Multiple Myeloma Profile in Brazil: A Retrospective Observational Analysis
Conditions: Multiple Myeloma
Sponsor: Takeda




Title: Multiple Myeloma Profile in Brazil: A Retrospective Observational Analysis
NCT Number: NCT03506386
Protocol Approve Date: 12 Feb 2018
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
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Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
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NDMM-5004 
Observational/Non-Interventional 
Study Protocol 
Version 12 Feb 2018 
Page 1 of 30 
Observational/Non-Interventional Study Protocol 
Short title: 
MMyBRave Study 
Title: 
Multiple Myeloma Profile in Brazil: A Retrospective Observational Analysis. 
Study ID: 
NDMM-5004 
Sponsor: 
Takeda Pharma Ltda. 
Rua do Estilo Barroco, 721 
04709-011 – São Paulo – Brasil 
Phone: +55 11 5188 4400  
Study phase:  Medical Affairs, Non-registration Company Sponsored (Observational). 
Date of version of protocol: 12 Feb 2018 
Pro
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NDMM-5004 
Observational/Non-Interventional 
Study Protocol 
 
Version 12 Feb 2018 
 
Page 4 of 30 
 
 
Summary 
 
Observational/Non-Interventional Study 
 
Short Title of Study 
MMyBRave Study   
 
Study sites 
Approximately 25 to 30 experienced hematology/oncology centers from Brazil are expected 
to participate.  
 
Objectives 
Relatively little is known about the incidence and clinical features of multiple myeloma (MM) 
in Brazil. There is a need to clarify demographic and clinical characteristics for this 
population of patients. The aim of this study is to investigate the demographic and clinical 
characteristics, as well as the patterns of care and treatment results, for patients with MM 
treated at selected hematology/oncology centers in Brazil. The primary objective is to 
present a descriptive analysis of demographic and clinical characteristics, as well as of the 
treatment patterns for MM in Brazil. The secondary objectives are to describe the treatment 
duration and the overall survival of patients with MM in Brazil.  
 
Methodology 
This is an observational, non-interventional study, with retrospective evaluation of data and 
no control group. Participation in the study will not influence the usual local standards for 
patient assessment and care. 
 
Number of subjects 
Between 1000 and 1500 patients are expected to participate.  
 
Diagnosis/Disease/Condition and main criteria for inclusion 
Eligible patients will have been diagnosed with active MM between January 1, 2008, and 
December 31, 2016, at any one of the participating centers, regardless of disease stage or 
treatment modality. Diagnosis of MM will have been made as per investigator’s discretion. 
 
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Observational/Non-Interventional 
Study Protocol 
 
Version 12 Feb 2018 
 
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Duration of data collection per patient 
For each patient, data collection will comprise the longest possible period of time since the 
diagnosis of MM (within the eligibility window of time, between January 1, 2008, and 
December 31, 2016) and the cut-off date for data collection (December 31, 2016), unless a 
patient has died or been lost to follow-up before that. The study is planned to last for 
approximately 24 months since its initiation (initiation defined as the initiation visit for the first 
site). 
 
Criteria for evaluation 
Population descriptors 
Data collected for the study will include identification data, demographic data, baseline data 
on MM, additional baseline laboratory data, initial treatment for MM, subsequent treatment 
for MM, and outcome data. Each variable will be represented and defined in the electronic 
Case Report Form to be used in the study. 
Main outcome variables 
The primary outcome variables are related to the primary objective of the study of describing 
the demographic and clinical characteristics, as well as of the treatment patterns. The 
secondary outcome variables, which are related to the secondary objectives, will be the 
treatment duration and the overall survival. Duration of treatment will be defined with respect 
to selected lines or regimens of interest, considering the time elapsed from each treatment 
initiation to discontinuation, and censoring patients who are lost to follow-up before 
discontinuation (patients who died before discontinuation will be considered as events for 
these analyses). Overall survival will be defined as the time elapsed between the date of 
diagnosis until death, with censoring of patients who are alive when last seen or who are lost 
to follow up. For patients enrolled within the last 1-year period of retrospective data 
collection, data will only be analyzed for demographic, clinical characteristics,  patterns and 
duration of treatment. 
Health economics 
No data for health-economic analyses will be collected.   
 
Statistical methods 
Descriptive analyses will include measures of central tendency and dispersion that are 
appropriate to the distribution of each quantitative variable. Normally distributed quantitative 
variables will be described by their range, mean and standard deviation, whereas 
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Observational/Non-Interventional 
Study Protocol 
 
Version 12 Feb 2018 
 
Page 6 of 30 
 
 
quantitative variables with non-normal distribution will be summarized by range, median and 
interquartile range. Qualitative variables will be described by frequencies and their 95% 
confidence interval, when appropriate. Quantitative variables will be compared between 
unpaired groups by t tests or Mann-Whitney tests, according to the underlying distributions 
of the variables. The chi-square test or Fisher’s exact tests will be used to compare groups 
of patients with respect to qualitative variables. Correlations between quantitative variables 
will be explored by correlation coefficients, when appropriate. Linear and logistic regression 
models will be used to explore the association between baseline variables and outcomes 
when adjusting for confounders, if appropriate. The analysis of treatment duration and 
overall survival will be performed with the method of Kaplan and Meier, with multivariate 
analysis by the Cox model to adjust for confounders, when appropriate. Differences between 
groups will be compared using the log rank test. 
 
