Phase II Trial of Combination of Ixazomib and Lenalidomide and Dexamethasone in Smoldering Multiple Myeloma
Phase: PHASE2
Conditions: Smoldering Multiple Myeloma
Sponsor: Dana-Farber Cancer Institute

Protocol Title: 
Phase II Trial of Combination of Ixazomib and Lenalidomide and Dexamethasone in Smoldering 
Multiple Myeloma  
NCT #: NCT02916771 
IRB Approval Date: 09/10/2016 

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TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS .....................................................7
PROTOCOL SUMMARY.............................................................................................................11
1.
OBJECTIVES....................................................................................................................13
1.1
Study Design..........................................................................................................14
1.2
Overview of Study Design.....................................................................................14
1.3
Number of Patients ................................................................................................14
1.4
Duration of Study...................................................................................................14
1.5
Primary Objectives.................................................................................................14
1.6
Secondary Objectives.............................................................................................14
2.
BACKGROUND ...............................................................................................................15
2.1
Multiple Myeloma .................................................................................................15
2.2
MGUS and SMM consistently precedes multiple myeloma..................................16
2.3
Molecular studies in MGUS and SMM .................................................................16
2.4
Definition of SMM ................................................................................................17
2.5
Definitions of High-Risk SMM .............................................................................18
2.6
Treatment of High-Risk SMM...............................................................................18
2.7
Ixazomib (MLN9708)............................................................................................19
2.8
Pharmacokinetics and Drug Metabolism...............................................................21
2.9
Clinical Trial Experience Using the Oral Formulation of Ixazomib .....................24
2.10
Relapsed and/or Refractory Multiple Myeloma ....................................................28
2.11
Newly Diagnosed Multiple Myeloma (NDMM)...................................................29
2.12
Clinical Trial Experience Using the Intravenous Formulation of Ixazomib..........29
2.13
Trial Rationale .......................................................................................................29
2.14
Potential Risks and Benefits ..................................................................................30
2.15
Correlative Studies Background ............................................................................30
3.
PARTICIPANT SELECTION...........................................................................................32
3.1
Eligibility Criteria..................................................................................................32
3.2
Exclusion Criteria ..................................................................................................34
3.3
Inclusion of Women and Minorities ......................................................................35
4.
REGISTRATION PROCEDURES ...................................................................................35
4.1
General Guidelines for DF/HCC Institutions ........................................................35
4.2
Registration Process for DF/HCC Institutions.......................................................36
4.3
General Guidelines for Other Investigative Sites ..................................................36
4.4
Registration Process for Other Investigative Sites.................................................36
5.
TREATMENT PLAN........................................................................................................36
5.1
Treatment Regimen................................................................................................37
5.2
Agent Administration.............................................................................................38
5.3
General Concomitant Medication and Supportive Care Guidelines......................40
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5.4
Management of Clinical Events.............................................................................42
5.5
Criteria for Taking a Participant Off Protocol Therapy.........................................44
5.6
Duration of Follow Up...........................................................................................45
5.7
Criteria for Taking a Participant Off Study ...........................................................45
6.
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................46
6.1
Recommended Ixazomib Criteria for Beginning or Delaying a Subsequent 
Treatment Cycle & Dose Modifications for Treatment Associated Toxicity........46
6.2
Lenalidomide .........................................................................................................49
6.3
Dexamethasone......................................................................................................50
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................51
7.1
Definitions..............................................................................................................51
7.2
Expected Toxicities................................................................................................52
7.3
Adverse Event Characteristics...............................................................................54
7.4
Expedited Adverse Event Reporting......................................................................55
7.5
DF/HCC Expedited Reporting Guidelines.............................................................55
7.6
Procedures for Reporting Serious Adverse Events to Millennium........................56
7.7
Product Complaints................................................................................................58
7.8
Expedited Reporting to Celgene............................................................................58
7.9
Expedited Reporting to the Food and Drug Administration (FDA) ......................61
7.10
Expedited Reporting to Hospital Risk Management .............................................61
7.11
Routine Adverse Event Reporting .........................................................................61
8.
PHARMACEUTICAL INFORMATION..........................................................................61
8.1
Ixazomib ................................................................................................................61
8.2
Lenalidomide .........................................................................................................64
8.3
Dexamethasone......................................................................................................66
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................67
9.1
Bone Marrow Aspirate Samples............................................................................68
9.2
Peripheral Blood Samples......................................................................................69
10.
STUDY CALENDAR .......................................................................................................71
11.
MEASUREMENT OF EFFECT .......................................................................................72
11.1
Development of symptomatic disease ...................................................................72
11.2
Antitumor Effect....................................................................................................72
12.
DATA REPORTING / REGULATORY REQUIREMENTS...........................................78
12.1
Data Reporting.......................................................................................................78
12.2
Data Safety Monitoring..........................................................................................78
13.
STATISTICAL CONSIDERATIONS...............................................................................79
13.1
Study Design/Endpoints ........................................................................................79
13.2
Sample Size, Accrual Rate and Study Duration ....................................................80
13.3
Stratification Factors..............................................................................................80
13.4
Interim Monitoring Plan ........................................................................................80
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13.5
Stopping Rule for Safety........................................................................................80
14.
PUBLICATION PLAN .....................................................................................................80
15.
REFERENCES ..................................................................................................................81
APPENDIX A: PERFORMANCE STATUS CRITERIA.............................................................86
APPENDIX B: SPECIMEN COLLECTION SCHEDULE ..........................................................87
APPENDIX C: SPECIMEN REQUISITION................................................................................88
APPENDIX D: ADDITIONAL CORRELATIVE STUDIES PROPOSED .................................89
APPENDIX E: DANA-FARBER/HARVARD CANCER CENTER MULTI-CENTER DATA 
AND SAFETY MONITORING PLAN.............................................................................90
1.
INTRODUCTION .............................................................................................................92
1.1
Purpose...................................................................................................................92
1.2
Multi-Center Data and Safety Monitoring Plan Definitions..................................92
2.
GENERAL ROLES AND RESPONSIBILITIES .............................................................93
2.1
DF/HCC Sponsor...................................................................................................93
2.2
Coordinating Center...............................................................................................93
2.3
Participating Institution..........................................................................................94
3.
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS .............................95
3.1
Protocol Distribution..............................................................................................95
3.2
Protocol Revisions and Closures ...........................................................................95
3.3
Informed Consent Requirements ...........................................................................95
3.4
IRB Documentation ...............................................................................................96
3.5
IRB Re-Approval...................................................................................................96
3.6
Participant Confidentiality and Authorization Statement......................................96
3.7
DF/HCC Multi-Center Protocol Registration Policy.............................................97
3.8
DF/HCC Protocol Case Number............................................................................97
3.9
Safety Assessments and Toxicity Monitoring .......................................................98
3.10
Data Management..................................................................................................99
4.
REQUISITIONING INVESTIGATIONAL DRUG........................................................100
5.
MONITORING: QUALITY CONTROL........................................................................100
5.1
Ongoing Monitoring of Protocol Compliance.....................................................100
5.2
Monitoring Reports..............................................................................................101
5.3
Accrual Monitoring..............................................................................................101
6.
AUDITING: QUALITY ASSURANCE .........................................................................101
6.1
DF/HCC Internal Audits......................................................................................101
6.2
Audit Notifications...............................................................................................101
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6.3
Audit Reports.......................................................................................................102
6.4
Participating Institution Performance ..................................................................102
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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
5-HT3
5-hydroxytryptamine 3 serotonin receptor
AE
adverse event
ALL
acute lymphoblastic leukemia
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myelogenous leukemia
ANC
absolute neutrophil count
API
active pharmaceutical ingredient
aPTT
activated partial thromboplastin time
Ara-C
Cytarabine
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus time curve
AUC24 hr
area under the plasma concentration versus time curve from zero to 24 hours
AUCinf
area under the plasma concentration versus time curve from zero to infinity
AUCτ
area under the plasma concentration versus time curve from zero to next dose
BCRP
breast cancer resistance protein
βhCG
beta-human chorionic gonadotropin
BID
bis in die; twice a day
BM
bone marrow
BSA
body surface area
BUN
blood urea nitrogen
BZD
Benzodiazepines
CBC
complete blood count
CFR
Code of Federal Regulations
CL
clearance, IV dosing
CLP
plasma clearance
CLTotal
total clearance
Cmax
single-dose maximum (peak) concentration  
CNS
central nervous system
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Abbreviation
Term
CO2
carbon dioxide
CR
complete remission 
CRM
continual reassessment method
CRP
C-reactive protein
CSF-1R
colony-stimulating factor 1 receptor
CT
computed tomography
Ctrough
single-dose end of dosing interval (trough) concentration
CV
coefficient of variation 
CYP
cytochrome P450
DDI
drug-drug interaction
DLT
dose-limiting toxicity
DME
drug metabolizing enzymes
DNA
deoxyribonucleic acid
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
ELISA
enzyme-linked immunosorbent assay
EOS
End of Study (visit)
EOT
End of Treatment (visit)
EU
European Union
FDA
United States Food and Drug Administration
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GGT
gamma glutamyl transferase
GI
Gastrointestinal
GLP
Good Laboratory Practices
GM-CSF
granulocyte macrophage-colony stimulating factor
GMP
Good Manufacturing Practice
Hb
Hemoglobin
Hct
Hematocrit
HDPE
high-density polyethylene
hERG
human ether-à-go-go related gene
HIV
human immunodeficiency virus
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Abbreviation
Term
HNSTD
highest nonseverely toxic dose
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
IV
intravenous; intravenously
IVRS
interactive voice response system
Ki
inhibition constant
KPS
Karnofsky Performance Status
LDH
lactate dehydrogenase
LFT
liver function test(s)
MedDRA
Medical Dictionary for Regulatory Activities
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
MRI
magnetic resonance imaging
MRU
medical resource utilization
MTD
maximum tolerated dose
MUGA
multiple gated acquisition (scan)
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NPO
nothing by mouth
NYHA
New York Heart Association
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PD
progressive disease (disease progression)
Pgp
P-glycoprotein
PK
pharmacokinetic(s)
PO
per os; by mouth (orally)
PR
partial response 
PRO
patient-reported outcome
PSA
prostate-specific antigen
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Abbreviation
Term
QD
quaque die; each day; once daily
QID
quater in die; 4 times a day
QOD
quaque altera die; every other day
QOL
quality of life
QTc
rate-corrected QT interval (millisec) of electrocardiograph
RBC
red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SC
Subcutaneous
SD
stable disease
SmPC
Summary of Product Characteristics
t1/2
terminal disposition half-life
TGI
tumor growth inhibition
Tmax
single-dose time to reach maximum (peak) concentration
UK
United Kingdom
ULN
upper limit of the normal range
US
United States
Vz
volume of distribution in the terminal phase
WBC
white blood cell
WHO
World Health Organization
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PROTOCOL SUMMARY
Study Title: Phase II Trial of Combination of Ixazomib and Lenalidomide and 
Dexamethasone in Smoldering Multiple Myeloma
Phase:  II
Number of Patients:  56
Study Objectives: 
Primary Objectives
• To determine the proportion of patients with high-risk smoldering multiple myeloma 
patients who are progression free at 2 years after receiving IRD combination therapy
Secondary Objectives
•
To assess the response rate of the combination in these patients 
•
To assess duration of response
•
To assess safety of the combination
•
To examine molecular evolution of the tumor cells 
•
To determine minimal residual disease (MRD) 
•
To assess time to progression and progression free survival
Overview of Study Design:  
This is a single arm phase II study using the combination of Ixazomib and lenalidomide + 
dexamethasone in patients with high-risk smoldering multiple myeloma. The study is 
designed to examine novel therapeutic combinations in patients with smoldering MM. 
Based on the activity of lenalidomide and dexamethasone in patients with SMM and 
based on the safety and activity profile of Ixazomib/len/dex in patients with untreated 
MM, we propose to examine in a phase II trial the activity of 
ixazomib/lenalidomide/dexamethasone (IRD) in patients with high-risk smoldering MM.
Study Population:  
SELECT INCLUSION CRITERIA
•
Age ≥ 18 years.
•
High-risk smoldering myeloma based on the new Rajkumar et al criteria for high-risk 
disease1. 
•
No evidence of CRAB criteria or new criteria of overt MM which includes the 
following:
o
Increased calcium levels (corrected serum calcium >0.25 mmol/dL above the 
upper limit of normal or >.275 mmol/dL) related to MM
o
Renal insufficiency (attributable to MM)
o
Anemia (Hb 2g/dL below the lower limit of normal or <10g/dL) related to MM
o
Bone lesions (lytic lesions or generalized osteoporosis with compression 
fractures)
o
No evidence of the following new criteria for active MM including the 
following:  Bone marrow plasma cells >60%, Serum involved/uninvolved FLC 
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ratio ≥100 (light chain smoldering MM is allowed), and MRI with more than 
one focal lesion.
•
ECOG Performance Status (PS) 0, 1, or 2. 
•
The following laboratory values obtained ≤ 21 days prior to registration:
o
ANC ≥ 1000/μL
o
PLT ≥ 75,000/μL 
o
Total bilirubin ≤ 1.5 mg/dL (If total is elevated check direct and if normal patient 
is eligible.)
o
AST ≤ 3 x institutional upper limit of normal (ULN)
o
ALT ≤ 3 x institutional upper limit of normal (ULN)
o
Calculated creatinine clearance ≥ 30 mL/min
SELECT EXCLUSION CRITERIA
•
Symptomatic Multiple Myeloma or any evidence of CRAB criteria. Any prior therapy 
for Multiple Myeloma should also be excluded. Bisphosphonates are not excluded 
•
Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy 
considered investigational. Prior therapy with bisphosphonate is allowed. Prior 
radiation therapy to a solitary plasmacytoma is allowed. 
Duration of Study:  5 years
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1. OBJECTIVES
Smoldering Multiple Myeloma (SMM) is a heterogeneous disease entity that includes patients who 
have a disease burden that is higher than that in patients with MGUS but who are not yet 
symptomatic2. The term SMM was first described by Greipp and Kyle et al in 19803 and was 
followed by many other descriptions terming it indolent MM4,  or Durie Salmon Stage I5. It was 
not until 2003 that the International Myeloma Working Group (IMWG) described the exact 
definition of this disease. SMM was defined as serum M-protein ≥3 g/dL and/or ≥10% monoclonal 
plasma cells in the bone marrow (BM), Table 16,7. While the incidence and prevalence of SMM in 
the population is not well defined, it has been estimated to represent approximately 8% to 20% of 
patients within the MM spectrum2.
Most recently, the IMWG further re-defined the group of patients who meet criteria for treatment 
and included asymptomatic SMM patients who are likely going to have end-organ damage in the 
near future, previously defined as “ultra-high-risk smoldering myeloma”. These include patients 
with bone marrow plasmacytosis ≥ 60% 8; an abnormal FLC-ratio ≥ 100 (involved kappa) or < 
0.01 (involved lambda) 9: and/or 2 or more focal bone marrow lesions detected by functional 
imaging including PET-CT and/or MRI 10,11. These patients should therefore not be considered 
SMM anymore but rather re-defined as patients with myeloma-defining events that require 
therapy. 
The overall risk of progression of SMM is 10% per year for the first 5 years and 3% per year for 
the next 5 years12. The most common factors used to stratify patients with SMM are the Mayo 
Clinic criteria12,13 and the Spanish PETHEMA criteria14. The Mayo Clinic criteria are based on the 
tumor burden defined by the serum protein level (by serum protein electrophoresis or light chain 
ratio) or by the percent bone marrow plasma cell involvement (see Table 2 )12,13, leading to risks 
of progression at 5 years of 25% for low risk, 51% for intermediate risk and 76% for high-risk 
individuals who have 1, 2 or 3 risk factors respectively12,13.  The risk stratification of the 
PETHEMA group is based on identifying the number of clonal plasma cells in the bone marrow 
by flow cytometry (≥ 95% ratio of abnormal neoplastic plasma cells to normal plasma cells) and 
reduction of uninvolved immunoglobulins, with 5 year-risk of progression being 4%, 46%, and 
72% for patients with 0, 1 or 2 risk factors, respectively14. 
The paradigm of therapy in Smoldering Multiple Myeloma (SMM) is changing as we develop 
better therapeutic agents that prevent end organ damage and improve survival of patients with 
multiple myeloma (MM)15-17. Indeed, recent studies of a phase III trial of lenalidomide and 
dexamethasone versus placebo showed improved response, progression free survival and overall 
survival in patients with high-risk smoldering MM compared to placebo control18. Therefore, there 
is a need to examine novel therapeutic combinations in patients with high-risk smoldering MM. 
Based on the activity of lenalidomide and dexamethasone in patients with high-risk SMM and 
based on the safety and activity profile of Ixazomib and lenalidomide in patients with relapsed 
MM19-22, we propose to examine the activity of Ixazomib, lenalidomide, and dexamethasone in 
patients with SMM. 
Our overarching hypothesis is that early therapeutic interventions in patients with 
smoldering MM will prevent/delay progression to overt MM. We will examine the in vivo
activity and safety of Ixazomib, lenalidomide, and dexamethasone in patients with high-risk 
SMM. 
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1.1
Study Design
This is a phase II study using the combination of Ixazomib and lenalidomide + dexamethasone in 
patients with high-risk smoldering multiple myeloma. 
1.2
 Overview of Study Design
This is a single arm phase II study using the combination of Ixazomib and lenalidomide + 
dexamethasone in patients with high-risk smoldering multiple myeloma. 
The study is designed to examine novel therapeutic combinations in patients with smoldering 
MM. Based on the activity of lenalidomide and dexamethasone in patients with SMM and based 
on the safety and activity profile of Ixazomib/len/dex in patients with untreated MM, we propose 
to examine in a phase II trial the activity of ixazomib/lenalidomide/dexamethasone (IRD) in 
patients with high-risk smoldering MM, including those with all risk factors of SMM.
1.3
   Number of Patients
A total of 56 patients will be included on this study. Enrollment includes patients who receive 
the first day of therapy.  Patients who are registered, but never start protocol therapy should be 
replaced.
1.4
   Duration of Study
A treatment cycle is defined as 28 consecutive days. 
Patients will receive 9 cycles of induction therapy followed by 15 cycles of maintenance therapy 
for a total of 24 months.   
For treatment cycles 1 and 2, a +/- 3 day window is allowed. For treatment cycles 3 through 24, a 
+/-7 day window is allowed. Treatment plan is designed to be administered on an outpatient basis, 
however if necessary, may be given as inpatient. 
1.5
Primary Objectives
•
To determine the proportion of high-risk smoldering multiple myeloma patients who are 
progression free (free of symptomatic Myeloma defining events) at 2 years after receiving 
Ixazomib and lenalidomide + dexamethasone combination therapy
1.6
Secondary Objectives
•
To assess the response rate of the combination in these patients
•
To assess time to progression and progression free survival
•
To assess duration of response
•
To assess safety of the combination
•
To examine molecular evolution of the tumor cells obtained 
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•
To determine minimal residual disease (MRD)
2. BACKGROUND
2.1
Multiple Myeloma
Multiple myeloma is a plasma cell neoplasm characterized by multifocal proliferation of clonal, 
long-lived plasma cells associated with an overproduction of monoclonal gammaglobulin 23. In 
2010 the International Myeloma Working Group (IMWG) defined monoclonal gammopathy of 
undetermined significance (MGUS) by the presence of serum M-protein < 3g/dL, clonal plasma 
cell population in the bone marrow < 10%, and the absence of end-organ damage such as 
hypercalcemia (serum calcium ≥ 11.5 mg/dL), renal insufficiency (serum creatinine ≥ 2 mg/dL), 
anemia (hemoglobin value below the lower limit of normal by more than 2 g/dL or hemoglobin 
value < 10 g/dL) and lytic bone lesions (CRAB features) that can be attributed to the plasma cell 
proliferative disorder 24. Smoldering multiple myeloma was defined by the presence of serum M-
protein ≥ 3 g/dL or IgA> 2g/ dL or urinary monoclonal protein > 500 mg/ dL and/or clonal bone 
marrow plasma cells ≥ 10% and the absence of CRAB features clinically. 
In a large population based study in Olmsted County, MN, Kyle et al. analyzed serum samples of 
more than 75% of residents, 50 years or older, within the county 25. They identified MGUS in 694 
of 21,463 patients tested (3.2%). While the overall prevalence was noted to be 3.2% (95 % CI, 3.0 
to 3.5), there was a significant age dependent increase in both sexes with the prevalence among 
persons 80 years of age or older 4 times as high as among those 50-59 years of age. Age-adjusted 
rates were higher in men (4.0 %, 95% C.I., 3.5 to 4.4) than in women (2.7%, 95% C.I., 2.4 to 3.0). 
In a subsequent study on a majority of the same patients from Olmsted County, Dispenzieri, et al,
used the free light chain assay (FREELITE) and showed that 0.8% of people older than 50 years 
had light chain-MGUS. The total MGUS prevalence including the light chain-MGUS cases was 
noted at 4.2% (95% C.I., 3.9 to 4.5%) 26. A limitation of both these studies was that 97.3% of the 
residents of Olmsted County were white. 
For SMM patients a M-protein ≥ 3 g/dL, a FLC ratio outside the range of 0.125 to 8, and ≥ 10% 
plasma cells in the bone marrow are considered as adverse factors in this model 12,13. The 5-year 
rate of progression in patients with 1, 2 and 3 risk factors was 25%, 51% and 76% respectively. 
