A Global, Prospective, Non-interventional, Observational Study of Presentation, Treatment Patterns, and Outcomes in Multiple Myeloma Patients - the INSIGHT - MM Study
Conditions: Multiple Myeloma
Sponsor: Takeda

CLINICAL STUDY PROTOCOL 
NCT Number: 
Study Title: 
Study Number: 
Protocol Version and Date: 
Version 3.0: 11-APRIL-2018 
NCT02761187 
A Global, Prospective, Non-interventional, Observational Study 
of Presentation, Treatment Patterns, and Outcomes in Multiple 
Myeloma Patients - the INSIGHT - MM Study
NSMM-5001

PROSPECTIVE OBSERVATIONAL STUDY PROTOCOL
A global, prospective, non-interventional, observational study of presentation, 
treatment patterns, and outcomes in multiplemyeloma
patients - the INSIGHT MM study
Sponsor:
Millennium Pharmaceuticals, Inc.,
a wholly owned subsidiary of Takeda Pharmaceutical 
Company Limited.
40 Landsdowne Street, Cambridge, 
MA 02139, USA
Study Number
NSMM-5001
Compound:
This is a non-interventional, observational study. Multiple 
myeloma will be treated as per standard therapy and/or with 
medicinal product prescribed by the treating healthcare 
provider based upon his/her clinical judgment.
Version of Protocol:
Version 3.0
Date of Protocol:
11 April 2018
Previous Protocol Date and 
Version:
Version 2.0 (12 October 2016)
CONFIDENTIAL
All financial and non-financial support for this study will be provided by Takeda. The concepts and 
information contained in this document or generated during the study are considered proprietary 
and may not be disclosed in whole or in part without the expressed, written consent of Takeda.
This non-interventional, observational study will be conducted according to Guidelines for Good 
Pharmacoepidemiology Practices (GPP).
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Protocol
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Protocol Approval – Sponsor Signatory
Study Title
A global, prospective, non-interventional, observational study of 
presentation, treatment patterns, and outcomes in multiplemyeloma 
patients - the INSIGHT MM study
Protocol Number
NSMM-5001
Protocol Date
11 April 2018
 PharmD, BCOP
, GMA Oncology Millennium Pharmaceuticals, Inc.
²__
_____________________
, PhD
GMA Research Oncology
Millennium Pharmaceuticals, Inc.
²___
__________________
 PhD
Observational Res Analytics 
Millennium Pharmaceuticals, Inc.
 PhD
 Safety Statistics
Safety Statistics & Real-World Data Research 
Millennium Pharmaceuticals, Inc.
PPD
PPD
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PPD
PPD
PPD
PPD
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PPD
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Property o
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For non-commercial use only and subject to the applicable Terms of Use
armaceu
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Analyti
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Protocol
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, MD, PhD
, 
 Hematology, GMA Oncology
Millennium Pharmaceuticals, Inc.
²___
__________________________
 MD, PhD
Global Medical Affairs Oncology
Millennium Pharmaceuticals, Inc.
, MD, PhD
US Oncology Medical 
Millennium Pharmaceuticals, Inc.
²__
____________________
Clinical Operations, GMA Research
Millennium Pharmaceuticals, Inc.
PPD
PPD
PPD
PPD
PPD
PPD
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Property of Takeda: For non-c
n-
rcial use only and subject to the applicable Terms of Use
___
___
MA Rese
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Study No. NSMM-5001
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Protocol
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Declaration by Treating Healthcare Provider
Study Title
A global, prospective, non-interventional, observational study of
presentation, treatment patterns, and outcomes in multiple myeloma 
patients – the INSIGHT MM study
Protocol Number
NSMM-5001
Protocol Date
11 April 2018
I confirm that I have read and understand this protocol entitled “A global, prospective, 
non-interventional, observational study of presentation, treatment patterns, and outcomes in 
multiple myeloma patients – the INSIGHT MM study”. I agree to conduct this study in accordance 
with the requirements of this protocol and also to protect the rights, safety, privacy, and well-being 
of study patients.
_______________________________________________________________________________
Signature of Investigator
Date
_______________________________________________________________________________
Investigator Name (print or type)
_______________________________________________________________________________
Investigator’s Title
_______________________________________________________________________________
Location of Facility (City, State/Provence, Country)
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Protocol 
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Table of Contents
Contents 
Protocol Approval – Sponsor Signatory ...................................................................................... 2 
Declaration by Treating Healthcare Provider .............................................................................. 4 
Table of Contents ......................................................................................................................... 5 
List of Tables ............................................................................................................................... 8 
Summary of Changes ................................................................................................................... 9 
Protocol Synopsis ....................................................................................................................... 13 
List of Abbreviations ................................................................................................................. 18 
Schedule of Assessments............................................................................................................ 20 
1. 
Introduction ....................................................................................................................... 25 
2. 
Study Objectives ................................................................................................................ 27 
2.1. Primary Objective .............................................................................................................. 27 
2.2. Secondary Objectives ........................................................................................................ 27 
3. 
Investigational Plan ........................................................................................................... 28 
3.1. Study Design ...................................................................................................................... 28 
3.1.1 Rationale of Study Design ........................................................................................ 29 
3.1.2 Potential Risk and Benefits ...................................................................................... 30 
3.1.3 Potential Selection Bias ........................................................................................... 30 
4. 
Patient and Site Selection and Withdrawal Criteria .......................................................... 32 
4.1 Selection of Study Population ............................................................................................ 32 
4.1.1 Inclusion Criteria ...................................................................................................... 32 
4.1.2 Exclusion Criteria .................................................................................................... 32 
4.2 Selection of Study Sites ..................................................................................................... 33 
4.3 Withdrawal of Patients from the Study .............................................................................. 33 
4.3.1 Reasons for Withdrawal ........................................................................................... 33 
4.3.1 Handling of Withdrawals ......................................................................................... 34 
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5 
Study Treatments ................................................................................................................ 35 
6 
Study Assessments and Collection of Data ........................................................................ 36 
6.1 BaselineAssessment .......................................................................................................... 36 
6.2 Multiple Myeloma Management ....................................................................................... 37 
6.3 Effectiveness ...................................................................................................................... 38 
6.4 Patient Self-Reported Outcomes ........................................................................................ 38 
6.4.1 European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire – Global Health Status/QoL Subscale .............................................. 39 
6.4.2 Quality of Life Questionnaire - 20-item Multiple Myeloma Module- Item 43 on 
Peripheral Neuropathy ............................................................................................. 39 
6.4.3 Treatment Satisfaction Questionnaire for Medication .............................................. 39 
6.4.4 Healthcare Resource Utilization .............................................................................. 39 
6.5 SafetyAssessments ............................................................................................................ 40 
6.5.1 Definitions of Adverse Events ................................................................................. 40 
6.5.2 Collecting and Recording of Adverse Events .......................................................... 41 
6.5.3 Reporting of Adverse Events ................................................................................... 42 
6.5.4 Assessment of Severity ............................................................................................ 43 
6.5.5 Relationship to Treatment......................................................................................... 44 
6.5.6 Other Safety Information ......................................................................................... 44 
6.5.7 Takeda Product Complaints or Product Quality Issues ............................................ 45 
6.6 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ................ 46 
7 
Statistical and AnalyticalPlan ............................................................................................ 47 
7.1 Outcome Measures ............................................................................................................ 47 
7.1.1 Primary Outcome Measures ..................................................................................... 47 
7.1.2 Secondary Outcome Measures ................................................................................. 47 
7.2 Sample Size Calculations .................................................................................................. 48 
7.3 Analysis Sets ...................................................................................................................... 50 
7.4 Subgroups of Interest ......................................................................................................... 50 
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7.5 Statistical Analysis Methodology ....................................................................................... 51 
7.5.1 PrimaryAnalysis ...................................................................................................... 51 
7.5.2 SecondaryAnalyses ................................................................................................. 51 
7.5.3 Interim Data Summaries .......................................................................................... 52 
7.5.4 Final Analysis ........................................................................................................... 53 
7.5.5 Study Reports ........................................................................................................... 53 
7.6 Data Quality Control .......................................................................................................... 53 
7.6.1 Data Management .................................................................................................... 53 
8 
Ethics ................................................................................................................................. 55 
8.1 Independent Ethics Committee or Institutional ReviewBoard ......................................... 55 
8.2 Ethical Conduct of the Study ............................................................................................. 55 
8.3 Patient Information and Consent ....................................................................................... 56 
9 
Healthcare Provider’s Obligations ..................................................................................... 57 
9.1 Confidentiality ................................................................................................................... 57 
9.2 Financial Disclosure and Obligations ................................................................................ 57 
9.3 Study Conduct and Adherence to Protocol ........................................................................ 57 
9.4 Adverse Events and Study Report Requirements .............................................................. 57 
9.5 Healthcare Provider’s Final Report.................................................................................... 58 
9.6 Records Retention .............................................................................................................. 58 
9.7 Publications ....................................................................................................................... 58 
10 
Study Management ............................................................................................................ 59 
10.1 Monitoring ......................................................................................................................... 59 
10.1.1 
Steering Committee ..................................................................................... 59 
10.1.2 
Monitoring of the Study .............................................................................. 59 
10.1.3 
Inspection of Records ................................................................................. 59 
10.2 Management of Protocol Amendments ..................................................................... 59 
10.2.1 Modifications of the Protocol ................................................................................. 59 
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10.3 Study Termination ............................................................................................................. 60 
11 
Reference List .................................................................................................................... 61 
12 
Appendices ........................................................................................................................ 64 
List of Tables
Table 1-1 
Protocol Amendment History and Summary of Changes .......................................... 9 
Table 1-2 
Data Collection Schedule ......................................................................................... 21 
Table 7-1 
Confidence Intervals of Estimated Proportions Based on Sample Size for Individual 
Groups .............................................................................................................................. 49 
Table 7-2 
Sample Size Needed to Detect Proportion Differences Between Sub-Groups ........ 50 
Table 12-1 
Modified IMWG Diagnosis Criteria for Active (Symptomatic) Myeloma 64 
Table 12-2 
Katz Index of Independence in Activities of Daily Living ......................... 65 
Table 12-3 
Lawton – Brody Instrumental Activities of Daily Living Scale ................. 66 
Table 12-4 
Charlson Comorbidity Index ...................................................................... 68 
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Summary of Changes
Table 1-1
Protocol Amendment History and Summary ofChanges
Version
Date
Summary of Changes
Version 1.0
12 February 2016
Original protocol
Version 2.0
12 October 2016
Editorial and administrative changes were made throughout the document 
for clarity. Redactions were made to Section 6.3 to avoid redundancy and 
improve clarity. The summary of significant changes includes the 
following:
Changes to Inclusion/Exclusion Criteria:
x
For newly diagnosed multiple myeloma (ND MM), patients will 
be enrolled within 3 months from initiation of treatment.
x
For relapsed/refractory multiple myeloma (R/R MM), only those 
patients who have received 1 to 3 prior lines of therapy will be 
enrolled. Data to be collected for R/R patients will include 
month and year of diagnosis and the regimens used in 1st, 2nd,
and 3rd line as applicable, whether stem cell transplant was part 
of 1st, 2nd, and 3rd line of therapy, whether 
consolidation/maintenance was part of 1st, 2nd, and 3rd line of 
therapy, also whether investigational therapy/treated on a clinical 
trial was part of any of these regimens.
x
Patients willing and able to complete Patient Reported Outcomes 
(PROs) in accordance with local regulatoryand data protection 
requirements will be enrolled.
Changes to Study Objectives, Outcomes and Analysis:
x
The primary and secondary analysis descriptions were modified.
Changes to Study Sites:
x
Australia and Africa were removed from the list of study sites.
Changes to Adverse Event Reporting:
x
Serious adverse events (SAEs), regardless of causality, in 
patients taking any Takeda drug must be reported to Cognizant 
within 24 hours of PPD learning about the event. When an SAE 
is reported in the electronic case report form (eCRF) for a patient 
that is on a Takeda product, the investigators will be asked to 
complete a standard SAE reporting form. The criteria used to 
define “serious” are outlined in the protocol. 
x
Serious adverse events occurring more than 30 days after the last 
dose of a Takeda drug generally do not need to be reported to 
Cognizant except for the circumstances outlined as follows:
o
New primary malignancies (i.e., all malignancies other 
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than the disease of indication) and progressive 
multifocal leukoencephalopathy need to be reported
indefinitely.
o
Pregnancy in a female patient, or female partner ofa
male patient, must be reported if the event occurs within 
90 days of the patient’s last dose of a Takeda drug.
o
Serious adverse events and non-serious adverse events 
(AEs) that are determined to be related to a Takeda 
product need to be reported indefinitely. Relatedness is 
determined by the healthcareprovider.
x
Serious adverse events in patients who have never taken a 
Takeda product will be recorded in the eCRF but do not need to 
be reported to Cognizant/Takeda. For SAEs in patients not 
taking Takeda drugs, if there is a reasonable possibility that the 
non-Takeda drug caused the event, local reporting requirements 
should be followed.
x
Non-serious AEs resulting in drug discontinuation or dose 
modification must be recorded in the eCRF.
o
If non-serious AEs resulting in drug discontinuation or 
dose modifications are related to a Takeda product, the 
adverse event form should be completed and the AE 
reported to Cognizant/Takeda.
o
Other non-serious AEs do not need to be reported to 
Cognizant/Takeda, but will be captured in the eCRF.
