Clinical and Sociodemographic Characterization of Multiple Myeloma Patients With Symptomatic Relapse and/or Refractory Disease in Spain
Conditions: Multiple Myeloma
Sponsor: Takeda




Title: CLINICAL AND SOCIODEMOGRAPHIC CHARACTERIZATION OF MULTIPLE 
MYELOMA PATIENTS WITH SYMPTOMATIC RELAPSE AND/OR REFRACTORY DISEASE 
IN SPAIN
NCT Number: NCT03188536
Protocol Approve Date: 31/03/2017
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 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.

CharisMMa Study
Observational Study Protocol 
Final Version   V1.0 
Page 1 of 53 
31/03/2017 
Observational Study Protocol 
Short title: 
Title: 
CharisMMa Study 
“CLINICAL AND SOCIODEMOGRAPHIC CHARACTERIZATION 
OF MULTIPLE MYELOMA PATIENTS WITH SYMPTOMATIC 
RELAPSE AND/OR REFRACTORY DISEASE IN SPAIN” 
Study code: TAK-MMR-2017-01 
Sponsor: 
Takeda Farmacéutica España S.A. 
C/ Alsasua, 20. 28023 – Madrid 
(Spain) Telephone: + 34 91 714 99 00 
Fax: 
+ 34 91 657 49 07 
Type of study: Observational Cross-Sectional Epidemiological Study 
Protocol version: Final V 1.0 
Date of protocol version: 31/03/2017 

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CharisMMa Study 
 
Observational Study Protocol 
 
Final Version   V1.0  
Page 7 of 53 
31/03/2017 
 
Calendar 
First patient first visit:  
 
 
 
June 2017 
Last patient last visit:  
 
 
 
May 2018 
Date of database close-out:  
 
 
June 2018 
Planned date for final study report:                        September 2018 
 
Funding source 
Takeda Farmacéutica España S.A. 
 
Participating sites 
The study will be performed in a total of 30 sites in Spain. 
 
Objectives 
Primary objective: 
 
To characterize the multiple myeloma (MM) patient with symptomatic relapse and/or 
refractory disease in Spain. 
 Secondary objectives: 
 
To evaluate how the clinical and sociodemographic findings of the MM patient with 
symptomatic relapse and/or refractory disease can affect the selection of treatment 
after the latest symptomatic relapse and/or refractory episode. 
 
To identify any new relevant variables that are not currently collected in clinical 
records and that could influence in the disease management at relapse 
 
To evaluate the quality of life of the MM patient with symptomatic relapse and/or 
refractory disease using the EORTC QLQ-C30 and EORTC QLQ-MY20 
questionnaires.  
 
To validate the psychometric properties of the Spanish translation of the EORTC 
QLQ-MY20 in MM patients with symptomatic relapse and/or refractory disease. 
 
To identify and quantify the use of healthcare resources since the latest symptomatic 
relapse and/or refractory episode.  
 
Methodology 
 
Observational, cross-sectional, multicenter study of 350 patients with test-retest analysis in 
40 patients. This study will not interfere in any way with the clinical and therapeutic 
management of the patient that will be conducted solely according to the criteria of the 
physician in line with standard clinical practice.  
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CharisMMa Study 
 
Observational Study Protocol 
 
Final Version   V1.0  
Page 8 of 53 
31/03/2017 
 
A total of 30 investigators from the Hematology Departments of 30 public hospitals 
throughout Spain will consecutively include a total of 350 patients attending a routine visit at 
their office and who meet the inclusion criteria, during a recruitment period of 12 months.  
The study will be performed in the context of a single visit, in which the patient will be invited 
to participate in the study, the protocol will be explained, and if the patient wishes to 
participate, he/she will be asked to sign an informed consent form.  
Study data will be collected in a single visit. Questionnaires will be completed by the patient 
and entered into the electronic case report form (eCRF) by the principal investigator 
(PI).Other data will be collected from the clinical records, examinations and tests performed 
according to the criteria of the physician and in line with standard clinical practice. For the 
test-retest analysis to validate the EORTC QLQ-MY20 questionnaire, a second 
questionnaire (EORTC QLQ-C30 and EORTC QLQ-MY20) will be provided to 40 patients to 
complete at home, 7 days after the visit, which should be returned to the site by post, in a 
pre-paid envelope. These 40 patients will be the first 2 patients enrolled in each site, until a 
total of 40 patients have been reached.  
Sociodemographic and clinical data corresponding to the time of the visit will be collected, 
along with health resource use since the latest symptomatic relapse and/or refractory 
episode. Clinical data from before the study visit will also be collected from the patients’ 
clinical records: diagnosis, prior relapses, and data on the latest symptomatic relapse and/or 
refractory episode.   
 