The time to progression with these risk factors was 10, 5.1 and 1.9 years respectively. Recently 
Rajkumar et al have proposed that SMM with > 60% plasma cells progress to multiple myeloma 
within 2 years in 95% cases and should be treated at diagnosis even in the absence of symptoms.8
Table 1: Mayo Clinic model for risk factors and % risk of progression for smoldering MM
Model
No. of Risk 
Factors
5-Year Progression %
Time to Progression 
(in years)
1
25
10
2
51
5.1
Mayo Clinic Model
Risk Factors:
•
M-protein ≥ 3.0g/dL
•
≥10% plasma cells in the BM
•
FLC ratio outside the range of 
0.125 to 8
3
76
1.9
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2.2
MGUS and SMM consistently precedes multiple myeloma
Since the early description of monoclonal gammopathy of undermined significance it was known 
that some cases of MGUS progressed to symptomatic myeloma but it was not clear whether all 
cases of myeloma are preceded by MGUS. In a study of more than 77,000 individuals, 55 to 74 
years of age, from a cancer screening trial, Landgren et al found 71 patients who developed 
multiple myeloma27. They performed serum protein electrophoresis, immunofixation and kappa-
lambda free light chain assay on prediagnostic samples in these patients. The study showed that 
patients who eventually developed multiple myeloma consistently had MGUS in the years 
preceding development of multiple myeloma. Interestingly, in half the patients, there was a steady 
increase in the M-protein before the development of symptomatic myeloma, while in the other half 
the M-protein stayed fairly stable. A second study by Weiss et al found a monoclonal gammopathy 
in 27 of 30 patients (90%) in sera 2 or more years before the diagnosis of myeloma 28. 
2.3
Molecular studies in MGUS and SMM
A recent study using SNP-based arrays compared MGUS, SMM and MM samples 29. They found 
copy number abnormalities in all stages. The incidence of genomic imbalance did increase from a 
median of 5/case for MGUS to 7.5/case for SMM and 12/case for MM. The study also noted certain 
genomic changes that were exclusive to MM including 11q and 21q gains and 16q and 22q 
deletions. Interestingly, the study found these abnormalities in a small subclone in MGUS patients 
indicating that most if not all of the chromosomal changes may be already present at the MGUS 
state.  These findings also support a possible role of ‘clonal tides’ in the evolution from precursor 
state to symptomatic myeloma as explained below.  
Two major pathways have been proposed as the early oncogenic events in the development of the 
myeloma cell based on chromosomal abnormalities noted in MGUS, SMM and MM- the non-
hyperdiploid and the hyperdiploid pathway. The main cytogenetic changes that have been 
observed in MGUS and SMM are indicated in the table below. 
Table 2: Cytogenetic abnormalities in MGUS, SMM and MM
Cytogenetic Abnormality
Involved Oncogene
MGUS%
SMM%
MM%
IgH Translocations
See below
40-50%
40-50%
50-70%
t(11;14)(q13;q32)
CCND1 
(Cyclin D1)
10-25%
10-25%
15%
t(4;14)(p16;q32)
FGFR3 and MMSET
2-9%
3-13%
10-15%
t(14;16)(q32;q23)
C-MAF
2-5%
2-5%
2-5%
Other IgH Translocations
•
t(6;14)(p21;q32)
•
t(14;20)(q32;q11) 
•
etc. 
CCND3 (Cyclin D3), 
MAFB, etc.
6-10%
1-10%
10%
13q Deletion 
Unknown
25-50%
35-50%
40-50%
Hyperdiploidy
Unknown
40-50%
40-50%
40-50%
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Other molecular studies in MGUS and SMM included microRNA studies. MicroRNAs are single 
stranded RNA molecules that regulate gene expression posttranscriptionally and are being 
implicated in a large number of cancers 30. A study comparing miRNA profiles of normal PC, 
MGUS, SMM and MM found overexpression of mir-21, mir-106~25 and mir181a and mir181b in 
MGUS and MM compared to normal PCs 31. The study also found mir-32 and mir17~92 clusters 
to be upregulated only in MM and not in any other forms. Mir 17~92 and Mir 106~25 are known 
to have a role in B cell development as well as B cell lymphomas targeting PTEN, E2F1, Bcl2 and 
BIM 30,31. The mir17 cluster has been shown to upregulated by the transcription factor c-Myc, 
which is considered a late event in myeloma progression 32-34. 
With the advances in deep sequencing techniques, we are now able to study the whole genome of 
myeloma cells and compare that to the normal human genome. Several studies employing these 
techniques are beginning to shift our understanding of the pathogenesis of myeloma. These studies 
have revealed that the previously held dogma that cancer progression occurred through a linear 
cumulative acquisition of mutational changes may be too simplistic. A new model of clonal 
heterogeneity is beginning to emerge 35. In fact tumor evolution may indeed proceed like 
Darwinian evolution with tumor progression involving a branching process with coexistent clonal 
heterogeneity. In this model various subclones exist in a dynamic equilibrium, competing for 
limited resources and over time the subclonal populations ebb and flow under environmental 
evolutionary pressures with alternating dominance of various subclones at different time points36-
40. Most of these studies were done on patients with symptomatic multiple myeloma and as similar 
studies involving MGUS and SMM emerge, our understanding of the pathogenesis of myeloma 
from these precursor states will continue to evolve. It is possible that the progression from 
myeloma precursor state to symptomatic disease also involves ‘clonal tides’ with expansion of a 
subclone leading to progression. Several previous studies have identified clonal heterogeneity in a 
subset of MGUS patients29,41,42. 
2.4
Definition of SMM
The diagnosis of smoldering (asymptomatic) multiple myeloma (SMM) is based on 43,44
•
Serum monoclonal protein (IgG or IgA)  3.0 g/dL or urinary monoclonal protein 500 
mg per 24 h and/or clonal bone marrow plasma cells 1060%. 
•
Absence of myeloma defining events or amyloidosis 
•
No evidence of the following CRAB criteria or other Myeloma defining events (MDE):
o
Increased calcium levels (corrected serum calcium >0.25 mmol/dL above the 
upper limit of normal or >.275 mmol/dL) related to MM
o
Renal insufficiency (attributable to MM)
o
Anemia (Hb 2g/dL below the lower limit of normal or <10g/dL) related to MM
o
Bone lesions (lytic lesions or generalized osteoporosis with compression 
fractures)
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New MDE criteria that indicates overt MM and not SMM 43,44
The following criteria are now incorporated with the CRAB criteria to indicate that patients meet 
criteria for therapy as symptomatic or overt MM: 
•
Bone marrow plasma cells > 60%
•
Serum involved/uninvolved FLC ratio ≥ 100, provided the absolute level of the involved 
free light chain is at least 100 mg/L and repeated twice*
•
MRI with two or more focal lesion that is at least 5 mm or greater in size
*If serum free light chain ratio is stable (not increasing) for greater than or equal to six 
months, the patient may be eligible after discussion with the overall PI (Free Light Chain 
Smoldering Myeloma)
2.5
Definitions of High-Risk SMM 
Based on the new defined high-risk criteria for smoldering myeloma based on 1 as described  in 
table 3 below:
Table 3 Bone marrow clonal plasma cells ≥10% and any one or more of the following:
Serum M protein ≥ 3.0g/dL 
IgA SMM
Immunoparesis with reduction of two uninvolved immunoglobulin isotypes
Serum involved/uninvolved free light chain ratio ≥8 (but less than 100)
Progressive increase in M protein level (Evolving type of SMM)†
Bone marrow clonal plasma cells 50–60%
Abnormal plasma cell immunophenotype (≥95% of bone marrow plasma cells are clonal) and 
reduction of one or more uninvolved immunoglobulin isotypes
t (4;14) or del 17p or 1q gain
Increased circulating plasma cells
MRI with diffuse abnormalities or 1 focal lesion
PET-CT with focal lesion with increased uptake without underlying osteolytic bone destruction
Monoclonal light chain excretion of 500mg/24 hours or higher*
† Increase in serum monoclonal protein by ≥10% on two successive evaluations within a 6 month period
* Monoclonal Light Chain Smoldering
2.6
Treatment of High-Risk SMM
In a randomized open-label phase 3 trial 18, 119 patients with high-risk smoldering myeloma were 
randomized to treatment or observation. Patients in the treatment group received an induction 
regimen (lenalidomide at a dose of 25 mg per day on days 1 to 21, plus dexamethasone at a dose 
of 20 mg per day on days 1 to 4 and days 12 to 15, at 4-week intervals for nine cycles), followed 
by a maintenance regimen (lenalidomide at a dose of 10 mg per day on days 1 to 21 of each 28-
day cycle for 2 years). The primary end point was time to progression to symptomatic disease. 
Secondary end points were response rate, overall survival, and safety. After a median follow-up 
of 40 months, the median time to progression was significantly longer in the treatment group than 
in the observation group (median not reached vs. 21 months; hazard ratio for progression, 0.18; 
95% confidence interval [CI], 0.09 to 0.32; P < 0.001). The 3-year survival rate was also higher in 
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the treatment group (94% vs. 80%; hazard ratio for death, 0.31; 95% CI, 0.10 to 0.91; P=0.03). A 
partial response or better was achieved in 79% of patients in the treatment group after the induction 
phase and in 90% during the maintenance phase. Toxic effects were mainly grade 2 or lower. Early 
treatment for patients with high-risk smoldering myeloma delays progression to active disease and 
increases overall survival. (NCT00480363).
2.7
Ixazomib (MLN9708) 
2.7.1
Preclinical Experience
Please refer to the current ixazomib Investigator’s Brochure (IB) and Safety Management 
Attachment (SMA).
2.7.2   
Clinical Experience
Ixazomib has been evaluated as an oral single agent in phase 1 studies that have included patients 
with advanced solid tumors, lymphoma, relapse/refractory MM (RRMM), and relapsed or 
refractory light-chain (AL) amyloidosis and demonstrated early signs of activity. Ongoing studies 
continue to investigate both single-agent ixazomib and ixazomib in combination with standard 
treatments. Based on encouraging preliminary data observed in patients with MM requiring 
systemic treatment, 2 phase 3 trials in newly diagnosed MM (NDMM) (C16014) and RRMM 
(C16010) patient populations are currently evaluating ixazomib in combination with Lenalidomide 
and Dexamethasone (LenDex) versus placebo/LenDex. Both trials are combining ixazomib at a 
weekly dose of 4.0 mg on Days 1, 8, and 15 in a 28-day cycle to a standard dose of lenalidomide 
with a weekly dexamethasone dose of 40 mg. Studies evaluating the safety and pharmacokinetic 
(PK) of ixazomib alone (in Japanese patients) and in combination with lenalidomide and 
dexamethasone in Asian adult patients (including Japanese patients) with a diagnosis of NDMM 
are ongoing.
As of 27 March 2013, preliminary clinical data is available for a total of 653 patients across 13 
studies. The emerging safety profile indicates that ixazomib is generally well tolerated. The 
adverse events (AEs) are consistent with the class-based effects of proteasome inhibition and are 
similar to what has been previously reported with VELCADE though the severity of some, for 
example peripheral neuropathy, is less. While some of these potential toxicities may be severe, 
they can be managed by clinical monitoring and standard medical intervention, or, as needed, dose 
modification or discontinuation.
Fatigue was the most common AE reported among 384 patients treated in the oral (PO) studies 
(47%). Other common AEs reported in the pooled intravenous (IV) and PO safety populations 
include nausea, thrombocytopenia, diarrhea, and vomiting. Rash is also a commonly reported 
treatment-emergent event; however, there is some variety in its characterization and causality 
resulting in different preferred terms to describe it. A high-level term outline of rash events 
includes rashes, eruptions and exanthems NEC; pruritus NEC; erythemas; papulosquamous 
conditions; and exfoliative conditions. The dose escalation phases of most trials reported in the IB
have now completed enrollment, and gastrointestinal (GI) symptoms were the common dose-
limiting toxicities (DLTs) when the use of prophylactic anti-emetics was not permitted per 
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protocol. In the expansion cohorts or phase 2 cohorts (as per each study), the incidence and severity 
of GI symptoms was mitigated by the use of the lower maximum tolerated dose 
(MTD)/recommended phase 2 dose (RP2D) (as per each study) and standard clinical usage of anti-
emetics and/or antidiarrheal medications as deemed appropriate. Prophylactic use of anti-emetics 
has not been required as with other agents but has been used according to standard practice and 
are effective.
The most frequent (at least 20%) treatment-emergent adverse events (TEAEs) reported with the 
PO formulation pooled from single-agent studies (n = 201) irrespective of causality to ixazomib, 
include nausea (53%), fatigue (51%), diarrhea (44%), thrombocytopenia (34%), vomiting (38%), 
decreased appetite (32%), fever (21%), and anemia (21%). The most frequent (at least 20%) 
TEAEs reported with the PO formulation pooled from combination trials (irrespective of the 
combination) (n = 173), irrespective of causality to ixazomib, include diarrhea (47%), fatigue 
(44%), nausea (38%), peripheral edema (35%), constipation (33%), insomnia (29%), 
thrombocytopenia (28%), anemia (26%), vomiting (26%), neutropenia (25%), back pain (24%), 
pyrexia (23%), peripheral edema (21%, each), fever (20%), cough (20%), hypokalemia (20%), 
neutropenia (20%), and upper respiratory tract infection (20%). Overall rash of all grades is 
reported in approximately 50% of patients and is more common when ixazomib is given in 
combination with lenalidomide where rash is an overlapping toxicity.
A recent study was published showing that IRD is highly effective in newly diagnosed MM 45. 
The study enrolled patients newly diagnosed with multiple myeloma aged 18 years or older with 
measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and no grade 2 
or higher peripheral neuropathy, and treated them with oral ixazomib (days 1, 8, 15) plus 
lenalidomide 25 mg (days 1-21) and dexamethasone 40 mg (days 1, 8, 15, 22) for up to 12 28-day 
cycles, followed by maintenance therapy with ixazomib alone. In phase 1, patients received 
escalating doses of ixazomib (1.68-3.95 mg/m(2)) to establish the recommended dose for phase 2. 
The primary endpoints were maximum tolerated dose for phase 1, and the rate of very good partial 
response or better for phase 2. Safety analyses were done in all patients who received at least one 
dose of study drug; efficacy analyses were done in all patients who received at least one dose of 
study drug at the phase 2 dose, had measurable disease at baseline, and had at least one post-
baseline response assessment. This study is registered at ClinicalTrials.gov, number 
NCT01217957. FINDINGS: Between Nov 22, 2010, and Feb 28, 2012, the study enrolled 65 
patients (15 to phase 1 and 50 to phase 2). Four dose-limiting toxic events were noted in phase 1: 
one at a dose of ixazomib of 2.97 mg/m(2) and three at 3.95 mg/m(2). The maximum tolerated 
dose of ixazomib was established as 2.97 mg/m(2) and the recommended phase 2 dose was 2.23 
mg/m(2), which was converted to a 4.0 mg fixed dose based on population pharmacokinetic 
results. Grade 3 or higher adverse events related to any drug were reported in 41 (63%) patients, 
including skin and subcutaneous tissue disorders (11 patients, 17%), neutropenia (eight patients, 
12%), and thrombocytopenia (five patients, 8%); drug-related peripheral neuropathy of grade 3 or 
higher occurred in four (6%) patients. Five patients discontinued because of adverse events. In 64 
response-evaluable patients, 37 (58%, 95% CI 45-70) had a very good partial response or better. 
INTERPRETATION: The all-oral combination of weekly ixazomib plus lenalidomide and 
dexamethasone was generally well tolerated and appeared active in newly diagnosed multiple 
myeloma. Additional detailed information regarding the clinical experience of ixazomib may be 
found in the IB, including information on the IV formulation. 
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2.8  Pharmacokinetics and Drug Metabolism
Clinical IV and PO PK data show that ixazomib citrate (measured as the biologically active boronic 
acid form of ixazomib [MLN2238]) has multi-exponential disposition with a rapid initial phase 
that is largely over by 4 hours. Oral ixazomib citrate is rapidly absorbed with a median single-dose 
first time of occurrence of maximum (peak) concentration (Tmax) of approximately 0.5 to 2.0 
hours and a terminal disposition half-life (t1/2) after multiple dosing of approximately 5 to 7 days 
[1]. Results of a population PK analysis (n = 137) show that there is no relationship between body 
surface area (BSA) or body weight and clearance (CL). Also, based on stochastic simulations for 
fixed dose, exposures are independent of the individual patient’s BSA [2]. Based on these data, a 
recommendation was made for fixed dosing in clinical trials. An absolute bioavailability of 67% 
was determined for ixazomib using the population PK analysis. Please refer to the current ixazomib 
IB and Safety Management Attachment (SMA) for information on the PK for IV doses of 
ixazomib.
Metabolism appears to be the major route of elimination for ixazomib, and urinary excretion of 
the parent drug is negligible (< 5% of dose). In vitro studies indicate that ixazomib is metabolized 
by multiple cytochrome P450s (CYPs) and non-CYP enzymes/proteins. The rank order of relative 
biotransformation activity of the 5 major human CYP isozymes was 3A4 (34.2%) > 1A2 (30.7%) 
> 2D6 (14.7%) > 2C9 (12.1%) > 2C19 (< 1%). Ixazomib is not an inhibitor of CYPs 1A2, 2C9, 
2C19, 2D6, or 3A4 nor a time-dependent inhibitor of CYP3A4/5. The potential for ixazomib 
treatment to produce drug-drug interactions (DDIs) via CYP inhibition is inferred to be low. 
However, there may be a potential for DDIs with a concomitant strong CYP3A4 or CYP1A2 
inhibitor or inducer because of the potential for first-pass metabolism when ixazomib is 
administered via the PO route and because of the moderate contribution of CYP3A4- and 
CYP1A2-mediated metabolism of ixazomib in human liver microsomes. Ixazomib may be a weak 
substrate of P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), and multidrug 
resistance associated protein (MRP2) efflux pump transporters. Ixazomib is not an inhibitor of 
Pgp, BCRP, and MRP2. The potential for DDIs with substrates or inhibitors of Pgp, BCRP, and 
MRP2 is, therefore, inferred to be low. Clinical Study C16009 (Arm 1) with ketoconazole, a strong 
CYP3A4 inhibitor, showed a 2-fold increase in area under the plasma concentration versus time 
curve (AUC) in the presence of ketoconazole. This resulted in the continued exclusion of strong 
CYP3A4 inhibitors in ongoing/planned clinical studies.
Further details on these studies are provided in the IB.
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Table 4
Clinical Studies of Oral Ixazomib
Trial/
Population
Description
Doses Investigated
C16003
RRMM
N = 60
PO, TW, single agent
0.24-2.23 mg/m2 TW
MTD:  2.0 mg/m2
DLT:  rash, thrombocytopenia
Closed to enrollment
C16004
RRMM
N = 60
PO, W, single agent
0.24-3.95 mg/m2 W
MTD:  2.97 mg/m2
DLT:  rash, nausea, vomiting, diarrhea
Closed to enrollment
C16005
NDMM
N = 65
PO, W, combination with 
LenDex 28-day cycle
1.68-3.95 mg/m2 W
MTD:  2.97 mg/m2
DLT:  nausea, vomiting, diarrhea, 
syncope
RP2Da:  4.0 mg fixed (switched to fixed 
dosing in phase 2, equivalent  to 
2.23mg/m2)
Closed to enrollment
C16006
NDMM
N = 20
PO, TW (Arm A- 42 day 
cycle) and W (Arm B- 28 day 
cycle), combination with 
Melphalan and Prednisone
Arm Aa:  3-3.7-mg fixed dose TW
DLT:  rash, thrombocytopenia, subileus
Arm Ba:  3-5.5-mg fixed dose, W
DLT:  Esophageal ulcer nausea, 
vomiting, hematemesis, 
thrombocytopenia, ileus, neurogenic 
bladder
MTD = 3.0 mg
C16007
RRAL
N = 27
PO, W, single agent
4-5.5-mg fixed dosea W
DLT:  thrombocytopenia, diarrhea, 
dyspnea, acute rise in creatinine, cardiac 
arrest 
MTD:  4.0  mg W
C16008
NDMM
N = 64
PO, TW, combination with 
LenDex 21-day cycle
3.0-3.7-mg fixed dosea W
MTD:  3.0 mg
Closed to enrollment
C16009
Solid tumors, 
Lymphomas
N = 54
PO, W, single agent
5.5-mg fixed dosea W
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Table 4
Clinical Studies of Oral Ixazomib
Trial/
Population
Description
Doses Investigated
C16010
RRMM
N = 200
PO, W, with LenDex versus 
placebo-LenDex
4.0 mg W
C16011
RRAL
N = 4
PO, W, with Dex versus 
physician’s choice of a Dex-
based regimen
4.0 mg W
C16013
RRMM
N = 9
PO, W, with LenDex
4.0 mg W
C16014
Symptomatic 
MM
N=701
PO, combination with 
LenDex
ixazomib 4.0 mg or matching placebo on 
Days 1, 8, and 15, plus Len 25 mg on 
Days 1-21 (10 mg if low creatinine 
clearance, with escalation to 15 mg if 
tolerated) and Dex 40 mg (or 20 mg if 
>75 years old) on Days 1, 8, 15, and 22
C16015
Symptomatic 
MM with 
normal renal 
function or 
severe renal 
impairment
N=28
PO, combination with Dex
Part A: ixazomib 3.0 mg on Day 1
Part B: ixazomib 4.0 mg on Days 1, 8, 
and 15, plus Dex 40 mg (or 20 mg if 
>75 years old) on Days 1, 8, 15 and 22 of 
a 28-day cycle
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Table 4
Clinical Studies of Oral Ixazomib
Trial/
Population
Description
Doses Investigated
C16017
RR follicular 
lymphoma
N=58
PO, W
4.0, 5.3, and 7.0 mg, W
Treatment at RP2D once determined.