Additional Enrollment Criteria:
x
Enrollment will include approximately 50% ND MM and 50% 
R/R MM patients. Patient numbers will be capped at the site
level.
Changes in the Informed Consent Process:
x
Reference to the “Legal guardian” was removed.
x
Information regarding pregnant partner informed consent form 
(ICF) was added.
Changes to Data Collection Schedule:
x
The data collection schedule was updated to include additional 
detail on study assessments and associated frequencies.
Changes to Baseline Assessments:
x
Baseline assessments for ND and R/R MM patients were 
modified.
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Changes to Multiple Myeloma Management:
x
Assessments for Multiple Myeloma Management were modified.
Changes to Patient Reported Outcomes (PROs)/electronic PROs and 
Questionnaires to Include:
x
Frequency of completion of PROs will be quarterly. PROs will 
not be collected at multiple myeloma-directed treatment change.
x
The Work Productivity and Activity Impairment Questionnaire 
for General Health (WPAI–GH) was removed.
x
The resource utilization questionnaire has been modified by 
excluding questions related to multiple myeloma treatment 
change.
x
The Activities of Daily Living (ADL) and Instrumental 
Activities of Daily Living (IADL) questionnaires will be 
completed annually by the treating healthcare provider 
(physician, physician’s assistant, nurse practitioner, etc.) in 
eCRFs.
x
PROs will be completed on an electronic device at home, an 
electronic device during on-site routine office visits or on paper 
during on-site routine office visits. No device will be given to 
the patient. Patient self-reported outcomes cannot be interviewer-
administered by anyone, including a caregiver or site staff.
Changes to Vital Status:
x
Patients withdrawing consent will be followed-up only for vital 
status until the end of the study or the patient’s death, whichever 
occurs earlier.
x
Patients withdrawing consent could be re-screened for the study 
based on their willingness and consent.
x
If the patient does not visit the site or complete PROs at the end 
of the quarterly visit the site will attempt to contact the patient 
via telephone. If the attempt is unsuccessful, and the patient 
remains inactive during the next quarter, the site will again 
attempt to contact the patient. A final attempt will be made to 
contact the patient, relative, close friend, or other physician via 
telephone if the patient has been inactive for a period of 9 
months. If this final attempt is unsuccessful, a certified letter will 
be sent to the patient’s last known address. If the patient fails to 
respond to the certified letter, that patient will be considered lost 
to follow-up.
x
The healthcare provider and/or caregiver will be contacted if the 
patient is lost to follow-up. The ICF will have the provision of a 
checkbox to be checked off so that the site can contact the 
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patient’s caregiver when needed.
x
The healthcare provider may search regional death 
indexes/registries for vital health statistics of lost to follow-up
patients as per routine practice. The date of follow-up will be 
noted for censoring purposes. 
Version 3.0
11 April 2018
Editorial and administrative changes were made throughout the document 
for clarity. The summary of significant changes includes the following:
Change to Sample Size:
x
To account for the reduction of total study sites, the total sample 
size for this study was reduced to 4200 patients from 5000
patients. The defined accrual period of three years will remain 
the same, ensuring timely data delivery to the larger multiple 
myeloma community.
Changes to PROs/electronic PROs and Questionnaires to Include:
To reduce patient and site burden, yet still allow for collection of critical
PRO items, the following changes were made: 
x
Electronic PRO (ePRO) collection will be discontinued. Patients 
will now be asked to complete paper PROs during routine on-
site office visits. 
x
The EuroQol, 5-dimension, 5-level questionnaire (EQ-5D-5L) 
was removed.
x
Items collected from the European Organization for Research 
and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire (EORTC QLQ-C30) tool was reduced. The 
Global Health Status/QoL subscale (items 29 and 30) will 
continue to be collected.
x
Items collected from the EORTC Quality of Life Questionnaire -
20-item Multiple Myeloma Module (EORTC QLQ-MY-20) tool 
was reduced. Item 43 measuring peripheral neuropathy will 
continue to be collected.
Changes to Data Collection Schedule:
x
Site assessments were removed as these are not being collected.
x
The data collection schedule was updated to include additional 
detail on study assessments and associated frequencies.
x
Patients who are lost to follow-up will be followed-up only for 
vital status until the end of the study or the patient’s death, 
whichever occurs earlier.
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Protocol Synopsis
This is a non-interventional, observational study; therefore, no study drug or medication will be 
provided. No change in the patients’ management (routine clinical care or treatments) will be 
required because of this study. However, patients will be asked to complete patient self-reported 
outcomes (PROs) during on-site routine office visits.
Protocol Number:
NSMM-5001
Title:
A global, prospective, non-interventional, observational study of
presentation, treatment patterns, and outcomes in multiple myeloma 
patients - the INSIGHT MM study
Sponsor:
Millennium Pharmaceuticals, Inc.
a wholly owned subsidiary of Takeda Pharmaceutical Company 
Limited.
40 Landsdowne Street, Cambridge, MA 02139, USA
Indication:
Multiple Myeloma
Rationale:
Although advances in chemotherapy and novel agents have improved 
the prognosis and increased disease-free survival for patients with 
multiple myeloma (MM), currently available data on presentation, 
treatment patterns, and outcomes for MM at the global level are 
limited. By establishing an international, non-interventional, 
observational study with multi-year inclusion and follow-up,
contemporary demographics and patterns of care for MM patients can 
be tracked longitudinally in a large, more generalizable population.
The main goals of this study include conducting prospective, 
non-interventional, observational research to gain a better
understanding of the disease presentation and patient characteristics, 
treatment patterns, and clinical outcomes associated with MM and the 
impact of treatment on safety, effectiveness, and health-related quality 
of life (HRQoL), on both a country-specific and global basis. With this 
purpose, this study will collect data on patterns of clinical presentation, 
management, and outcomes.
Objectives:
Primary objective:
x
Describe contemporary, real-world patterns of patient 
characteristics, clinical disease presentation, therapeutic 
regimen chosen, and clinical outcomes in patients with newly 
diagnosed [ND] MM and patients with relapsed/refractory 
[R/R] MM.
Secondary objectives:
x
Describe patient characteristics, clinical disease presentation, 
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therapeutic regimen chosen, and clinical outcomes in ND and 
R/R MM patients by type of treatment facility and country.
x
Describe patterns and durations of treatment combinations, 
sequencing, retreatment, and continuous versus fixed duration 
treatment strategies; and the clinical outcomes associated with 
different treatment regimens.
x
Describe factors associated with treatment initiation, treatment 
modification, or treatment change over time, including whether 
treatment at relapse was initiated due to biochemical 
progression versus symptomatic progression.
x
Describe HRQoL and healthcare resource utilization (HRU).
x
Explore associations between patient characteristics, clinical 
disease presentation, therapeutic regimen chosen, and clinical
outcomes.
Patient Population:
Adult (18 years of age or older) patients with ND MM, or adult 
patients with R/R MM.
Study Design:
This is a prospective, global, non-interventional, observational study. 
This is a non-interventional study as defined in the Directive 
2001/20/EC and will follow the Good Pharmacoepidemiology 
Practices guidelines. No study drug or medications will be provided. 
No modification of standard care will be assigned per protocol. The 
assignment of an eligible patient to a therapy shall be decided by the 
treating healthcare provider and not by the study protocol, and the 
prescription of such therapy or medicinal product shall be wholly 
separate from the decision to include the patient in the study. No 
change in the patients’ management (routine clinical care or 
treatments) will be required because of this study.
However, patients will be asked to complete paper PROs during on-
site routine office visits.
Eligible patients will be identified and followed prospectively.
Information regarding patient characteristics, diagnosis, and previous 
treatments will be recorded based on review of hospital or clinic 
records. Multiple myeloma management data and safety data will be 
obtained as part of routine office visits.
If the patient does not visit the site per the defined data collection 
schedule, the site will attempt to contact the patient via telephone. If 
the attempt is unsuccessful, and the patient remains inactive 
throughout the next evaluation period, the site will again attempt to 
contact the patient. A final attempt will be made to contact the patient, 
relative, close friend, or other physician via telephone if the patient has 
been inactive for a period of 9 months. If this final attempt is 
unsuccessful, a certified letter will be sent to the patient’s last known 
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address. If the patient fails to respond to the certified letter, that patient 
will be considered lost to follow-up.
Attempts to collect the vital health status of patients who are not 
available for data collection for more than 9 months and therefore 
considered lost to follow-up, will occur. The healthcare provider 
and/or caregiver will be contacted if the patient is lost to follow-up and 
healthcare provider may search regional death indexes/registries for 
vital health statistics.
PROs will be completed in paper format while the patient is on-site for 
routine office visits. Patients will complete PROs at study entry and 
then quarterly while the patient remains on the study. Patient self-
reported outcomes cannot be interviewer-administered by anyone, 
including a caregiver or site staff.
Estimated Study 
Duration:
Patients will be enrolled over a period of 3 years, and each included 
patient will be evaluated and followed-up for a period of at least 5 
years, until death, or the end of the study, whichever comes first. It is 
expected that the study will end after all patients in the study have 
completed at least 5 years of follow-up, are lost to follow-up, or have 
died during the study period. 
Patients withdrawing consent will be followed-up only for vital status 
until death or the end of the study. The date of follow-up will be noted 
for censoring purposes. The healthcare provider and/or caregiver will 
be contacted if the patient is lost to follow-up and healthcare provider 
may search regional death indexes/registries for vital health statistics.
Assessments:
Demographic and biometric data; general medical history; and MM 
history, baseline data at inclusion, and disease presentation, will be 
recorded.
Multiple myeloma management will be assessed based on previous 
and current treatments and changes to treatment and reason(s).
Effectiveness will be assessed based on response to each regimen; 
progression status on each regimen; time to next therapy; and vital 
status, date of death, and cause of death.
Safety will be assessed based on the serious adverse events (SAEs) 
and non-serious adverse events (AEs) leading to treatment 
discontinuation (temporary and permanent) or drug modification, and 
second primary malignancies collected during the study.
Patient self-reported outcomes will be collected using the following 
tools: Items 29 and 30 measuring global QoL and health status from
the European Organization for Research and Treatment of Cancer 
(EORTC) Quality of Life Questionnaire (EORTC QLQ-C30), item 43 
measuring peripheral neuropathy from the EORTC Quality of Life 
Questionnaire - 20-item Multiple Myeloma Module (EORTC 
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QLQ-MY-20), and the 9-item Treatment Satisfaction Questionnaire 
for Medication (TSQM-9). A patient survey will be conducted at 
baseline and a healthcare resource utilization survey will be completed 
by patients quarterly while the patient remains on the study.
The frailty index is based on the Charlson Comorbidity Index, the Katz 
Index of Independence in Activities of Daily Living (ADL), and the 
Lawton Instrumental Activities of Daily Living (IADL) scales, all of
which will be completed by the treating healthcare provider annually 
in electronic case report forms (eCRFs).
Healthcare resource utilization will be assessed including, but not 
limited to, inpatient and intensive care unit admissions, length of stay, 
outpatient clinic visits, and emergency room visits.
Study Treatment:
This is a prospective, global, non-interventional, observational study. 
Treatment will not be determined or altered by participation in this 
study, with patients receiving usual therapy as determined by their 
treating healthcare provider. No additional treatments or procedures 
will be utilized for this study. However, patients will be asked to 
complete PROs.
Patients can also be enrolled in an observational or interventional 
study while participating in this study.
Sample Size:
The study will attempt to enroll approximately 4200 patients globally. 
The planned sample size is intended to provide enough patients to 
characterize treatments in a broad population. A sample size of 268 
patients in each of any 2 comparison subgroups will have at least 80% 
power to detect a difference between two proportions given that the 
true difference is at least 12%. Enrollment will include approximately 
50% ND MM and 50% R/R MM patients.
Patient numbers may be capped at the site level.