Given the nature of the study, there is potential for several types of biases related to the 
profile of Study Sites, to patient selection, and to the availability of follow-up information. In 
order to minimize such potential biases, every effort will be made to select Study Sites with 
broad geographic and socioeconomic representation within Brazil. Moreover, investigators 
will be encouraged to enroll all eligible patients, in order to minimize selection bias that may 
result from excluding patients who have been lost to follow-up or who may have had 
irregular follow-up at the Study Site. Importantly, investigators will also provide data on 
patients who have been diagnosed within the eligibility period but are already deceased, with 
the aim of minimizing the risk of overestimating the overall survival of patients from Brazil 
with MM, something that could happen if only surviving patients were analyzed. Finally, 
investigators will be encouraged to provide information on the maximum possible period of 
follow-up for each patient still alive, preferably until the closest possible date to the cut-off 
date of 31 December 2016.  
 
 
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Version 12 Feb 2018 
 
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Table of Contents 
1 
Administrative information................................................................................................ 2 
1.1 
Contacts ................................................................................................................. 2 
1.2 
Approval ................................................................................................................. 3 
2 
Introduction .................................................................................................................... 10 
3 
Study Objectives ............................................................................................................ 11 
3.1 
Primary Objectives ............................................................................................... 12 
3.2 
Secondary Objectives ........................................................................................... 12 
4 
Study Administrative Structure ....................................................................................... 12 
4.1 
Study Sites ........................................................................................................... 12 
4.2 
Sponsor Personnel ............................................................................................... 12 
4.3 
Essential Documents ............................................................................................ 12 
5 
Ethics ............................................................................................................................ 13 
5.1 
Ethical conduct of the Study ................................................................................. 13 
5.2 
Ethics  Review Board and Authorities ................................................................... 13 
6 
Study Design and Plan .................................................................................................. 14 
6.1 
Study Schedule .................................................................................................... 15 
6.2 
Discussion of Study Design .................................................................................. 16 
6.3 
Selection of Study Population ............................................................................... 17 
6.4 
Treatments ........................................................................................................... 17 
7 
Conduct ......................................................................................................................... 18 
8 
Safety Reporting ............................................................................................................ 21 
8.1 
Definitions............................................................................................................. 21 
8.2 
Classification of severity and outcome .................................................................. 22 
8.3 
Collection of Adverse Events, Special Situation Reports and Product Quality 
Issues ................................................................................................................... 23 
8.4    Pharmacovigilance contact details…….…………………........................................24  
9 
Data Quality Control and Assurance .............................................................................. 24 
9.1 
Quality Control ...................................................................................................... 24 
9.2 
Audit from Quality Assurance Unit ........................................................................ 24 
9.3 
Inspection by ERB or Competent Authority ........................................................... 25 
9.4 
Data Management ................................................................................................ 25 
9.4.1 
Data Collection Tools and Flow ............................................................... 25 
10 Statistical Methods and Determination of Sample Size .................................................. 26 
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10.1 Statistical Analysis Plan ........................................................................................ 26 
10.2 Interim Analyses ................................................................................................... 27 
10.3 Handling of missing data ...................................................................................... 27 
10.4 Determination of Sample Size .............................................................................. 28 
11 Reports .......................................................................................................................... 28 
12 Publications ................................................................................................................... 28 
13 Archiving of Study Documentation ................................................................................. 28 
14 References .................................................................................................................... 29 
 
 
 
 
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List of Abbreviations and Definition of Terms 
 
ADR:              Adverse Drug Reaction 
AE:                 Adverse Event 
CRAB:  
HyperCalcemia, Renal failure, Anemia, and Bone lesions 
eCRF:  
Electronic Case Report Form 
FLC:   
Free light chain 
FISH:   
Fluorescent in situ hybridization 
GPP:  
Good Pharmacoepidemiology Practices 
ICD-10: 
International Classification of Diseases, 10th revision 
IMWG:  
International Myeloma Working Group 
ERB:  
Ethics Review Board 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MM: 
 
Multiple myeloma 
MRI:   
Magnetic resonance imaging 
OS: 
 
Overall survival 
SADR:  
Serious Adverse Drug Reaction 
SAE:   
Serious Adverse Events 
SDV:  
Source Data Verification 
SSR:  
Special Situation Report 
WHO-Drug: 
World Health Organization Drug Dictionary 
 
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Chapter 2 Introduction 
 
Multiple myeloma (MM), a multifocal plasma-cell neoplasm characterized by the production 
of monoclonal protein and skeletal destruction [1], is one of the most frequent hematological 
malignancies, accounting for nearly 1% of all cancers and 15% of hematologic neoplasms 
[2, 3]. Until 2014, MM was defined by the presence of at least 10% plasma cells in the bone 
marrow (or a tissue biopsy), serum or urine monoclonal protein, and end-organ damage 
denoted by the CRAB acronym: hypercalcemia, renal failure, anemia, and bone lesions [1]. 
More recently, the International Myeloma Working Group (IMWG) updated the diagnostic 
criteria for MM, adding three biomarkers that can be used to diagnose the disease in 
patients without CRAB features: clonal bone marrow plasma cells ≥60%, serum free light 
chain (FLC) ratio ≥100 (as long as the involved FLC level is ≥100 mg/L), or more than one 
focal lesion on magnetic resonance imaging (MRI) [4]. These changes were implemented in 
order to enable earlier diagnosis and the initiation of effective therapy to prevent end-organ 
damage, and most patients diagnosed through the three biomarkers have what was 
previously termed “smoldering myeloma”. Of note, the spectrum of plasma-cell neoplasms 
also includes several premalignant states (collectively referred to as monoclonal 
gammopathies of undetermined significance) and other malignant disorders, such as primary 
amyloidosis and plasma-cell leukemia.  
 