C16018
Advanced 
solid tumors 
or 
hematologic 
malignancies 
with varying 
degrees of 
liver 
dysfunction
N=45
Part A: PO, Day 1 of 15-day 
cycle
Part B: PO, W
1.5 mg (severe hepatic impairment), 2.3 
mg (moderate hepatic impairment), or 4.0 
mg (normal hepatic function)
TB-
MC010034
RRMM
N = 10
PO, W
4.0 mg, W
Single agent: 4.0 mg
Combination with Rd
Abbreviations:  RRAL = Relapsed and/or refractory Primary systemic light chain (AL) 
amyloidosis; BSA = body surface area; Dex=dexamethasone; DLT = dose-limiting 
toxicity; IV = intravenously; LenDex = lenalidomide plus dexamethasone; MTD = 
maximum tolerated dose; NDMM = newly diagnosed multiple myeloma; PO = orally; 
RR= relapsed and/or refractory; RRAL= relapsed and/or refractory systemic light chain 
amyloidosis RRMM = relapsed and/or refractory multiple myeloma; TBD = to be 
determined; TW = twice weekly; W = weekly; RP2D= recommended phase 2 dose.
Note that blinded data from pivotal Studies C16010 and C16011 are not included.  
a Approximate BSA and fixed dosing equivalence:  3 mg~ equivalent to 1.68 mg/m2 BSA 
dosing; 4.0 mg ~ equivalent to 2.23 mg/m2 BSA dosing; and 5.5 mg~ equivalent to 2.97 
mg/m2 BSA dosing.
2.9   Clinical Trial Experience Using the Oral Formulation of Ixazomib
As of 27 March 2013, a total of 507 patients with differing malignancies (multiple myeloma, AL 
amyloidosis, nonhematologic cancers, and lymphoma) have been treated in studies evaluating the 
oral ixazomib formulation.  These patients have been treated with different doses of ixazomib 
either as a single-agent treatment (in 201 patients) or in combination with currently clinically 
available treatments (in 306 patients). Information regarding the ongoing studies, patient 
populations, and doses investigated is included in Table 4.
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Overview of the Oral Formulation of Ixazomib
The emerging safety profile indicates that ixazomib is generally well tolerated.  The adverse events 
(AEs) are consistent with the class-based effects of proteasome inhibition and are similar to what 
has been previously reported with VELCADE though the severity of some, for example peripheral 
neuropathy, is less.  While some of these potential toxicities may be severe, they can be managed 
by clinical monitoring and standard medical intervention, or, as needed, dose modification or 
discontinuation.  
In the 4 ongoing studies (C16003, C16004, C16007, and C16009) investigating single-agent oral 
ixazomib in patients with differing malignancies (multiple myeloma, AL amyloidosis, 
nonhematologic cancers, and lymphoma), a total of 201 patients have been treated as of 27 March 
2013. These patients have been treated with different doses of ixazomib as they are all phase 1 
trials. An overview of the most frequent (at least 10%) AEs occurring in the pooled safety 
population from single-agent oral ixazomib studies (C16003, C16004, C16007, and C16009) are 
shown in Table 5.
Table 5
Most Common (At Least 10% of Total) Treatment-Emergent Adverse Events in 
Oral Single-Agent Studies
Primary System Organ Class
Preferred Term
Oral Single Agent
Total
n = 201
n (%)
Subjects with at Least One Adverse Event
197 (98)
Gastrointestinal disorders
160 (80)
Nausea
106 (53)
Diarrhoea
88 (44)
Vomiting
77 (38)
Constipation
46 (23)
Abdominal pain
33 (16)
General disorders and administration site conditions
151 (75)
Fatigue
103 (51)
Pyrexia
51 (25)
Oedema peripheral
27 (13)
Asthenia
31 (15)
Nervous system disorders
92 (46)
Headache
29 (14)
Dizziness
26 (13)
Neuropathy peripheral
21 (10)
Metabolism and nutrition disorders
107 (53)
Decreased appetite
64 (32)
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Table 5
Most Common (At Least 10% of Total) Treatment-Emergent Adverse Events in 
Oral Single-Agent Studies
Primary System Organ Class
Preferred Term
Oral Single Agent
Total
n = 201
n (%)
Dehydration
37 (18)
Blood and lymphatic system disorders
98 (49)
Thrombocytopenia
68 (34)
Anaemia
42 (21)
Neutropenia
29 (14)
Lymphopenia
20 (10)
Skin and subcutaneous tissue disorders
90 (45)
Rash maculara
23 (11)
Musculoskeletal and connective tissue disorders
93 (46)
Back pain
24 (12)
Arthralgia
28 (14)
Respiratory, thoracic and mediastinal disorders
78 (39)
Cough
28 (14)
Dyspnoea
30 (15)
Infections and infestations
89 (44)
Upper respiratory tract infection
31 (15)
Source: Ixazomib Investigator’s Brochure Edition 7
Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities, version 15.0.
Subject Incidence: A subject counts once for each preferred term.  Percentages use the number of treated subjects as the denominator.
a. Note that rash maculopapular and rash macular represent the 2 most common terms used to describe rash.
As of 27 March 2013, there are 5 studies actively enrolling patients with multiple myeloma to 
investigate oral ixazomib in combination with standard combination regimens.  
The most frequent (at least 10%) AEs occurring in the pooled safety population from Studies 
C16005, C16006, C16008, and C16013 are shown for all grades (Table 4).  Note that in 
combination trials, related is defined as related to any study drug in the combination regimen.
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Table 6 
Most Common (At Least 10% of Total) Treatment-Emergent Adverse Events in 
Oral Combination Studies
Primary System Organ Class
      Preferred Term
Total Oral Combo Agent
(5/6/8/13)
n = 173
n (%)
Subjects with at Least One Adverse Event
163 (94)
Gastrointestinal disorders
139 (80)
Nausea
65 (38)
Diarrhoea
81 (47)
Vomiting
51 (29)
Constipation
57 (33)
General disorders and administration site conditions
132 (76)
Fatigue
76 (44)
Pyrexia
39 (23)
Oedema peripheral
61 (35)
Asthenia
20 (12)
Nervous system disorders
115 (66)
Headache
28 (16)
Dizziness
34 (20)
Neuropathy peripheral
45 (26)
Metabolism and nutrition disorders
91 (53)
Decreased appetite
25 (14)
Hypokalaemia
34 (20)
Blood and lymphatic system disorders
88 (51)
Thrombocytopenia
49 (28)
Anaemia
45 (26)
Neutropenia
43 (25)
Lymphopenia
20 (12)
Skin and subcutaneous tissue disorders
102 (59)
Rash maculopapulara
29 (17)
Rash maculara
22 (13)
Musculoskeletal and connective tissue disorders
99 (57)
Back pain
42 (24)
Pain in extremity
31 (18)
Arthralgia
22 (13)
Respiratory, thoracic and mediastinal disorders
80 (46)
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Table 6 
Most Common (At Least 10% of Total) Treatment-Emergent Adverse Events in 
Oral Combination Studies
Primary System Organ Class
      Preferred Term
Total Oral Combo Agent
(5/6/8/13)
n = 173
n (%)
Cough
36 (21)
Dyspnoea
26 (15)
Infections and infestations
92 (53)
Upper respiratory tract infection
35 (20)
Psychiatric disorders
73 (42)
Insomnia
50 (29)
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, non-Hodgkin’s disease, Hodgkin’s disease, relapsed and/or refractory multiple myeloma 
[RRMM, relapsed or refractory systemic light chain amyloidosis [RRAL], and newly diagnosed 
multiple myeloma [NDMM] 45to date46.
Though additional data are needed to characterize the clinical benefit of this drug, the emerging 
data supports the ongoing development of ixazomib.
2.10    Relapsed and/or Refractory Multiple Myeloma
The early development of ixazomib in patients with RRMM involves 2 studies (C16003 and 
C16004) with similar objectives, but each investigated 1 of the 2 dosing schedules commonly used 
with the first-in-class proteasome inhibitor, VELCADE.
Study C16003 is an open-label, dose escalation, phase 1 study of ixazomib dosing on a twice-
weekly schedule on Days 1, 4, 8, and 11 of a 21-day cycle in adult patients with RRMM47.  Study 
C16004 is an open-label, dose escalation, phase 1 study of ixazomib dosing on a weekly schedule 
on Days 1, 8, and 15 of a 28-day cycle in adults patients with RRMM48. Both studies have now 
completed enrollment.  The DLTs in Study C16003 were rash macular and thrombocytopenia and 
the DLTs in C16004 were nausea, diarrhea, vomiting, and erythema multiforme.
In the dose escalation component of both studies, patients had multiple myeloma that had relapsed 
following at least 2 lines of therapy that must have included bortezomib, thalidomide (or 
lenalidomide), and corticosteroids.  In both studies, when the MTD was established, cohorts of 
patients representing the heterogeneous patient population currently seen in clinical practice were 
to be enrolled into 1 of 4 expansion cohorts, including a relapsed and refractory cohort, a 
carfilzomib cohort, a proteasome inhibitor-naïve cohort, and a VELCADE-relapsed cohort.
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Final study results are currently being analyzed, but preliminary data suggest that ixazomib has 
anti-tumor activity in heavily pretreated MM patients, with durable responses/disease control, and 
is generally well tolerated. Please refer to the ixazomib IB and SMA for further information. 
2.11    Newly Diagnosed Multiple Myeloma (NDMM)
Multiple research paths are being explored in patients with NDMM with a focus on evaluating 
ixazomib in combination with agents commonly used across treatment settings.  The development 
of ixazomib in combination with lenalidomide with dexamethasone (LenDex) in patients with 
NDMM who are transplant eligible or ineligible involves 2 studies (C16005 and C16008) with 
similar study designs except for a few key differences, namely the schedules of ixazomib and 
dexamethasone45.  Ixazomib is also being evaluated in combination with melphalan and prednisone 
(MP) for patients who are not transplant eligible due to age or coexisting morbidity (in Study 
C16006). 
All 3 studies are phase 1/2, with phase 1 focusing on safety and phase 2 on efficacy (and further 
characterization of safety).  Please refer to the ixazomib IB and SMA for further information. 
2.12 Clinical Trial Experience Using the Intravenous Formulation of Ixazomib
See the IB for descriptions of the 2 studies that investigated IV ixazomib in advanced solid tumors 
and advanced lymphoma (Studies C16001 and C16002, respectively).
2.13 Trial Rationale 
Based on the activity of lenalidomide and dexamethasone in patients with SMM and based on the 
safety and activity profile of Ixazomib/len/dex in patients with untreated MM (ASH 2014), we 
propose to examine in a phase II trial the activity of ixazomib/lenalidomide/dexamethasone (IRD) 
in patients with high-risk smoldering MM.  
Patients who develop symptomatic disease will receive induction therapy with standard therapeutic 
options for multiple myeloma including combinations such as those of proteasome inhibitors, 
immunomodulators and steroids or cyclophosphamide, proteasome inhibitors and dexamethasone.  
Patients who are eligible for stem cell collection will have the option to collect stem cells during 
the course of therapy on this trial at the time of best response (CR or VGPR) or after 9 cycles of 
induction therapy. If we observe any problems with stem cell collection, we will follow the current 
standard guidelines of using cyclophosphamide or plerixafor mobilization. Based on data using 
combination therapies for induction, there has been no major concerns regarding stem cell 
collections after treatment with those agents. 
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2.14  Potential Risks and Benefits
Please refer to the current ixazomib IB and SMA.
The clinical benefit of ixazomib continues to be studied in a comprehensive and global 
development plan that involves studies sponsored by Millennium.  Ixazomib appears to show 
early signs of anti-tumor activity as evidenced by at least 50% reduction in disease burden in 
some patients, including patients that have been heavily pretreated as well as those with newly 
diagnosed MM, and prolongs stabilization of the underlying disease in other patients across all 
ongoing trials.  The preliminary findings are favorable when considering historical and currently 
available therapies for the patient populations evaluated.  Though additional data are needed to 
characterize the clinical benefit of this drug, the emerging data supports expanded development 
of ixazomib for the treatment of patients with advanced malignancy. This study will be 
conducted in compliance with the protocol, good clinical practice (GCP), applicable regulatory 
requirements, and International Conference on Harmonisation (ICH) guidelines.
2.15 Correlative Studies Background
2.15.1 DNA and RNA sequencing of tumor cells 
The "clonal evolution" model of cancer emerged amid ongoing advances in technology, especially 
in recent years during which next generation sequencing has provided ever higher resolution 
pictures of the genetic changes in cancer cells and heterogeneity in tumors where tumor 
progression proceeds in a branching rather than in a linear manner, leading to substantial clonal 
diversity and coexistence of wide genetic heterogeneity49,50. The genomic complexity in MM was 
recently corroborated by massive parallel-sequencing studies displaying the lack of a universal 
driving mutation35. Recent studies have shown intraclonal heterogeneity that occurs at different 
stages of progression in MM36,37. Most recently, exome sequencing confirmed that the 
heterogeneity observed in the transformation from MGUS/SMM to MM is likely to be an essential 
feature of clonal evolution and disease progression51,52. Point mutations such as N-RAS, K-RAS, 
MYC up-regulation53, and gain or loss of chromosome 1q or 1p seem to correlate with disease 
progression from MGUS and SMM34. A progressive increase in the incidence of copy number 
abnormalities from MGUS to SMM and to MM has been recently observed54. 
We plan to perform exome sequencing and RNA sequencing studies on tumor cells obtained at the 
time of screening as well as from subsequent bone marrow biopsy samples to examine clonal 
heterogeneity, resistant clones at best response and at time of end of study or tumor progression. 
The tumor research samples will be collected at the time of scheduled bone marrow biopsies. From 
these samples, high quality DNA (for tumor cells) and RNA for both exome sequencing and RNA 
sequencing will be obtained. In brief, BM aspirates will be obtained after informed consent. The 
tumor cells will be collected using CD138+ bead selection (over 90% purity based on prior 
publications)35,36. For samples that have a small fraction of plasma cells, we will use flow sorting 
for CD138/CD38/CD56 and CD19-ve to obtain a pure malignant plasma cell population based on 
prior published markers of malignant plasma cells55. Germline DNA will also be obtained from a 
buccal swab from all patients. 
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Exome sequencing of tumor cells: Whole-exome capture libraries will be constructed from 
100ng of tumor and normal DNA followed by shearing, end repair, phosphorylation and ligation 
to barcoded sequencing adapters. The DNA will be size-selected to exonic hybrid capture using 
SureSelect v2 Exome bait (Agilent, CA). Samples will be multiplexed and sequenced on Illumina 
HiSeq flowcells with the goal of an average depth of coverage of 100x. The resulting data will be 
analyzed with the current Illumina pipeline, which generates data files (BAM files). The details of 
the current analysis pipeline are published elsewhere35,56. Briefly, somatic single nucleotide 
variants are determined using the MuTect algorithm57.  Indels and translocations are determined 
by the algorithms IndelLocator and dRanger, respectively. The MutSig algorithm identifies genes 
in which the observed mutations are inconsistent with what would be expected at random58. To 
accurately assess the significance of mutations, MutSig takes into account several covariates, 
which influence the background mutation model. These include the expression level of genes (for 
which published gene expression data of MM samples can be used), and other gene characteristics 
observed empirically to co-vary with mutation rate: local relative replication time59, and open vs. 
closed chromatin status60. Focal as well as arm-level copy number variations will be determined 
based on whole exome sequencing and subsequent application of the GISTIC algorithm61. All 
bioinformatics analysis will be performed by Dr. Shi and Michor, who are expert 
Bioinformaticians and have analyzed the data shown in the preliminary data. 
RNA sequencing of tumor cells. For RNA Sequencing, poly-A selection and cDNA synthesis 
will be performed, followed by library preparation, sequencing (76bp or 101bp paired reads), and 
sample identification with quality control. Details of experimental design are described in62,63-65. 
We will perform library construction using a non-strand specific Illumina TruSeq Protocol and 
sequence coverage to 100M total reads. Analysis will be performed as described in the preliminary 
data and in previous studies63-65.
Single-cell sequencing of the tumor microenvironment. Investigators at the Broad Institute and 
Harvard Medical School have recently developed the technology of droplet sequencing (Drop-
seq). In addition, multiple publications have shown that that single-cell RNA sequencing (RNA-
seq) of the tumor microenvironment can define genotypic and phenotypic states of tumor cells and 
surrounding microenvironment, and that the microenvironment affected the gene expression 
program of tumor cells and their resistance to therapy. We will apply similar techniques in this 
study to evaluate the tumor microenvironment and assess specific changes in cell type and 
transcriptional signature of BM niche cells that correlate with tumor progression or resistance to 
therapy. 
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3. PARTICIPANT SELECTION
3.1
Eligibility Criteria
3.1.1 Age ≥ 18 years.
3.1.2 Must meet criteria of high-risk smoldering MM based on the criteria 
described below:
Definition of high-risk SMM:
•
Bone marrow clonal plasma cells ≥ 10% and ≤ 60% and any one 
or more of the following: 
o
Serum M protein ≥3.0g/dL (IgA, IgG, IgM, or IgD) 
o
IgA SMM
o
Immunoparesis with reduction of two uninvolved 
immunoglobulin isotypes
o
Serum involved/uninvolved free light chain ratio ≥8 (but 
less than 100)

Free Light Chain Smoldering Myeloma patients as 
defined in section 2.4 are not excluded
o
Progressive increase in M protein level (Evolving type of 
SMM)

Increase in serum monoclonal protein by ≥10% on 
two successive evaluations within a 6-month period
o
Bone marrow clonal plasma cells 50-60%
o
Abnormal plasma cell immunophenotype (≥ 95% of bone 
marrow plasma cells are clonal) and reduction of one or 
more uninvolved immunoglobulin isotypes
o
t (4;14) or del 17p or 1q gain
o
Increased circulating plasma cells
o
MRI with diffuse abnormalities or 1 focal lesion 
o
PET-CT with one focal lesion with increased uptake 
without underlying osteolytic bone destruction
o
Urine monoclonal light chain excretion ≥500 mg/24 hours
3.1.3 ECOG Performance Status (PS) 0, 1, or 2 (Appendix A)
3.1.4 The following laboratory values obtained ≤ 21 days prior to registration and 
confirmed prior to the first dose of study drug:
•
ANC ≥ 1000/μL
•
PLT ≥ 75,000/μL. Platelet transfusions to help patients meet eligibility 
criteria are not allowed within 3 days before study enrollment.
•
Total bilirubin ≤ 1.5 mg/dL (If total is elevated check direct and if 
normal patient is eligible.)
•
AST ≤ 3 x institutional upper limit of normal (ULN)
•
ALT ≤ 3 x institutional upper limit of normal (ULN)
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•
Calculated creatinine clearance ≥ 30 mL/min
3.1.5 Ability to understand and the willingness to sign a written informed consent 
before performance of any study-related procedure not part of normal medical 
care, with the understanding that consent may be withdrawn by the subject at 
any time without prejudice to future medical care.
3.1.6 Female patients who are postmenopausal for at least 1 year before the 
screening visit or are surgically sterile. Females of childbearing potential* 
must have a negative serum or urine pregnancy test with a sensitivity of at 
least 50 mIU/mL within 10 – 14 days and again within 24 hours prior to 
prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 
days as required by Revlimid REMS®) and must either commit to continued 
abstinence from heterosexual intercourse or begin TWO acceptable methods 
of birth control, one highly effective method and one additional effective 
method AT THE SAME TIME, at least 28 days before she starts taking 
lenalidomide. Female patients must agree to practice two effective methods 
of birth control from the time of signing the informed consent form though 
90 days after the last dose of study drug 
* A female of childbearing potential is a sexually mature female who: 
•
Has not undergone a hysterectomy (the surgical removal of the 
uterus) or bilateral oophorectomy (the surgical removal of both 
ovaries) or 
•
Has not been naturally postmenopausal (amenorrhea following 
cancer therapy does not rule out childbearing potential) for at 
least 24 consecutive months (i.e., has had menses at any time 
during the preceding 24 consecutive months) 
3.1.7 All study participants must be registered into the mandatory Revlimid 
REMS® program, and be willing and able to comply with the requirements 
of the REMS® program.
3.1.8 Females of reproductive potential must adhere to the scheduled pregnancy 
testing as required in the Revlimid REMS® program.
3.1.9
Men must agree to use a latex condom during sexual contact with a female 
of childbearing potential even if they have had a successful vasectomy 
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 (eg, 
calendar, 
ovulation, 
symptothermal, 
post-ovulation 
methods] 
and 
withdrawal are not acceptable methods of contraception.)