Statistical Methods:
Statistical analysis will be performed using SAS® software Version 9.2 
or later.
Population characteristics and all relevant primary and secondary 
outcomes will be summarized as mean, standard deviation, minimum, 
maximum, median, 25th and 75th percentile, and 95% confidence 
interval (CI) of the mean for continuous variables; and count and 
proportion with 95% CI of the proportion for categorical data. Counts 
of non-missing observations will be included. Event rates and 95% CIs 
for selected outcomes will also be summarized. Descriptive statistics 
will be used to describe patient characteristics, disease presentations, 
treatment patterns, safety assessments, clinical outcomes, economic 
outcomes, and HRQoL outcomes observed during the study period.
Treatment patterns will be summarized according to subgroups based 
on clinically relevant factors.
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Multivariable analysis of economic outcomes and PROs will be 
conducted using appropriate regression models. HRQoL outcomes will 
be summarized using descriptive statistics and longitudinal analysis.
All data collected for SAEs and non-serious AEs leading to treatment 
discontinuation (temporary and permanent) or drug modification, and 
second primary malignancies will be summarized. Since this is a 
disease-focused non-interventional, observational study with potential 
complicated confounding between treatment assignments and 
outcomes, all comparative effectiveness analyses will be considered 
exploratory.
Date of Protocol:
11 April 2018
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List of Abbreviations
Abbreviation
Definition
ADL
Activities of daily living
AE
Adverse event
BUN
Blood urea nitrogen
CFR
Code of Federal Regulations
CI
Confidence interval
CRAB
Calcium, renal failure, anemia, and bone damage
CT
Computed tomography
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EORTC
European Organization for Research and Treatment of Cancer
FDA
Food and Drug Administration
FISH
Fluorescence in situ hybridization
FLC
Free light chain
GEP
Gene expression profiling
GPP
Good Pharmacoepidemiology Practices
HRQoL
Health-related quality of life
HRU
Healthcare resource utilization
IADL
Instrumental activities of daily living
ICF
Informed consent form
ICH
International Council for Harmonisation
IEC
Independent ethics committee
IMWG
International Myeloma Working Group
IRB
Independent review board
ISS
International Staging System
LDH
Lactate dehydrogenase
MGUS
Monoclonal gammopathy of unknown significance
MM
Multiple myeloma
MRD
Minimal residual disease
MRI
Magnetic resonance imaging
NCCN
National Comprehensive Cancer Network
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Abbreviation
Definition
ND
Newly diagnosed
NGS
Next-generation sequencing
OS
Overall survival
PET
Positron emission tomography
PFS
Progression-free survival
PRO
Patient self-reported outcomes
QALY
Quality adjusted life year
QLQ-C30
Quality of Life Questionnaire – 30 item Cancer
QLQ-MY-20
Quality of Life Questionnaire - 20-item Multiple Myeloma Module
R-ISS
Revised International Staging System
R/R
Relapsed/refractory
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
Steering Committee
SMM
Smoldering multiple myeloma
SPEP
Serum protein electrophoresis
TSQM
Treatment Satisfaction Questionnaire for Medication
TSQM-9
9-Item Treatment Satisfaction Questionnaire for Medication
UPEP
Urine protein electrophoresis
US
United States
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Schedule of Assessments
The Data Collection Schedule is provided in Table 1-2. The schedule of data collection will not 
interfere with the standard schedule of routine office visits for MM patients.
No information will be collected until the patient has provided consent to participate in the 
study.
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Table 1-2 
Data Collection Schedule
Frequency
Inclusion
Quarterly from Inclusion
Annually from Inclusion
Visit Window
1 month
±1 month
Obtaining informed consent
X
Inclusion/Exclusion criteria
X
Demographic information1
X
Medical evaluation: Height
X
X
Medical evaluation: Weight
X
X
Vital status
X
Insurance information
X
X
Relevant past medical history2
X
Multiple myeloma medical history, disease characteristics and 
staging, diagnostic and presenting symptoms for MM3
X
Frailty status4: Charlson Comorbidity Index, Katz Index of 
Independence in ADL, Lawton IADL scale
X
X
ECOG performance status
X 
X 
Follow-up medical evaluation
X
Vaccinations
X 
X 
Bone marrow evaluations, Cytogenetics, FISH, MRD, GEP, 
NGS and investigational analysis, if available in clinical 
records
X 
X
Laboratory results (hematology and chemistry)5
X 
X
Laboratory test results (paraprotein evaluation/SPEP)6
X 
X
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Frequency
Inclusion
Quarterly from Inclusion
Annually from Inclusion
Visit Window
1 month
±1 month
Laboratory results HevyLite (if available)
X 
X
Laboratory results (UPEP) (if available)7
X 
X
Imaging results (if available)8
X 
X
Multiple myeloma related radiation therapy
X
Multiple myeloma related surgeries and other procedures
X 
Multiple myeloma therapy prior to study entry (ND MM)9
X 
Multiple myeloma therapy prior to study entry (R/R MM)10
X 
Multiple myeloma therapy status (ND MM and R/R) (includes 
reason for not receiving therapy)
X 
X 
Administered/prescribed MM therapy drugs for regimen 
(current regimen)11
X 
X 
Multiple myeloma regimen therapy plan12
X 
X 
Response assessment for a regimen, MRD (if available)13
X 
X 
Patient Baseline Survey
X 
Patient self-reported outcomes14
(Note: PRO completion can occur any time during a visit quarter. See 
footnote for details)
X 
X14
Stem cell transplants
X 
X 
Multiple myeloma supportive care
X 
X 
Healthcare resource utilization15
(Note: HRU is completed by both the HCP and the patient quarterly. 
See footnote for details)
X
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Frequency
Inclusion
Quarterly from Inclusion
Annually from Inclusion
Visit Window
1 month
±1 month
Study Discontinuation16
X 
Safety assessments (AE/SAE)17
X 
X 
Pregnancy reporting
X 
X 
Abbreviations: ADL, activities of daily living; AE, adverse event; BUN, blood urea nitrogen; CRAB, calcium, renal failure, anemia, and bone damage; CT, 
computed tomography; ECOG, Eastern Cooperative Oncology Group; eCRF, electronic case report form; FISH, fluorescence in situ hybridization; FLC, free light 
chain; GEP, gene expression profiling; HCP, healthcare provider; HRU, healthcare resource utilization; IADL, instrumental activities of daily living; LDH, lactate 
dehydrogenase; MGUS, monoclonal gammopathy of unknown significance; MM, multiple myeloma; MRD, minimal residual disease; MRI, magnetic resonance 
imaging; ND, newly diagnosed; NGS, next-generation sequencing; PET, positron emission tomography; PRO, patient self-reported outcomes;
R/R, relapsed/refractory; SAE, serious adverse event; SMM, smoldering multiple myeloma; SPEP, serum protein electrophoresis; UPEP, urine protein 
electrophoresis. 
1 
Including age, sex, race, ethnicity (optional based on country requirements), from PRO and height, weight, and geographic region.
2 
Relevant medical history includes peripheral neuropathy, hypertension, thromboembolism, osteopenia/osteoporosis, cataracts, arrhythmias, assessments if 
available: Echocardiogram, multigated acquisition scan (MUGA), Myelodysplastic Syndromes (MDS), MM-related radiation therapy, MM-related 
procedures/surgeries, myeloma/skeletal-related procedures,other surgeries/procedures, and vaccinations.
3 
Multiple myeloma medical history at initial diagnosis, if available, will include: disease stage at initial diagnosis, serum Beta-2 microglobulin, serum 
albumin, LDH, cytogenetics/FISH risk, bone lesions, calcium, BUN, creatinine, hemoglobin, MGUS/SMM, CRAB symptoms; and medical history prior to 
study inclusion, if available: bone marrow, FLC, MRI, M-component, immunofixation, PET/CT, GEP, amyloidosis, plasmacytoma, central nervous system 
involvement, and stem cell transplant.
4 
The frailty index will be based on the Charlson Comorbidity Index (Charlson et al. 1987), the Katz Index of Independence in ADL (Katz 1983), and the
Lawton IADL scales (Lawton and Brody 1969), all of which will be completed by the treating healthcare provider annually ineCRFs.
5 
Hematology and Chemistry laboratory test results of known prognostic, predictive markers. Baseline Hematology: white blood cell count, absolute 
neutrophil count, hemoglobin, and platelet count. Baseline Chemistry: calcium, creatinine, alkaline phosphatase, total bilirubin, aspartate aminotransferase, 
alanine aminotransferase, LDH. Albumin, and serum Beta-2 microglobulin, if available in clinical records. Quarterly Hematology: white blood cell count, 
absolute neutrophil count, hemoglobin, and platelet count; Quarterly Chemistry: calcium, creatinine, total bilirubin, albumin, and serum Beta-2
microglobulin, if available in clinical records.
6 
Paraprotein laboratory test results, if available: serum protein electrophoresis (SPEP) (serum total protein, m-spike level, serum immunofixation, serum
quantitative immunoglobulins), Serum FLCs.
7 
UPEP (24-hour urine, urine M-spike/BJP, urine immunofixation), or spot urine (protein, urine immunofixation). If both 24-hour and spot urine were tested, 
provide only the 24-hour urine results.
8 
Imaging tests include skeletal survey, standard CT, MRI, PET/CT, bone mineral density, whole body assessments (low dose CT and MRI, if done for 
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myeloma evaluation).
9 
For patients with ND MM only. Regimen, treatment durations and reasons for initiation ofregimen.
10
For patients with R/R MM only. Therapy prior to study entry including 1st, 2nd, and 3rd relapses and details for number of previous lines of therapy, 
regimens used in 1st, 2nd, and 3rd line as applicable; whether stem cell transplant was part of 1st, 2nd, and 3rd line of therapy, and whether 
consolidation/maintenance was part of 1st, 2nd, and 3rd line of therapy; also, whether investigational therapy/treated on a clinical trial was part of any of 
these regimens.
11
Administered/prescribed MM therapy drugs for regimen for current treatment (including treatment received at study entry), including individual drug, 
dose, route, schedule, duration and dose modification and reasons for medicationchanges.
12
MM regimen therapy plan includes current (including regimen at study entry) regimen, line of therapy, phase of regimen, reason for initiation of this
regimen (includes relapse), treatment intent of the regimen, duration, part of interventional clinicaltrial.
13
Response assessment for a regimen includes MRD, if assessed, best response achieved during the evaluation period, progression, and time to next therapy.
14
Global Health Status/QOL scale (2 items) from the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - 
C30 (EORTC QLQ-C30), a single item on peripheral neuropathy from the EORTC Quality of Life Questionnaire - 20-item Multiple Myeloma Module 
(EORTC QLQ-MY-20), and the 9-item Treatment Satisfaction Questionnaire for Medication (TSQM-9). A patient baseline survey will be conducted at
study entry. The + 1 month visit window does not apply to PRO collection; PROs may be collected from the patient at any time within the defined 
quarterly visit schedule.
15
Including but not limited to inpatient and intensive care unit admissions, reasons for admission, length of stay, outpatient clinic visits, and emergency room 
visits. The healthcare resource utilization questionnaire is completed by the investigator in the eCRF; in this case, the frequency will be +1 month. Hospice 
details will also be collected on eCRFs. A healthcare resource utilization questionnaire will also be completed by the patient in the paper PRO packet. 
16
Study discontinuation includes date and cause of death. After withdrawal or loss to follow-up, the patient’s vital status will be assessed. The healthcare 
provider may search regional death indexes/registries for vital health statistics of lost to follow-up patients as per routine practice.
17
All serious AEs and non-serious AEs regardless of causality leading to treatment discontinuation (temporary or permanent) or drug modification, and
second primary malignancies will be recorded on the eCRFs. All SAEs and non-serious AEs regardless of causality leading to treatment discontinuation 
(temporary or permanent) or drug modification of Takeda products will be reported following Section 6.5.3.  
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1. Introduction
Multiple myeloma (MM) is a clonal plasma cell disorder that accounts for 1% of all cancers and 
10% of hematologic malignancies (National Comprehensive Cancer Network [NCCN] 2015). It 
is the second most common hematologic malignancy, with an estimated worldwide incidence of 
114,000 new cases and 80,000 deaths in 2012 (Ferlay et al. 2013). In the United States (US), the 
estimated annual incidence in 2015 was 26,850 new cases and 11,240 deaths (National Cancer 
Institute 2015). In Europe, the estimated annual incidence in 2012 was 38,900 new cases and 
24,300 deaths (Ferlay et al. 2013). 