Treatment for MM has evolved significantly along the past two decades, with the most 
important therapeutic advances being the introduction of high-dose chemotherapy [5], 
bisphosphonates [6], and novel classes of systemic anticancer agents, such as immune 
modulators [7-9], proteasome inhibitors [10-12], and monoclonal antibodies [13, 14]. As a 
result of these improvements, the expected median overall survival (OS) in newly-diagnosed 
MM has increased over the past two decades from around 2 years to approximately 5 years 
among transplantation-ineligible patients treated with current regimens [15-18], and typically 
longer in the transplantation setting [19, 20]. Unfortunately, many of these treatments are not 
available in Brazil or other countries with limited resources, where treatment patterns may 
vary widely and often differ from published guidelines [21]. The extent to which such 
shortcomings in treatment availability affect patient outcomes is currently unknown. 
 
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The epidemiological features of MM have been more extensively investigated in some 
countries and ethnic groups. It is well known, for example, that the incidence of MM is higher 
in blacks than in whites [22], and lower in Asia than in the US and Western Europe, despite 
a progressive increase in this incidence in some Asian countries [23]. Since the clinical 
features of MM may also differ across world regions, it is important to characterize the profile 
of this disease in different geographic locations [24]. In addition to the contribution of 
environmental factors, such as obesity and diet [25, 26], the incidence of MM is likely to be 
influenced by genetic constitution [27]. Relatively little is known about the incidence and 
clinical features of MM in Brazil, a country where relatively free miscegenation of populations 
of Native American, Mediterranean and African ancestry has occurred for several centuries. 
In Brazil, for example, the nationwide incidence of MM is largely unknown, because the 
disease does not appear in the annual estimates provided by the National Cancer Institute 
[28].  
 
Despite this relative paucity of information, previous observational studies have shown the 
feasibility of collecting demographic and clinical data that may help in understanding the 
local characteristics of MM in Brazil, as well as in assessing outcomes and planning 
treatment policies [29-31]. In the latest observational study in Brazil, patients who had the 
diagnosis of MM were accrued as late as December 2007 [31]. Given recent advances in 
diagnosis and therapy for MM, the current observational study will allow for further and more 
contemporary insight about this disease in Brazil, especially with regard to patient 
demographic and clinical features, patterns of care, and treatment results. This will allow for 
continued monitoring of improved outcomes from the use of the more novel interventions, as 
well as to assess existing gaps and unmet needs in comparison with other countries and 
health-care settings. 
 
Chapter 3 Study Objectives 
 
The aim of this study is to investigate the demographic and clinical characteristics, as well as 
the patterns of care and treatment results, for patients with MM treated at selected 
experienced hematology/oncology centers in Brazil and who had their disease diagnosed 
between January 1, 2008, and December 31, 2016.  
 
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3.1 Primary Objectives 
The primary objective is to present a descriptive analysis of demographic and clinical 
characteristics of these patients, as well as of the treatment patterns for MM in Brazil.  
 
3.2 Secondary Objectives 
The secondary objectives are to describe the treatment duration and OS for these patients, 
and to investigate factors potentially associated with OS, such as disease stage and other 
baseline prognostic features. 
 
 
Chapter 4 Study Administrative Structure 
 
4.1 Study Sites 
The study is planned to be conducted in 25 to 30 Study Sites that represent the five 
geographic regions of Brazil. These Study Sites will be experienced hematology/oncology 
centers selected due to their large experience in treating patients with MM and willingness to 
participate in the study. 
 
4.2 Sponsor Personnel 
Takeda Brazil Research Team will keep a record of all relevant sponsor personnel, and 
other medical and drug safety staff responsible for the study.  
 
4.3 Essential Documents 
The following essential documents must be received by Sponsor before the study is initiated 
at a site: 
 Written agreement between Takeda Pharma Ltda. (Takeda Brazil), Principal 
Investigator, Study Site Responsible/Clinic/Hospital and Administrative Intervenient as 
locally applicable. 
 Signed and dated protocol agreement and amendment agreements, if any, with the 
original signature of the Site Responsible. 
 Subject Information Sheet and Informed Consent Form in local language (approved by 
Ethics Review Boards [ERBs]). 
 Written ERB approval according to local regulations. 
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 Authority approval according to local regulations. 
 
Chapter 5 Ethics 
 
Given the observational nature of this study, no impact on the patients is expected, except 
for collection of informed consent to use of their data. Thus, patient care and outcomes are 
not expected to be influenced by study participation. Two different situations are expected 
with regard to patient participation in the study, always considering patients who have been 
diagnosed with MM within the eligibility window for participation: (1) patients who are already 
deceased or have been lost to follow-up; and (2) and patients who are alive and not lost to 
follow-up.  
 
5.1 Ethical conduct of the Study 
This study will be conducted in accordance with the protocol, the current version of the 
Declaration of Helsinki [32], Good Pharmacoepidemiology Practices (GPP) [33], and local 
regulations, with special attention to data protection. Sponsor will ensure that the protocol, 
any amendments and the Subject Information Sheet/Informed Consent Form are submitted 
to the relevant ERBs, according to local requirements. For patients who are already 
deceased or have been lost to follow-up, Study Sites will request from the relevant ERB a 
waiver to obtain informed consent, according to the local regulations. Takeda as the sponsor 
is responsible for meeting the International Conference of Harmonization requirement for 
yearly updates to the ERBs, if applicable. 
 
5.2 Ethics  Review Board and Authorities 
ERB 
According to applicable regulations, the Site Study Responsible will notify or obtain approval 
from the relevant ERB for the protocol, any amendments and the Subject Information 
Sheet/Informed Consent Formsubmit required documents to the ERB, such as: 
 periodic updates on the progress of the study; 
 notification of the end-of-study; 
 a summary of the study results.  
Sponsor will keep an updated list of all submission and approval dates of all documents 
submitted to the ERB. Copies of the documents will be distributed upon request. 
 