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3.2
Exclusion Criteria
3.2.1
No evidence of CRAB* criteria or new criteria of active MM which including the 
following:
•
Increased calcium levels (corrected serum calcium > 0.25 mmol/dL 
above the upper limit of normal or > 0.275 mmol/dL) related to MM
•
Renal insufficiency (attributable to MM)
•
Anemia (Hb 2g/dL below the lower limit of normal or <10g/dL) related 
to MM
•
Bone lesions (lytic lesions or generalized osteoporosis with 
compression fractures)
•
Bone marrow plasma cells > 60%
•
Serum involved/uninvolved FLC ratio ≥ 100, provided the absolute 
level of the involved free light chain is at least 100 mg/L and repeated 
twice
•
MRI with two or more focal lesion that is at least 5 mm or greater in 
size
*Participants with CRAB criteria that are attributable to 
conditions other than the disease under study may be eligible
3.2.2
Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary 
therapy considered investigational. Prior therapy with bisphosphonate is allowed. 
Prior radiation therapy to a solitary plasmacytoma is allowed. 
3.2.3
Serious medical or psychiatric illness likely to interfere with participation in this 
clinical study.
3.2.4
Diagnosed or treated for another malignancy within 2 years of enrollment, with 
the exception of complete resection of basal cell carcinoma or squamous cell 
carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after 
curative therapy.
3.2.5
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements.
3.2.6
Pregnant or nursing women will be excluded from the study because lenalidomide 
is an agent with the potential for teratogenic or abortifacient effects.  
3.2.7
History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to ixazomib or lenalidomide. 
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3.2.8
Known seropositive for or active viral infection with human immunodeficiency 
virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV).  Patients who 
are seropositive because of hepatitis B virus vaccine are eligible. 
3.2.9
Major surgery within 14 days before first dose of ixazomib.
3.2.10 Known Amyloid involvement.
3.2.11 Myeloma-related central nervous system involvement.
3.2.12 Systemic treatment, within 14 days before the first dose of ixazomib with strong 
CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, 
phenobarbital), or use of Ginkgo biloba or St. John’s wort.
3.2.13 Known GI disease or GI procedure that could interfere with the oral absorption 
or tolerance of ixazomib including difficulty swallowing.
3.2.14 Grade 2 peripheral neuropathy or higher or grade 1 with pain on clinical 
examination during the screening period.
3.2.15 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.
3.2.16 Previous treatment with ixazomib, or participation in a study with ixazomib 
whether treated with ixazomib or not.
3.3
Inclusion of Women and Minorities
3.3.1
Both men and women of all races and ethnic groups are eligible for this trial.
4. REGISTRATION PROCEDURES
4.1
General Guidelines for DF/HCC Institutions
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied.
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist.
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the subject must be taken off-study in 
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the CTMS (OnCore) with an appropriate date and reason entered.  
4.2
Registration Process for DF/HCC Institutions
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.  
4.3
General Guidelines for Other Investigative Sites
Eligible participants will be entered on study centrally at DFCI by the Project Manager.  All sites 
should call the Project Manager to verify study status and slot availability. 
Following registration, participants should begin protocol therapy as soon as feasible. Issues that 
would cause treatment delays should be discussed with the Overall PI.  If a participant does not 
receive protocol therapy following registration, the participant’s registration on the study must be 
canceled.  The Project Manager should be notified of cancellations as soon as possible.
4.4
Registration Process for Other Investigative Sites
To register a participant, the following documents should be completed by the research nurse or 
data manager and e-mailed to the Research Project Manager:
•
Copy of labs and clinical information that satisfy inclusion criteria
•
Signed participant consent form
•
HIPAA authorization form
•
Registration Form 
The research nurse or data manager at the participating site will then call 
or e-mail 
the Research Project Manager, to verify eligibility. To complete 
the registration process, the Coordinator will follow DF/HCC Standard Operating Procedure for 
Human Subject Research Titled Subject Protocol Registration (SOP #: REGIST-101) and register 
the participant on the protocol.  The coordinator will fax or e-mail the participant study number, 
and if applicable the dose treatment level, to the participating site.  The coordinator will also call 
the research nurse or data manager at the participating site and verbally confirm registration
Treatment may not begin without confirmation from the Coordinating Center that the 
participant has been registered. 
NOTE: Same day treatment registrations will only be accepted with prior notice and 
discussion with DFCI.
5. TREATMENT PLAN
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5.1
Treatment Regimen
Treatment will consist of 9 cycles of induction therapy followed by maintenance therapy for a total 
of 24 months. A treatment cycle is defined as 28 consecutive days. 
For treatments cycle 1 and 2, a +/- 3 day window is allowed. For treatments cycle 3 through 24 a 
+/-7 day window is allowed. 
No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the participant's malignancy.
Induction Cycles  
 Table 7: Ixazomib and Lenalidomide and Dexamethasone Combination (Cycles 1-9)
Agent
Pre-medications/ 
Precautions
Dose
Route
Schedule
Cycle 
Length
Ixazomib
Should not be taken 
with food
4 mg
Oral
Days 1, 8, 15
Lenalidomide
None
25 mg
Oral
Days 1–21 of 
each cycle
Dexamethasone
Take with food; 
Recommended to be 
taken in the morning
40 mg
Oral
Days 1, 8, 15, 22
28 days
Maintenance Cycles
Table 8: Ixazomib and Lenalidomide Combination (Cycles 10-24)†
Agent
Pre-medications/ 
Precautions
Dose
Route
Schedule
Cycle 
Length
Ixazomib
Should not be taken 
with food
4 mg*
Oral
Days 1,8, 15
Lenalidomide
None
15 mg**
Oral
Days 1–21 of 
each cycle 
28 days
* If patient was dose reduced during the induction phase for ixazomib below 4mg, then 
maintenance phase starts at that dose reduction and not at the higher 4 mg dose.
** If patient was dose reduced during the induction phase for lenalidomide below 15mg, then 
maintenance phase starts at that dose reduction and not at the higher 15 mg dose.
†After discussion with the overall principal investigator, high-dose dexamethasone may be re-
added during maintenance due to biochemical progression (progressive increase in SPEP [25% 
and an absolute increase of 0.5g/dL] or UPEP [25% and an absolute increase of 200mg/24hours] 
on 2 successive evaluations as determined by the IMWG response criteria or documented 
progression by the FreeLiteTM progressive disease criteria in the absence of serum or urine 
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involvement). If approved by the overall PI, dexamethasone should be given as an oral dose of 
40mg on days 1, 8, 15, and 22. 
The participant will be requested to maintain a medication diary.  The medication diary and 
empty pill containers will be returned to clinic staff at the end of each cycle.
Stem cell collection using standard mobilization procedures of the Institute can be performed for 
patients who are eligible and will be performed at the time of best remission or after 9 cycles of 
therapy. Patients may delay treatment for up to 3 weeks after stem cell collection is complete. 
During maintenance, patients may return to clinic every 3 cycles beginning with cycle 10. If this 
option is utilized, a 3-month supply of ixazomib will be supplied by the investigational pharmacy 
at each visit. Lenalidomide may be shipped from the investigational pharmacy to the patient’s 
home for each cycle the patient does not return to clinic, according to local practice. 
5.2
Agent Administration
The order in which the drugs are administered does not matter. 
5.2.1
Ixazomib
The ixazomib drug product is provided in strengths of 4.0-, 3.0-, and 2.3-mg and 2.0-, 0.5-, and 
0.2 mg capsules as the active boronic acid. The different dose strengths are differentiated by 
both capsule size and color as described in table 9 below:
Table 9: Ixazomib Capsule Description
Dose 
Strength
Capsule Size
Capsule Color
4.0 mg
Size 4
Ivory
3.0 mg
Size 3
Light gray
2.3 mg
Size 2
Light pink
2.0 mg
Size 2
Swedish orange
0.5 mg
Size 3
Dark green
0.2 mg
Size 4
White opaque
For additional details, please see the ixazomib IB.
For more detailed information regarding ixazomib product information please refer to Section 8.1. 
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 6.1).
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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. The prescribed administration of 
ixazomib doses in this study is 4 mg ixazomib in a 28-day cycle. 
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.
5.2.1.1 Dose Delay or Interruption
Please refer to section 6.1 of the protocol
5.2.2
Lenalidomide
Lenalidomide will be given as a single daily oral dose of 25 mg per day on days 1–21 followed by 
a 7-day rest period for cycles 1–9 and 15 mg per day on days 1-21 for cycles 10–24. A window of 
+/-7 days is allowed, except cycles 1 and 2 which will be +/- 3 days. Dose modification guidelines 
are described in Section 6.2 (Dose Modifications/Delays). 
Lenalidomide capsules should be swallowed whole, and should not be broken, chewed or opened. 
Administration of lenalidomide will be at approximately the same time each day. Drug may be 
taken with or without food. If a dose is missed and less than 12 hours has elapsed since the missed 
dose, the patient can take the dose for that day. If more than 12 hours has elapsed since missing a 
dose at the normal time, the patient should not take the dose, but take the next dose at the normal 
time on the following day. If a dose is missed, it should be taken as soon as possible on the same 
day. If a dose is vomited, the dose should not be made up and the participant should continue with 
the regular schedule of the drug at the next dose. A drug diary will be provided to participants to 
record oral administration of doses.
Participants who take more than the prescribed dose of lenalidomide should be instructed to seek 
emergency medical care if needed and contact study staff immediately. Participants experiencing 
adverse events may need study treatment modifications (see Section 6.2).
Lenalidomide related resources will be provided to all patients prior to receiving lenalidomide 
therapy as part of the Revlimid REMS program. For more information regarding program 
registration and drug ordering, refer to section 8.2.  
5.2.2.1 Dose Delay or Interruption
Please refer to sections 6.1 and 6.2 of the protocol. 
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5.2.3
Dexamethasone 
Dexamethasone will be obtained from commercial supply in this study. This may lead to added 
costs for the participant or the participant’s insurance company. 
Dexamethasone will be given as a single oral dose on days 1, 8, 15, and 22 of each 28 day cycle 
during the induction phase of this study (Cycles 1-9 only). 
Dexamethasone should be taken at approximately the same time each day. It is recommended that 
dexamethasone be taken in the morning to reduce insomnia. Each dose should be taken with food. 
If a dose of dexamethasone is vomited, the participant should continue with the regular schedule 
of the drug at the next dose. If a dose is missed and less than 12 hours has elapsed since the missed 
dose, the patient may take the dose for that day. If more than 12 hours has elapsed since missing a 
dose at the normal time, the patient should not take the dose, but take the next dose at the normal 
time on the following day. A drug diary will be provided to participants to record oral 
administration of doses.
At the treating investigator’s discretion, dexamethasone may be given as a split dose over 2 
consecutive days.
5.2.3.1 Dose Delay or Interruption
Please refer to section 6.3 of the protocol. 
Dose modification guidelines are described in Section 6.3 (Dose Modifications/Delays).
5.3
General Concomitant Medication and Supportive Care Guidelines
5.3.1
Medications and supportive care 
•
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.
•
Stem cell mobilization will be allowed at the time of best response or at the end of 
induction therapy (after 9 cycles) for patients who are eligible for stem cell 
transplant. Standard mobilization treatment (with GCSF or with cyclophosphamide 
or plerixafor, etc) will be used based on Institutional guidelines. Patients may delay 
treatment for up to 6 to 8 weeks for mobilization purposes. Filgrastim is allowed 
per standard protocol for stem cell mobilization if stem cell mobilization will be 
performed. This will be allowed per standard procedure of stem cell collection per 
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Institutional guidelines.
•
Use of white cell growth factors [Filgrastim or acceptable equivalent] is allowed 
for management of treatment induced neutropenia at physician discretion. 
Filgrastim should be given according to the ASCO guidelines. Pegfilgrastim is not 
to be used in replace of filgrastim. 
•
Patients should be transfused with red cells and platelets as clinically indicated and 
according to institutional guidelines. 
•
Patients will receive bisphosphonates per recommendations of myeloma therapy. 
A note will be placed about patients who are not receiving bisphosphonates for 
clinical reasons such as osteonecrosis of the jaw. 
•
Nausea/Vomiting: If nausea and/or vomiting is noted at any point in time, 
premedication with prochlorperazine or other antiemetics may be used before 
future doses.  Antiemetics, including 5-HT3 serotonin receptor antagonists, may be 
used as needed at the discretion of the investigator. 
•
If nausea persists in spite of the use of standard antiemetics additional symptom 
management should be as per standard antiemetic guidelines. 
•
Diarrhea: 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.
•
Thromboprophylaxis is required for all participants. Participants may receive 
daily aspirin administration (81 or 325 mg), daily enoxaparin (40 mgs), or low 
molecular weight heparin (type Innohep® 4500 UI anti-Xa as needed) or equivalent 
to decrease the risk of thromboembolic complications. Aspirin prophylaxis will be 
the preferred first choice unless contraindicated. It is recommended that if the 
platelet count falls below 30,000/mm3, thromboprophylaxis be held to minimize 
the risk of bleeding and then resumed when platelet counts are equal to or above 
this level.
•
Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided with 
impaired renal function given reported NSAID-induced renal failure in patients 
with decreased renal function.
•
Prophylaxis Against Risk of Reactivation of Herpes Infection virus: 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 
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antivirals may be initiated as clinically indicated at the discretion of the treating 
investigator.  Other antivirals are also acceptable.
•
Systemic treatment with any of the following metabolizing enzyme inducers 
should be avoided, unless there is no appropriate alternative medication for 
the patient’s use (Rationale:  If there were to be a DDI with an inducer, ixazomib 
exposure would be less; therefore, there would be a reduced chance of an AE.  
However, there may be less chance for an antitumor effect, but that is not an 
absolute reason to be taken off ixazomib):
o
Strong CYP3A inducers:  rifampin, rifapentine, rifabutin, carbamazepine, 
phenytoin, and phenobarbital
o
Excluded foods and dietary supplements include St. John’s Wort and 
Ginkgo Biloba
•
The following procedures are prohibited during the study.
o
Any antineoplastic treatment with activity against MM, other than study 
drugs
o
Radiation therapy (note that, in general, the requirement for local radiation 
therapy indicates disease progression)
5.4
Management of Clinical Events 
•
Erythematous Rash With or Without Pruritus Rash with or without pruritus has 
been reported with ixazomib, primarily at the higher doses tested and when given 
with agents where rash is an overlapping toxicity.  The rash may range from limited 
erythematous areas, macular and/or small papular bumps that may or may not be 
pruritic over a few areas of the body, to a more generalized eruption that is 
predominately on the trunk or extremities.  Rash has been most commonly 
characterized as maculopapular or 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. 
o
Symptomatic measures such as antihistamines or corticosteroids (oral or 
topical) have been successfully used to manage rash and have been used 
prophylactically in subsequent cycles.  The use of a topical, IV, or oral 
steroid (eg, prednisone ≤ 10 mg per day or equivalent) is permitted.  
o
Management of a Grade 3 rash may require intravenous antihistamines or 
corticosteroids.  Administration of ixazomib (and/or other causative agent 
if given in combination) should be modified per protocol and re-initiated at 
a reduced level from where rash was noted 
o
In line with clinical practice, a dermatology consult that include a 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 
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developed a rash (eg, using a thick, alcohol-free emollient cream on dry 
areas of the body or oral or topical antihistamines).  
o
A rare risk is Stevens-Johnson Syndrome, a severe and potentially life-
threatening rash with skin peeling and mouth sores, 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 will be monitored regularly as outlined in the 
protocol with additional testing obtained according to standard clinical practice. 
Thrombocytopenia may be severe but has been manageable with platelet 
transfusions according to standard clinical practice. Ixazomib administration 
should be modified as noted as per dose modification recommendations in the 
protocol when thrombocytopenia occurs (see Section 6.1). Therapy can be 
reinitiated at a reduced level upon recovery of platelet counts. A rare risk is 
thrombotic thrombocytopenic purpura (TTP), a rare blood disorder where blood 
clots form in small blood vessels throughout the body characterized by 
thrombocytopenia, petechiae, fever, or possibly more serious signs and symptoms. 
TTP should be managed symptomatically according to standard medical practice.
•
Neutropenia. Blood counts will be monitored regularly as outlined in the protocol 
with additional testing obtained according to standard clinical practice.  
Neutropenia may be severe but has been manageable.  Growth factor support is not 
required but may be considered according to standard clinical practice.  Ixazomib 
administration should be modified as noted as per dose modification 
recommendations in the protocol when neutropenia occurs (see Section 6.1).  
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.
o
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.
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•
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.
•
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: 
o
Postmenopausal for at least 1 year before the screening visit, or
o
Surgically sterile, or
o
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
o
Agree to practice true abstinence, when this is in line with the 
preferred and usual lifestyle of the subject.  (Periodic abstinence 
[eg, calendar, ovulation, symptothermal, postovulation methods] 
and withdrawal are not acceptable methods of contraception.)
•
Male patients, even if surgically sterilized (ie, status postvasectomy) 
must agree to 1 of the following:
o
Practice effective barrier contraception during the entire study 
treatment period and through 90 days after the last dose of study 
drug, or
o
Agree to practice true abstinence, when this is in line with the 
preferred and usual lifestyle of the subject.  (Periodic abstinence 
[eg, calendar, ovulation, symptothermal, postovulation methods for 
the female partner] and withdrawal are not acceptable methods of 
contraception.)
5.5
Criteria for Taking a Participant Off Protocol Therapy
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.  
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In the absence of treatment delays due to adverse event(s), treatment may continue for 24 cycles 
or until one of the following criteria applies:
•
Progression to overt Multiple Myeloma
•
Intercurrent illness that prevents further administration of treatment
•
Unacceptable adverse event(s)
•
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements
•
Participant decides to withdraw from the protocol therapy
•
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant.
When a participant is removed from protocol therapy and/or is off of the study, the relevant Off-
Treatment/Off-Study information will be updated in OnCore.
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI,
5.6
Duration of Follow Up
Participants will be followed for 3 years after removal from protocol therapy or until progression 
to active symptomatic MM, whichever occurs first.  Participants removed from protocol therapy 
for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse 
event.
5.7
Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:
•
Lost to follow-up
•
Withdrawal of consent for data submission
•
Death
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). In addition, the study team will ensure Off 
Treatment/Off Study information is updated in OnCore in accordance with DF/HCC policy 
REGIST-101.
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6. DOSING DELAYS/DOSE MODIFICATIONS
6.1
Recommended Ixazomib Criteria for Beginning or Delaying a Subsequent 
Treatment Cycle & Dose Modifications for Treatment Associated Toxicity
For a new cycle of treatment to begin during induction, the patient must meet the following criteria:
•
ANC must be ≥ 1,000/μL.
•
Platelet count must be ≥ 75,000/μL.
•
All other clinically significant, study drug related non hematologic toxicity must have 
resolved to ≤ Grade 1 or to baseline condition
If the participant fails to meet the above-cited criteria for initiation of a new cycle of treatment 
during induction, dosing will be delayed for 1 week. At the end of that time, the participant should 
be re-evaluated to determine whether the above criteria have been met. If the participant continues 
to fail to meet the above-cited criteria, delay therapy and continue to re-evaluate. The maximum 
delay for toxicity before treatment is permanently discontinued will be 3 weeks, however delays 
due to other circumstances should be discussed with the Principal Investigator.  Delays of > 3 
weeks must be discussed with the Principal Investigator.  Re-treatment will be at the discretion of 
the Principal Investigator. 
During maintenance, the above pre-treatment criteria must only be met every 3 months during 
cycles when a provider is seen. During cycles when the patient does not return to clinic, sites must 
follow local guidelines for pre-treatment criteria.
There is no specific pre-treatment criteria for lenalidomide during induction or maintenance. Sites 
should follow local guidelines for beginning a new cycle of treatment with lenalidomide.   
If any one of the study medications is permanently discontinued for toxicity, the patient may 
remain on the study at the discretion of the investigator.
Table 10: Ixazomib Dose Adjustments
Dose Level
Dose
Starting Dose
4.0 mg
-1
3.0 mg
-2
2.3 mg
-3
Discontinue
If ixazomib is reduced for any toxicity, the dose may not be re-escalated.  
A delay of up to 14 days will be allowed for participants for non-AE related events (i.e.; vacation, 
family emergency, etc) after discussion with the overall PI. 
For both Ixazomib and lenalidomide the investigator may discuss considerations for dose 
modifications and symptom management with the Principal Investigator.
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Treatment modifications due to Ixazomib or lenalidomide-related AEs are outlined in Tables 
11 and 12.
Table 11:  Ixazomib and Lenalidomide Dose Adjustments for Hematologic Toxicities
Within-Cycle Dose Modifications (other than Day 1)
Criteria
Action
Platelet count ≤ 30,000/μL
or 
ANC ≤ 500/μL
•
Ixazomib dose should be held.  Lenalidomide dose should 
be held.
•
Complete blood count (CBC) with differential should be 
repeated at least every other day until the ANC and/or 
platelet counts have exceeded the pre-specified values on 
at least 2 occasions.  
•
Upon recovery (1st occurrence), lenalidomide may be 
reinitiated with 1 dose level reduction depending on the 
attribution of the toxicity to the study agent. Do not dose 
reduce ixazomib. Upon recurrence of the toxicity (2nd
occurrence), ixazomib may be reinitiated with 1 dose level 
reduction depending on the attribution of the toxicity to the study 
agent.
Dose Modifications for Subsequent Treatment Cycles on Day 1
Criteria
Action
Delay of > 2 weeks in the start of a 
subsequent cycle due to lack of 
toxicity recovery as defined in 
Section 6.3.1 
ANC < 1,000/μL
Platelet count < 75,000/μL
•
Hold ixazomib and lenalidomide until resolution as per 
criteria Section 6.1.