Multiple myeloma is largely a disease of older people. The median age at diagnosis is 69 years, 
and approximately 2/3 of people are over age of 65 at the time of diagnosis (Ailawadhi 2012,
NCCN 2015). Also, MM is more common in men than women, and in black people compared to 
other races (Alexander 2007). Although the reasons for these differences are not clearly 
understood, risk factors such as obesity, socioeconomic status, and workplace environment and 
exposures may have a role. The incidence of MM is increasing slowly; this may be related to an 
aging population, as well as to increasing obesity rates. However, deaths from MM are 
decreasing year-on-year: the 5-year survival rate in the US was 27% in 1975 compared to 53% 
from 2008 to 2010 (National Cancer Institute 2015, Pulte 2015), and in Europe was 
approximately 40% between 2006 and 2008 (Sant 2014). 
The improvement in overall survival (OS) is likely due to the introduction of more effective 
treatments, both in general as well as through individualization and sequencing of therapies 
based on identification of important patient sub-groups with the use of advanced diagnostics 
(e.g., fluorescence in situ hybridization [FISH] and high-throughput gene expression profiling 
[GEP]). The introduction of novel classes of agents with increased efficacy, including 
proteasome inhibitors (bortezomib, carfilzomib, and ixazomib) and immunomodulatory agents 
(thalidomide, lenalidomide, and pomalidomide), has played a role in increasing both the 
progression-free survival (PFS) and the OS of these patients, and has changed the natural history 
of the disease. In addition, agents with new mechanisms of action such as panobinostat (histone 
deacetylase inhibitor) and daratumumab and elotuzumab (monoclonal antibodies) have recently 
been approved in the US and the submission of these agents for approval globally is underway. 
The investigation continues with these agents, other agents with the same or similar mechanisms
of action as well as agents with novel mechanisms of action. Treatment landscape for patients 
with MM is rapidly changing and it is anticipated that treatment changes will continue for the 
foreseeable future.
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Although advances in chemotherapy and novel agents have improved the prognosis and disease-
free survival for patients with MM, currently available data on presentation, treatment patterns, 
and outcomes for MM at global level are limited. By establishing an international non-
interventional, observational study with multi-year inclusion and follow-up, contemporary 
demographics and patterns of care for MM patients can be tracked longitudinally in a large, 
more generalizable population.
The main goals of this study include conducting prospective, non-interventional, observational 
research to gain a better understanding of the disease presentation and patient characteristics, 
treatment patterns, and clinical and economic outcomes associated with MM and the impact of 
treatment on safety, effectiveness, health-related quality of life (HRQoL), and healthcare 
resource utilization (HRU), on both a country-specific and global basis. With this purpose, this 
study will collect data on patterns of clinical presentation, management, and outcomes.
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2. Study Objectives
2.1. Primary Objective
The primary objective of this study is to describe contemporary, real-world patterns of patient 
characteristics, clinical disease presentation, therapeutic regimen chosen, and clinical outcomes 
in patients with newly diagnosed [ND] MM, and patients with relapsed/refractory [R/R] MM.
2.2. Secondary Objectives
The secondary objectives of this study are to:
x
Describe patient characteristics, clinical disease presentation, therapeutic regimen 
chosen, and clinical outcomes in ND and R/R MM patients by type of treatment facility 
and country.
x
Describe patterns and durations of treatment combinations, sequencing, retreatment, and 
continuous versus fixed duration treatment strategies; and the clinical outcomes 
associated with different treatment regimens.
x
Describe factors associated with treatment initiation, treatment modification, or 
treatment change over time; including whether treatment at relapse was initiated due to 
biochemical progression versus symptomatic progression.
x
Describe HRQoL and HRU.
x
Explore associations between patient characteristics, clinical disease presentation, 
therapeutic regimen chosen, and clinical outcomes.
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3. Investigational Plan
3.1. Study Design
This is a prospective, global, non-interventional, observational study. The purpose of this study 
is to describe contemporary, real-world presentation, therapies, and clinical outcomes in patients 
with MM. Therefore, no modification of standard care is assigned per protocol. This is a non-
interventional, observational study; therefore, no study drug or medications will be provided. 
No change in the patients’ management (routine clinical care or treatments) will be required 
because of this study. However, patient self-reported outcomes (PROs) will be completed during 
on-site routine office visits. 
This is a non-interventional study as defined in the Directive 2001/20/EC (The European
Parliament and the Council of the European Union 2001) and will follow the Good 
Pharmacoepidemiology Practices (GPP) guidelines (Epstein 2005). 
Eligible patients will be identified and followed prospectively. Information regarding patient 
characteristics, diagnosis, and previous treatments will be recorded based on review of hospital 
or clinic records. Multiple myeloma management data and safety data will be obtained as part of 
routine office visits. Patients who are not available for data collection for more than 9 months 
will have a follow-up for survival. The site will have made 3 possible attempts to contact the 
patient by the time this 9-month period is reached. The healthcare provider and/or caregiver will 
be contacted if the patient is lost to follow-up. The healthcare provider may search regional 
death indexes/registries for vital health statistics of lost to follow-up patients as per routine 
practice. Patient self-reported outcomes will be collected during on-site routine office visits.
Patients will complete PROs at study entry and then quarterly thereafter while the patient 
remains on the study. The HRU will also be assessed quarterly while the patient remains on the 
study. 
This study will attempt to enroll approximately 4200 patients globally. Patients will be enrolled 
over a period of approximately 3 years, and each included patient will be evaluated and 
followed-up for a period of at least 5 years, until death, withdrawal of consent to participate, or 
the end of the study, whichever comes first. It is expected that the study will end after all 
patients in the study have completed at least 5 years of follow-up, are lost to follow-up, or have 
died prior to study end. 
Patients lost to follow-up will be followed-up only for vital status until the end of the study or 
the patient’s death, whichever occurs earlier. The date of follow-up will be noted for censoring 
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purposes. Patients will not be asked to travel to the site only for this study. Multiple myeloma 
management data and safety data will be obtained as part of selected routine office visits.
The data collected for this study are detailed in Section 6 and the Data Collection Schedule is 
provided in Table 1-2. 
3.1.1 Rationale of Study Design
An observational design is used as it will not interfere with patient’s treatment as prescribed and 
directed by the healthcare provider. The schedule of data collection is also in agreement, and 
will not interfere with the standard schedule of routine office visits for MM patients. No 
additional treatments or diagnostic or monitoring procedures will be utilized for this study. 
However, patients will be asked to complete PROs in paper format during on-site routine office 
visits.  
The need for HRQoL endpoints in MM studies to better inform treatment decisions in cancer 
has been increasingly recognized (Kvam et al. 2009). Furthermore, regulatory agencies and 
health technology assessment bodies are increasingly considering PROs, such as physical 
functioning and symptoms, in their deliberations. The European Organization for Research and 
Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) instrument has been 
recommended for use in oncology trials (Basch et al. 2012) and is widely utilized in clinical 
trials and in global registries. The psychometric properties of the measure have been established 
(Aaronson et al. 1993) and the clinically meaningful difference in scores of the global quality of 
life health status scale, which will be assessed as a standalone scale in this study, has been 
determined in MM populations (Wisløff et al. 1996; Kvam et al. 2011). In addition to EORTC 
QLQ-C30, the common symptom of peripheral neuropathy will be assessed by a single item of
the EORTC Quality of Life Questionnaire - 20-item Multiple Myeloma Module (QLQ-MY-20) 
(Stead et al. 1999). Additional information on these questionnaires is provided in Section 6.4.
To capture patient satisfaction with MM-directed therapy, including the important dimension of 
convenience, the Treatment Satisfaction Questionnaire for Medication (TSQM) will be 
administered to patients in its 9-item version (TSQM-9) (Bharmal et al. 2009). The TSQM is 
also a widely-used questionnaire in the context of oncology (Escudier et al. 2009). Additional 
information on the TSQM-9 is provided in Section 6.4.3.
To incorporate data from a wide range of countries, initial recruitment will start in the US with 
other countries included as soon as sites are identified, selected for submission, approved as per 
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local regulatory requirements, and ready for patient recruitment.
The study has been designed as a non-interventional, observational study, with a specified target 
sample size of approximately 4200 patients globally, tied to achievable rates of patient inclusion 
during 3 years, and with a follow-up of a minimum of 5 years, until death, withdrawal of 
consent to participate, or the end of the study, whichever comes first. Enrollment will include 
approximately 50% ND MM and 50% R/R MM patients. Patient numbers will be capped at the 
site level. This target is sufficient to achieve a satisfactory degree of precision and to provide 
valuable data on the study objectives (see Section 7.2). Patients withdrawing consent could be 
re-screened for the study based on their willingness and consent. Patients lost to follow-up will 
be followed-up only for vital status until the end of the study or the patient’s death, whichever 
occurs earlier. The healthcare provider and/or caregiver will be contactedif the patient is lost to 
follow-up. The healthcare provider may search regional death indexes/registries for vital health 
statistics of lost to follow-up patients as per routine practice. The date of follow-up will be noted 
for censoring purposes. 
3.1.2 Potential Risk and Benefits 
Patients included in the study will undergo routine clinical assessment; treatment will not be 
determined or altered by participation in this study, with patients receiving usual therapy as 
determined by their treating healthcare provider during their care. No additional treatments or 
procedures will be utilized for this study, although patients will be asked to complete PROs. 
Therefore, no specific risks have been identified other than the potential for loss of 
confidentiality. Every effort will be made to protect patient confidentiality: the data analysis will 
be performed using only masked data (see Section 7.6.1). Informed consent containing detailed 
information about potential benefits and risks for the patient will be required from all patients.
Although patients included in this study might not receive any benefit from the study, the study 
will promote better understanding of contemporary demographics, patterns of care, and 
outcomes for MM patients in a large, more generalizable population. This new information will 
be shared with the medical community. 
3.1.3 Potential Selection Bias
Due to the nature of the study design and because the patients are being selected by the 
healthcare providers, the possibility of sample selection bias due to “convenience” sampling 
must be considered. Reasonable efforts will be made to include a sample of MM patients who 
represent the general population of MM patients in any specific country. This may include 
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regular monitoring of included and screened patients, periodic adjustments in inclusion caps and 
other such efforts. During the analysis phase, statistical adjustments may also be implemented to 
further address bias and/or confounding that persist despite best efforts to capture representative 
sample. The statistical analysis plan (SAP) will describe these approaches in detail.
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4. Patient and Site Selection and Withdrawal Criteria
4.1 Selection of Study Population
Patients cared for at participating clinics who meet study eligibility criteria will be approached 
for formal consent to participate in the study.
4.1.1 Inclusion Criteria
Each patient must meet all of the following criteria to be included in this study:
1. Is 18 years of age or older.
2. Is experiencing one of the following:
a.
Newly diagnosed MM within 3 months from initiation of treatment with 
documented month and year of diagnosis, criteria met for diagnosis, stage, and 
MM-directed treatment history, including duration.
b. Relapsed/refractory MM who have received 1 to 3 prior lines of therapy with 
documented data in the medical record regarding diagnosis (month and year), the 
regimens used in 1st, 2nd, and 3rd line as applicable, whether stem cell transplant 
was part of 1st, 2nd, and 3rd line of therapy, whether consolidation/maintenance 
was part of 1st, 2nd, and 3rd line of therapy, also whether investigational 
therapy/treated on a clinical trial was part of any of these regimens.
3. Patients willing and able to complete PROs in accordance with local regulatory and data 
protection requirements will be enrolled.
4. Is willing and able to sign informed consent to participate.
4.1.2 Exclusion Criteria
Patients meeting any of the following criteria will be excluded from the study:
1. Patients reporting to a site in this study for a second opinion (consultation only) or 
patients whose frequency of consult and follow-up are not adequate for quarterly 
electronic case report form (eCRF) completion.
2. Participation in another study (observational or interventional) that prohibits 
participation in this study.
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4.2 Selection of Study Sites
Patients will be recruited to this study from sites across the world that may include North 
America, Europe, Asia, and South America. In addition, this study has the potential to partner 
with MM registries or other observational MM studies, with the goal to build a global MM 
observational study.
The healthcare providers in each participating country will be recruited to reach an adequate 
sample of sites based on the following selection criteria:
x
All participating healthcare providers and sites must provide care for MM patients.
x
Each site must be represented by a healthcare provider who is a full-time member of the 
hospital or clinic staff, who agrees to serve as the principal MM healthcare provider or 
oversee MM healthcare for patients who may be included at their respective hospital or 
clinic under the care of a Sub-Investigator, and who agrees to ensure that the scientific 
and ethical requirements in this protocol are followed.
4.3 Withdrawal of Patients from the Study
The duration of the study is defined for each patient as the date that signed written informed 
consent is provided through the end of the follow-up period, death, or the end of the study. 