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Authorities 
Takeda Brazil Research Team will send required documents to the competent authority 
and/or other national or regional authorities. Takeda Brazil Research Team will keep an 
updated list of submission and approval dates and a copy of all documents submitted.   
 
For patients who are alive and not lost to follow-up, the Site Study Responsible must give 
the patient (and if applicable, legal guardian) oral and written information about the study in a 
form that the patient (and if applicable, legal guardian) can understand, and obtain the 
patient’s (and if applicable, the legal guardian’s) written consent before collection of 
identifiable patient information (hereinafter referred to as personal data). Before consenting, 
the patient (and if applicable, legal guardian) must be left with ample time to consider and to 
pose questions. Since the study is observational, the consent only concerns the data 
collection per se and is not consent to any interventional procedure or treatment. The patient 
must agree that sponsor personnel, their representatives or ERB or competent authority 
personnel (national or other) may require direct access to the patient’s data/personal records 
which were collected, processed and stored in an anonymous form.  The patient must agree 
that his/her data will be processed and stored in an anonymous form for evaluation of this 
study and any later overviews. Data may also be transferred in anonymous form to third 
parties, e.g., other companies or authorities, that may be located in other countries with 
potentially different regulations for data. The patients and, if applicable, legal guardian, have 
the right to withdraw their consent at any time without prejudice. In the Informed Consent 
Form it is stated that if consent is withdrawn, any data collected before withdrawal of consent 
will be kept. The original, signed Informed Consent Forms must be kept on the Site. For 
details, see the Subject Information Sheet and Informed Consent Form. 
 
For patients who are already deceased or have been lost to follow-up, a waiver regarding 
Subject Consent will be obtained from the relevant ERB before study initiation. Informed 
Consent will therefore not be obtained for these patients. On the other hand, data may also 
be transferred in anonymous form to third parties, e.g., other companies or authorities, that 
may be located in other countries with potentially different regulations for data. 
 
Chapter 6 Study Design and Plan 
 
This study is a ‘non-interventional study’ as defined in G-STND-PV-006, G-SOP-MA-005, 
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and the Directive 2001/20/EC [34]; moreover, the study will follow the guidelines for GPP 
[33]. This means that: 
 
The assignment of a patient to a particular therapeutic strategy is not decided in advance 
by the study protocol but falls within current practice; 
 
No additional diagnostic or monitoring procedures shall be applied to the patients; 
 
Epidemiological methods shall be used for the analysis of collected data. 
 
6.1 Study Schedule 
 
Planned start of study: 
 
 
 
May 2018 
Planned collection of first data point: 
 
June 2018 
Planned last patient in: 
 
 
 
May 2019 
Planned collection of the last data point: 
 
August 2019 
Planned completion of the Study Report: 
 
July 2020 
  
The Start of Study is defined as the date of first Site Initiation Visit. The End of study is 
defined as the last data point collected.  
The study report should be signed within 12 months after the collection of the last data point. 
 
The study timeline is represented schematically below: 
 
 
 
Takeda Brazil Research Team will ensure that End-of-Study notification is submitted to the 
concerned authorities and ERB for each site, as locally required. 
 
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Takeda Brazil Research Team and Global Research will ensure that the study plan and 
results are posted on “Clinicaltrials.gov” and, if required by local authorities, on other study 
registries.  
 
Based on upcoming knowledge, Takeda might choose to terminate the study prematurely. In 
such case the study sites, ERBs and authorities will be informed promptly. 
 
6.2 Discussion of Study Design   
This is a multicenter, observational study of patients with MM in Brazil. As an observational 
study, it will retrospectively collect demographic and clinical data for various analyses. 
Treatment and patient evaluation will be left to the discretion of the Study Sites and local 
standards of care, which will not be influenced by the study. Participating investigators from 
each Study Site will collect patient data from institutional charts using a structured electronic 
Case Report Form (eCRF), entering them in a central database for analysis. Despite the 
explicit objective of characterizing patients from Brazil with MM, there is potential for several 
types of biases, including those related to the profile of Study Sites, to patient selection, and 
to the availability of follow-up information. In order to minimize such potential biases, every 
effort will be made to select Study Sites with broad geographic and socioeconomic 
representation. Moreover, investigators will be encouraged to enroll all eligible patients, in 
order to minimize selection bias that may result from excluding patients who have been lost 
to follow-up or who may have had irregular follow-up at the Study Site. Importantly, 
investigators will also provide data on patients who have been diagnosed within the eligibility 
period but are already deceased, with the aim of minimizing the risk of overestimating the 
OS of patients from Brazil with MM, something that could happen if only surviving patients 
were analyzed. This is particularly important, given that data collection will occur potentially 
several years after the actual patient treatment. Finally, investigators will be encouraged to 
provide information on the maximum possible period of follow-up for each patient still alive, 
preferably until the closest possible date to the cut-off date (31 December 2016), with the 
aim of obtaining more precision in long-term OS estimates. To the extent possible, statistical 
analyses will be conducted to adjust for known confounders when comparisons are made 
between groups of patients formed according to selected demographic or clinical 
characteristics.  
 