Number of patients 
A sample size of 350 patients has been calculated on the basis of an estimation of a 
proportion in case of maximum indetermination (proportion of 50%) with a 95% confidence 
interval and a precision of 5%, in the MM population with symptomatic relapse and/or 
refractory disease, approximately 3,4807 patients in Spain in 2016. This represents the 
inclusion of at least 10% of the population with relapsing or refractory MM (RRMM). 
According to previous publications on questionnaire validation in other languages22, 20 
patients are sufficient for a test-retest analysis. Taking into account the possibility of 
questionnaires with invalid data and those that might not be returned after 7 days, we 
decided to ask 40 patients to complete the second questionnaire.  
 
 
 
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CharisMMa Study 
 
Observational Study Protocol 
 
Final Version   V1.0  
Page 9 of 53 
31/03/2017 
 
Study disease and main inclusion criteria 
Multiple myeloma. 
Adult patients with a diagnosis of MM who have received at least one previous treatment line 
and have experienced symptomatic relapse and/or refractory disease in the previous 6 
months, who are still in follow-up at the time of the study visit.  
 
Data collection 
All study data will be collected in a specifically designed electronic CRF. 
Only 40 of the study patients will be needed to send a second questionnaire (EORTC QLQ-
C30 and QLQ-MY20) by post, in a pre-paid envelope. 
 
Study variables 
Sociodemographic variables in the study visit 
 
Age (years) 
 
Sex 
 
BMI (kg/m2) 
 
Area of residence 
 
Educational level 
 
Cohabitation  
 
Degree of dependence 
 
Working situation 
 
Need for financial assistance 
 
Healthy habits: 
o Physical activity 
o Smoking habit (yes/no) 
o Alcohol use (yes/no) 
 
Clinical variables on diagnosis and during previous relapses 
 
Age at diagnosis 
 
Type of MM: heavy chain, light chain, Bence-Jones protein 
 
ISS disease stage at time of diagnosis  
 
CRAB signs at time of diagnosis 
 
Cytogenetic abnormalities at time of diagnosis  
 
Risk according to cytogenetic profile at diagnosis 
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CharisMMa Study 
 
Observational Study Protocol 
 
Final Version   V1.0  
Page 10 of 53 
31/03/2017 
 
 
Previous relapses (before the latest): Number of previous treatment lines; Number of 
previous relapses; Treatments used (therapeutic group); Refractory to treatment 
prescribed? (yes/no); Response time 
 
Transplant ECOG on diagnosis 
 
Clinical variables at latest symptomatic relapse and/or refractory episode 
 
Date of latest symptomatic relapse and/or refractory episode. 
 
ISS disease stage at latest symptomatic relapse and/or refractory episode. 
 
CRAB signs at latest symptomatic relapse and/or refractory episode. 
 
Other clinical variables in latest symptomatic relapse and/or refractory episode 
(number and site of plasmacytoma, diffuse osteopenia, fractures, neurological 
symptoms, infections, paraprotein levels, free light chain levels in serum/urine, and 
LDH). 
 
Cytogenetic abnormalities at latest symptomatic relapse and/or refractory episode  
 
Risk according to cytogenetic profile at relapse  
 
Treatment started after latest symptomatic relapse and/or refractory episode (line 
number, treatment [therapeutic group]) 
 
Concomitant diseases at time of latest symptomatic relapse and/or refractory 
episode. 
 