•
Upon recovery, reduce lenalidomide 1 dose level, 
depending on the attribution of the toxicity to the study 
agent.   If lenalidomide has been reduced during the cycle, 
consider a dose reduction of ixazomib upon reinitiating the 
subsequent cycle.
•
The maximum delay before treatment should be 
discontinued will be 3 weeks or at the discretion of the PI.
Dose Modifications for Subsequent Treatment Cycles
Criteria
Action
All Hematologic Toxicities
For any hematologic toxicity that occurs during a cycle but 
recovers in time for the start of the next cycle:
•
 If dose was reduced within the cycle, start the next cycle 
at that same dose.
•
If due to toxicity timing, ie, 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.
•
Do not reduce the dose both within a cycle and at the 
start of the cycle for the same most severe toxicity.
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Table 12: Ixazomib and Lenalidomide Dose Adjustments for Non-Hematologic Toxicities
Adverse Event 
Severity
Action on Study Drug
Further Considerations
Grade 1 
Peripheral 
Neuropathy
No action
Grade 1 signs and symptoms:  
asymptomatic; without pain or 
loss of function; clinical or 
diagnostic observations only 
deep tendon reflexes or 
parasthesia
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) 
Grade 2 
Peripheral 
Neuropathy 
with pain 
or 
Grade 3
Hold Ixazomib until 
resolution to Grade ≤ 1 
without pain or baseline
Reduce study drug to next 
lower dose upon recovery
Grade 3 signs and symptoms:  
severe symptoms; limiting 
self-care ADL; assistive 
device indicated 
New or 
Worsening 
Peripheral 
Neuropathy
(CTCAE v.4.0)
Grade 4 
Peripheral 
Neuropathy
Discontinue Ixazomib
Grade 4 signs and symptoms: 
Life threatening 
consequences; urgent 
intervention indicated
Rash
Grade 2
Symptomatic 
recommendations as per 
section 5.3 and 5.4
Hold Ixazomib or 
lenalidomide depending on 
the attribution until 
resolution to Grade < 1 or 
baseline
Non-Hematologic 
toxicities judged 
to be related to 
study drug
Grade 3
If not recovered to < Grade 
1 or baseline within 3 
weeks:
Reduce Ixazomib or 
lenalidomide depending on 
the attribution to next 
lower dose upon return to 
< Grade 1 or baseline
Symptomatic 
recommendations noted in 
Section 5.3 and 5.4
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Table 12: Ixazomib and Lenalidomide Dose Adjustments for Non-Hematologic Toxicities
Adverse Event 
Severity
Action on Study Drug
Further Considerations
Non-Hematologic 
toxicities judged 
to be related to 
study drug
Grade 3
Subsequent recurrence 
Grade 3 that does not 
recover to < Grade 1 or 
baseline within 3 weeks
• Hold study drug until 
resolution to Grade < 1 
or baseline
• Reduce study drug to 
next lower dose 
Monitor closely, take 
appropriate medical 
precautions, and provide 
appropriate symptomatic care
Non-Hematologic 
toxicities judged 
to be related to 
study drug
Grade 4 
Consider permanently 
discontinuing the 
offending study drug 
(depending on attribution).  
Exceptions are cases in which 
the investigator determines the 
patient is obtaining a clinical 
benefit 
If the patient discontinues either Ixazomib or lenalidomide, he or she does not need to come off 
protocol therapy.
If ixazomib is reduced for any toxicity, the dose may not be re-escalated.
6.2
Lenalidomide 
See dose modifications described above in tables 11 and 12. 
Table 13:  Lenalidomide Dose Reduction
Dose Level
Lenalidomide Dose
0
25 mg
-1
20 mg
-2
15 mg
-3
10 mg
-4
5 mg
If lenalidomide is reduced for any toxicity, the dose may not be re-escalated.
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6.3
Dexamethasone
Table 14: Dexamethasone Dose Modifications 
Gastrointestinal
Grade 1-2  
Treat with H2 blockers, sucralfate, or omeprazole. 
If symptoms persist despite above measures, 
decrease dexamethasone by 1 dose level
Dyspepsia
Gastric or 
Duodenal Ulcer
Gastritis
≥ Grade 3 
(requiring 
hospitalization 
or surgery)
Hold dexamethasone until symptoms adequate 
controlled. Restart and decrease 1 dose level of 
current dose along with concurrent therapy with 
H2 blockers, sucralfate, or omeprazole. If 
symptoms persist despite above measures, 
discontinue dexamethasone and do not resume.
Acute Pancreatitis
All Grades
Discontinue dexamethasone and do not resume.
Cardiovascular
Edema
(limiting function and 
unresponsive to therapy or 
anasarca)
≥ Grade  3 
Diuretics as needed, and decrease dexamethasone 
dose by 1 dose level;
If edema persists despite above measures, decrease 
dose another level and do not resume if symptoms 
persist despite second reduction.
Neurology
Confusion or Mood 
Alterations
(interfering with function 
+/- interfering with 
activities of daily living)
≥ Grade 2 
Hold dexamethasone until symptoms resolve. 
Restart with 1 dose level reductions.
If symptoms persist despite above measures, 
discontinue dexamethasone and do not resume.
Musculoskeletal
Muscle Weakness 
(symptomatic and 
interfering with function 
+/- interfering with 
activities of daily living)
≥ Grade 2 
Decrease dexamethasone 1 dose lever. 
If weakness persists despite above measures 
decrease by 1 dose level. 
Discontinue dexamethasone and do not resume if 
symptoms persist.
Metabolic
Hyperglycemia 
≥ Grade 3 
Treatment with insulin or oral hypoglycemics as 
needed. 
If uncontrolled despite above measures, decrease 
dose level by 1 dose level until levels are 
satisfactory.
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If the patient discontinues dexamethasone, he or she does not need to come off protocol therapy.
Table 15: Dexamethasone dose reduction
Dose Level
Dexamethasone Dose
0
40 mg
-1
20 mg
-2
10 mg
 If dexamethasone is reduced for any toxicity, the dose may not be re-escalated.
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
7.1   Definitions
       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. CTCAE version 4.03 will be used for this 
study.
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.  
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).
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•
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 one of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent.   Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse; any organism, virus, or infectious 
particle (eg, 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 the 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/μL 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.
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The following 
list of reported and/or potential AEs (Section 7.2) and the characteristics of an observed AE 
(Section 7.3) will determine whether the event requires expedited reporting in addition to routine 
reporting.
7.2
Expected Toxicities
7.2.1
Adverse Events List(s)
7.2.1.1 Adverse Event List of Ixazomib 
As of 27 March 2013, preliminary clinical data is available for a total of 653 patients across 13 
studies. The emerging safety profile indicates that ixazomib is generally well tolerated. The 
adverse events (AEs) are consistent with the class-based effects of proteasome inhibition and are 
similar to what has been previously reported with VELCADE though the severity of some, for 
example peripheral neuropathy, is less. While some of these potential toxicities may be severe, 
they can be managed by clinical monitoring and standard medical intervention, or, as needed, dose 
modification or discontinuation.
Fatigue was the most common AE reported among 384 patients treated in the oral (PO) studies 
(47%). Other common AEs reported in the pooled intravenous (IV) and PO safety populations 
include nausea, thrombocytopenia, diarrhea, and vomiting. Rash is also a commonly reported 
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treatment-emergent event; however, there is some variety in its characterization and causality 
resulting in different preferred terms to describe it. A high-level term outline of rash events 
includes rashes, eruptions and exanthems NEC; pruritus NEC; erythemas; papulosquamous 
conditions; and exfoliative conditions. The dose escalation phases of most trials reported in the IB
have now completed enrollment, and gastrointestinal (GI) symptoms were the common dose-
limiting toxicities (DLTs) when the use of prophylactic anti-emetics was not permitted per 
protocol. In the expansion cohorts or phase 2 cohorts (as per each study), the incidence and severity 
of GI symptoms was mitigated by the use of the lower maximum tolerated dose 
(MTD)/recommended phase 2 dose (RP2D) (as per each study) and standard clinical usage of anti-
emetics and/or antidiarrheal medications as deemed appropriate. Prophylactic use of anti-emetics 
has not been required as with other agents but (as outlined in Section 6.7) has been used according 
to standard practice and are effective.
The most frequent (at least 20%) treatment-emergent adverse events (TEAEs) reported with the 
PO formulation pooled from single-agent studies (n = 201) irrespective of causality to ixazomib, 
include nausea (53%), fatigue (51%), diarrhea (44%), thrombocytopenia (34%), vomiting (38%), 
decreased appetite (32%), fever (21%), and anemia (21%). The most frequent (at least 20%) 
TEAEs reported with the PO formulation pooled from combination trials (irrespective of the 
combination) (n = 173), irrespective of causality to ixazomib, include diarrhea (47%), fatigue 
(44%), nausea (38%), peripheral edema (35%), constipation (33%), insomnia (29%), 
thrombocytopenia (28%), anemia (26%), vomiting (26%), neutropenia (25%), back pain (24%), 
pyrexia (23%), peripheral edema (21%, each), fever (20%), cough (20%), hypokalemia (20%), 
neutropenia (20%), and upper respiratory tract infection (20%). Overall rash of all grades is 
reported in approximately 50% of patients and is more common when ixazomib is given in 
combination with lenalidomide where rash is an overlapping toxicity.
Additional detailed information regarding the clinical experience of ixazomib may be found in the 
IB, including information on the IV formulation.  
7.2.1.2 Adverse Event List for Lenalidomide
Events that have occurred in >10% of individuals treated with lenalidomide include neutropenia, 
anemia, thrombocytopenia, fatigue, rash, diarrhea, constipation, nausea, loss of appetite, itching, 
dry skin, muscle cramps, lack or loss of strength, dizziness, insomnia, swelling of the extremities, 
headache, back and joint pain, fever, cough, upper respiratory infection, and dyspnea.
Events that have occurred in >1% of individuals treated with lenalidomide include risk of DVT, 
PE, and blood clots that could lead to stroke, heart attack, or organ failure, febrile neutropenia, 
atrial fibrillation, pneumonia or lung infections, sepsis, dehydration and renal failure.
Events that have occurred in <1% of individuals treated with lenalidomide include rare treatment-
emergent adverse events of angioedema, serious skin reactions including Stevens-Johnson 
syndrome (SJS) and toxic epidermal necrolysis (TEN) or an allergic skin reaction similar to that 
seen with thalidomide, tumor lysis syndrome (TLS), tumor flare reaction (TFR), and 
rhabdomyolysis. In addition, lenalidomide has been shown to increase the level of digoxin in the 
blood in some patients. Patients will be instructed to inform their doctor if taking digoxin.
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There may be an increased risk of second cancers in patients who are on lenalidomide maintenance 
therapy after a bone marrow transplant.
7.2.1.3 Adverse events list of Dexamethasone
Events that have occurred in 10-15% of individuals treated with dexamethasone include increased 
appetite, weight gain, sleep disturbance, hypertension, fluid retention, ankle swelling, bruising, 
infection, mood changes, slow wound healing, depression, and hyperglycemia, which may lead to 
fatigue, weight loss, excessive thirst and frequent urination. Events that have occurred in 1-9% of 
individuals treated with dexamethasone include loss of appetite, muscle twitching, increased thirst, 
frequent urination, increased perspiration, diarrhea, nausea, headache, bone thinning, spinal 
fracture or fracture of bones, tachycardia, fungal infections. Events that have occurred in <1% of 
individuals treated with dexamethasone include blurred vision, personality changes, stomach 
ulcers with bleeding that may cause hematemesis, blood in the stool and abdominal pain. Other, 
less frequent, events may include bowel perforation, irritation and bleeding of the esophagus, heart 
failure, allergic reaction that may lead to facial redness, shortness of breath, abdominal cramps and 
hypotension, convulsions, brain swelling, dizziness, cataracts, glaucoma and increased blood 
pressure in the eye, development of diabetes, pancreatic inflammation, abdominal swelling, 
hypokalemia, DVT or PE, malaise, swelling and/or redness of skin, allergic skin reactions, itching, 
hirsutism, muscle weakness or loss of muscle mass, rupture of tendons, menstrual cycle 
disturbances, facial puffiness, leading to the appearance of a “moon face” hormonal disturbances, 
and hiccups. 
7.3
Adverse Event Characteristics
•
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded 
from the CTEP web site:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
•
Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.
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7.4
Expedited Adverse Event Reporting 
7.4.1
Investigators must report to the Overall PI any serious adverse event (SAE) that 
occurs after the initial dose of study treatment, during treatment, or within 30 days 
of the last dose of treatment on the local institutional SAE form. 
7.4.2
For multi-institution studies where a DF/HCC investigator is serving as the 
Overall Principal Investigator, each participating institution must abide by the 
reporting requirements set by the DF/HCC. This applies to any medical event 
equivalent to an unexpected grade 2 or 3 with a possible, probable or definite 
attribution, grade 4 toxicities, and grade 5 (death) regardless of study phase or 
attribution.
7.5
DF/HCC Expedited Reporting Guidelines
Investigative sites within DF/HCC and DF/PCC will report SAEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy. 
Other investigative sites will report SAEs to their respective IRB according to the local IRB’s 
policies and procedures in reporting adverse events. A copy of the submitted institutional SAE 
form should be forwarded to the Overall PI within the timeframes detailed in the table below.  
Table 17- DF/HCC Reportable AEs
Attribution
Gr. 2 & 3 
AE
Expected
Gr. 2 & 3 AE 
Unexpected
Gr. 4 AE 
Expected
Gr. 4 AE
Unexpected
Gr. 5 AE 
Expected or 
Unexpected
Unrelated
Unlikely
Not required
Not required
5 calendar 
days#
5 calendar 
days
24 hours*
Possible
Probable
Definite
Not required
5 calendar 
days
5 calendar 
days#
5 calendar 
days
24 hours*
# If listed in protocol as expected and not requiring expedited reporting, event does not need to 
be reported.
* For participants enrolled and actively participating in the study or for AEs occurring within 30 
days of the last intervention, the AE should be reported within 24 hours of learning of the event.
The Overall PI will submit SAE reports from outside institutions to the DFCI OHRS according to 
DFCI IRB policies and procedures in reporting adverse events. 
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 6 half lives after product administration, the investigational product will 
be permanently discontinued in an appropriate manner (e.g., dose tapering if necessary for subject 
safety). 
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Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated. The investigator must immediately notify 
the Millennium and Celgene (or designee) Medical Monitor of this event and complete and 
forward an SAE Form to Millennium and Celgene (or designee) within 24 hours and in accordance 
with SAE reporting procedures described in this section.  
7.6  Procedures for Reporting Serious Adverse Events to Millennium
AEs may be spontaneously reported by the patient and/or in response to an open question from 
study personnel or revealed by observation, physical examination, or other diagnostic 
procedures.  Any clinically relevant deterioration in laboratory assessments or other clinical 
finding is considered an AE.  When possible, signs and symptoms indicating a common 
underlying pathology should be noted as one comprehensive event.  For serious AEs, the 
investigator must determine both the intensity of the event and the relationship of the event to 
study drug administration. 
AEs which are serious must be reported to Millennium Pharmacovigilance (or designee) from 
the first dose of study drug through 30 days after administration of the last dose of ixazomib. 
Any SAE that occurs at any time after completion of ixazomib treatment or after the designated 
follow-up period that the sponsor-investigator and/or sub-investigator considers to be related to 
any study drug must be reported to Millennium Pharmacovigilance (or designee).  In addition, 
new primary malignancies that occur during the follow-up periods must be reported, regardless 
of causality to study regimen, for a minimum of three years after the last dose of the 
investigational product, starting from the first dose of study drug. All new cases of primary 
malignancy must be reported to Millennium Pharmacovigilance (or designee).   
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 
 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.   
Regardless of expectedness or causality, all SAEs (including serious pretreatment events) must 
also be reported in English to Millennium Pharmacovigilance (or designee):
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
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•
Results in death (including also spontaneous and therapeutic abortion, fetal and neonatal 
death, any death of an infant which occurs within 28 days of birth subsequent to in utero
exposure to Study Drug), 
•
Is life-threatening,
•
Requires hospitalization or prolongation of existing hospitalization,
•
Results in persistent or significant disability or incapacity, or 
•
Is a congenital anomaly or birth defect. 
Serious adverse events (SAE) are defined above.  The investigator must inform Celgene in writing 
using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 24 hours of being 
aware of the event.  The written report must be completed and supplied to Celgene by facsimile 
within 24 hours.  The initial report must be as complete as possible, including an assessment of 
the causal relationship between the event and the investigational product(s).  Information not 
available at the time of the initial report (e.g., an end date for the adverse event or laboratory values 
received after the report) must be documented on a follow-up report.  A final report to document 
resolution of the SAE is required.  The Celgene tracking number (RV-CL-MM-PI-006919) and 
the institutional protocol number should be included on SAE reports (or on the fax cover letter) 
sent to Celgene.  A copy of the fax transmission confirmation of the SAE report to Celgene should 
be attached to the SAE and retained with the patient records.
Pregnancy
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or
disease state) of a female subject occurring while the subject is on lenalidomide, or within 28 days 
of the subject’s last dose of lenalidomide, are considered immediately reportable events. 
Lenalidomide is to be discontinued immediately. The pregnancy, suspected pregnancy, or positive 
pregnancy test must be reported to Celgene Drug Safety immediately by facsimile or email using 
the Pregnancy Initial Report Form. The female subject should be referred to an obstetrician-
gynecologist, preferably one experienced in reproductive toxicity for further evaluation and 
counseling.
The Investigator will follow the female subject until completion of the pregnancy and must notify 
Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or abnormal 
outcome) using the Pregnancy Follow-up Report Form.  If the outcome of the pregnancy was 
abnormal (e.g., spontaneous or therapeutic abortion), the Investigator should report the abnormal 
outcome as an AE. If the abnormal outcome meets any of the serious criteria, it must be reported 
as an SAE to Celgene Drug Safety immediately by facsimile, or other appropriate method, within 
24 hours of the Investigator’s knowledge of the event using the SAE Report Form.
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, within 24 hours of the Investigator’s 
knowledge of the event using the SAE Report Form. 
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An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as SAEs.
7.8.1
Protocol-Specific Expedited Adverse Event Reporting Exclusions
There are no protocol specific exclusions. 
7.9
Expedited Reporting to the Food and Drug Administration (FDA)
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA.
7.10 Expedited Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant safety 
reports or sentinel events that require reporting according to institutional policy. 
7.11 Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions.
8. PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with the Ixazomib and lenalidomide 
administered in this study can be found in Section 7.
8.1
Ixazomib
8.1.1
Description
The chemical name is: B-[(IR)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3- 
methylbutyl]boronic acid. Ixazomib, also known as MLN9708 and Ninlaro, is an oral 
proteasome inhibitor. The molecular formula is C20H23BCl2N2O9. The molecular weight is 
517.12. 
8.1.2
Form
Ixazomib is provided by Millennium in capsule form as outlined in the table below:
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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
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. 
8.1.3
Storage and Stability
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 as 
directed on the label.  Do not store about 30oC.  Do not freeze. 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 
should be given only 1 cycle of medication at a time, unless in maintenance, when they may receive 
3 cycles worth. Patients should be instructed to store the medication as directed on the label for 
the duration of each cycle. Do not store above 30oC.  Do not freeze. 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.
8.1.4
Handling
Because ixazomib is an investigational agent, it should be handled with due care. Patients should 
be instructed not to chew, break, or open capsules. In case of contact with broken capsules, raising 
dust should be avoided during the clean-up operation. The product may be harmful by inhalation, 
ingestion, or skin absorption. Gloves and protective clothing should be worn during cleanup and 
return of broken capsules and powder to minimize skin contact.
The area should be ventilated and the site washed with soap and water after material pick-up is 
complete. The material should be disposed of as hazardous medical waste in compliance with 
federal, state, and local regulations.
In case of contact with the powder (eg, from a broken capsule), skin should be washed immediately 
with soap and copious amounts of water for at least 15 minutes. In case of contact with the eyes, 
copious amounts of water should be used to flush the eyes for at least 15 minutes. Medical 
personnel should be notified. Patients are to be instructed on proper storage, accountability, and 
administration of ixazomib, including that ixazomib is to be taken as intact capsules.
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8.1.5
Availability
The study drug ixazomib capsules will be provided by Millennium free of charge.  The study drug 
will be labeled and handled as open-label material, and packaging labels will fulfill all 
requirements specified by governing regulations.  
8.1.6
Preparation, Reconstitution, and Dispensing
Ixazomib is an anticancer drug and as with other potentially toxic compounds caution should be 
exercised when handling ixazomib capsules.
During Induction, 1 cycles worth of ixazomib will be provided at each cycle day 1, and patients 
will not be required to take doses in clinic.  
During maintenance, patients may return to clinic every 3 cycles beginning with cycle 10. If this 
option is utilized, a 3 month supply of ixazomib will be supplied by the investigational pharmacy 
at each visit. 
Patients are to be instructed on proper storage, accountability, and administration of ixazomib, 
including that ixazomib is to be taken as intact capsules.
8.1.7
Administration
Ixazomib will be given daily on days 1, 8, and 15 of each 28 day cycle on an out-patient basis. 
At all times when dispensing ixazomib protocol therapy, study site personnel will review the 
instructions, printed on the packaging, with participants.
