdeja J, Niesvizky R, Lonial S, Vesole D, Hamadani M, et al.  MLN9708, an 
investigational proteasome inhibitor, combined with lenalidomide and dexamethasone in 
previously untreated multiple myeloma patients: Evaluation of weekly and twice-weekly 
dosing regimens. [Abstract] 17th Congress of the European Hematology Association 
Amsterdam, The Netherlands(June 14-17, 2012): Abstract #1144,2012 
11.  San Miguel J, Hájek R, Špicka I, Chen C, Gutierrez AE, Schusterbauer C, et al.  Oral 
MLN9708, an investigational proteasome inhibitor, in combination with melphalan and 
prednisone in patients with previously untreated multiple myeloma: A phase 1 study. 
[Abstract] 17th Congress of the European Hematology Association Amsterdam, The 
Netherlands(June 14-17, 2012): Abstract #0293,2012 
12.  Berdeja J, Richardson P, Lonial S, Nievizky R, Hui AM, Berg D, et al. (2011). Phase 1/2 Study 
of Oral MLN9708, A Novel, Investigational Proteasome Inhibitor, in Combination with 
Lenalidomide and Dexamethasone in Patients with Previously Untreated Multiple 
Myeloma (MM). 52rd ASH Annual Meeting and Exposition. San Diego, CA: Abstract 
#478,2011 
13.  Richardson P, Berdeja J, Niesvizky R, Lonial S, Hari P, Berg D, et al. (2012). Oral weekly 
MLN9708, an investigational proteasome inhibitor, in combination with lenalidomide and 
dexamethasone in patients (pts) with previously untreated multiple myeloma (MM): A 
phase 1/2 study. Annual Meeting of the American Society of Clinical Oncology (ASCO). 
Chicago, IL: Abstract #8033,2012 
14.  Kumar S, Niesvizky R, Berdeja J, Bensinger W, Zimmerman T, Berenson JR, Liu G, et al. 
(2013). Safety and Pharmacokinetics of Weekly MLN9708, an Investigational Oral 
Proteasome Inhibitor, Alone and in Combination. [Abstract] Clinical Lymphoma 
Myeloma and and Leukemia 13 (Suppl. 1): S154, #P230,2013 
15.  Gupta N, Saleh M, Venkatakrishnan K. (2011). Flat-Dosing Versus BSA-Based Dosing for 
MLN9708, An Investigational Proteasome Inhibitor: Population Pharmacokinetic (PK) 
Analysis of Pooled Data From 4 Phase-1 Studies. [Abstract] Blood 118(21): San Diego, 
CA: Abstract #1433,2011 
16.  Kumar S, Flinn I, Richardson P, Hari P, Callander N, Noga S, et al. Randomized, multicenter, 
phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, 
cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood 
119(19), 4375-4382,2012. 
 17.  Richardson P, Hofmeister C, Rosenbaum C, Htut M, Vesole D, Berdeja J, et al. Twice-Weekly 
Oral MLN9708 (Ixazomib Citrate), An Investigational Proteasome Inhibitor, In 
Combination With Lenalidomide (Len) and Dexamethasone (Dex) In Patients (Pts) With 
Newly Diagnosed Multiple Myeloma (MM): Final Phase 1 Results and Phase 2 Data. 
ASH Annual Meeting Abstracts, Abstract #535,2013.  
 18.  Moreau P, Facon T, Attal M, Hulin C, Michallet M, Maloisel F, et al. Comparison of 200 

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mg/m2 melphalan and 8 Gy total body irradiation plus 140 mg/m2 melphalan as 
conditioning regimens for peripheral blood stem cell transplantation in patients with newly 
diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myélome 
9502 randomized trial.  Blood 99(3): 731-5,2002 
 19.  Vesole D, Crowley JJ, Catchatourian R, Stiff PJ, Johnson DB, Cromer J, et al.  High-dose 
melphalan with autotransplantation for refractory multiple myeloma: results of a 
Southwest Oncology Group phase II trial.  J Clin Oncol 17(7): 2173-9,1999 
 20.  Attal M, Harousseau JL, Facon T, Guilhot F, Doyen C, Fuzibet JG, et al.  Single versus 
double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 349(26): 
2495-502,2003 
 21.  Cavo M, Cellini C, Zamagni E, Tosi P, Cangini D, Tacchetti P, et al.  Superiority of double 
over single autologous stem cell transplantation as first-line therapy for multiple myeloma. 
[Abstract] Blood 104 (Part 1)(11): 155a-6a, Abstract #536,2004 
 22.  Shustik C, Belch A, Robinson S, Rubin SH, Dolan SP, Kovacs MJ, et al.  A randomised 
comparison of melphalan with prednisone or dexamethasone as induction therapy and 
dexamethasone or observation as maintenance therapy in multiple myeloma: NCIC CTG 
MY.7.  Br J Haematol 136(2): 203-11,2007 
 23.  Myeloma Trialists' Collaborative Group: Interferon as therapy for multiple myeloma: an 
individual patient data overview of 24 randomized trials and 4012 patients. Br J Haematol 
113(4): 1020-34,2001 
 24.  Barlogie B, Tricot G, Anaissie E, Shaughnessy J, Rasmussen E, van Rhee F, et al.  
Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 
354(10): 1021-30,2006 
 25.  Attal M, Harousseau JL, Leyvraz S, Doyen C, Hulin C, Benboubker L, et al. Maintenance 
therapy with thalidomide improves survival in patients with multiple myeloma. Blood 
108(10): 3289-94,2006 
 26.  Spencer A, Prince HM, Roberts AW, Prosser IW, Bradstock KF, Coyle L, et al.  
Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival 
of multiple myeloma patients undergoing a single autologous stem-cell transplantation 
procedure. J Clin Oncol 27(11): 1788-93,2009 
 27.  Lokhorst HM, van der HB, Zweegman S, Vellenga E, Croockewit S, van Oers MH, et al.  A 
randomized phase 3 study on the effect of thalidomide combined with adriamycin, 
dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in 
patients with multiple myeloma. Blood 115(6): 1113-20,2010 
 28.  Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM, et al.  The role of 
maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and 
meta-analysis. Blood 119(1): 7-15,2012 