Variables in the study visit 
 
Current treatment (therapeutic group) 
 
Oral vs IV 
 
Distance between home and hospital (km) 
 
Type of transport used 
 
Hospital visits required for latest treatment (number of visits/month) 
 
Cost of transport to the hospital to receive treatment (Euros/month) 
 
Use of healthcare resources since the latest symptomatic relapse and/or refractory 
episode 
 
Evaluation of quality of life 
 
EORTC QLQ-C30 questionnaire  
 
 EORTC QLQ-MY20 questionnaire 
 
 
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CharisMMa Study 
 
Observational Study Protocol 
 
Final Version   V1.0  
Page 11 of 53 
31/03/2017 
 
Statistical methods 
A descriptive analysis of all variables will be used to characterize the profile of MM patients 
with symptomatic relapse and/or refractory episode: 
- 
For qualitative variables, the number and percentage of patients in each category will 
be used. 
- 
For quantitative variables, central tendency and dispersion measurements will be 
presented. 
To evaluate which clinical and sociodemographic findings are related with the selection of 
treatment after symptomatic relapse, the relationship between the sociodemographic 
variables collected during the study visit and the clinical variables collected at the time of the 
latest symptomatic relapse and/or refractory episode will be evaluated. 
 
For qualitative variables, numbers and percentages of the variable categories for 
each treatment will be presented. To evaluate the relationship with treatment, Chi-
squared or Fisher’s exact tests will be performed and the resulting p-value will be 
presented. When the relationship with treatment has statistical significance a post-
hoc analysis will be performed. 
 
For quantitative variables, central tendency and dispersion descriptions will be 
presented for each treatment. To evaluate the relationship with treatment, ANOVA or 
non-parametric Kruskal-Wallis tests will be performed and the resulting p-value will 
be presented. When the relationship with treatment has statistical significance a post-
hoc analysis will be performed. 
 
To evaluate psychometric properties of the Spanish version of the EORTC QLQ-MY20 
questionnaire, a feasibility, reliability and validity analysis will be performed.  
 
 
 
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CharisMMa Study 
 
Observational Study Protocol 
 
Final Version   V1.0  
Page 12 of 53 
31/03/2017 
 
Table of contents 
1 
Administrative details ....................................................................................................... 2 
1.1 
Contacts ................................................................................................................. 2 
2 
Introduction .................................................................................................................... 15 
3 
Study objectives ............................................................................................................ 16 
3.1 
Primary objective .................................................................................................. 16 
3.2 
Secondary objectives ........................................................................................... 16 
4 
Administrative study structure ........................................................................................ 17 
4.1 
Coordinators Investigators study .......................................................................... 17 
4.2 
Participating sites ................................................................................................. 17 
4.3 
Sponsor personnel: .............................................................................................. 17 
4.4 
Contract research organization (CRO) .................................................................. 18 
4.5 
Essential documents ............................................................................................ 18 
5 
Ethics ............................................................................................................................ 18 
5.1 
Risk-benefit evaluation ......................................................................................... 18 
5.2 
Ethical aspects of the study .................................................................................. 19 
5.3 
Confidentiality and data protection ........................................................................ 19 
5.4 
Clinical Research Ethics Committee and Health Authorities ................................. 20 
5.5 
Patient information and informed consent ............................................................. 21 
5.6 
Protocol amendments ........................................................................................... 22 
6 
Study design .................................................................................................................. 22 
6.1 
Study timing .......................................................................................................... 23 
6.2 
Rationale for study design .................................................................................... 24 
6.3 
Selection of the study population .......................................................................... 24 
6.4 
Treatments ........................................................................................................... 25 
7 
Study procedures .......................................................................................................... 25 
7.1 
Study variables ..................................................................................................... 25 
7.1.1 
Sociodemographic variables ................................................................... 25 
7.1.2 
Clinical variables on diagnosis and during previous relapses .................. 27 
7.1.3 
Clinical variables at latest symptomatic relapse and/or refractory episode28 
7.1.4 
Variables in the study visit ....................................................................... 30 
7.2 
Data source .......................................................................................................... 31 
7.3 
QoL questionnaires .............................................................................................. 31 
8 
Pharmacovigilance ........................................................................................................ 33 
8.1 
Definitions............................................................................................................. 33 
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CharisMMa Study 
 
Observational Study Protocol 
 
Final Version   V1.0  
Page 13 of 53 
31/03/2017 
 
8.2 
Classification ........................................................................................................ 34 
8.3 
Notification of adverse events and adverse reactions ........................................... 35 
9 
Data quality control and assurance ................................................................................ 37 
9.1 
Quality control ...................................................................................................... 37 
9.2 
Quality Assurance Unit Audits .............................................................................. 37 
9.3 
CREC and health authority inspections ................................................................ 37 
9.4 
Data management ................................................................................................ 37 
9.4.1 
Tools for data collection and flow ............................................................ 38 
10 Statistical methods and calculation of the sample size ................................................... 38 
10.1 Statistical analysis plan......................................................................................... 38 
10.2 Interim analyses ................................................................................................... 40 
10.3 Sample size calculation ........................................................................................ 40 
11 Reports .......................................................................................................................... 41 
12 Publication of results ...................................................................................................... 41 
13 Study documentation archives ....................................................................................... 41 
14 Funding ......................................................................................................................... 41 
15 References .................................................................................................................... 42 
 