Patients may withdraw their consent at any time and for any reason without prejudice to their 
future medical care by the healthcare provider or at the study site. In case of withdrawal, 
patients will have the right to be remembered and the right to be forgotten in accordance with 
local regulatory and data protection rules. These rights will be included in the informed consent 
form (ICF).
Patients withdrawing consent can be re-screened for the study based on their willingness and 
consent. They will be followed-up only for vital status until the end of the study or the patient’s 
death, whichever occurs earlier. The ICF will have the provision of a checkbox to be checked 
off so that the site can contact the patient’s caregiver when needed.
4.3.1 Reasons for Withdrawal
Treatment will not be determined or altered by participation in this study, with patients receiving 
usual therapy as determined by their treating healthcare provider during their care. Patients can 
also be enrolled in another observational or interventional study while participating in this study.
The reasons for patients not completing the study will be recorded. A patient may be withdrawn 
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from the study for any of the following reasons:
x
The patient withdraws consent.
x
If the patient enrolls in another observational or interventional study that requires 
withdrawal from this study, the patient may be re-included into this study when the
patient’s participation in the other study is completed.
Patient participation in this study may be discontinued without patient consent at any time at the 
discretion of the healthcare provider, Takeda, or a regulatory authority. The healthcare provider 
will also withdraw a patient if Takeda terminates the study.
4.3.1 Handling of Withdrawals
When a patient withdraws from the study, the reason(s) for withdrawal shall be recorded by the 
treating healthcare provider on the relevant page in the eCRF, including reasons for “lost to 
follow-up” if necessary. Every attempt will be made by the site to document the reason of study 
withdrawal.
If the patient does not visit the site at the end of the quarterly visit, the site will attempt to 
contact the patient via telephone. If the attempt is unsuccessful, and the patient remains inactive 
during the next quarter, the site will again attempt to contact the patient. A final attempt will be 
made to contact the patient, relative, close friend, or other physician via telephone if the patient 
has been inactive for a period of 9 months. If this final attempt is unsuccessful, a certified letter 
will be sent to the patient’s last known address.
If the patient fails to respond to the certified letter, that patient will be considered lost to follow-
up. The primary healthcare provider and/or caregiver will be contacted if the patient is lost to 
follow-up for vital status. The healthcare provider may search regional death indexes/registries 
for vital health statistics of lost to follow-up patients as per routine practice. The date of follow-
up will be noted for censoring purposes.
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5
Study Treatments
This is a prospective, global, non-interventional, observational study where patients included 
will undergo routine clinical care under the supervision of an authorized healthcare provider. 
Treatment will not be determined or altered by participation in this study, with patients receiving 
usual therapy as determined by their treating healthcare provider during their care. Patients can 
also be enrolled in an observational or interventional study while participating in this study. No 
additional treatments or procedures will be utilized for this study. However, patients will be 
asked to complete PROs and questionnaires including healthcare utilization.
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6
Study Assessments and Collection ofData
Before collecting any data, all potential patients will sign an ICF. Patients will have the 
opportunity to have any questions answered before signing the ICF. The healthcare provider 
must address all questions raised by the patient. Refer to Section 8.3 for additional details on 
patient’s consent. 
Refer to data collection schedule provided in Table 1-2 for more information. 
6.1 BaselineAssessment
Baseline data will include, but will not be limited to, the following questions related to medical 
history prior study inclusion and status at study inclusion. 
For ND and R/R: 
x
Demographic and biometric information including age, sex, race, ethnicity (optional, 
based on country requirements), height, weight, insurance information and geographic 
region. 
x
Date of initial diagnosis (including month and year for R/R and day, month and year for 
ND) and criteria used International staging system (ISS)/revised ISS (R-ISS).
x
Medical history at initial diagnosis, if available, will include: disease characteristics, 
stage by ISS or R-ISS, presence of bone lesions, relevant baseline laboratory values, 
history of monoclonal gammopathy of unknown significance/smoldering multiple 
myeloma (MGUS/SMM).
x
Frailty status, including Charlson Comorbidity Index, Katz Index of Independence in 
activities of daily living (ADL), and Lawton instrumental activities of daily living 
(IADL) scale, as well as Eastern Cooperative Oncology Group (ECOG) performance 
status.
x
Medical history data prior to study inclusion, if available: relevant medical history to be 
captured as detailed in the eCRF, including vaccination history and stem cell transplants. 
x
Medical evaluation (collected at baseline and quarterly) as detailed in the eCRF.
Therapy prior to study entry: 
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x
For ND: phase of treatment, regimen, treatment durations and reasons for initiation of 
regimen, response evaluation and assessment, and minimal residual disease (MRD) (if 
done). 
x
For R/R: including 1st, 2nd, and 3rd relapses and number of previous lines of therapy,
regimens used in 1st, 2nd, and 3rd line as applicable; whether stem cell transplant was part 
of 1st, 2nd, and 3rd line of therapy, whether consolidation/maintenance was part of 1st, 2nd,
and 3rd line of therapy; also, whether investigational therapy/treated on a clinical trial 
was part of any of these regimens; and response evaluation, MRD (if done). 
6.2 Multiple Myeloma Management
The following information will be collected to assess MM management:
Therapy at inclusion: 
x
For ND and R/R: current therapy, including regimens and drugs; and reasons for not 
receiving a therapy, if any.
Quarterly assessment:
x
Changes to treatment from previous evaluation period including line of therapy, regimen, 
drug, schedule and duration, dose modifications, and reason(s) for medication changes at 
inclusion and quarterly during the study.
x
Hematology/chemistry form will be completed based on laboratory values obtained 
closest to the beginning of the most recent cycle of therapy (if available) or the 
laboratory values closest to the quarterly eCRF completion date.
x
History of radiation therapy.
x
History of MM-related surgeries and/or other procedures.
x
Stem cell transplant, if done. 
x
MM-supportive care, if received.
x
HRU, overnight hospital admissions, emergency room visits (see Section 6.3).
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x
Safety assessment (see Section 6.5).
x
Pregnancy assessment (see Section 6.6).
x
Frailty status will be measured yearly.
Study status for patient continuation to the next evaluation period will be assessed. 
6.3 Effectiveness
The following information will be collected quarterly during the study to assess effectiveness 
of MM management:
x
Bone marrow evaluation, FISH, cytogenetics, MRD, positron emission tomography 
(PET)/computed tomography (CT), next-generation sequencing (NGS), GEP, serum 
para-protein evaluation (SPEP), HevyLite (if available), urine protein electrophoresis 
(UPEP) laboratory results. HevyLite and UPEP will also be collected at inclusion, if
available.
x
Imaging results for all assessment performed within an evaluation period, if done for
MM assessment.
x
Response to each regimen (per the International Myeloma Working Group Uniform 
Response Criteria for Multiple Myeloma) (Durie BG, et al. 2006)
x
Progression status on each regimen.
x
Time to next therapy.
x
Vital status, date of death, and cause of death. 
6.4 Patient Self-Reported Outcomes 
Patient self-reported outcomes; including the Global Health Status/QoL subscale from the 
EORTC QLQ-C30, a single item on peripheral neuropathy from the EORTC QLQ-MY-20, and 
TSQM-9, will be assessed at study inclusion and quarterly thereafter. A baseline questionnaire 
will be completed at inclusion and HRU will be assessed quarterly. Patient self-reported 
outcomes will be collected on paper forms during on-site routine office visits. Patient 
self-reported outcomes cannot be interviewer-administered by anyone, including a caregiver or 
site staff.
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6.4.1 European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire – Global Health Status/QoL Subscale
The EORTC QLQ-C30 (Aaronson et al. 1993) was designated to assess HRQoL in a wide range 
of cancer patient populations. The Global Health Status scale/QoL scale includes 2 questions 
measured with a 7-point numeric rating scale (very poor to excellent). Raw scores are converted 
into scale scores ranging from 0 to 100. A higher score represents better HRQoL.
6.4.2 Quality of Life Questionnaire - 20-item Multiple Myeloma Module-
Item 43 on Peripheral Neuropathy
The EORTC QLQ-MY-20 (Stead et al. 1999) was designed in collaboration with the EORTC 
Quality-of-Life Study Group as a MM-specific module to be administered with the EORTC 
QLQ-C30. Item 43 of the measure assesses the symptom of peripheral neuropathy, or tingling in 
the hands and feet, using a 4-point Likert scale ranging from “Not at all” to “Very much”. A
high score represents a high level of the symptom. 
The EORTC QLQ-MY-20 item will be administered following the EORTC QLQ-C30 items.
6.4.3 Treatment Satisfaction Questionnaire for Medication
The TSQM-9 (Bharmal et al. 2009) will be administered at enrolment and quarterly thereafter to 
capture patient satisfaction with MM-directed therapy, including the important dimension of 
convenience. The TSQM-9 includes 9 items on a 5-point or 7-point Likert type scale and covers 
3 domains, corresponding to distinct aspects related to the satisfaction of patients with their 
treatment (effectiveness, convenience, and global satisfaction). The TSQM-9 is a reduced 
version of the 14-item TSQM which includes 9 of the original questions but excludes the 5 
TSQM questions related to side effects of medication. Higher scores on the TSQM-9 indicate 
higher satisfaction, better perceived effectiveness, and better convenience.
6.4.4 Healthcare Resource Utilization
Healthcare resource utilization for routine MM treatment will be assessed quarterly including, 
but not limited to, inpatient and intensive care unit admissions, reasons for admission, length of 
stay, outpatient clinic visits, and emergency room visits. Healthcare resource utilization will be 
assessed first, before the standard PRO questionnaires. 
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6.5 Safety Assessments
Safety will be assessed by the documentation and collection of serious adverse events (SAEs) 
and non-serious AEs leading to treatment discontinuation (temporary and permanent) or drug 
modification, and second primary malignancies.
6.5.1 Definitions of AdverseEvents
Adverse Events
Adverse event 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 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 new event, or worsening of a previous condition.
Adverse Drug Reaction
For the purposes of this study, an adverse drug reaction is an AE that is considered related to 
MM treatments, or to other treatments according to the definition above.
Serious Adverse Event
An SAE is an AE that meets any of the following criteria:
x
Is fatal or life threatening, i.e., in the view of the healthcare provider, places the patient 
at immediate risk of death from the reaction as it occurred. An event 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. For example, drug-
induced hepatitis that resolved without evidence of hepatic failure would not be 
considered life threatening, even though drug-induced hepatitis can be fatal.
x
Results in persistent or significant disability or incapacity. Disability is defined asa
substantial disruption of a person's ability to conduct normal life functions.
x
Requires inpatient hospitalization or prolongation of an existing hospitalization. 
Symptoms or conditions led to the hospitalization (e.g., dehydration, and shortness of 
breath) will be documented. Planned hospital admissions or surgical procedures for an 
illness or disease that existed before the patient used the drug are not to be considered 
AEs unless the condition deteriorated in an unexpected manner during treatment (e.g., 
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surgery was performed earlier or later than planned).
x
Is a congenital anomaly/birth defect.
x
Is amalignancy.
x
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 (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious
agent.
Seriousness serves as a guide for defining regulatory reporting obligations.
6.5.2 Collecting and Recording of AdverseEvents
All SAEs, regardless of causality or expectedness, and non-serious AEs resulting in drug 
discontinuation (temporary or permanent) or dose modification will be collected from the 
patient medical records and captured in the eCRF. Multiple myeloma is a disease with high
morbidity and high mortality, therefore this study will only collect SAEs and non-serious AEs
resulting in drug discontinuation (temporary or permanent) or dose modification.
When an SAE is reported in the eCRF for a patient that is on a Takeda Oncology product the 
investigators will be asked to complete a standard SAE reporting form. All secondary primary 
malignancies must be collected, regardless of causality, upon awareness of the new primary 
malignancy for a minimum of 3 years after the last dose of ixazomib or other MM therapies.
Sufficient information should be recorded to enable the AE to be fully described and collected in 
the eCRF. If an SAE is present, the following information should be collected in the eCRF:
x
A description of theAE.
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x
Start and stop dates of theAE.
x
Outcome of AE.
x
Actions taken by the health-care provider (especially if the actions involved stopping a 
drug or dose modification).
x
Causal relationship to treatment, to concurrent medical conditions, to medical or surgical 
procedures, or to other unknown or suspected causes, or to concomitant drug(s).
x
Severity of the SAE.
x
Seriousness criteria met.
6.5.3 Reporting of Adverse Events
All SAEs, regardless of casualty or expectedness, and non-serious AEs leading to treatment 
discontinuation (temporary and permanent) or drug modification, and second primary 
malignancies will be recorded on the appropriate page in the eCRF on a quarterly basis.