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6.3 Selection of Study Population 
Study Sites will be selected based on their clinical expertise, expected commitment to 
patient accrual for the study, and geographic location, in order to ensure broad 
representation within the country. A total of 25 to 30 tertiary-care, experienced 
hematology/oncology centers are estimated to participate in the study, and the total number 
of patients expected is 1000 to 1500. The institutional charts from Study Sites, along with 
reports of results from laboratory and imaging studies, will constitute the source documents, 
and data from such charts will be collected using a study-specific eCRF by the Site 
Responsible or their designees. Each patient should be included in the study only once. For 
Study Sites with a system that allows identification of patients with MM electronically, e.g., 
using International Classification of Diseases, 10th revision (ICD-10), this will be the 
preferred method of patient screening for eligibility. For Study Sites without such capabilities, 
patient screening will rely on manual selection of institutional charts or other means. In these 
cases, every effort should be made to identify every possible eligible patient. 
 
In order to be eligible for the study, patients should meet all of the following criteria: 
o Provision of written informed consent, for patients who are alive and not lost to 
follow-up (for patients already deceased or lost follow up, informed consent should 
have been waived by the corresponding ERB); 
o Documented diagnosis of MM by the responsible physician between January 1, 
2008, and December 31, 2016; 
o Adults≥18 years of age; 
o Absence of any plasma-cell disorder other than MM; 
o Absence of any immunoglobulin-related disorder other than MM. 
 
Data erroneously collected from patients who are alive and not lost to follow-up, and for who 
written informed consent is not available, will not be included in or will be deleted from the 
database. 
 
6.4 Treatments 
Treatment and evaluation for patients who are alive and not lost to follow up will be done 
according to local standards of care for each Study Site and will not be influenced by the 
study. 
 
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Chapter 7 Conduct 
 
Data will be collected for each patient from diagnosis of MM (within the period of interest, 
i.e., between January 1, 2008, and December 31, 2016) until the cut-off date for data 
collection, December 31, 2016. Main data collected for the study will include: 
 
Identification data 
 
 
Study ID 
 
Site ID 
 
Patient number  
 
Informed consent obtained/waived and date 
Demographic data 
 
 
Year of birth 
 
Gender 
 
Birthplace 
 
Race 
Baseline data on 
MM 
 
 
Date of inclusion in the study  
 
Date of diagnosis of MM 
 
Criteria utilized for the diagnosis of MM 
 
MM features upon diagnosis 
o At least 10% plasma cells in the bone marrow (or a 
tissue biopsy) 
o Serum or urine monoclonal protein 
o Evidence of end-organ damage (CRAB features) 
o In the absence of CRAB features: 
 
Clonal bone marrow plasma cells ≥60% 
 
Serum FLC ratio ≥100 (as long as the 
involved FLC level is ≥100 mg/L) 
 
More than one focal lesion on magnetic 
resonance imaging (MRI) 
 
Monoclonal component   
 
Bone marrow involvement (% plasma cells)  
 
Date of bone marrow exam  
 
Bone lesions  
 
Extramedullary plasmocytoma(s)  
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 
Cytogenetics 
 
Date of cytogenetics  
 
Type of cytogenetics (FISH or conventional kariotype) 
 
Cytogenetics abnormalities (del 17p, t(4; 14), others) 
 
Date of FISH  
 
Durie-Salmon stage upon diagnosis  
 
International Staging System stage upon diagnosis  
Additional baseline 
laboratory data 
 
 
Hemoglobin level upon diagnosis 
 
Date of hemoglobin level  
 
Albumin level upon diagnosis 
 
Date of albumin level  
 
Creatinine level upon diagnosis  
 
Date of creatinine level  
 
Beta2-microglobulin level upon diagnosis  
 
Date of beta2-microglobulin level  
 
Total serum calcium level upon diagnosis 
 
Date of total serum calcium level  
 
Ionized serum calcium level upon diagnosis 
 
Date of ionized serum calcium level 
 
Lactic dehydrogenase level upon diagnosis  
 
Date of lactic dehydrogenase level  
Initial treatment for 
MM 
 
 
Participation in clinical trial(s) 
 
Systemic treatment given  
 
Date of first cycle  
 
Date of discontinuation 
 
Transplantation planned  
 
Transplantation administered 
 
Transplantation type 
 
Number of transplantations performed 
 
Date of Day zero of each transplantation 
 
Bisphosphonate use with initial treatment 
 
Denosumab use with initial treatment 
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 
Radiotherapy use 
 
Other treatments used 
Subsequent 
treatment for MM 
 
 
Participation in clinical trial(s) 
 
Second systemic treatment given  
 
Date of first cycle of second systemic treatment 
 
Date of discontinuation of second systemic treatment 
 
Third systemic treatment given  
 
Date of first cycle of third systemic treatment 
 
Date of discontinuation of third systemic treatment 
 
Fourth systemic treatment given  
 
Date of first cycle of fourth systemic treatment 
 
Date of discontinuation of fourth systemic treatment 
 
Transplantation planned at any time after initial treatment 
 
Transplantation administered at any time after initial 
treatment 
 
Transplantation type at any time after initial treatment 
 
Number of transplantations performed 
 
Date of Day zero of each transplantation 
 
Bisphosphonate use at any time after initial treatment 
 
Denosumab use at any time after initial treatment 
 
Radiotherapy use at any time after initial treatment 
 
Other treatments used at any time after initial treatment 
Outcome data 
 
 
Vital status on last follow-up visit 
 
Date of last follow-up visit for living patients  
 
Date of death  
General information 
 
Observations  
 
Additional details about variables and types of data fields will be provided in the eCRF. 
 