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 or drink) 
at least 1 hour before or 2 hours after a meal.  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.  
8.1.8
Ordering
The investigator or designee will order ixazomib from Millennium, according to the ordering 
instructions provided by company.
8.1.9
Accountability
Study drug will be administered or dispensed only to eligible patients under the supervision of 
the investigator or identified sub-investigator(s).  The appropriate study personnel will maintain 
records of study drug receipt and dispensing.
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8.1.10 Destruction and Return
Investigational ixazomib (expired or end of study) should be destroyed on site according to the 
institution’s standard operating procedure.  Be sure to document removal and destruction on drug 
accountability logs.
8.2
Lenalidomide
8.2.1
Description
Lenalidomide (REVLIMID®), a thalidomide analogue, is an immunomodulatory agent with 
antiangiogenic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -2H- isoindol-2-
yl) piperidine-2,6-dione and it has the following chemical structure: 3-(4-amino-1-oxo 1,3-
dihydro-2H-isoindol-2-yl) piperidine-2,6-dione. The empirical formula for lenalidomide is 
C13H13N3O3, and the gram molecular weight is 259.3.
8.2.2
 Form
Lenalidomide is off-white to pale-yellow solid powder. It is soluble in organic solvent/water 
mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic solvents and 
low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 0.4 
to 0.5 mg/ml. Lenalidomide has an asymmetric carbon atom and can exist as the optically active 
forms S(-) and R(+), and is produced as a racemic mixture with a net optical rotation of zero.
Lenalidomide is available for this study as 5 and 25 mg capsules for oral administration. Each 
capsule contains lenalidomide as the active ingredient and the following inactive ingredients: 
lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.
8.2.3
Storage and Stability
At the study site, all investigational study drugs will be stored in a locked, safe area to prevent 
unauthorized access. Lenalidomide should be stored at room temperature away from direct 
sunlight and protected from excessive heat and cold.    
8.2.4
Handling
Females of childbearing potential should not handle or administer lenalidomide unless they are 
wearing gloves.
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and the 
environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment.
8.2.5
Availability
Celgene Corporation will supply Revlimid® (lenalidomide) to study participants at no charge 
through Celgene’s Revlimid Risk Evaluation and Mitigation Strategy™ (REMS) (formerly known 
as RevAssist® Program, Research). Each patient’s individual drug supply will be delivered to the 
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site by the drug courier Biologics and be distributed to the patient through the research side of the 
pharmacy of that site.
Further information about the Revlimid REMS® program is available at 
www.celgeneriskmanagement.com.
8.2.6
Preparation
Lenalidomide is an oral drug, and does not require specific preparation details.
8.2.7
Administration
Lenalidomide will be given daily on days 1-21 of each 28 day cycle
At all times when dispensing lenalidomide protocol therapy, study site personnel will review the 
instructions, printed on the packaging, with participants. 
8.2.8
Ordering
Lenalidomide (Revlimid®) will be provided to research subjects for the duration of their 
participation in this trial at no charge to them or their insurance providers.  Lenalidomide will be 
provided in accordance with the Celgene Corporation’s Revlimid REMS® program.  Per standard 
Revlimid REMS® program requirements,  all physicians who prescribe lenalidomide for research 
subjects enrolled into this trial, and all research subjects enrolled into this trial, must  be registered 
in, and must comply with, all requirements of the Revlimid REMS® program.  
Drug will be shipped on a per patient basis by the contract pharmacy to the clinic site. 
Only enough lenalidomide for one cycle of therapy will be supplied to the patient each cycle.
Lenalidomide will be shipped directly to the clinic site.   Bottles will contain a sufficient number 
of capsules for one cycle of dosing.   
During maintenance, patients may return to clinic every 3 cycles beginning with cycle 10. If this 
option is utilized, lenalidomide may be shipped from the investigational pharmacy to the patient’s 
home for each cycle the patient does not return to clinic, according to local practice. 
8.2.9
Accountability
The Investigator or designee is responsible for taking an inventory of each shipment of study drug 
received, and comparing it with the accompanying study drug accountability form.  
8.2.10 Destruction and Return
If study drugs (those supplied by the sponsor or sourced by the investigator) are to be destroyed 
on site, it is the investigator’s responsibility to ensure that arrangements have been made for the 
disposal, procedures for proper disposal have been established according to applicable regulations, 
guidelines and institutional procedures, and appropriate records of the disposal have been 
documented. The unused study drugs should be destroyed per institutional policies. 
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If any study drug is lost or damaged, its disposition should be documented in the source documents.   
Patients will be instructed to return empty bottles or unused capsules to the clinic site.  
8.3
Dexamethasone
8.3.1
Description
Dexamethasone is a synthetic adrenocortical steroid. Corticosteroids are naturally occurring 
chemicals produced by the adrenal glands located above the kidneys. Corticosteroids affect the 
function of many cells within the body and suppress the immune system. Corticosteroids also block 
inflammation and are used in a wide variety of inflammatory diseases affecting many organs. 
The molecular weight for dexamethasone is 392.47. It is designated chemically as 9- fluoro-
11β,17,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione. Dexamethasone is stable in air 
and almost insoluble in water. 
8.3.2
Form
Dexamethasone is a white to practically white, odorless, crystalline powder. It is available in 2 or 
4 mg tablets (commercially) for oral administration. Each tablet contains dexamethasone as the 
active ingredient, and the following inactive ingredients: calcium phosphate, lactose, magnesium 
stearate, and starch. The tablet shell may contain the following: D&C Yellow 10, FD&C Yellow 
6, and/or FD&C Blue 1.
8.3.3
Storage and Stability
At the study site, all investigational study drugs will be stored in a locked, safe area to prevent 
unauthorized access. Dexamethasone should be stored at controlled room temperature, 68-77◦F
(20-25◦C) and not frozen, and according to label requirements.
8.3.4
Handling
Dexamethasone should be handled by trained pharmacy staff. The use of gloves and other 
appropriate protective clothing is recommended as necessary.
8.3.5
Availability
Dexamethasone supply will be obtained through commercial supply.
8.3.6
Preparation
Dexamethasone is an oral drug, and does not require specific preparation details.
8.3.7
Administration
During induction therapy, participants will receive dexamethasone as a single oral daily dose on 
Days 1, 8 and 15 and 22 of cycles 1-9. 
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8.3.8
Ordering
Dexamethasone will be ordered from retail pharmacy using commercial drug supply.
8.3.9
Accountability
As drug is from commercial supply, sites should keep records per their institutional policies. 
8.3.10 Destruction and Return
At the end of the study, unused supplies of dexamethasone should be destroyed and documented 
according to institutional policies.
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
This trial will provide samples SMM patients treated with Ixazomib, lenalidomide and 
dexamethasone to comprehensively characterize the MM genome and immune cells function and 
define molecular events driving development and progression of MM. Please see Appendix D for 
a listing of further proposed correlative studies.
We will attempt to obtain samples on all patients who consent to the optional studies at the 
following time points: before therapy, at the end of cycle 9 or at the time of response confirmation 
if prior to Cycle 9, at the time of response determination (CR), and at disease relapse, and at the 
time of completion of the study. It is anticipated that approximately 90% of samples collected will 
be adequate for sequencing studies proposed.  Participants may decline sample collection at any 
timepoint.
The tumor cells will be collected as described below. From these samples, high quality DNA (for 
tumor cells) and RNA (for tumor cells and immune cells) for both exome sequencing and RNA 
sequencing will be obtained. Germline DNA will be also obtained from a buccal swab from all 
patients at any time point of the study.  
Peripheral blood and bone marrow derived mononuclear cells will undergo immunologic 
assessments to assess the impact of therapy on general measures of cellular immunity, MM 
reactive T cells, and antigen specific immunity.   The percentage of circulating and bone marrow 
derived regulatory immune cells will be determined. 
Peripheral blood and bone marrow samples will be collected per the collection time described in 
the table of sample collection. Minimum residual disease (MRD) will be assessed as standard of 
care at the time of CR or VGPR by Adaptive using spiked-in reference sequences.  Clinical bone 
marrow aspirate samples should be collected per institutional guidelines and sent to Adaptive for 
analysis.
Single-cell sequencing will be performed on patients prior to treatment and at the end of induction. 
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9.2
 Peripheral Blood Samples
Collection of peripheral blood specimens (including serum and plasma) for exploratory analysis 
will be optional for this trial, except for the screening sample, which is mandatory. Purple top and 
red top tube collections will be obtained at the same timepoints as bone marrow samples for 
correlative studies (see Section 10 for list of required timepoints, and Appendix B for specific 
instructions). These collections will be taken at the time of routine blood collection timepoints 
required for this study. Specimens will be processed on site according to instructions below and 
shipped (via traceable carrier) to Dana-Farber Cancer Institute. Once the shipment is received, 
samples will be subsequently processed, analyzed, and stored at Dana-Farber.
9.2.1
Specimens Required: 2 x 10 mL Purple Top Tubes (K2EDTA) and 1 x 6 mL red 
top tube, should be collected Mondays to Thursdays for same-day shipment.
9.2.2
Shipping Information: Label all specimens with the following:
•
Subject Initials, Subject study number (will include protocol number), Visit at 
which sample was drawn (screening, response or relapse/progression), Date 
sample drawn (mm/dd/yyyy), Time sample drawn (24 hour clock)
9.2.3
Processing Information: Once collected, the vacutainers will be refrigerated and 
and stored according to instructions below. There is no required processing for 
purple top tubes at each participating site prior to shipment.
9.2.4
Shipping Instructions: Shipments must be sent on the day of collection and cannot 
be batched.
Processing Information: 
Invert each tube 5 times at blood collection to ensure adequate mixing of anticoagulant with blood 
immediately after the blood collection. Package tubes at room temperature and wrap in a liberal 
amount of paper towel around the tubes to ensure adequate insulation of the specimen(s) and 
absorption in the event of a breakage. Place wrapped specimen in a biohazard labeled Ziploc bag 
with a fridge pack and zip close. Wrap bubble wrap around the bag and place in a cardboard box. 
If space remains in the box, stuff with extra paper towel to reduce shifting of samples. Complete 
the shipping requisition form using the address listed below. Prepare the package for shipping, 
applying packing tape as needed. Ship the package using FedEx or UPS next day or overnight 
delivery the same day the sample was collected. Please only ship Monday-Thursday, as the lab is 
only able to accept Saturday shipments with 1 week advance notice. With each shipment, please 
include the following:
1. An inventory sheet including a complete list of samples shipped (patient number, 
timepoint, study #) must accompany each shipment. Please sign and date the form, and 
retain a copy for site record maintenance. See Appendix C for Sample Requisition Form
2. An electronic copy (Word or Excel) of the sample list must also be sent via email and 
include the tracking number of the package. The listing must also include a contact name, 
address and phone number of the person who is responsible for the shipment.
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10. STUDY CALENDAR 
Screening evaluations are to be conducted within 28 days prior to registration. If bone marrow biopsy, research aspirate, and 
imaging assessments are completed within 6 weeks of registration, they do not need to be repeated at screening. Baseline 
assessments are to be conducted on C1D1 of initial therapy. C1D1 must occur within 6 weeks of registration.  If screening 
assessments are performed within 7 days of C1D1, disease assessments do not need to be repeated. All assessments must be 
performed prior to administration of any study medication. Study assessments and medications should be administered within 
+/- 3 days (during cycles 1-2) and +/- 7 days (during cycles 3-24) of the protocol-specified date, unless otherwise noted. See 
below for detailed scheduled of assessments. Study medications will be administered according to the schedule and 
guidelines outlined in Section 5.
Pre-registration
Cycles 1-24 (28 days) 3
Event 
Monitoring
Tests and procedures
≤ 28 
days 
prior to 
registrat
ion
≤ 21 
days 
prior to 
registrat
ion
Day 1 of 
cycles 1-
91
Every 3 
months for 
Cycles 10-
24
Cycle 10
Day 1/ Or 
to 
confirm 
CR8
End of 
Tx (± 2 
weeks)
Every 3 
Months (± 
2 weeks)13
History and exam, height, weight. 
Performance Status
X
X
X
X
X
Toxicity Notation
X
X
X
Hematology group (WBC w/ diff, 
PLT, Hgb, ANC)
X
X 
X
X
X
Chemistry4
X
X
X
X
X
Direct & total bilirubin2
X
X
X
X
Free light chain assay
X
X
X
X
X
Serum and Urine Immunofixation 
(SPEP and UPEP) with quantitative 
immunoglobulins9
X
X
X
X
X
β2M and LDH
X
X
X
X
Metastatic Bone Survey and MRI of 
the Full Spine 
OR 
PET/CT 12
X
X
EKG
X
X
Serum or urine pregnancy test11
X
X
Unilateral bone marrow aspirate and 
biopsy5
X
X
X
Research bone marrow aspirate6
X5
X6
X6
Research Blood7
X7
X7
X7
X7
X7
Buccal Swab10
X
1- Cycle 1, Day 1 laboratory values need to meet eligibility criteria
2- Direct bilirubin to be obtained if total bilirubin is abnormal
3- Scheduling allows for +/- 3 days cycles 1-2 and +/- 7 days for cycle 3 and beyond
4- Chemistry includes sodium, potassium, chloride, bicarbonate, bun, creatinine, calcium, glucose, albumin, ALT (SGPT), total protein, AST (SGOT), total bilirubin, magnesium, and 
phosphorus
5- These procedures should also be done at any time during the course of the study to confirm CR   Aspirate should be collected and sent out to Adaptive for MRD analysis at baseline and 
at time of VGPR or suspected CR
6- Research bone marrow aspirate and biopsy at the same time of clinically indicated bone marrow biopsy and to confirm response  
7- Peripheral blood samples for correlative studies
8- If BM biopsy performed within 3 weeks of C10D1, or confirmation of CR BM biopsy performed within 3 weeks of stem cell collection, do not need to repeat BM biopsy
9- If the participant’s disease response is not followed primarily via a UPEP and Urine immunofixation, these tests may be done only at screening, end of treatment, and as clinically indicated 
during treatment and follow-up  
10-The buccal swab can be performed at any timepoint during study participation  
11-Pregnancy tests are only required for women of childbearing potential 10-14 days prior to registration, 24 hours prior to prescribing lenalidomide for C1 and every day 1 post C1
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12-A CD of scans at screening and end of treatment is required to be sent to the lead site for central review  Screening scans should be sent with the eligibility packet to the lead site- This 
requirement includes a full body skeletal survey in addition to spinal MRI  OR  the patient may have only a low dose PET CT
Note: Research blood and bone marrow studies of all cycles after cycle 1 are voluntary and do not exclude patients from participating 
13 – Participants unable to come in for follow up every 3 months can be allowed to come in every 6 months for follow up at PI discretion in accordance with standard of care follow-up 
frequency  
11. MEASUREMENT OF EFFECT
11.1 Development of symptomatic disease
In this study, the final endpoint is development of symptomatic MM that requires therapy. 
This is defined as one of the following criteria (CRAB and Myeloma defining events< MDE):
•
Increased calcium levels (corrected serum calcium >0.25 mmol/dL above the upper limit of normal or 
>.275 mmol/dL) due to myeloma 
•
Renal insufficiency (attributable to myeloma); 
•
Anemia (Hb 2g/dL below the lower limit of normal or <10g/dL) due to myeloma
•
Bone lesions (lytic lesions or generalized osteoporosis with compression fractures)
•
Or any MYELOMA DEFINING EVENTS (MDE) as follows:
o
Clonal bone marrow plasma cell percentage > 60%8
o
An abnormal FLC-ratio ≥100 (involved kappa) or <0.01 (involved lambda)9
o
2 or more focal lesions on MRI or PET-CT studies10,11
For measurement of response:
In this study, patients must have measurable disease (see Section 11.2.1). The disease response will be assessed 
using criteria based on the International Myeloma Working Group Uniform Response Criteria in Section 11.2.3.1. 
If the only measurable parameter is serum immunoglobulins free light chain (FLC), the participant will be 
followed by FreeLite™ Disease Response Criteria provided in Section 11.2.4.
Disease response by the Modified EBMT Response Criteria in Section 11.2.5.2 will also be collected on 
participants as a secondary measure.
The same method of assessment and technique should be used for disease measurement at baseline and 
during follow-up. Disease response should be confirmed by two consecutive assessments.
11.2 Antitumor Effect 
11.2.1 Disease Parameters
Measurable disease: Measurable disease is disease that can be measured either by serum or urinary evaluation 
of the monoclonal component or by serum assay of
FLC and is defined by at least one of the following three measurements:
•
Serum M-protein > 0.5 g/dl
•
Urine M-protein > 200 mg/24 h
•
Serum FLC assay: Involved FLC level > 10 mg/dl (> 100 mg/l) provided serum FLC ratio is 
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abnormal.
11.2.2 Methods for Evaluation of Measurable Disease
All baseline evaluations should be performed on Cycle 1, Day 1 of initial therapy. Response will be assessed by 
M-protein quantification, protein electrophoresis and immunofixation from serum and a 24-hour urine 
collection. A serum sample for FreeLiteTM testing will be obtained. In addition, bone marrow aspiration and 
biopsy, as well as skeletal survey will be performed to determine overall response or confirm response.
The same method of assessment and technique should be used for disease measurement at 
baseline and during follow-up.
11.2.3 Response Criteria
A confirmation measurement for disease response assessments is required in this protocol.
11.2.3.1International Myeloma Working Group Response Criteria
Response criteria for all categories and subcategories of response except CR are applicable only to patients 
who have ‘measurable’ disease, as defined in Section 11.1.1 All response categories require two 
consecutive assessments made at any time before the institution of any new therapy; all categories also 
require no known evidence of progressive or new bone lesions if radiographic studies were performed. 
Radiographic studies are not required to satisfy these response requirements.
Response
Criteria for Response
Stringent CR 
(sCR)
CR as defined below plus normal free light chain ratio and absence of 
clonal cells in bone marrow* by immunohistochemistry or 
immunofluorescence.**
*Confirmation with repeat bone marrow biopsy is not needed.
**Presence/absence of clonal cells is based upon the k/λ ratio. An 
abnormal k/l ratio by immunohistochemistry and/or immunofluorescence 
requires a minimum of 100 plasma cells for analysis. An abnormal ratio 
reflecting presence of an abnormal clone is k/λ of > 4:1 or < 1:2.
Complete 
Response (CR)
Negative immunofixation on the serum and urine and disappearance of 
any soft tissue plasmacytomas and <5% plasma cells in bone marrow.
*Confirmation with repeat bone marrow biopsy is not needed.
Very Good Partial 
Response (VGPR)
Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis or 90% or greater reduction in serum M-protein plus 
urine M-protein level <100mg per 24 hours.
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Partial Response 
(PR)
> 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by 
> 90% or to < 200mg per 24 hours.  If the serum and urine M-protein are 
unmeasurable, a > 50% decrease in the difference between involved and 
uninvolved free light chain levels is required in place of the M-protein criteria 
(definition of measurable disease in Section 10.2.3). If serum and urine M-
protein are unmeasurable, and serum free light assay is also unmeasurable, > 
50% reduction in plasma cells is required in place of M-protein, provided 
baseline bone marrow plasma cell percentage was > 30%. In addition to the 
above listed criteria, if present at baseline, a > 50% reduction in the size of soft 
tissue plasmacytomas is also required.
Stable Disease 
(SD)
Not meeting criteria for CR, VGPR, PR or progressive disease. 
This is not recommended as an indicator of response; stability of 
disease is best described by providing the time to progression 
estimates.
Progressive 
Disease (PD)
> 25% increase of serum M-protein (which must also be an absolute increase of > 
0.5 g/dL) and/or urine M-protein (which must also be an absolute increase of > 
200 mg/24hr). If serum and urine M-protein are unmeasurable, there must be an 
absolute increase of > 10 mg/dL between involved and uninvolved FLC levels. 
PD is also measured by an absolute increase in bone marrow plasma cells > 10%.  
In addition to the above listed criteria, progression may also be measured by a 
definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in the size of existing bone lesions or soft tissue plasmacytomas 
or development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.65 
mmol/L) that can be attributed solely to the plasma cell proliferative disorder.
*Clarifications to IMWG criteria for coding CR and VGPR in patients in whom the only measurable disease is 
by serum FLC levels: CR in such patients indicates a normal FLC ratio of 0.26 to 1.65 in addition to CR criteria 
listed above. VGPR in such patients requires a > 90% decrease in the difference between involved and uninvolved 
FLC levels.
†Clarifications for coding PD: Bone marrow criteria for PD are to be used only in patients without measurable 
disease by M protein and by FLC levels. The “25% increase” refers to M protein, FLC, and bone marrow results, 
and does not refer to bone lesions, soft tissue plasmacytomas, or hypercalcemia and the “lowest response
value” does not need to be a confirmed value.
11.2.4 Criteria for Molecular CR and Minimal Residual Disease (MRD) measurement
We will measure MRD via Adaptive’s LymphoSIGHT platform in Dana-Farber Cancer Institute patients who 
achieve VGPR or better to determine the number of patients who are MRD negative vs MRD positive.
11.2.4.1MRD Analysis 
MRD will be performed via LymphoSIGHT, flow cytometry, or both. 
MRD will be carried out according to the LymphoSIGHTTM method (Adaptive Inc,) using clinical bone marrow 
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aspirate samples66. Prior studies have compared this technique to the traditional MRD immunofluorescence 
technique, as previously reported 67 and showed that MRD by LymphoSight is a sensitive method that can be 
used in future clinical practice. 