In patients taking any Takeda Oncology drug, SAEs and non-serious AEs leading to treatment 
discontinuation (temporary and permanent) or dose modification, and secondary primary 
malignancies will be captured in eCRFs, and the investigators will be asked to complete a 
standard SAE reporting form. The event will then be reported automatically via email to Takeda 
Case processing (Cognizant) or designee within 24 hours after entry into the clinical database.
Serious adverse events occurring more than 30 days after the last dose of a Takeda drug 
generally do not need to be reported. There are some exceptions with longer reporting periods, 
as follows:
x
New primary malignancies (i.e., all malignancies other than the disease of indication) 
and progressive multifocal leukoencephalopathy need to be reported indefinitely.
x
Pregnancy in a female patient, or female partner of a male patient, must be reported if 
the event occurs within 90 days of the patient’s last dose of a Takedadrug.
x
Serious adverse events and non-serious AEs that are determined to be related to a Takeda 
product must be reported indefinitely. Relatedness is determined by the healthcare
provider.
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Serious adverse events in patients who have never taken a Takeda product will be recorded in 
the eCRF but do not need to be reported to Cognizant/Takeda. For SAEs in patients not taking 
Takeda drugs, if there is a reasonable possibility that the non-Takeda drug caused the event, 
local reporting requirements should be followed.
The Takeda Department of Pharmacovigilance or designee will be provided access to the 
database to view the information.
All SAEs and non-serious AEs collected during the study will be included in the studyreport 
and all SAEs and AEs, as required, will be reported by the sponsor to the regulatoryagencies in 
accordance with reporting requirements.
6.5.4 Assessment of Severity
The healthcare provider will use the most recent version of the National Cancer Institute the 
Common Terminology Criteria for Adverse Events in the evaluation of AEs.
Severity grades will be collected on the AE/SAE form for patients taking Takeda Oncology
products:
x
Grade 1 Mild: asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
x
Grade 2 Moderate: minimal, local or noninvasive intervention indicated; limiting age-
appropriate IADL*.
x
Grade 3 Severe or medically significant but not immediately life-threatening:
hospitalization indicated; disabling; limiting self-care ADL**.
x
Grade 4: Life-threatening consequences; urgent intervention indicated.
x
Grade 5: Death related to AE
*IADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc.
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.
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Not all Grades are appropriate for all AEs. Therefore, some AEs are listed with fewer than 5
options for Grade selection. Grade 5 (death) is not appropriate for some AEs and therefore is not 
an option.
Note that “severe” is not synonymous with “serious.” An AE may be assessed as severe without 
meeting the criteria for an SAE.
6.5.5 Relationship to Treatment
The following definitions of relationship should be used to characterize the suspected causality 
of each SAE as either related or not related to any MM treatment including ixazomib or 
bortezomib. This assessment should be based on the healthcare provider’s consideration of all 
available information about the event, including temporal relationship to drug administration, 
recognized association with drug product/class, pharmacological plausibility, and alternative 
etiology (e.g., underlying illness, concurrent conditions, concomitant treatments):
x
Related: There is a reasonable possibility that the drug caused the event.
x
Not related: There is not a reasonable possibility that the drug caused theevent.
6.5.6 Other Safety Information
Other Safety Information
The following events, whether or not they are associated with an AE, should be reported to 
Takeda within 24 hours of a Takeda employee or representative (e.g., contract research 
organization) learning about it:
Special situation reports:
x
Pregnancy in a female patient, or female partner of a male patient, within 90 days of the 
patient’s last dose of a Takeda drug. 
x
Infant exposure due to breastfeeding
x
Overdose: Accidental or intentional overdose. Clinical judgement should always be 
applied. 
x
Drug Abuse, misuse or medication error: Intentional excessive use of a drug, which is 
accompanied by harmful physical or psychological effects. Any unintentional error in 
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the prescribing, dispensing, or administration of a drug while in the control of the 
healthcare professional or patient.
x
Suspected transmission of an infectious agent by a Takeda product.
x
Lack of efficacy of Takeda product.
x
Accidental occupational exposure: This refers to exposure to a drug, as a result of 
one’s professional or non-professional occupation.
x
Medication error: This refers to any unintentional error in the prescribing, dispensing, 
or administration of a drug while in the control of the healthcare professional or patient.
x
Use of falsified medicinal product
Product Quality Issues (Product defects related to):
x
Safety
x
Identity
x
Strength
x
Quality, purity, or physical characteristics
x
Packaging or design of the product
x
Labelling
6.5.7 Takeda Product Complaints or Product Quality Issues
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, physical characteristics or stability of a drug 
product. Individuals who identify a potential Takeda product complaint situation should 
immediately contact Takeda and report the event. Product quality issues may be reported with or 
without an associated AE. Whenever possible, the associated Takeda product should be 
maintained in accordance with the label instructions pending further guidance from a Takeda 
Quality representative.
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Phone: 1-844-ONC-TKDA (1-844-662-8532) 
E-mail: GlobalOncologyMedinfo@takeda.com
Fax: 1-800-881-6092 
Hours: Mon-Fri, 9 a.m. – 7 p.m. ET 
Product complaints in and of themselves are not AEs. If a product complaint results into an 
SAE, an SAE form should be completed and sent to Millennium Pharmacovigilance as indicated 
in Section 6.5.3.
6.6 Procedures for Reporting Drug Exposure During Pregnancyand Birth
Events
Pregnancy in a female patient, or female partner of a male patient, must be reported if the event 
occurs within 90 days of the patient’s last dose of a Takeda drug. 
If a woman becomes pregnant while taking any Takeda product, this must be captured in the 
eCRF. The outcome of the pregnancy should be reported once known. 
If a female partner of a male patient becomes pregnant while the male patient is being treated 
with Takeda product, this must also be captured in the eCRF. Every effort should be made to 
determine the final pregnancy outcome. There will be a separate ICF for data collection of the 
pregnant partner and the newborn. 
For Takeda Product Complaints
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7
Statistical and AnalyticalPlan
A complete description of the statistical analyses and methods will be provided in the SAP, 
which will be finalized prior to database lock. The detailed analysis plan will be based on the 
GPP (Epstein 2005) and the Agency for Healthcare Research and Quality’s Registries for 
Evaluating Patient Outcomes: A User’s Guide (Agency for Healthcare Research and Quality
2014). 
7.1 Outcome Measures
7.1.1 Primary Outcome Measures
The primary outcome measures for describing contemporary, real-world patterns of patient 
characteristics, clinical disease presentation, therapeutic regimen chosen, and clinical outcomes 
in patients with ND MM, and patients with R/R MM are:
x
Patient demographics, co-morbidities;
x
Diagnostic and presenting symptoms; ECOG performance status, frailty status, 
assessment of myeloma cytogenetic risk, and ISS/R-ISS stage.
x
Myeloma-directed therapeutic regimens, duration of each line of therapy, stem cell 
transplant status.
x
Overall survival, progression status and response to each regimen (per International 
Myeloma Working Group [IMWG]) criteria [Durie BG,et al. 2006]), and time to next 
therapy.
7.1.2 Secondary Outcome Measures
The secondary outcome measures of this study are:
x
Patterns of treatment combinations, sequencing, and retreatment; and clinical outcomes 
for different strategies.
x
Treatment duration and clinical outcomes between continuous treatment and fixed 
duration treatment strategy.
x
Factors associated with treatment initiation, treatment modification, or treatment change 
over time, including whether treatment at relapse was initiated due to biochemical 
progression versus symptomatic progression. 
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x
Health-related quality of life, treatment satisfaction, and HRU.
x
Associations between patient characteristics, clinical disease presentation, therapeutic 
regimen chosen, and clinical outcomes. 
x
All SAEs and non-serious AEs leading to treatment discontinuation (temporary and 
permanent) or drug modification, and second primary malignancies.
7.2 Sample Size Calculations
The study will attempt to enroll approximately 4200 patients globally. The patients included will 
receive various treatment regimens as determined by their healthcare provider. The planned
sample size is intended to provide a sufficient number of patients to characterize treatments in a 
broad population. Enrollment will include approximately 50% ND MM and 50% R/R MM 
patients. Patient numbers will be capped at the site level.
The planned sample size will maintain a reasonable level of estimation precision of statistics 
such as proportions and event rates, as well as some level of statistical power to detect 
differences in studies subgroups. The justifications are given below. 
The Score method for a 95% confidence interval (CI) of a proportion (p) is given by [2np + z^2 
± z * SQRT (z^2 + 4npq)] / 2(n + z^2) (Newcombe 1998), where: 
SQRT = square root n = group size 
p = proportion estimate 
z = standard normal with a 2-tailed probability alpha q = 1 – p 
Table 7-1 provides CIs of estimated proportions for individual subgroups. According to the 
table, a sample size of 270 patients, for a proportion estimate of 0.5 the 95% CI is from 0.441 to 
0.559, and for a proportion estimate of 0.9 the 95% CI is from 0.858 to 0.930. 
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Table 7-1 
Confidence Intervals of Estimated Proportions Based on Sample Size for 
Individual Groups
Proportion
n
LCL
UCL
Proportion
n
LCL
UCL
0.5
100
0.404
0.596
0.5
1000
0.469
0.531
0.6
100
0.502
0.691
0.6
1000
0.569
0.630
0.7
100
0.604
0.781
0.7
1000
0.671
0.728
0.8
100
0.711
0.867
0.8
1000
0.774
0.824
0.9
100
0.826
0.945
0.9
1000
0.880
0.917
0.5
270
0.441
0.559
0.5
4200
0.485
0.515
0.6
270
0.541
0.657
0.6
4200
0.585
0.615
0.7
270
0.643
0.752
0.7
4200
0.686
0.714
0.8
270
0.748
0.843
0.8
4200
0.788
0.812
0.9
270
0.858
0.930
0.9
4200
0.891
0.909
Abbreviations: LCL, lower confidence limit; UCL, upper confidence limit.
Comparisons between proportions of 2 groups are based on the reference proportion (p0) and 
the effect size (i.e., the difference, delta) between the proportions. Table 7-2 provides sample 
sizes obtained from SAS® PROC POWER using Pearson’s chi-squared test with a 2-sided 
critical level alpha of 0.05 and 80% power. 
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Table 7-2
Sample Size Needed to Detect Proportion Differences Between Sub-Groups
p0
delta
n per 
group
p0
delta
n per 
group
p0
delta
n per 
group
50%
2%
9806
50%
8%
609
50%
14%
196
60%
2%
9336
60%
8%
564
60%
14%
176
70%
2%
8080
70%
8%
471
70%
14%
141
80%
2%
6039
80%
8%
329
80%
14%
90
50%
4%
2448
50%
10%
388
50%
16%
149
60%
4%
2311
60%
10%
356
60%
16%
133
70%
4%
1977
70%
10%
294
70%
16%
105
80%
4%
1447
80%
10%
199
80%
16%
64
50%
6%
1086
50%
12%
268
60%
6%
1016
60%
12%
244
70%
6%
859
70%
12%
198
80%
6%
615
80%
12%
131
A formal hypothesis will not be tested in this study.
A sample size of 268 in each of any 2 comparison subgroups will have at least 80% power to 
detect a difference between 2 proportions given the true difference is at least 12%.
7.3 Analysis Sets
All patients included in the study will be considered for analysis. Disposition, demographic, 
baseline data at inclusion, treatment, and outcomes will be summarized by cohorts for all 
patients.
7.4 Subgroups of Interest
Subgroup analysis may be performed using baseline covariates of interest, including:
x
Two distinct cohorts: 1) ND MM and 2) R/R MM
x
Geographic region and country
x
Type of treatment facility – academic versus community
x
Patient attributes (demographics and clinical presentation), such as frail patients, elderly 
patients, and patients with baseline comorbidities of interest (e.g., renal and cardiac 
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function, peripheral neuropathy) 
x
Disease presentation – stage, risk category
x
Treatment choices
Other subgroups may be defined in the SAP. 
7.5Statistical AnalysisMethodology
Since this is a non-interventional, observational study, there can be potential complicated 
confounding between treatment assignments and outcomes, extensive missing data, and 
included patient samples which do not represent real world clinical practices. Therefore, all 
analyses from this study should be considered exploratory in nature. 
Statistical analysis will be performed using SAS® software (SAS Institute, Inc, Cary, North 
Carolina) Version 9.2 or later. 