 
 
 
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Chapter 8 Safety Reporting 
 
8.1 Definitions 
 
Adverse Events  
An adverse event (AE) is any untoward medical occurrence in a subject administered a 
medicinal product and which does not necessarily have to have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, a new disease or worsening in severity or frequency 
of a concomitant disease, temporally associated with the use of a medicinal product, 
whether or not the event is considered causally related to the use of the product.  
Although abnormal laboratory values are typically not considered AEs, the following 
considerations may result in an abnormal laboratory value being considered an AE: 
A laboratory test result that meets the criteria for an SAE 
A laboratory test result that requires the subject/patient to receive specific corrective therapy 
A laboratory abnormality that leads to discontinuation of therapy 
A laboratory abnormality that the health care provider considers to be clinically significant 
 
Serious Adverse Events 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
 
 
Results in death. Note that death is an outcome of an event. The event(s) causing 
death should be recorded. 
 
In the view of the Health care provider, places the subject/patient at immediate risk of 
death (a life threatening event); however, this does not include an event that, had it 
occurred in a more severe form, might have caused death 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Results in a congenital anomaly/birth defect 
 
An SAE may also be any other medically important event that, in the opinion of the 
Health care provider, may jeopardize the subject/patient or may require intervention 
to prevent one of the other outcomes listed in the definition above.  (Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or convulsions occurring at home that do not require an inpatient 
hospitalization.) 
 
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Adverse Drug Reactions 
An adverse drug reaction (ADR) is an AE for which there is at least a reasonable suspicion 
of a causal relationship between an AE and a suspected medicinal product. 
 
Product Quality Issues 
A Product Quality Issue (PQI) refers to defects related to the safety, identity, strength, 
quality, or purity of the product or with the physical characteristics, packaging, labeling, or 
design of the product. 
 
Special Situation Reports  
A Special Situation Report (SSR) includes any of the following events: 
 
Pregnancy: Any case in which a pregnancy patient is exposed to a Takeda Product 
or in which a female patient or female partner of a male patient becomes pregnant 
following treatment with Takeda Product. Exposure is considered either through 
maternal exposure or via semen following paternal exposure. 
 
Breastfeeding: Infant exposure from breast milk 
 
Overdose: All information of any accidental or intentional overdose 
 
Drug abuse, misuse or medication error: All information on medicinal product abuse, 
misuse or medication error (potential or actual) 
 
Suspected transmission of an infectious agent: All information on a suspected (in the 
sense of confirmed or potential) transmission of an infectious agent by a medicinal 
product.  
 
Lack of efficacy of Takeda Product 
 
Occupational exposure 
 
Use outside the terms of the marketing authorization, also known as “off-label” 
 
Use of falsified medicinal product 
 
A SSR should be reported even if there is no associated AE. 
 
 
8.2 Classifications of severity and outcome 
 
 
Severity 
Severity is a clinical observation and describes the intensity of the event. 
 
Mild: Transient symptoms, no interference with the subject’s daily activities 
 
Moderate: Marked symptoms, moderate interference with the subject’s daily activities 
 
Severe: Considerable interference with the subject’s daily activities. 
 
 
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Outcome  
 Fatal: The subject died due to the event. If the subject died due to other circumstances 
than the event the outcome should be stated as ‘Not recovered’ or ‘Recovering’ 
 Recovered/Resolved: The subject has fully recovered from the event or the condition has 
returned to the level observed at baseline. 
 Recovering/Resolving: The event is improving but the subject is still not fully recovered 
 Not Recovered/Not Resolved: The event is ongoing at the time of reporting and the 
subject has still not recovered. 
 Recovered with Sequelae/Resolved with Sequelae: As a result of the event, the subject 
suffered persistent and significant disability/incapacity (e.g. became blind, deaf or 
paralysed). 
 
Unknown: If Outcome is not known or not reported. 
 
8.3 Collection of Adverse Events, Special Situation Reports and Product 
Quality Issues 
 
Collection and notifying of Adverse Events, Special Situation Reports and Product Quality 
Issues to Takeda Pharmacovigilance 
SAEs, AEs, ADRs, SSRs and PQIs in the medical record/source data that are part of the 
study objectives or endpoints 
Events/issues which are part of the study objectives or endpoints will be systematically 
identified and collected from medical records or other applicable source records, and 
summarized as part of any interim analysis and in the final study report. Such events do not 
need to be notified as individual reports to Takeda Pharmacovigilance.  
SAEs, AEs, SSRs and PQIs in the medical records/other applicable source data that are not 
part of the study objectives and endpoints 
Events/Issues which are not part of the study objectives and endpoints will not be abstracted 
or collected from medical records/ source records. 
SAEs, AEs, ADRs, SSRs and PQIs spontaneously reported to the investigator(s) or research 
team  
If during the conduct of the study the investigator(s) or a member of the research team is 
spontaneously informed by a healthcare professional or patient of an SAE, AE, ADR, SSR or 
PQI where the event/issue pertains to a Takeda product (or unbranded generic), such 
information should be forwarded to their local Takeda Pharmacovigilance department within 
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9.3 Inspection by ERB or Competent Authority 
Representatives from the ERB or Competent Authority may in rare cases wish to inspect the 
study on site. Upon receiving notification of such inspection, the Study Site Responsible 
must immediately contact Takeda Brazil Research Team and must make the records 
available as requested. The Inspector must be reminded up front that consent to access 
personal data has been waived from the patients in this study who were already deceased or 
lost to follow-up upon study initiation. 
 
9.4 Data Management 
Data Management will be carried out according to a Data Management Plan, which will be 
written and approved before the design of the study database is finalized. The data 
management provider should approve all data formats before the data collection tools are 
made available to the sites. If the written informed consent of a patient is known not to be 
available in spite of being required, data for this patient are not entered into or are deleted 
from the database. If a patient is erroneously included in the study more than once, only the 
data relating to the first inclusion will be kept in the database and made available for 
analysis. Data from later inclusions will be transferred to the first dataset when relevant, i.e., 
if collected within the data collection time frame.  
 