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 29.  Maiolino A, Hungria VT, Garnica M, Oliveira-Duarte G, Oliveira LC, Mercante DR, et al.  
Thalidomide plus dexamethasone as a maintenance therapy after autologous 
hematopoietic stem cell transplantation improves progression-free survival in multiple 
myeloma.  Am J Hematol 87(10): 948-52,2012 
 30.  Stewart AK, Trudel S, Bahlis NJ, White D, Sabry W, Belch A, et al.  A randomized phase 3 
trial of thalidomide and prednisone as maintenance therapy after ASCT in patients with 
MM with a quality-of-life assessment: the National Cancer Institute of Canada Clinicals 
Trials Group Myeloma 10 Trial. Blood 121(9): 1517-23,2013 
 31.  Rawstron AC, Child JA, de Tute RM, Davies FE, Gregory WM, Bell SE, et al.  Minimal 
residual disease assessed by multiparameter flow cytometry in multiple myeloma: impact 
on outcome in the Medical Research Council Myeloma IX Study.  J Clin Oncol 31(20): 
2540-7,2013 
 32.  Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D, et al.  
Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as 
consolidation therapy after autologous hematopoietic stem cell transplantation in patients 
with newly diagnosed multiple myeloma. Blood 120(1): 9-19,2012 
 33.  McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, et al.  
Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 
366(19): 1770-81,2012 
 34.  Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T, et al.  Lenalidomide 
maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 366(19): 
1782-91,2012 
 35.  Attal M, Lauwers-Cances V, Marit G, Caillot D, Facon T, Hulin C, et al.  Lenalidomide 
maintenance after stem-cell transplantation for multiple myeloma: follow-up analysis of 
the IFM 2005-02 trial. [Abstract] Blood 122(21): Abstract #406,2013 
 36.  Gay F, Cavallo F, Caravita T, Cavalli M, Nagler A, Montefusco V, et al.  Maintenance 
therapy with lenalidomide significantly improved survival of yong newly diagnosed 
multiple myeloma patients. [Abstract] Blood 122(21): Abstract #2089,2013 
 37.  Sonneveld P, Schmidt-Wolf IG, van der Holt B, el Jarari L, Bertsch U, Salwender H, et al.  
Bortezomib induction and maintenance treatment in patients with newly diagnosed 
multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 
trial.[Erratum appears in J Clin Oncol. 2012 Oct 10;30(29):3654].  J Clin Oncol 30(24): 
2946-55,2012 
38.  Mellqvist UH, Gimsing P, Hjertner O, Lenhoff S, Laane E, Remes K, et al.  Bortezomib 
consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic 
Myeloma Study Group randomized phase 3 trial.  Blood 121(23): 4647-54,2013 
39.  Sahebi F, Frankel PH, Farol L, Krishnan AY, Cai JL, Somlo G, et al.  Sequential bortezomib, 
dexamethasone, and thalidomide maintenance therapy after single autologous peripheral 

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stem cell transplantation in patients with multiple myeloma. Biol Blood Marrow 
Transplant 18(3): 486-92,2012 
 
 

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12. APPENDICES 
12.1 Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all predisease 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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12.2 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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12.3 Package Insert for Lenalidomide 
 
 
 

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12.4 Evaluation and Counseling of Patient 
The patient will be completely evaluated. The protocol will be discussed thoroughly with the 
patient and family and the attending physicians will describe all known risks to the patient. 
Alternative forms of therapy will be presented as objectively as possible and the risks and hazards 
of the procedure explained to the patient. Consent will be obtained using forms approved by the 
Institutional Review Board of the Fred Hutchinson Cancer Research Center. A summary of the 
conference will be dictated for the medical record. 
 
Study personnel must obtain documented consent from each potential patient prior to entering in a 
clinical study. Consent must be documented by obtaining the dated signature both of the patient and 
of the person conducting the consent discussion on the consent form. 
If the patient is illiterate, an impartial witness should be present during the entire informed consent 
reading and discussion. Afterward, the patient should sign and date the informed consent, if 
capable. The impartial witness should also sign and date the informed consent along with the 
individual who read and discussed the informed consent (i.e., study staff personnel). 
If the patient is legally incompetent (i.e., a minor or mentally incapacitated), the written consent of 
a parent, legal guardian or legal representative must be obtained.  Depending on local law or review 
committee requirements such consent may also need to be signed by an impartial witness. 
Patients who are non-English speaking will be consented per FHCRC standard procedure. 
A copy of the signed and dated consent form should be given to the patient before participation in 
the study. 
The initial informed consent form and any subsequent revised written informed consent form, and 
written information must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
patient or his/her legally acceptable representative should be informed in a timely manner if new 
information becomes available that may be relevant to the patient’s willingness to continue 
participation in the trial. The communication of this information should be documented. 
 
 

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12.5 Protocol Registration 
Patients will be assigned to the protocol by the attending physician and registered through the 
FHCRC Registration Office (206-667-4728), Monday through Friday, 8 a.m. to 4 p.m.  Registration 
will be through the final clinical coordinator sheet. After hours, the Registration Office can be 
reached by paging 206-995-7437.