For MM diagnostic samples, genomic DNA will be amplified using locus-specific primer sets for the 
immunoglobulin heavy-chain locus (IGH) complete (IGH-VDJH), IGH incomplete (IGH-DJH), and 
immunoglobulin κ locus (IGK). The amplified product will be subjected to sequencing, and the sequences and 
frequencies of the different clonotypes in the sample will be obtained. Myeloma gene rearrangements will be 
identified. Patients in whom a high-frequency myeloma clone (>5%) is not identified will be excluded from the 
MRD analysis. MRD will be assessed in patients with a high-frequency myeloma clone using the IGH-VDJH and 
IGK or IGH-VDJH, IGH-DJH, and IGK assays. Once the absolute amount of total cancer-derived molecules 
present in a sample will be determined, a final MRD measurement will be calculated, providing the number of 
cancer-derived molecules per 1 million cell equivalents. In cases in which 2 or more tumor clones existed, the 
clone with the highest MRD value will be reported. Molecular CR will be defined according to the International 
Myeloma Working Group (IMWG) consensus recommendations68.
11.2.4.2Modified EBMT Response Criteria
Response
Criteria for Responsea
Complete Response
 (CR)
Requires all of the following:
Disappearance of the original monoclonal protein from the blood and urine 
on at least two determinations for a minimum of six weeks by 
immunofixation studies.
< 5% plasma cells in the bone marrow on at least two determinations 
for a minimum of six weeks. b 
No increase in the size or number of lytic bone lesions (development 
of a compression fracture does not exclude response).c
Disappearance of soft tissue plasmacytomas for at least six weeks.
Near Complete 
Response
(nCR)
Requires the following:
Same as CR, but immunofixation studies continue to show presence 
of the monoclonal protein
Very Good Partial 
Response
(VGPR)
Requires the following:
> 90% reduction in serum M-protein plus urine M-protein level <100mg 
per 24 hours on at least two determinations for a minimum of six weeks.
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Partial response 
(PR)
PR includes participants in whom some, but not all, criteria for CR are 
fulfilled providing the remaining criteria satisfy the requirements for PR.  
Required all of the following:
≥ 50% reduction in the level of serum monoclonal protein for at 
least two determinations six weeks apart.
If present, reduction in 24-hour urinary light chain excretion by either ≥90%
or to < 200 mg for at least two determinations six weeks apart.
≥ 50% reduction in the size of soft tissue plasmacytomas (by 
clinical or radiographic examination) for at least six weeks.
No increase in size or number of lytic bone lesions (development of 
compression fracture does not exclude response).c
Minimal response 
(MR)
MR included participants in whom some, but not all, criteria for PR 
were fulfilled, providing the remaining criteria satisfied the 
requirements for MR. Required all of the following:
≥ 25% to 49% reduction in the level of serum monoclonal protein for at 
least two determinations six weeks apart.
If present, a ≥ 50 to 89% reduction in 24-hour light chain excretion, 
which still exceeds 200 mg/24 h, for at least two determinations six 
weeks apart.
≥ 25-49% reduction in the size of plasmacytomas (by clinical or 
radiographic examination) for at least six weeks.
No increase in size or number of lytic bone lesions (development of 
compression fracture does not exclude response).c
No change (NC)
Not meeting the criteria for MR or PD.
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Response
Criteria for Responsea 
Progressive 
disease (PD) 
(for 
participants not 
in CR)
Requires one or more of the following:
> 25% increased in the level of serum monoclonal paraprotein, which must 
also be an absolute increase of at least 5 g/L and confirmed on a repeat 
investigation.
> 25% increased in 24-hour urinary light chain excretion, which must 
also be an absolute increase of at least 200 mg/24 h and confirmed on a 
repeat investigation.
> 25% increased in plasma cells in a bone marrow aspirate or on trephine 
biopsy, which must also be an absolute increase of at least 10%.
Definite increase in the size of existing lytic bone lesions or soft 
tissue plasmacytomas.
Development of new bone lesions or soft tissue plasmacytomas (not 
including compression fracture).
Development of hypercalcemia (corrected serum calcium >11.5 mg/dL 
or 2.8 mmol/L not attributable to any other cause).
Relapse from CR
Required at least one of the following:
Reappearance of serum or urinary paraprotein on immunofixation or 
routine electrophoresis confirmed by at least one follow-up and 
excluding oligoclonal immune reconstitution.
≥ 5% plasma cells in the bone marrow aspirate or biopsy.
Development of new lytic bone lesions or soft tissue plasmacytomas or 
definite increase in the size of residual bone lesions (not including 
compression fracture).
Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL 
or 2.8 mmol/L not attributable to any other cause)e.
a   Based on the criteria reported by Blade et al., 1998.
b   Per Blade et al., 1998, if absence of the monoclonal protein is sustained for 6 weeks it is not necessary to repeat the bone marrow except in participants with 
nonsecretory myeloma where the marrow examination must be repeated after an interval of at least 6 weeks to confirm CR.
c   Per Blade et al., 1998, skeletal X-Rays are not required for the definition of response, but if performed there must be no evidence of progression of bone disease 
(no increase in size or number of lytic bone lesions).
d   It is suggested that the reference point for calculating any increase should be the lowest value of the preceding confirmed response (MR, PR or CR) or the 
baseline value if there is no previous confirmed response.
e   Other clinical data may be requested by the IRC, as necessary, to assess the cause of the hypercalcemia.
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11.2.5 Duration of Response and Endpoint Definitions
Duration of overall response: The duration of overall response is measured as the time from initiation of 
first response to first documentation of disease progression or death. Patients who have not progressed or died 
are censored at the date last known progression-free.
Duration of overall complete response: The duration of overall CR is progression or death. Patients 
who have not progressed or died are censored at the date last known progression-free.
Time to progression:  Time to progression is defined as the time of randomization until progression.  Patients 
who have died without evidence of progression are censored in the TTP analysis at the time of death and patients 
who are alive without progression are censored at the last disease assessment.
11.2.6 Progression-Free Survival
Progression-Free Survival (PFS): the primary endpoint in this study. PFS is defined as the time from randomization 
to the disease progression or death from any cause. Patients who have not progressed or died are censored at the date 
last known progression-free.
11.2.7 Response Review
Central review of disease response assessments is not planned.
12. DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse Events: 
List and Reporting Requirements).
12.1 Data Reporting
12.1.1 Method
The ODQ will collect, manage, and perform quality checks on the data for this study.
12.1.2 Responsibility for Data Submission
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or data forms to the ODQ 
according to the schedule set by the ODQ. Data should be entered within 14 business days of the 
corresponding visit and within 14 business days of the end of a cycle for any forms to be completed per 
cycle.
12.2 Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and accrual data 
from this study. The committee is composed of clinical specialists with experience in oncology and who have no 
direct relationship with the study. Information that raises any questions about participant safety will be addressed 
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with the Overall PI and study team.
The DSMC will review each protocol up to four times a year or more often if required to review toxicity and 
accrual data. Information to be provided to the committee may include: up-to-date participant accrual; current 
dose level information; DLT information; all grade 2 or higher unexpected adverse events that have been reported; 
summary of all deaths occurring with 30 days of intervention for Phase I or II protocols; for gene therapy 
protocols, summary of all deaths while being treated and during active follow-up; any response information; audit 
results, and a summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request. 
13.  STATISTICAL CONSIDERATIONS
13.1 Study Design/Endpoints
The primary endpoint of this phase II study is to determine the proportion of patients with high-risk smoldering 
multiple myeloma (SMM) patients who are progressive free at 2 years after receiving therapy with 
Ixazomib/lenalidomide and dexamethasone. The secondary objectives include toxicities, objective response rate, 
time to progression, duration of response, and overall survival.
The proportion of patients who achieve progression free at 2 years will be compared to the rate published for the 
high-risk SMM. By the Mayo Clinic model for risk factors, the median time to progression for patients with high-
risk SMM was only 1.9 years. Therefore, a 2-year progression-free rate of 50% will not be considered promising. 
We assume that the true 2-year progression-free rate is 70%. With a type I error of 5% and power of 90%, 53 
eligible patients will be required in a single-stage design. The probability of concluding that the treatment is 
effective if the true rate is 50% is 0.05 and is 0.91 if the true rate is 70%. Assuming an ineligibility rate of 5%, 
we will accrue 56 patients to the trial in order to have 53 eligible patients.  Any patients who are registered, but 
do not start study treatment will be replaced.
13.1.1 Analysis of Primary Endpoint
Time to progression (TTP) is defined as the time from protocol therapy initiation until documented progression, 
censored at date last known progression-free for those who have not progressed. At time of final analysis, the 2-
year progression-free rate will be estimated using the Kaplan-Meier method with 95% confidence interval. All 
patients who have received one dose of study treatment will be included for the TTP analysis, including those 
who die or are lost to follow-up within 2 years.
13.1.2 Analysis of Secondary Endpoints
The objective response rate (partial response or better according to the modified IMWG criteria) and the 
proportion of patients with a MRD, CR, PR or MR will be reported with 90% exact binominal confidence interval 
(CI). 
To estimate the duration of response (time from objective response to disease progression or death, or date last 
known progression-free and alive for those who have not progressed or died), progression-free survival (time 
from protocol therapy initiation to the disease progression or death from any cause, censored at date last known 
progression free for those who have not progressed or died), and overall survival (time from protocol therapy 
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initiation to death or date last known alive), the Kaplan-Meier method will be used. 
Safety analysis will be conducted using the Safety Population defined as any patient receiving one dose of study 
treatment. For toxicity reporting, all adverse events and laboratory abnormalities will be graded and analyzed 
using CTCAE version 4 as appropriate. 
13.2 Sample Size, Accrual Rate and Study Duration
A total of 56 patients will be enrolled. Any patients who are registered but do not start study treatment will be 
replaced.  We expect 1.5 years of active accrual (approximately 2 patients per month) and 3 years of follow-up 
of patients.
The final analyses of progression-based endpoints, such as estimating the 2-year progression-free rate and 
estimating the TTP distribution, will be conducted at the end of the study, which will occur after either all subjects 
have progressed or died or 3-years after the initiation of therapy of the last subject enrolled, whichever occurs 
first.
13.3 Stratification Factors 
There are no stratification factors. 
13.4 Interim Monitoring Plan
The study will be monitored by the DFCI Data Safety Monitoring Committee (DSMC). The DSMC will meet at 
least four times a year and more often if needed (e.g., for safety review). For each meeting, the study will be 
reviewed for safety and progress toward completion. Copies of the toxicity reports prepared by the DSMC 
meetings will be distributed to the Principal Investigator. The Principal Investigator will then distribute to 
subinvestigators. Any DSMC recommendations for changes to the study will be distributed to the Principal 
Investigator and then circulated to sub- investigators by the Principal Investigator. No interim analysis of the 
outcome data is planned. 
13.5 Stopping Rule for Safety
All participants will be evaluable for treatment-related toxicity from the time of therapy initiation. The serious 
adverse event (SAE) is defined as any grade 3 adverse events that affect organ function (cardiac, hepatic, 
thromboembolic) or grade 4/5 non-hematologic AEs.  We anticipate that the rate of SAE is low in this study 
population and there is no pre-defined stopping rule for safety. 
14. PUBLICATION PLAN
The results should be made public within 24 months of reaching the end of the study. The end of the study is the 
time point at which the last data items are to be reported, or after the outcome data are sufficiently mature for 
analysis, as defined in the section on Sample Size, Accrual Rate and Study Duration. If a report is planned to be 
published in a peer-reviewed journal, then that initial release may be an abstract that meets the requirements of 
the International Committee of Medical Journal Editors. A full report of the outcomes should be made public no 
later than three (3) years after the end of the study. 
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15. REFERENCES
1. Rajkumar SV, Landgren O, Mateos MV: Smoldering multiple myeloma. Blood, 2015
2. Dispenzieri A, Stewart AK, Chanan-Khan A, et al: Smoldering multiple myeloma requiring treatment: time 
for a new definition? Blood 122:4172-81, 2013
3. Kyle RA, Greipp PR: Smoldering multiple myeloma. N Engl J Med 302:1347-9, 1980
4. Alexanian R: Localized and indolent myeloma. Blood 56:521-5, 1980
5. Durie BG, Salmon SE: A clinical staging system for multiple myeloma. Correlation of measured myeloma 
cell mass with presenting clinical features, response to treatment, and survival. Cancer 36:842-54, 1975
6. Kyle RA, Durie BG, Rajkumar SV, et al: Monoclonal gammopathy of undetermined significance (MGUS) 
and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression 
and guidelines for monitoring and management. Leukemia 24:1121-7, 2010
7. International Myeloma Working G: Criteria for the classification of monoclonal gammopathies, multiple 
myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 121:749-
57, 2003
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multiparameter flow cytometry predict unsustained complete response after autologous stem cell transplantation 
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APPENDIX A: PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease.
0
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of disease.
80
Normal activity with effort; some 
signs or symptoms of disease.
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).
70
Cares for self, unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs.
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.
50
Requires considerable assistance and 
frequent medical care.
40
Disabled, requires special care and 
assistance.
3
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
20
Very sick, hospitalization indicated. 
Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.
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APPENDIX B: SPECIMEN COLLECTION SCHEDULE
Sample Time 
Point2
Container1,
Sample Type
Shipping Method
Recipient
3 x 10mL Purple Top
1 x 6mL Red Top
Peripheral Blood
2x10mL Purple Top
1x3mL Purple Top
Bone Marrow 
Aspirate
Fridge pack same day
Baseline
1x buccal swab
Saliva
Ambient same day
DFCI Bone 
Marrow Sample
Cycle1 Day 1
(Pre Dose)
2 x 10mL Purple Top
1 x 6mL Red Top 
Peripheral Blood
Fridge pack same day
DFCI
Cycle 2-9 Day 1, 
Cycle 10+ every 3 
cycles (i.e. Cycle 
13, 16, 19, etc.)
2 x 10mL Purple Top
1 x 6mL Red Top 
Peripheral Blood
Fridge pack same day
DFCI
2 x 10mL Purple Top
1 x 6mL Red Top
Peripheral Blood
End of Cycle 9
(Cycle 10 Day 1)
2 x 10mL Purple Top
Bone Marrow 
Aspirate
Fridge pack same day
DFCI
3 x 10mL Purple Top
1 x 6mL Red Top 
Peripheral Blood
Confirm Complete 
Response 3
2 x 10mL Purple Top
1 x 3mL Purple Top
Bone Marrow 
Aspirate
Fridge pack same day
DFCI Bone 
Marrow Sample
2 x 10mL Purple Top
1 x 6mL Red Top 
Peripheral Blood
End of Treatment 
and/or Disease 
Progression
2 x 10mL Purple Top
Bone Marrow 
Aspirate
Fridge pack same day
DFCI
Clinically Indicated
2 x 10mL Purple Top
Bone Marrow 
Aspirate
Fridge pack same day
DFCI
1 Purple Top= K2EDTA Tube; Red Top= No Additive
2 Samples at all time points are voluntary, and do not exclude patients from treatment
3 For definition of Complete Response, please refer to section 11.2.3. 
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APPENDIX D: ADDITIONAL CORRELATIVE STUDIES PROPOSED
1. Exome sequencing of tumor cells. Whole-exome capture libraries will be constructed from 100ng of tumor 
and normal DNA followed by shearing, end repair, phosphorylation and ligation to barcoded sequencing 
adapters. The DNA will be size-selected to exonic hybrid capture using SureSelect v2 Exome bait (Agilent, 
CA). Samples will be multiplexed and sequenced on Illumina HiSeq flowcells with the goal of an average 
depth of coverage of 100x. The resulting data will be analyzed with the current Illumina pipeline, which 
generates data files (BAM files). The details of the current analysis pipeline are published elsewhere. Briefly, 
somatic single nucleotide variants are determined using the MuTect algorithm. Indels and translocations are 
determined by the algorithms IndelLocator and dRanger, respectively. The MutSig algorithm identifies genes 
in which the observed mutations are inconsistent with what would be expected at random. To accurately assess 
the significance of mutations, MutSig takes into account several covariates, which influence the background 
mutation model. These include the expression level of genes (for which published gene expression data of 
MM samples can be used), and other gene characteristics observed empirically to co-vary with mutation rate: 
local relative replication time, and open vs. closed chromatin status. Focal as well as arm-level copy number 
variations will be determined based on whole exome sequencing and subsequent application of the GISTIC 
algorithm.
2. RNA sequencing of tumor cells.  For RNA Sequencing, poly-A selection and cDNA synthesis will be 
performed, followed by library preparation, sequencing (76bp or 101bp paired reads), and sample 
identification with quality control. Details of experimental design are described in. We will perform library 
construction using a non-strand specific Illumina TruSeq Protocol and sequence coverage to 100M total reads. 
Analysis will be performed as described in the preliminary data and in previous studies.
3. Immune cell characterization in peripheral blood. Peripheral blood derived mononuclear cells will 
undergo immunologic assessments to assess the impact of therapy on general measures of cellular immunity, 
MM reactive T cells, and antigen specific immunity. The percentage of circulating and bone marrow derived 
regulatory T cells, NK cells and MDSCs will be determined. The percent of PD-1 and other checkpoint 
regulators on immune cells will also be measured. Levels of naive, effector and central memory cells will be 
quantified. T cell proliferative response to tetanus toxoid and PHA mitogen will be determined. NK cell 
mediated cytotoxicity will be measured. 
4.
Integration of clinical correlation with genomic data obtained from these samples compared to those 
obtained from the PCROWD trial where MGUS and SMM samples are obtained and patients are 
followed for observation.  Here, we plan to use a portal along with infrastructure support from Celgene to 
correlate the data obtained from the RV-CL-MM-PI-006919 trial along with samples obtained from patients 
on observation only 
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DFCI IRB Protocol #: 16-313
APPENDIX E: DANA-FARBER/HARVARD CANCER CENTER MULTI-CENTER DATA AND 
SAFETY MONITORING PLAN
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TABLE OF CONTENTS
1.
INTRODUCTION .............................................................................................................92
1.1
Purpose...................................................................................................................92
1.2
Multi-Center Data and Safety Monitoring Plan Definitions..................................92
2.
GENERAL ROLES AND RESPONSIBILITIES .............................................................93
2.1
DF/HCC Sponsor...................................................................................................93
2.2
Coordinating Center...............................................................................................93
2.3
Participating Institution..........................................................................................94
3.
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS .............................95
3.1
Protocol Distribution..............................................................................................95
3.2
Protocol Revisions and Closures ...........................................................................95
3.3
Informed Consent Requirements ...........................................................................95
3.4
IRB Documentation ...............................................................................................96
3.5
IRB Re-Approval...................................................................................................96
3.6
Participant Confidentiality and Authorization Statement......................................96
3.7
DF/HCC Multi-Center Protocol Registration Policy.............................................97
3.8
DF/HCC Protocol Case Number............................................................................97
3.9
Safety Assessments and Toxicity Monitoring .......................................................98
3.10
Data Management..................................................................................................99
4.
REQUISITIONING INVESTIGATIONAL DRUG........................................................100
5.
MONITORING: QUALITY CONTROL........................................................................100
5.1
Ongoing Monitoring of Protocol Compliance.....................................................100
5.2
Monitoring Reports..............................................................................................101
5.3
Accrual Monitoring..............................................................................................101
6.
AUDITING: QUALITY ASSURANCE .........................................................................101
6.1
Audit Plan: DF/HCC Sponsored Trials ...............................................................101
6.2
Audit Notification................................................................................................101
6.3
Audit Reports.......................................................................................................102
6.4
Participating Institution Performance ..................................................................102
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1. INTRODUCTION
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan (DF/HCC DSMP) 
outlines the procedures for conducting a DF/HCC Multi-Center research protocol. The DF/HCC DSMP 
serves as a reference for any sites external to DF/HCC that are participating in a DF/HCC clinical trial.
1.1
Purpose
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-Center protocol 
will comply with Federal Regulations, Health Insurance Portability and Accountability Act (HIPAA) 
requirements and applicable DF/HCC Standard Operating Procedures.       
1.2
Multi-Center Data and Safety Monitoring Plan Definitions
DF/HCC Multi-Center Protocol:  A research protocol in which one  or more outside institutions are 
collaborating with Dana-Farber/Harvard Cancer Center where  a DF/HCC investigator is the sponsor. 
DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) Network Clinical Trial Affiliates. 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center consortium members (Dana-Farber 
Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth Israel Deaconess Medical Center 
(BIDMC), Boston Children’s Hospital (BCH), Brigham and Women’s Hospital (BWH) responsible for the 
coordination, development, submission, and approval of a protocol as well as its subsequent amendments 
per the DFCI IRB and applicable regulatory guidelines (CTEP, Food and Drug Administration (FDA), 
Office of Biotechnology Activities (OBA) etc.).  The Lead Institution is typically the home of the DF/HCC 
Sponsor. The Lead Institution also typically serves as the Coordinating Center for the DF/HCC Multi-
Center Protocol.  
DF/HCC Sponsor:  The person sponsoring the submitted Multi-Center protocol who takes responsibility 
for initiation, management and conduct of the protocol at all research locations. In applicable protocols, 
the DF/HCC Sponsor will serve as the single liaison with any regulatory agencies. The DF/HCC Sponsor 
has ultimate authority over the protocol and is responsible for the conduct of the study at DF/HCC and all 
Participating Institutions. In most cases the DF/HCC Sponsor is the same person as the DF/HCC Overall 
Principal Investigator; however, both roles can be filled by two different people. 