The current Standard Coding Instructions for coding of medical history, concomitant illness 
(Medical Dictionary for Regulatory Activities, MedDRA), concomitant medication (World 
Health Organization Drug Dictionary, WHO-Drug) and adverse events/reactions (MedDRA) 
must be followed. 
 
The subjects will be identified in the database only by Study ID, Site ID, patient number, year 
of birth, and gender. These identifiers will be captured and kept in the database for analysis.  
 
9.4.1 Data Collection Tools and Flow 
All data collected for the purpose of this study will be entered, stored and retrieved with the 
use of an electronic eCRF specifically designed for the study. The system will comprise a 
web-based interface for use by investigators, and a central database for storage and 
retrieval. The database will be physically stored at a data center designated by Takeda or 
the appointed vendor, with appropriate measures for back-up of data and stability of the 
system. The system will ensure patient confidentiality, as well as security and confidentiality 
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of the data for the duration of the study. Each Site Responsible or designee will receive from 
Takeda or the appointed vendor a login name and a password, and will hold the 
responsibility for data entry into the system. Investigators will be able to access the database 
for the whole duration of the study. The database will contain single-choice, multiple-choice 
and open-field options for the entry of patient demographic and clinical data. Moreover, the 
system will allow for automatic data checks and the negation of queries based on 
programming logic.  
 
Given that source documents (institutional charts and reports of results from laboratory and 
imaging studies) will not necessarily be available for auditing in the future, the Site 
Responsible will ensure that data collection for the study be done in a proper way and by 
individuals who are under their direct supervision. Moreover, the Site Responsible will 
ensure data are attributable, accurate, complete, contemporaneous, and consistent. The 
Site Responsible must sign off the complete data set for each subject, confirming the 
collected data.  Serious and non-serious AE collected according section 8 should be signed 
off separately, in a specific form, by a study team member previously trained. 
 
10 Statistical Methods and Determination of Sample Size 
 
The statistical analyses will be performed by Takeda or an appointed vendor. This section 
describes the statistical analyses as foreseen at the time of planning the study, and further 
details are provided in the Statistical Analysis Plan. Any known deviations from the planned 
analyses, the reason for such deviations and all alternative or additional statistical analyses 
that may be performed as well as the final statistical analysis will be described in a revised 
Statistical Analysis Plan before completion of data collection. All later deviations or 
alterations will be summarised in the Final Study Report. 
 
10.1 Statistical Analysis Plan 
This study is observational, and epidemiological methods will be employed for data analysis. 
Before analysis, all data entered in the database will be assessed for completeness and 
coherence. Descriptive analyses will be performed of all collected data, except data 
collected only for the purpose of data cleaning, i.e., all data listed in section 7. Descriptive 
analyses will include measures of central tendency and dispersion that are appropriate to the 
distribution of each variable. As a general rule, normally distributed quantitative variables will 
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be described by their range, mean and standard deviation, whereas quantitative variables 
with non-normal distribution will be summarized by range, median and interquartile range. 
Qualitative variables will be described by frequencies and their 95% confidence interval. 
Quantitative variables will be compared between unpaired groups by t tests or Mann-
Whitney tests, according to the underlying distributions of the variables. The chi-square test 
or Fisher’s exact tests will be used to compare groups of patients with respect to qualitative 
variables. Correlations between quantitative variables will be explored by correlation 
coefficients, when appropriate. Linear and logistic regression models will be used to explore 
the association between baseline variables and outcomes when adjusting for confounders, if 
appropriate. The analysis of treatment duration and OS will be performed with the method of 
Kaplan and Meier, with multivariate analysis by the Cox model to adjust for confounders, 
when appropriate. Differences between groups will be compared using the log rank test. OS 
will be defined as the time elapsed between the date of diagnosis until death, with censoring 
of patients who are alive when last seen or who are lost to follow up. Duration of treatment 
will be defined with respect to selected lines or regimens of interest, considering the time 
elapsed from their initiation to their discontinuation, and censoring patients who are lost to 
follow-up before discontinuation (patients who die before discontinuation will be considered 
as events for these analyses). The role of transplantation will be investigated using landmark 
analysis, in order to control for guaranteed-survival bias. No subgroup analyses are planned 
regarding Study Site, but other subgroup analyses may be performed to assess outcomes in 
selected patients subsets defined by baseline characteristics. 
 
Site Responsible and their designees should make every effort to ensure that data collection 
is as complete as possible. Techniques for imputation of missing data will not be employed. 
For further details of the statistical analyses, please refer to the Statistical Analysis Plan. 
 
10.2 Interim Analyses 
A partial analysis is planned for this study when around 50% of the forecasted number of 
patients is enrolled. 
 
10.3 Handling of missing data 
Given that all analyses are descriptive in nature, no imputation of missing data will be 
performed, except when detailed in the SAP. 
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10.4 Determination of Sample Size 
Given the observational nature of this study, its main objective of describing demographic 
and clinical features of patients with MM, and the lack of specific hypothesis regarding 
treatment effects or other objective measures, the sample size for the study is not 
determined on the basis of statistical assumptions, but rather on the expected number of 
patients that will be feasibly accrued by the Study Sites. Considering the number and 
expected commitment of Study Sites, and a recruitment period of 24 months, between 1000 
and 1500 patients are expected to be enrolled.  
 
Chapter 11 Reports 
 
A Non-Interventional Study Report based on the results obtained will be prepared and 
submitted to Global Research for distribution. The Final Study Report should be available 
within 1 year from collection of the last data point, and the Study Sites will be informed about 
the results when the report is finalized. 
 
Chapter 12 Publications 
 
Takeda aims to have the results of this study published. Takeda has the right to use the data 
and results for regulatory purposes and for internal presentation within the company and to 
partners.  
 