ANNEX: 
1. Sample patient information sheet .................................................................................... 45 
2. Informed consent form .................................................................................................... 48 
3. Case report form ............................................................................................................. 49 
4. Coordinating Investigator Commitment (sample) ............................................................. 49 
5. Participating Investigator Commitment (sample) ............................................................. 49 
6. Appoval of Clinical research ethics committee ................................................................ 49 
7. Financial agreement ........................................................................................................ 49 
8. Adverse reaction report form (sample) ............................................................................ 50 
9. EORTC QLQ-MY20 questionnaire, MM module .............................................................. 51 
10. EORTC QLQ-C30 questionnaire ................................................................................... 51 
11. ECOG scale .................................................................................................................. 52 
12. Principal investigators by site: ....................................................................................... 53 
 
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CharisMMa Study 
 
Observational Study Protocol 
 
Final Version   V1.0  
Page 14 of 53 
31/03/2017 
 
Abbreviations 
 
AE: 
 
Adverse event 
AR:  
 
Adverse reaction 
BMI: 
 
Body mass index 
CRAB: 
Calcium, Renal insufficiency, Anemia or Bone lesions  
CREC:  
Clinical research ethics committee  
CRF:  
Case report form 
CRO:  
Contract research organization 
ECOG: 
Eastern Cooperative Oncology Group 
EORTC: 
European Organization for Research and Treatment of Cancer 
FISH:  
Fluorescent in situ hybridization  
GCP:  
Good clinical practice 
GPP:  
Good pharmacoepidemiological practice 
IC: 
 
Informed consent 
ICH: 
 
International Conference on Harmonization 
ISS 
International Staging System 
LDH:  
Lactate dehydrogenase 
LOC:  
Local Operating Company 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MM: 
 
Multiple myeloma 
PI:  
 
Principal investigator 
PIS: 
 
Patient information sheet 
QoL:   
Quality of life 
RRMM: 
Relapsing/refractory multiple myeloma 
SAE:  
Serious adverse event 
SAR:   
Serious adverse reaction 
 