Population characteristics (including demographics, medical conditions, duration of disease, 
and types of therapy used at study entry) and all relevant primary and secondary outcomes 
measures will be summarized as mean, standard deviation, minimum, maximum, median, 25th
and 75th percentile, and 95% CI of the mean for continuous variables as appropriate; and count 
and proportion with 95% CI of the proportion for categorical data as appropriate. Counts of 
non- missing observations will be included. Event rates (e.g., per 1000 patient-years) and 95% 
CIs for selected outcomes will also be summarized. Descriptive statistics will be used to 
describe treatment patterns, safety assessments, clinical outcomes, economic outcomes, and 
HRQoL self-reported outcomes observed during the study period. Sample representativeness 
will be assessed based on published statistics, if available.
7.5.1 Primary Analysis
Disease presentation and patient characteristics, therapies, and clinical outcomes will be 
summarized descriptively, as explained above for the Primary Outcome Measures 
(Section 7.1.1). In addition, summaries will be performed within selected subgroups 
(Section 7.4), based on clinically relevant cohorts of interest. 
7.5.2 Secondary Analyses
Healthcare resource utilization, treatment satisfaction, and patient self-reported HRQoL 
outcomes will be summarized using descriptive statistics. Associations between (a) MM therapy 
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regimens, disease attributes (e.g., stage and risk category), and patient attributes (e.g., age and 
frailty status); and (b) patient HRQoL and HRU will be assessed through confounding-adjusted 
regression. Changes in HRQoL will be assessed with longitudinal analysis. 
Serious AEs and non-serious AEs leading to treatment discontinuation (temporary and 
permanent) or drug modification, and second primary malignancies will be summarized 
according to the treatment a patient receives at the time of onset, or to the last treatment a 
patient receives within a time interval (to be pre-specified in the SAP) number of days prior to 
the time of onset. Details will be provided in the SAP.
Patterns of treatment combinations, sequencing, repeated therapies, durations, and treatment 
strategies (e.g. continuous versus fixed duration) will be summarized using descriptive statistics 
and within some of the subgroups outlined in Section 7.4. Factors associated with treatment 
initiation, modification, or change at relapse will also be described with descriptive statistics.
To address potential confounding due to the observational nature of the study design, 
multivariable adjustment methods, such as the Cox Proportional Hazards regression models 
(Klein et al. 2003), propensity score based regressions, or propensity score matching techniques 
(Rosenbaum et al. 1983) will be used for the exploratory analyses (Sturmer et al. 2006) of 
clinical outcomes (e.g. OS, progression status and response to each regimen, and time to next 
therapy) and therapy regimens, disease presentation and patient characteristics. This will 
provide adjusted estimates for some of the comparisons of clinical outcomes. Important model 
covariates to minimize bias include number and type of prior therapies, age, sex, race, 
cytogenetic risk, ISS stage, frailty status, and other appropriate factors. Patterns of therapy 
regimens may be considered in the statistical models.
Contemporary practices and treatment dose relationships with outcomes will also be explored. 
7.5.3 Interim Data Summaries
Data summaries will be generated while the study is on-going in order to summarize patient 
characteristics and to generate data for publication, as appropriate.
Interim data summaries and reports, as well as grouped reports for patient organizations and 
other healthcare providers, are planned to understand initial baseline characteristics at inclusion. 
Additional interim analyses will be performed on a biannual basis or as directed by the Steering 
Committee (SC). Details of the interim data summaries will be provided in the SAP.
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7.5.4 Final Analysis
The final analysis will be conducted approximately 5 years after the last patient is enrolled. The 
final report will encompass all planned analyses, including a description of the complete study 
population, as described above and in the SAP.
7.5.5 Study Reports
At least 3 study reports are planned for this study. The initial report is planned after at least 
1000 patients have been included. A second study report is planned to occur after 2000 patients 
are enrolled of which 200 patients have been dosed with ixazomib. Additional interim study 
report(s) may be generated as directed by the SC. The final analysis report will be conducted as 
described in Section 7.5.4. The planned analyses for each study report will be described in the 
SAP.
7.6 Data Quality Control
The handling of data, including data quality assurance, will comply with regulatory guidelines 
(e.g., GPP) and applicable Takeda standards.
To increase the quality and consistency of data in this study, training will be provided for the 
study coordinator and principal healthcare provider.
7.6.1 Data Management
The healthcare provider agrees to maintain accurate eCRFs and patient medical charts as part of 
the case histories.
The principal healthcare provider or study coordinator at each participating site will submit 
study data via a secure internet data capture system maintained by PPD and accessed by the 
PPD project staff.
Clinical data management will be performed in accordance with applicable Takeda standards 
and data cleaning procedures to ensure the integrity of the data, as outlined in the data 
management plan. The members of the SC will have access to summarized statistical data. 
Takeda, the study biostatisticians and epidemiologists, the data analysts, and the project 
coordinators assigned to the study by PPD will have access to individual hospital, clinic, or 
patient-level masked data.
All PPD staff involved in the handling of data has passed the collaborative institutional training 
initiative course on the protection of human research patients and are trained on Food and Drug 
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Administration (FDA) 21 Code of Federal Regulations (CFR), International Council for 
Harmonisation (ICH), GPP, and other guidelines and regulations as described in Section 8.2.
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8
Ethics
8.1 Independent Ethics Committee or Institutional Review Board
Independent ethics committee (IEC)/Independent review board (IRB) must be constituted 
according to the applicable local law and requirements, and only when required. Each site will 
require documentation noting all names and titles of members who comprise the respective 
IEC/IRB. If any member of the IEC/IRB has direct participation in this study, written 
notification regarding his or her abstinence from voting must also be obtained.
When IEC/IRB are required according to the applicable local law and requirements, the 
protocol, informed consent, advertisements to be used for the recruitment of study patients (if
permitted), and any other written information regarding this study to be provided to the patient, 
including questionnaires, must be approved by the IEC/IRB before study onset.
Documentation of all IEC/IRB approvals will be maintained by the site and will be available for 
review by Takeda or its designee.
All IEC/IRB approvals should be signed by the IEC/IRB chairman or designee and must 
identify the IEC/IRB name and address, the study protocol by title or protocol number or both, 
and the date approval or a favorable opinion was granted.
Sites must adhere to the requirements stipulated by their respective IEC/IRB. This may include 
notification to the IEC/IRB regarding any amendments or updates to the documents initially 
submitted, materials intended for viewing by patients, local safety reporting requirements and 
reports, and updates regarding the ongoing review of the healthcare provider.
8.2 Ethical Conduct of the Study
This study will be conducted in accordance with the following guidance:
x
Local ethical guidelines
x
European directives on protection of human patients in research
x
Declaration of Helsinki
x
The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance
Guidelines
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x
Good Pharmacoepidemiology Practice Guidelines
x
Other local, national-specific relevant guidelines, laws, or regulations
Each participating principal healthcare provider will be responsible for assuring Takeda or 
designee that this study is conducted in accordance with all regulations of their hospital.
8.3 Patient Information and Consent
A written informed consent in compliance with local regulatory authority regulations and FDA 
Title 21 CFR Part 50, ICH, GPP, and other local, national-specific relevant guidelines and 
regulations, including authorization to use the patient medical records, shall be obtained from 
each patient before entering the study. An informed consent template may be provided to study 
sites. If the ICF is revised during the course of the study, all active participating patients must 
sign the revised form. There will be a separate ICF for data collection of the pregnant partner 
and the newborn.
Before recruitment and inclusion in the study, each patient will be given a full explanation of 
the study and be allowed to read the approved ICF. The ICF will have the provision of a 
checkbox to be checked off so that the site can contact the patient’s caregiver when needed. 
Once the healthcare provider is assured that the patient understands the implications of 
participating in the study, the patient will be asked to give consent (and assent if applicable) to 
participate in the study by signing the ICF.
The healthcare provider shall retain the signed original ICF(s) and give a copy of the signed 
original form to the patient.
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9
Healthcare Provider’s Obligations
The following administrative items are meant to guide the healthcare provider in the conduct of 
the study but may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the 
IEC/IRB but may not result in protocol amendments.
9.1 Confidentiality
Patient data will not be released without the written permission of the patient, except as 
necessary for monitoring and auditing by Takeda, its designee, or regulatory authorities.
The healthcare provider and all employees and co-workers involved with this non-
interventional, observational study may not disclose or use for any purpose other than 
performance of the study any data, record, or other unpublished, confidential information 
disclosed to those individuals for the purpose of the study. Prior written agreement from Takeda 
or its designee must be obtained for the disclosure of any said confidential information to other 
parties.
9.2 Financial Disclosure and Obligations
Healthcare providers are required to provide financial disclosure information to allow Takeda to 
submit the complete and accurate certification or disclosure statements required under FDA 21 
CFR 54, ICH, and local, national specific relevant guidelines. In addition, the healthcare 
provider must provide to Takeda a commitment to promptly update this information if any 
relevant changes occur during the course of the investigation and for 1 year following the 
completion of the study.
Neither Takeda nor designee is financially responsible for testing or treatment of any medical 
condition that may be detected. In addition, in the absence of specific arrangements, neither 
Takeda nor designee is financially responsible for the treatment of the patient’s disease.
9.3 Study Conduct and Adherence to Protocol
The healthcare provider agrees that the study will be conducted in accordance with the protocol, 
the principles of the declaration of Helsinki and GPP guidelines, and all national, state, and 
local, specific relevant guidelines, laws or regulations.
9.4 Adverse Events and Study Report Requirements
By participating in this non-interventional, observational study, the healthcare provider agrees 
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to submit reports of SAEs according to the timeline and method outlined in the protocol. In 
addition, the healthcare provider agrees to submit reports to the study site IEC/IRB as stipulated 
by his or her respective IEC/IRB.
9.5 Healthcare Provider’s Final Report
Upon completion of the study, the healthcare provider, where applicable, should inform the 
institution; the healthcare provider/institution should provide the IEC/IRB with a summary of 
the study’s outcome and Takeda and regulatory authorities with any reports required.
9.6 Records Retention
PPD will retain study data for a minimum of 3 years following the final publication of study 
findings or discontinuation of the study, or as per local legislation. These documents should be 
retained for a longer period, however, if required by the applicable regulatory requirements or 
by an agreement with Takeda. It is the responsibility of Takeda to inform the healthcare 
provider/institution as to when these documents no longer need to be retained.
9.7 Publications
Takeda owns all data submitted, results, reports, findings, discoveries, and any other 
information collected during this study. Therefore, Takeda may use data from the present study, 
or in the form of a report, with or without comments and with or without analysis, in order to 
submit to government or health authorities where required by law.
PPD will retain masked data to perform analyses for use in scientific publications in support of 
the SC, which has full rights to publication based on data from this study and will have access 
to the data allowing for appropriate scientific review and reporting of study results.
Masked, grouped subsets of these data may be shared with qualified researchers for 
development of specific analyses that are approved by both the SC and Takeda.
The SC is committed to present and publish the results of this study, using only clean and 
quality-controlled data in order to ensure the accuracy of published results. Additional details on 
how publications will be coordinated will be presented in the SC charter.
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10 Study Management
10.1 Monitoring
10.1.1 Steering Committee
Steering Committee of MM experts, selected by Takeda and representing the different 
participating countries, will provide support and advice for this study, and will oversee its 
scientific validity.
Details on the SC responsibilities, on the members of the SC, and on the Executive Committee 
to act on behalf of the SC between regular SC meetings, will be provided in the SC charter.
10.1.2 Monitoring of the Study
The monitor, as a representative of Takeda, has the obligation to follow the study closely. 
Takeda and/or designee will guarantee a sufficient study data monitoring level, as detailed in site 
management plan.
All aspects of the study will be monitored by Takeda, the SC, or their designee, for compliance 
with applicable government regulation with respect to current GPP guidelines and current 
standard operating procedures.
10.1.3 Inspection of Records
Takeda or designee may visit the study site to evaluate study conduct and compliance with 
protocols, standard operating procedures, GPP guidelines, and applicable regulatory 
requirements. The Takeda quality assurance unit, independent of the Clinical Research 
Department, is responsible for determining the need for (and timing of) a study site visit. Each 
healthcare provider must accept that regulatory authorities and Takeda or PPD representatives 
may conduct inspections to verify compliance of the study with GPP guidelines.
Healthcare providers and their relevant personnel must be available during the monitoring visits 
and possible audits or inspections and sufficient time must be devoted to the process.
10.2 Management of Protocol Amendments
10.2.1 Modifications of the Protocol
No changes or amendments to this protocol may be made by the participating healthcare 
providers or administrators or by the sponsor after the protocol has been agreed to and signed by 
both parties unless such change(s) or amendment(s) has/have been fully discussed and agreed 
upon by the participating healthcare providers or administrators and the sponsor.
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No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favorable opinion of a written amendment by the IEC/IRB, except when the change 
involves only logistics or administration. Amendments must be reviewed and approved by 
Takeda or its designee.