Chapter 13 Archiving of Study Documentation 
 
During the course of the study the Site Responsible must as a minimum file the essential 
documents (Section 4.4), the protocol, any amendments, the list of participating subjects, the 
written informed consents, the eCRFs and the progress reports in the Study Site File. After 
final database lock, the Site Responsible must as a minimum store the list of participating 
subjects and the signed Informed Consent Forms on site for 25 years. The Site Responsible 
should store additional study documentation for a longer period of time as required by any 
local regulations and/or hospital requirement. 
 
 
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Chapter 14 References 
 
1. 
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related disorders: a report of the International Myeloma Working Group. Br J Haematol 2003; 
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2. 
Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin 2017; 67: 7-
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Blade J, Cibeira MT, Fernandez de Larrea C, Rosinol L. Multiple myeloma. Ann 
Oncol 2010; 21 Suppl 7: vii313-319. 
4. 
Rajkumar SV, Dimopoulos MA, Palumbo A et al. International Myeloma Working 
Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014; 15: e538-
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Attal M, Harousseau JL, Stoppa AM et al. A prospective, randomized trial of 
autologous bone marrow transplantation and chemotherapy in multiple myeloma. 
Intergroupe Francais du Myelome. N Engl J Med 1996; 335: 91-97. 
6. 
Djulbegovic B, Wheatley K, Ross J et al. Bisphosphonates in multiple myeloma. 
Cochrane Database Syst Rev 2002; CD003188. 
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Singhal S, Mehta J, Desikan R et al. Antitumor activity of thalidomide in refractory 
multiple myeloma. N Engl J Med 1999; 341: 1565-1571. 
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Richardson PG, Schlossman RL, Weller E et al. Immunomodulatory drug CC-5013 
overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. 
Blood 2002; 100: 3063-3067. 
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Schey SA, Fields P, Bartlett JB et al. Phase I study of an immunomodulatory 
thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J Clin Oncol 2004; 
22: 3269-3276. 
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Richardson PG, Barlogie B, Berenson J et al. A phase 2 study of bortezomib in 
relapsed, refractory myeloma. N Engl J Med 2003; 348: 2609-2617. 
11. 
O'Connor OA, Stewart AK, Vallone M et al. A phase 1 dose escalation study of the 
safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in 
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Kumar SK, Bensinger WI, Zimmerman TM et al. Phase 1 study of weekly dosing with 
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Lonial S, Dimopoulos M, Palumbo A et al. Elotuzumab Therapy for Relapsed or 
Refractory Multiple Myeloma. N Engl J Med 2015; 373: 621-631. 
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Palumbo A, Chanan-Khan A, Weisel K et al. Daratumumab, Bortezomib, and 
Dexamethasone for Multiple Myeloma. N Engl J Med 2016; 375: 754-766. 
15. 
Benboubker L, Dimopoulos MA, Dispenzieri A et al. Lenalidomide and 
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Facon T, Mary JY, Hulin C et al. Melphalan and prednisone plus thalidomide versus 
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Palumbo A, Bringhen S, Caravita T et al. Oral melphalan and prednisone 
chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly 
patients with multiple myeloma: randomised controlled trial. Lancet 2006; 367: 825-831. 
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18. 
Palumbo A, Hajek R, Delforge M et al. Continuous lenalidomide treatment for newly 
diagnosed multiple myeloma. N Engl J Med 2012; 366: 1759-1769. 
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Attal M, Lauwers-Cances V, Marit G et al. Lenalidomide maintenance after stem-cell 
transplantation for multiple myeloma. N Engl J Med 2012; 366: 1782-1791. 
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Palumbo A, Cavallo F, Gay F et al. Autologous transplantation and maintenance 
therapy in multiple myeloma. N Engl J Med 2014; 371: 895-905. 
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Kerbauy LN, Parmar S, Kutner JM et al. Hematological approaches to multiple 
myeloma: trends from a Brazilian subset of hematologists. A cross-sectional study. Sao 
Paulo Med J 2016; 134: 335-341. 
22. 
Benjamin M, Reddy S, Brawley OW. Myeloma and race: a review of the literature. 
Cancer Metastasis Rev 2003; 22: 87-93. 
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Huang SY, Yao M, Tang JL et al. Epidemiology of multiple myeloma in Taiwan: 
increasing incidence for the past 25 years and higher prevalence of extramedullary myeloma 
in patients younger than 55 years. Cancer 2007; 110: 896-905. 
24. 
Kim K, Lee JH, Kim JS et al. Clinical profiles of multiple myeloma in Asia-An Asian 
Myeloma Network study. Am J Hematol 2014; 89: 751-756. 
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Friedman GD, Herrinton LJ. Obesity and multiple myeloma. Cancer Causes Control 
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26. 
Brown LM, Gridley G, Pottern LM et al. Diet and nutrition as risk factors for multiple 
myeloma among blacks and whites in the United States. Cancer Causes Control 2001; 12: 
117-125. 
27. 
Morgan GJ, Johnson DC, Weinhold N et al. Inherited genetic susceptibility to multiple 
myeloma. Leukemia 2014; 28: 518-524. 
28. 
Brasil. Ministério da Saúde. Instituto Nacional de Câncer. Estimativa 2016: Incidência 
de Câncer no Brasil. Available at http://www.inca.gov.br/estimativa/2016/ (Accessed 
15/06/2017). In. 
29. 
Hungria VT, Maiolino A, Martinez G, et al. South American Multiple Myeloma Study: 
Epidemiological and clinical characteristics of 751 patients. Haematologica 2005; 90 (s1): 
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