 
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CharisMMa Study 
 
Observational Study Protocol 
 
Final Version   V1.0  
Page 15 of 53 
31/03/2017 
 
2 
Introduction 
Multiple myeloma (MM) is a proliferative clonal disorder of cytogenetically heterogeneous 
plasma cells.4 It is the second most common blood cancer5 and accounts for more than 10% 
of all blood cancers, and 1% of all cancers.6 Incidence in Europe is estimated at 4.5-
6.0/100,000 cases/year.6 An estimated 6,080 patients with a diagnosis of MM were being 
treated in Spain in 2016, including patients receiving first-line treatment who are transplant 
candidates, non-candidates, and patients on second, third and fourth-line treatment.7  
MM is biologically complex disease, and, as a consequence, the clinical profile is variable.9 
Symptomatic MM is characterized by signs of systemic damage, summarized under the 
acronym CRAB (Calcium, Renal insufficiency, Anemia or Bone lesions).8 Another 
characteristic of the disease is immune system damage that can lead to severe infections.9  
MM is a recurrent, progressive disease that is still incurable today. Almost all MM patients, 
including those who maintain prolonged response to first-line treatment, end up relapsing, 
and some of them also develop resistance to the drugs administered.10 Moreover, the 
disease becomes more and more aggressive with each relapse, and remissions achieved 
with successive lines of treatment tend to become shorter.11 The recurrent or refractory 
patient, then, is still a clinical and therapeutic challenge.10, 12  
In recent years there has been a significant improvement, thanks to the development of new 
drugs with different mechanisms of action13 leading to a considerable change in the MM 
treatment paradigm, particularly for relapsing or refractory patients who until now had few 
therapeutic options.12, 14 
Nevertheless, the therapeutic management of these patients does not depend uniquely on 
the availability of new drugs: the characteristics of the patient, the clinical aspects of the 
disease14-16, and other considerations, such as comorbidities and sociodemographic 
conditions also play a part.14, 17-19 Various patient risk factors, such as age, general status, 
and the individual's history of toxicity to previous treatments will also influence the treatment 
strategy.20 Various studies have demonstrated the significant impact of comorbidities on 
mortality18 and disease progress in each patient.9,19 
Since this disease is long term in many cases, it is equally important to evaluate the patient's 
opinion of the impact on their quality of life of not only the disease, but also the side effects 
of the treatments. This information may help the physician select the most appropriate 
treatment in order to achieve better therapeutic adherence and satisfaction. The EORTC 
QLQ-C30 questionnaire20 and the QLQ-MY20 module21 are self-administered tools 
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commonly used in the evaluation of quality of life in MM patients. The Spanish version of this 
tool has been validated, with the exception of its psychometric properties.21, 22 
An accurate epidemiological characterization of this population may be useful for the 
appropriate assignation of resources, as shown in a recent study performed on a French 
national register of hematological diseases.23 No registries or published data are available 
on the therapeutic management of the MM patient according to their characteristics, and 
data on results obtained in standard clinical practice are scarce. No epidemiological studies 
have been performed in MM patients that might contribute to defining if treatments 
administered are adjusted to the patient’s characteristics and how these affect their quality of 
life (QoL). Taking into account that relapsed or refractory MM patients in particular may be 
exposed to long cycles of treatment with drugs with a not inconsiderable risk of adverse 
events, the outcome of which may depend on previously administered treatments, the 
hematologist's choice of therapeutic strategy is crucial, and must be made in consideration 
of the patient as a whole, and not only in terms of their disease. 
Accordingly, then, the aim of this study is to characterize the profile of the relapsed and/or 
refractory MM patient in Spain. The secondary objective, among others, is to evaluate the 
feasibility, reliability and validity of the Spanish version of the EORTC QLQ-MY20 for this 
type of patient.  
The study findings will foreseeably generate new useful hypotheses for expanding the 
knowledge base of MM and the course and impact of the disease according to patient 
profile. 
3 
Study objectives 
3.1 Primary objective 
 
To characterize the multiple myeloma (MM) patient with symptomatic relapse and/or 
refractory disease in Spain.  
3.2 Secondary objectives 
 
To evaluate how the clinical and sociodemographic findings of the MM patient with 
symptomatic relapse and/or refractory disease can affect the selection of treatment 
after the latest symptomatic relapse and/or refractory episode. 
 
To identify any new relevant variables that are not currently collected in clinical 
records and that could influence in the disease management at relapse To evaluate 
the quality of life of the MM patient with symptomatic relapse and/or refractory 
disease using the EORTC QLQ-C30 and EORTC QLQ-MY20 questionnaires.   
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

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CharisMMa Study 
 
Observational Study Protocol 
 
Final Version   V1.0  
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The procedures required for study conduct involve only the collection of certain 
sociodemographic data or data from the clinical records, and completion of the EORTC 
QLQ-C30 and EORTC QLQ-MY20 quality of life questionnaires during a routine clinical visit.  
The information obtained from this study will be clinical and epidemiological in nature, and is 
expected to add to the knowledge of characteristics of the relapsed or refractory MM patient 
in Spain, and may contribute in the future to the improvement in the knowledge of the 
disease management. 
5.2 
Ethical aspects of the study 
The study will be performed in accordance with the provisions of the protocol, the 
Declaration of Helsinki (Fortaleza, 2013), Good Pharmacoepidemiological Practice (GPP) 
guidelines, and locally applicable regulations, primarily Order SAS 3470/2009.  
If, during this study, new information emerges that would affect its conduct, the Sponsor will 
prepare the necessary amendments to the protocol, the PIS, or both, and these will be sent 
to the corresponding CREC for their evaluation and opinion according to applicable 
regulations.  
Takeda Farmacéutica España S.A., as the sponsor, is responsible for complying with ICH 
requirements for annual update reports to the CREC.  
 