10.3 Study Termination
Takeda can decide at any time and for any reason to prematurely stop or to interrupt the study. 
This decision will be communicated in writing to the participating healthcare providers and the
IRB/IECs.
The end of this non-interventional, observational study is defined as the date on which all 
patients in the study have completed at least 5 years of follow-up, are lost to follow-up, or have 
died.
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11 Reference List
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and 
Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical 
trials in oncology. J Natl Cancer Inst. 1993; 85(5):365-76. 
Ailawadhi S, Aldoss IT, Yang D, et al. Outcome disparities in multiple myeloma: a SEER- 
based comparative analysis of ethnic subgroups. Br J Haematol. 2012; 158(1):91-8. 
Alexander DD, Mink PJ, Adami HO, et al. Multiple myeloma: a review of the epidemiologic 
literature. Int J Cancer. 2007; 120:40-61. 
Agency for Healthcare Research and Quality (US). Registries for Evaluating Patient Outcomes 
User's Guide. Last updated: October 2014. Accessed 21 December 2015. Available at: 
http://archive.ahrq.gov/news/events/conference/2011/thorpe/index.html.
Basch E, Abernethy AP, Mullins CD, et al. Recommendations for incorporating patient- 
reported outcomes into clinical comparative effectiveness research in adult oncology. J Clin 
Oncol. 2012; 30(34):4249-55. 
Bharmal M, Payne K, Atkinson MJ, et al. Validation of an abbreviated Treatment Satisfaction 
Questionnaire for Medication (TSQM-9) among patients on antihypertensive medications. 
Health Qual Life Outcomes. 2009; 7:36. 
Charlson ME, Pompei P, Ales KL, MacKenzie CR: A New Method of Classifying Prognostic 
Comorbidity in Longitudinal Studies: Development and Validation. J Chronic Dis. 1987; 
40:373-383. 
Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple 
myeloma. Leukemia 2006; 20(9):1467-73. 
Epstein M; International Society of Pharmacoepidemiology (ISPE). Guidelines for good 
pharmacoepidemiology practices (GPP). Pharmacoepidemiol Drug Saf. 2005; 14(8):589-95. 
Accessed 21 December 2015. Available at: https://www.pharmacoepi.org/about/index.cfm
Escudier B, Szczylik C, Hutson TE, et al. Randomized phase II trial of first-line treatment with 
sorafenib versus interferon Alfa-2a in patients with metastatic renal cell carcinoma. J Clin 
Oncol. 2009; 27(8):1280-9. Erratum in: J Clin Oncol. 2009; 27(13):2305. 
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Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and 
Mortality Worldwide: IARC CancerBase No. 11. Lyon, France: International Agency for 
Research on Cancer. 2013. Accessed 21 October 2015. Available at: http://globocan.iarc.fr
Katz S. Assessing self-maintenance: activities of daily living, mobility, and instrumental 
activities of daily living. J Am Geriatr Soc. 1983; 31(12):721-7. 
Klein JP, Moeschberger ML. Survival Analysis: Techniques for Censored and Truncated Data 
2nd edition. Springer-Verlag, New York, NY, 2003. 
Kvam AK, Fayers P, Hjermstad M, et al. Health-related quality of life assessment in randomised 
controlled trials in multiple myeloma: a critical review of methodology and impact on treatment 
recommendations. Eur J Haematol. 2009; 83(4):279-89. 
Kvam AK, Fayers PM, Wisløff F. Responsiveness and minimal important score differences in 
quality-of-life questionnaires: a comparison of the EORTC QLQ-C30 cancer-specific 
questionnaire to the generic utility questionnaires EQ-5D and 15D in patients with multiple 
myeloma. Eur J Haematol. 2011; 87(4):330-7. 
Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental 
activities of daily living. Gerontologist 1969; 9(3):179-86. 
National Cancer Institute. Surveillance, epidemiology, and end results program, Stat Fact 
Sheets: Myeloma. Accessed 16 November 2015. Available at: 
http://seer.cancer.gov/statfacts/html/mulmy.html
National Comprehensive Cancer Network (NCCN) guidelines version 3.2015 Multiple 
Myeloma. Accessed 16 November 2015. 
Newcombe RG. Two sided confidence intervals for the single proportion: comparison of 
seven methods. Stat Med 1998; 17(8):857-72. 
Pulte D, Jansen L, Castro FA, et al. Trends in survival of multiple myeloma patients in Germany 
and the United States in the first decade of the 21st century. Br J Haematol. 2015; 171:189-96. 
Rosenbaum PR, Rubin DB. The central role of propensity score in observational studies for 
causal effects. Biometrika.1983; 70(1):41-55. 
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Sant M, Minicozzi P, Mounier M, et al. Survival for haematological malignancies in Europe 
between 1997 and 2008 by region and age: results of EUROCARE-5, a population-based study. 
Lancet Oncol. 2014; 15(9): 931-42.
Stead ML, Brown JM, Velikova G, et al. Development of an EORTC questionnaire module to 
be used in health-related quality-of-life assessment for patients with multiple myeloma. Br J 
Haematol. 1999; 104(3):605-11.
European Organization for Research and Treatment of Cancer Study Group on Quality of Life. 
Br J Haematol. 1999; 104(3):605-11.
Sturmer T, Joshi M, Glynn RJ, et al. A review of the application of propensity score methods 
yielded increasing use, advantages in specific settings, but not substantially different estimates 
compared with conventional multivariable models. J Clin Epidemiology 2006; 59(5):437-47.
The European Parliament and the Council of the European Union. Directive 2001/20/EC of the 
European Parliament and of the Council of 04 April 2001 on the approximation of the laws, 
regulations and administrative provisions of the Member States relating to the implementation 
of good clinical practice in the conduct of clinical trials on medicinal products for human use. 
Off J Eur Communities. 2001; L121:34-44.
Wisløff F, Eika S, Hippe E, et al. Measurement of health-related quality of life in multiple 
myeloma. Nordic Myeloma Study Group. Br J Haematol. 1996; 92(3):604-13.
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12 Appendices
Table 12-1
Modified IMWG Diagnosis Criteria for Active (Symptomatic) Myeloma
Diagnosis of Multiple Myeloma Requires:
&ORQDOERQHPDUURZSODVPDFHOOVSHUFHQWRUH[WUDPHGXOODU\SODVPDF\WRPDWKH
presence of a plasma cell tumor), plus at least one of the following two features:
1. Evidence of damage to the body as a result of the plasma cell growth 
damage:
o
Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher 
than the upper limit of normal or >2.75 mmol/L (>11 mg/dL)
o
Renal insufficiency: creatinine clearance <40 mL per min or serum 
creatinine >177 μmol/L (>2 mg/dL)
o
Anaemia: haemoglobin value of >20 g/L below the lower limit of 
normal, or a haemoglobin value <100 g/L
o
Bone lesions: 1 or more osteolytic lesions on skeletal radiography, 
CT, or PET-CT
or
2. Detection of one of the following findings:
o
SHUFHQWSODVPDFHOOVLQWKHERQHPDUURZ
o
Free light chain (FLC) ratio of 100 or more (provided involved FLC 
level is at least 100 mg/L)
o
MRI showing more than one lesion (involving bone or bone marrow)
Source: Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, et al. International Myeloma 
Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538-48.
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Table 12-2
Katz Index of Independence in Activities of Daily Living
Activities
Points (1 or 0)
Independence
(1 Point)
NO supervision, direction or 
personal assistance
Dependence
(0 Points)
WITH supervision, direction, 
personal assistance or total care.
BATHING
Points:____________
(1 POINT) Bathes self completely or 
needs help in bathing only a single 
part of the body such as the back, 
genital area or disabled extremity.
(0 POINTS) Need help with bathing 
more than one part of the body, 
getting in or out of the tub or shower. 
Requires total bathing.
DRESSING
Points:____________
(1 POINT) Get clothes from closets 
and drawers and puts on clothes and 
outer garments complete with 
fasteners. May have help tying 
shoes.
(0 POINTS) Needs help with
dressing self or needs to be 
completely dressed.
TOILETING
Points:____________
(1 POINT) Goes to toilet, gets on 
and off, arranges clothes, cleans 
genital area without help.
(0 POINTS) Needs help transferring 
to the toilet, cleaning self or uses 
bedpan or commode.
TRANSFERRING
Points:____________
(1 POINT) Moves in and out of bed 
or chair unassisted. Mechanical 
transfer aids are acceptable.
(0 POINTS) Needs help in moving 
from bed to chair or requires a 
complete transfer.
CONTINENCE
Points:____________
(1 POINT) Exercises complete 
self-control over urination and 
defecation.
(0 POINTS) Is partially or totally 
incontinent of bowel or bladder.
FEEDING
Points:____________
(1 POINT) Gets food from plate into 
mouth without help. Preparation of 
food may be done by another person.
(0 POINTS) Needs partial or total 
help with feeding or requires 
parenteral feeding.
TOTAL POINTS:________ SCORING: 6 = High (patient independent)
0 = Low (patient very dependent)
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Table 12-3
Lawton – Brody Instrumental Activities of Daily Living Scale
Scoring: For each category, circle the item description that most closely resembles the client’s highest 
functional level (either 0 or 1).
A. Ability to Use Telephone
E. Laundry
1. Operates telephone on own initiative-looks 
up and dials numbers, etc.
2. Dials a few well-known numbers
3. Answers telephone but does not dial
4. Does not use telephone at all
1
1
1
0
1. Does personal laundry completely
2. Launders small items-rinses stockings, etc.
3. All laundry must be done by others
1
1
0
B. Shopping
F. Mode of Transportation
1. Takes care of all shopping needs
independently
2. Shops independently for small purchases
3. Needs to be accompanied on any shopping 
trip
4. Completely unable to shop
1
0
0
0
1. Travels independently on public 
transportation or drives own car
2. Arranges own travel via taxi, but does not
otherwise use public transportation
3. Travels on public transportation when
accompanied by another
4. Travel limited to taxi or automobile with
assistance of another
5. Does not travel at all
1
1
1
0
0
C. Food Preparation
G. Responsibility for Own Medications
1. Plans, prepares and serves adequate meals 
independently
2. Prepares adequate meals if supplied with 
ingredients
3. Heats, serves and prepares meals, or
prepares meals, or prepares meals but does not 
maintain adequate diet
4. Needs to have meals prepared and served
1
0
0
0
1. Is responsible for taking medication in 
correct dosages at correct time
2. Takes responsibility if medication is 
prepared in advance in separate dosage
3. Is not capable of dispensing own 
medication
1
0
0
D. Housekeeping
H. Ability to Handle Finances
1. Maintains house alone or with occasional 
assistance (e.g. "heavy work domestic help")
2. Performs light daily tasks such as dish
washing, bed making
3. Performs light daily tasks but cannot
maintain acceptable level of cleanliness
4. Needs help with all home maintenance tasks
5. Does not participate in any housekeeping 
tasks
1
1
1
1
0
1. Manages financial matters independently
(budgets, writes checks, pays rent, bills, goes 
to bank), collects and keeps track of income
2. Manages day-to-day purchases, but needs 
help with banking, major purchases, etc.
3. Incapable of handling money
1
1
0
Score
Score
Total score_____________________
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A summary score ranges from 0 (low function, dependent) to 8 (high function, independent) for women 
and 0 through 5 for men to avoid potential gender bias.
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Table 12-4 
Charlson Comorbidity Index
Predicts 10-year survival in patients with multiple comorbidities (Charlson et al. 1987). 
Age
<50 years
50-59 years
60-69 years
70-79 years
\HDUV
0
1
2
3
4
Diabetes mellitus
None
Uncomplicated
End-organ damage
0
1
2
Liver disease
None
Mild
Moderate to severe
0
1
3
Malignancy
None
Any leukemia, lymphoma, or localized solid tumor 
Metastatic solid tumor
0
2
6
AIDS
No
Yes
0
6
Moderate to severe CKD
No
Yes
0
2
CHF
No
Yes
0
1
Myocardial infarction
No
Yes
0
1
COPD
No
Yes
0
1
Peripheral vascular disease
No
Yes
0
1
CVA or TIA
No
Yes
0
1
Dementia
No
Yes
0
1
Hemiplegia
No
Yes
0
2
Connective tissue disorder
No
Yes
0
1
Peptic ulcer disease
No
Yes
0
1
Total score________
Note: liver disease, diabetes, and cancer inputs are mutually exclusive (e.g. do not give points for 
both “mild liver disease” and “moderate or severe liver disease”). 
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10-year survival = 0.983^(eCCI x 0.9), where CCI = Charlson Comorbidity Index.
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