Participating Institution:  An institution that is outside the DF/HCC and DF/PCC consortium that is 
collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC Investigator.  The Participating 
Institution acknowledges the DF/HCC Sponsor as having the ultimate authority and responsibility for the 
overall conduct of the study.   
Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract Research Organization 
(CRO), etc.) that provides administrative support to the DF/HCC Sponsor in order that he/she may fulfill 
the responsibilities outlined in the protocol document and DSMP, and as specified in applicable regulatory 
guidelines (i.e. CTEP Multi-Center Guidelines). In general, the Lead Institution is the Coordinating Center 
for the DF/HCC Multi-Center Protocol. 
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DF/HCC Office of Data Quality (ODQ): A group within DF/HCC responsible for ensuring high-quality 
standards are used for data collection and the ongoing management of clinical trials, auditing, and data and 
safety monitoring. ODQ also coordinates quality assurance efforts related to multi-center clinical research.
DF/HCC Clinical Trials Research Informatics Office (CTRIO): A group within DF/HCC responsible 
for providing a comprehensive data management platform for managing clinical trial data.
2. GENERAL ROLES AND RESPONSIBILITIES
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and the Participating 
Institutions are expected to adhere to the following general responsibilities: 
2.1
DF/HCC Sponsor
The DF/HCC Sponsor, Irene Ghobrial, MD will accept responsibility for all aspects of conducting a 
DF/HCC Multi-Center protocol which includes but is not limited to: 
•
Oversee the coordination, development, submission, and approval of the protocol as well as 
subsequent amendments. 
•
Ensure that the investigators, study team members, and Participating Institutions are qualified and 
appropriately resourced to conduct the protocol.  
•
Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the protocol.
•
Ensure all Participating Institutions are using the correct version of the protocol.
•
Ensure that each participating investigator and study team member receives adequate protocol 
training (and/or a Site Initiation Visit prior to enrolling participants) and throughout trial’s conduct 
as needed.
•
Ensure the protocol will be provided to each participating site in a language understandable to all 
applicable site personnel when English is not the primary language. 
•
Monitor progress and overall conduct of the study at all Participating Institutions. 
•
Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable (i.e. FDA) 
reporting requirements are met. 
•
Review data and maintain timely submission of data for study analysis. 
•
Act as the single liaison with FDA, as applicable.
•
Ensure compliance with all requirements as set forth in the Code of Federal Regulations, applicable 
DF/HCC requirements, HIPAA requirements, and the approved protocol.
•
Commit to the provision that the protocol will not be rewritten or modified by anyone other than 
the DF/HCC Sponsor.
•
Identify and qualify Participating Institutions and obtain accrual commitments prior to extending 
the protocol to that site.
•
Monitor accrual and address Participating Institutions that are not meeting their accrual 
requirements. 
2.2
Coordinating Center 
The general responsibilities of the Coordinating Center may include but are not limited to:
•
Assist in protocol development. 
•
Maintain FDA correspondence, as applicable.
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•
Review registration materials for eligibility and register participants from Participating 
Institutions in the DF/HCC clinical trial management system (CTMS).
•
Distribute protocol and informed consent document updates to Participating Institutions as needed.
•
Oversee the data collection process from Participating Institutions.
•
Maintain documentation of Serious Adverse Event (SAE) reports and deviations/violation 
submitted by Participating Institutions and provide to the DF/HCC Sponsor for timely review and 
submission to the DFCI IRB, as necessary. 
•
Distribute serious adverse events reported to the DF/HCC Sponsor that fall under the DFCI IRB 
Adverse Event Reporting Policy to all Participating Institutions.
•
Provide Participating Institutions with information regarding DF/HCC requirements that they will 
be expected to comply with.
•
Carry out plan to monitor Participating Institutions either by on-site or remote monitoring. 
•
Maintain Regulatory documents of all Participating Institutions which includes but is not limited 
to the following: local IRB approvals/notifications from all Participating Institutions, 
confirmation of Federal Wide Assurances (FWAs) for all sites,  all SAE submissions, Screening 
Logs for all sites, IRB approved consents for all sites
•
Conduct regular communications with all Participating Institutions (conference calls, emails, etc.) 
and maintain documentation all relevant communications.
2.3
Participating Institution
Each Participating Institution is expected to comply with all applicable federal regulations and DF/HCC 
requirements, the protocol and HIPAA requirements. 
The general responsibilities for each Participating Institution may include but are not limited to:
•
Document the delegation of research specific activities to study personnel.
•
Commit to the accrual of participants to the protocol.
•
Submit protocol and/or amendments to their local IRB.
•
Maintain regulatory files as per sponsor requirements.
•
Provide the Coordinating Center with regulatory documents or source documents as requested.
•
Participate in protocol training prior to enrolling participants and throughout the trial as required 
(i.e. teleconferences).
•
Update Coordinating Center with research staff changes on a timely basis.
•
Register participants through the Coordinating Center prior to beginning research related activities. 
•
Submit Serious Adverse Event (SAE) reports to local IRB per institutional requirements and to the 
Coordinating Center, in accordance with DF/HCC requirements. 
•
Submit protocol deviations and violations to local IRB per institutional requirements and to the 
DF/HCC Sponsor in accordance with DF/HCC requirements.
•
Order, store and dispense investigational agents and/or other protocol mandated drugs per federal 
guidelines and protocol requirements.
•
Have office space, office equipment, and internet access that meet HIPAA standards.
•
Participate in any quality assurance activities and meet with monitors or auditors at the conclusion 
of a visit to review findings.
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•
Promptly provide follow-up and/or corrective action plans for any monitoring queries or audit 
findings.
3. DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS
The following section will clarify DF/HCC Requirements and further detail the expectations for participating 
in a DF/HCC Multi-Center protocol. 
3.1
Protocol Distribution
The Coordinating Center will distribute the final DFCI IRB approved protocol and any subsequent 
amended protocols to all Participating Institutions.   
3.2
Protocol Revisions and Closures
The Participating Institutions will receive notification of protocol revisions and closures from the 
Coordinating Center.  It is the individual Participating Institution’s responsibility to notify its IRB of these 
revisions.
•
Non-life-threatening revisions: Participating Institutions will receive written notification of 
protocol revisions regarding non-life-threatening events from the Coordinating Center. Non-life-
threatening protocol revisions must be IRB approved and implemented within 90 days from receipt 
of the notification.
•
Revisions for life-threatening causes: Participating Institutions will receive immediate 
notification from the Coordinating Center concerning protocol revisions required to protect lives 
with follow-up by fax, mail, e-mail, etc.  Life-threatening protocol revisions will be implemented 
immediately followed by IRB request for approval.
•
Protocol closures and temporary holds: Participating Institutions will receive notification of 
protocol closures and temporary holds from the Coordinating Center. Closures and holds will be 
effective immediately.  In addition, the Coordinating Center, will update the Participating 
Institutions on an ongoing basis about protocol accrual data so that they will be aware of imminent 
protocol closures.
3.3
Informed Consent Requirements
The DF/HCC approved informed consent document will serve as a template for the informed consent for 
Participating Institutions. The Participating Institution consent form must follow the consent template as 
closely as possible and should adhere to specifications outlined in the DF/HCC Guidance Document on 
Model Consent Language for PI-Initiated Multi-Center Protocols.  This document will be provided 
separately to each Participating Institution upon request.
Participating Institutions are to send their version of the informed consent document and HIPAA 
authorization, if a separate document, to the Coordinating Center for review and approval prior to 
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submission to their local IRB. The approved consent form must also be submitted to the Coordinating 
Center after approval by the local IRB for all consent versions.
The Principal Investigator (PI) at each Participating Institution will identify the physician members of the 
study team who will be obtaining consent and signing the consent form for therapeutic protocols. 
Participating institutions must follow the DF/HCC requirement that only attending physicians obtain 
informed consent and re-consent for all interventional drug, biologic, or device research.  
3.4
IRB Documentation
The following must be on file with the Coordinating Center:
•
Initial approval letter of the Participating Institution's IRB. 
•
Copy of the Informed Consent Form(s) approved by the Participating Institution’s IRB. 
•
Participating Institution’s IRB approval for all amendments.
•
Annual approval letters by the Participating Institution's IRB.
3.5
IRB Re-Approval
Verification of IRB re-approval from the Participating Institutions is required in order to continue research 
activities.  There is no grace period for continuing approvals.
The Coordinating Center will not register participants if a re-approval letter is not received from the 
Participating Institution on or before the anniversary of the previous approval date.  
3.6
Participant Confidentiality and Authorization Statement
In 1996, Congress passed the first federal law covering the privacy of health information known as the 
Health Insurance Portability and Accountability Act (HIPPA). Any information, related to the physical or 
mental health of an individual is called Protected Health Information (PHI). HIPAA outlines how and under 
what circumstances PHI can be used or disclosed. 
In order for covered entities to use or disclose protected health information during the course of a study, 
the study participant must sign an authorization statement.  This authorization statement may or may not 
be separate from the informed consent document.  The Coordinating Center, with the approval from the 
DFCI IRB and will provide a consent template, with information regarding authorization for the disclosure 
of protected health information. 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in its trials. 
However, because of the nature of these trials, certain protected health information must be collected. 
DF/HCC has chosen to use authorizations, signed by the participant in the trial, rather than limited data 
sets with data use agreements.
3.6.1
 DF/HCC Multi-Center Protocol Confidentiality
All documents, investigative reports, or information relating to the participant are strictly confidential. 
Whenever reasonably feasible, any participant specific reports (i.e. Pathology Reports, MRI Reports, 
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Operative Reports, etc.) submitted to the Coordinating Center should be de-identified. It is recommended 
that the assigned protocol case number (as described below) be used for all participant specific documents. 
Participant initials may be included or retained for cross verification of identification. 
3.7
DF/HCC Multi-Center Protocol Registration Policy
3.7.1
 Participant Registration and Randomization 
Please see sections 4.3 and 4.4 of the protocol document for specific guidelines on the registration process 
and requirements.  
Treatment may not begin without confirmation from the Coordinating Center that the 
participant has been registered. 
3.7.2
 Initiation of Therapy
Participants must be registered with the DF/HCC CTMS before the initiation of treatment or other protocol-
specific interventions. Treatment and other protocol-specific interventions may not be initiated until the 
Participating Institution receives confirmation of the participant’s registration from the Coordinating 
Center. The DF/HCC Sponsor and DFCI IRB must be notified of any violations to this policy.
3.7.3
 Eligibility Exceptions
No exceptions to the eligibility requirements for a protocol without DFCI IRB approval will be permitted. 
All Participating Institutions are required to fully comply with this requirement. The process for requesting 
an eligibility exception is defined below.
3.8
DF/HCC Protocol Case Number
At the time of registration, the following identifiers are required for all subjects: initials, date of birth, 
gender, race and ethnicity. Once eligibility has been established and the participant successfully registered, 
the participant is assigned a unique protocol case number.  Participating Institutions should submit all de-
identified subsequent communication and documents to the Coordinating Center, using this case number 
to identify the subject.  
3.8.1
Protocol Deviations, Exceptions and Violations
Federal Regulations require an IRB to review proposed changes in a research activity to ensure that 
researchers do not initiate changes in approved research without IRB review and approval, except when 
necessary to eliminate apparent immediate hazards to the participant. DF/HCC requires all departures 
from the defined procedures set forth in the IRB approved protocol to be reported to the DF/HCC Sponsor, 
who in turn is responsible for reporting to the DFCI IRB.
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For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” to describe 
departures from a protocol. All Participating Institutions must adhere to these requirements for reporting 
to the DF/HCC Sponsor and will follow their institutional policy for reporting to their local IRB.
3.8.2
 Definitions
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-approved protocol 
which is prospectively approved prior to its implementation.
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g.
enrollment of a participant who does not meet all inclusion/exclusion criteria.
Protocol Violation: Any protocol departure that was not prospectively approved by the IRB prior to its 
initiation or implementation. 
3.8.3
 Reporting Procedures
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the medical record 
and/or regulatory documents to describe all protocol exceptions, deviations and violations. The DF/HCC 
Sponsor will also be responsible for ensuring that all protocol violations/deviations are promptly reported 
per DFCI IRB guidelines. 
Participating Institutions: Protocol deviations require prospective approval from the DFCI IRB. The 
Participating Institution must submit the deviation request to the Coordinating Center who will then submit 
the deviation request to the DFCI IRB. Upon DFCI IRB approval the deviation is submitted to the 
Participating Institution IRB, per institutional policy. A copy of the Participating Institution’s IRB report 
and determination will be forwarded to the Coordinating Center within 10 business days after the original 
submission.  The deviation may not be implemented without all required approvals.
All protocol violations must be sent to the Coordinating Center in a timely manner. The Coordinating 
Center will provide training for the requirements for the reporting of violations. 
Coordinating Center:  Upon receipt of the violation/deviation report from the Participating Institution, the 
Coordinating Center will submit the report to the DF/HCC Sponsor for review. Subsequently, the 
Participating Institution’s IRB violation/deviation report will be submitted to the DFCI IRB for review per 
DFCI IRB reporting guidelines. DF/HCC will forward all violation reports to CTEP via an internal 
DF/HCC process, as applicable.
3.9
Safety Assessments and Toxicity Monitoring
The study teams at all participating institutions are responsible for protecting the safety, rights and well-
being of study participants. Recording and reporting of adverse events that occur during the course of a 
study help ensure the continuing safety of study participants. 
All participants receiving investigational agents and/or other protocol mandated therapy will be evaluated 
for safety. The safety parameters include all laboratory tests and hematological abnormalities, physical 
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examination findings, and spontaneous reports of adverse events reported by participants.  All toxicities 
encountered during the study will be evaluated according to the NCI criteria specified in the protocol. 
Life-threatening toxicities must be reported immediately to the DF/HCC Sponsor via the Coordinating 
Center. 
Additional safety assessments and toxicity monitoring will be outlined in the protocol.
3.9.1
Guidelines for Reporting Serious Adverse Events 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are detailed in protocol 
section 7.
Participating Institutions must report the SAEs to the DF/HCC Sponsor and the Coordinating Center 
following the DFCI IRB Adverse Event Reporting Policy. 
The Coordinating Center will maintain documentation of all Participating Institution Adverse Event reports 
and be responsible for communicating to all participating investigators, any observations reportable under 
the DFCI IRB Reporting Requirements.  Participating Institutions will review and submit to their IRB 
according to their institutional policies and procedures
3.9.2
Guidelines for Processing IND Safety Reports 
The DF/HCC Sponsor will review all IND Safety Reports and ensure that all IND Safety Reports are 
distributed to the Participating Institutions. Participating Institutions will review/submit to their IRB 
according to their institutional policies and procedures.
3.10
Data Management
DF/HCC CTRIO develops case report forms (CRF/eCRFs), for use with the protocol.  These forms are 
designed to collect data for each study. DF/HCC CTRIO provides a web based training for all eCRF users.
3.10.1
Data Forms Review
Data submissions are monitored for timeliness and completeness of submission. If study forms are received 
with missing or questionable data, the submitting institution will receive a written or electronic query from 
the DF/HCC Office of Data Quality, Coordinating Center, or designee. 
Responses to all queries should be completed and submitted within 14 calendar days.  
Responses may be returned on the written query or on an amended paper case report form, or in the case 
of electronic queries, within the electronic data capture (eDC) system. In the case of a written query for 
data submitted on a paper case report form, the query must be attached to the specific data being re-
submitted in response.  
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If study forms are not submitted on schedule, the Participating Institution will periodically receive a 
Missing Form Report from the Coordinating Center noting the missing forms. 
4. REQUISITIONING INVESTIGATIONAL DRUG
The ordering of investigational agent is specified in the protocol section 8.
Participating Institutions should order their own agent regardless of the supplier. (i.e., NCI or a 
pharmaceutical company.) 
If the agent is commercially available, check with the local Director of Pharmacy and/or the Research 
Pharmacy to ensure that the agent is in stock. If the agent is not stocked, ensure that the agent can be ordered 
once the protocol is approved by the local IRB. 
If the agent is investigational, ensure that the pharmacy will be able to receive and store the agent according 
to state and federal requirements. The local IRB should be kept informed of who will supply the agent (i.e., 
NCI or a pharmaceutical company) so that any regulatory responsibilities can be met in a timely fashion. 
5. MONITORING: QUALITY CONTROL
The quality control process for a clinical trial requires verification of protocol compliance and data 
accuracy. The Coordinating Center, with the aid of the DF/HCC Office of Data Quality, provides quality 
control oversight for the protocol.
5.1
Ongoing Monitoring of Protocol Compliance
The Participating Institutions may be required to submit participant source documents to the Coordinating 
Center for monitoring. Participating Institution may also be subject to on-site monitoring conducted by the 
Coordinating Center. 
The Coordinating Center will implement ongoing monitoring activities to ensure that Participating 
Institutions are complying with regulatory and protocol requirements, data quality, and participant safety. 
Monitoring practices may include but are not limited to source data verification, and review and analysis 
of eligibility requirements, informed consent procedures, adverse events and all associated documentation, 
review of study drug administration/treatment, regulatory files, protocol departures reporting, pharmacy 
records, response assessments, and data management. At a minimum, the DF/HCC Lead Institute, or 
designee, will monitor each participating site twice a year while patients are receiving treatment. Should a 
Participating Institution be monitored once and then not accrue any additional patients or participant visits, 
then a second monitoring visit may not be necessary.
Additionally, regular and ongoing communication with Participating Institutions will be accomplished by 
holding all site teleconferences at least monthly. An agenda and the minutes from the meeting will be 
supplied to all call participants. The Lead Institution will keep in close touch with the Participating 
Institutions via email and phone. 
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On-Site Monitoring: On-site monitoring will occur at least once per year. Participating Institutions will 
be required to provide access to participants’ complete medical record and source documents for source 
documentation verification during the on-site visit. In addition, upon request from a monitor or auditor, 
Participating Institutions should provide access to regulatory documents, pharmacy records, local policies 
related to the conduct of research, and any other trial-related documentation maintained by the participating 
site. If there are concerns for protocol compliance, issues that impact subject safety or the integrity of the 
study are found, or trends identified based on areas of need, additional monitoring visits may be scheduled. 
On site monitoring visits can be supplemented with virtual monitoring assessments, provided that the 
minimum monitoring frequencies are adhered to. 
Virtual Monitoring: The Coordinating Center will request source documentation from Participating 
Institutions as needed to complete monitoring activities. Participating Institutions will be asked to forward 
de-identified copies of participants’ medical record and source documents to the Coordinating Center to 
aid in source documentation verification.
5.2
Monitoring Reports
The DF/HCC Sponsor will review all monitoring reports to ensure protocol compliance. The DF/HCC 
Sponsor may increase the monitoring activities at Participating Institutions that are unable to comply with 
the protocol, DF/HCC Sponsor requirements or federal and local regulations. 
5.3
Accrual Monitoring
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish accrual requirements 
for each participating institution. Accrual will be monitored for each participating institution by the 
DF/HCC Sponsor or designee. Sites that are not meeting their accrual expectations may be subject to 
termination.
The expectation for this study is that each site should accrue three patients per site/annually.  
6. AUDITING: QUALITY ASSURANCE
Auditing is a method of Quality Assurance and involves the systematic and independent examination of all 
trial related activities and documents.  Audits determine if evaluated activities were appropriately 
conducted and whether data was generated, recorded and analyzed, and accurately reported per the 
protocol, applicable Standard Operating Procedures (SOPs), and the Code of Federal Regulations (CFR).
6.1
DF/HCC Internal Audits
All Participating Institutions are subject to audit by the DF/HCC Office of Data Quality (ODQ). Typically, 
approximately 3-4 participants would be audited at the site over a 2 day period. If violations which impact 
participant safety or the integrity of the study are found, more participant records may be audited. 
6.2
Audit Notifications
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It is the Participating Institution’s responsibility to notify the Coordinating Center of all scheduled audit 
dates (internal or NCI) and re-audit dates (if applicable), which involve this protocol. All institutions will 
forward a copy of final audit and/or re-audit reports and corrective action plans (if applicable) to the 
Coordinating Center, within 12 weeks after the audit date. 
6.3
Audit Reports 
The DF/HCC Sponsor will review all final audit reports and corrective action plans, if applicable. The 
Coordinating Center, must forward any reports to the DF/HCC ODQ per DF/HCC policy for review by the 
DF/HCC Audit Committee. For unacceptable audits, the DF/HCC Audit Committee would forward the 
final audit report and corrective action plan to the DFCI IRB as applicable.
6.4
Participating Institution Performance
The DF/HCC Sponsor and the DFCI IRB, is charged with considering the totality of an institution’s 
performance in considering institutional participation in the protocol.
Participating Institutions that fail to meet the performance goals of accrual, submission of timely and 
accurate data, adherence to protocol requirements, and compliance with state and federal regulations, may 
be recommended for a six-month probation period. Such institutions must respond with a corrective action 
plan and must demonstrate during the probation period that deficiencies have been corrected, as evidenced 
by the improved performance measures. Participating Institutions that fail to demonstrate significant 
improvement will be considered by the DF/HCC Sponsor for revocation of participation. A DF/HCC 
Sponsor and/or the DFCI IRB may terminate a site’s participation if it is determined that a site is not 
fulfilling its responsibilities as described above.
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