5.3 
Confidentiality and data protection 
Data collected for the study will be handled in concordance with the provisions of the 
European Directive 95/46/EC and its transposition to the Personal Data Protection Act 
15/1999, 13 December 1999 (and subsequent regulations) and Act 41/2002, 14 November 
2002, regulating patient autonomy and rights and obligations in the area of clinical 
information and documentation. 
Each patient included in the study will be assigned a participation code, so that no identifying 
personal data (name, surnames, clinical record number, date of birth, etc.) will appear in the 
electronic CRF of the study. 
The principal investigator (PI) is responsible for maintaining an updated record (code list) of 
all subjects, linking their personal data with the code assigned for this study, for the follow-up 
of subjects and study coordination. This record will be kept in the strictest confidence in the 
study site, and only the investigator and other members of the study team will have full 
knowledge of the subject's identity. 
The patient will be informed, as stated in the PIS, that the Sponsor personnel or 
representative, the study monitor, and/or the responsible authorities may require direct 
access to the patients’ clinical records and data for auditing purposes. 
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5.4 
Clinical Research Ethics Committee and Health Authorities  
Clinical Research Ethics Committee 
The Sponsor, by way of the study CRO, 
 
will submit the required documents to the corresponding CREC for their evaluation and 
approval.  
They are also responsible for sending additional documents such as: 
 
Periodical updates on study progress.  
 
Notification of study completion.  
 
Summary of study results.  
Takeda Farmacéutica España S.A., by way of the CRO, will maintain an updated list of all 
submissions and approval dates of the documents presented to the CREC and will provide a 
copy of these documents to the individual responsible for the study in the site.  
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Health Authorities 
The Sponsor, by way of the study CRO, will submit the documents required for processing 
the study to the responsible health authorities. Takeda Farmacéutica España S.A. by way of 
the CRO, will maintain an updated list of submissions and approval dates and a copy of all 
documents submitted.   
 
5.5 
Patient information and informed consent 
The investigator must provide all necessary oral and written information on the study to each 
patient, so that the patient can understand the scope of the study and give, if they wish, their 
written consent to participate. Before making the decision, the patient must be given 
sufficient time to discuss any question they may have and for those questions to be 
resolved.  
Given the observational nature of the study, consent refers to access to significant clinical 
records data and completion of the QoL questionnaires, and not to any clinical, diagnostic or 
therapeutic procedure.  
All participating patients have the right to withdraw their previously given consent any time 
they want, with no need to provide explanations and without affecting their medical care in 
any way.  
If new information should emerge during the course of the study that might require a change 
in the PIS, this will be provided as soon as possible to the patients so that they can give their 
consent again, if they agree. 
The rights, safety and wellbeing of the study patients are the most important aspects to be 
taken into account and must prevail over the interests of science and society. 
The study personnel involved in the conduct of this observational study will be qualified in 
terms of education, training and experience for performing their corresponding tasks. 
 
 
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5.6 Protocol amendments 
The study will be conducted as described in the approved protocol.  
If a substantial amendment is made that requires a significant modification of any aspect of 
the protocol and/or PIS:  
 
The PIS and IC must be revised and sent to the CREC for review and approval.  
 
The revised form must be used to obtain consent from patients who are already 
included in the study if they are affected by the amendment, and  
 
The new form must be used to obtain consent from new patients before inclusion. 
Any significant deviation must be documented in the CRD and reported to the CREC. 
 
6 
Study design 
Observational cross-sectional multicenter study. This study will not interfere in any way with 
the clinical and therapeutic management of the patient that will be conducted solely 
according to the criteria of the physician in line with standard clinical practice.  
A total of 30 investigators from the Hematology Departments of 30 public hospitals 
throughout Spain will consecutively include a total of 350 patients attending a routine visit at 
their office and who meet the inclusion criteria, during a recruitment period of approximately 
12 months.  
In the study visit, the patient will be invited to participate in the study, the protocol will be 
explained, and if they wish to participate, they will be asked to sign an informed consent 
form.  
During the study visit, sociodemographic and clinical data and the QoL questionnaires20,21 
corresponding to the time of the visit and clinical data from before the study visit (diagnosis, 
previous relapses before the latest, and data on the latest symptomatic relapse and/or 
refractory episode) will be collected from the patients’ clinical records, examinations and 
tests performed according to the criteria of the physician and in line with standard clinical 
practice. 
Data will also be collected for the evaluation of the use of healthcare resources after the 
latest relapse and/or refractory episode (number of hospital admissions, number of days 
admitted, visits to the emergency room, visits to specialists, etc.). 
For the test-retest analysis to validate the EORTC QLQ-MY20 questionnaire, a second 
questionnaire (EORTC QLQ-C30 and EORTC QLQ-MY20) will be provided to 40 patients to 
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31/03/2017 
 
complete at home, 7 days after the visit, which should be returned to the site by post, in a 
pre-paid envelope. These 40 patients will be the first 2 patients enrolled in each site, until a 
total of 40 patients have been reached. 
Data will be recorded in an electronic CRF.  
 
6.1 Study timing 
First patient first visit:  
 
 
 
Jun 2017 
Last patient last visit:  
 
 
 
May 2018 
Date of database close-out:  
 
 
June 2018 
Planned date for final study report: 
September 2018 
 
 
2017 
2018 
 
Jan 
Feb 
Mar 
Apr 
May 
Jun 
Jul 
Aug 
Sept 
Oct 
Nov 
Dec 
Jan 
Feb 
Mar 
Apr 
May 
Jun 
Jul 
Aug 
Sep 
Oct 
Nov 
Dec 
CREC 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study start 
 
 
X X X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recruitment 
 
 
 
 
 
X X X X X X X X X X 
X X  
 
 
 
 
 
 
Single visit 
 
 
 
 
 
X X X X X X X X X X 
X X  
 
 
 
 
 
 
End 
of 
study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
Database 
closure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Analysis 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
X 
 
 
 
 
 
Final report 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Publication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Takeda Farmacéutica España S.A., by way of the CRO, will duly notify the corresponding 
CREC of study completion, in accordance with the local regulations applicable to the study.  
Takeda Farmacéutica España S.A. guarantees that the results will be published on the 
“clinicaltrials.gov” website and any other website required by applicable local regulations.  
Takeda may, in the light of future findings, decide to suspend the study prematurely. In this 
case, the corresponding CREC and health authorities will be duly notified.  
 
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6.2 
Rationale for study design   
The cross-sectional design is appropriate for describing the characteristics of a population 
with respect to a series of variables at a certain point in time. 
 
The aim of this study is to evaluate the characteristics of symptomatic relapsed or refractory 
MM patients, so the cross-sectional design of this study is considered appropriate. The 
selected design is considered appropriate for validating the questionnaire which will be 
performed as a complementary activity. 
Cross-sectional studies are optimal for estimating prevalence, for simultaneously studying 
multiple resulting variables and for identifying potential associations between certain factors 
and the outcome of interest. Thus, these studies are useful for generating hypotheses that 
can be subsequently evaluated in other studies with more appropriate designs, since 
transversal studies are limited by being unable to establish a cause-effect relationship or 
sequentiality. However, they have the advantage of avoiding the patient attrition associated 
with follow-up studies.24, 25  
Information provided by cross-sectional studies is generally used for developing and 
planning population health strategies.24  
The evaluation of the psychometric properties of the EORTC QLQ-MY20 is designed 
according to the method used for original evaluation of the instrument and in subsequent 
evaluations of translated versions.21, 22, 26  
 
6.3 
Selection of the study population 
Inclusion Criteria 
 
Adults (≥ 18 years) of both sexes. 
 
Patients with a diagnosis of MM who have received at least one previous treatment 
line.  
 
Patients who have experienced symptomatic relapse and/or refractory disease in the 
6 months before the study. 
 
Patients who continue in follow-up at the time of the study visit. 
 
Patients currently treated in the site who have clinical records available.  
 
Patients capable of understanding and completing the questions in the EORTC QLQ-
C30, and EORTC QLQ-MY20 questionnaires. 
 
 
 
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Exclusion criteria 
 
Patients who do not agree to participate in the study or who do not give written 
informed consent.  
 
6.4 
Treatments 
Not applicable. This is an observational study and no medications will be administered. 
 
7 
Study procedures 
7.1 Study variables 
7.1.1 Sociodemographic variables 
 
Current age (years) 
 
Sex: 
o Female 
o Male  
 
BMI (kg/m2) 
 
Area of residence 
o Rural 
o Urban 
 
Educational level: 
o Illiterate 
o No studies (can only read/write) 
o Primary studies 
o Secondary studies 
o University studies 
 
Cohabitation:  
o Lives alone 
o Lives with the family 
o Lives alone with help from a caregiver 
 
Daily 
 
2-3 times/week 
 
Permanent 
 
Night-time  
 
Degree of dependence: 
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o Independent 
o Dependent Grade I: individual requires help to perform Activities of Daily 
Living (ADL) at least once a day or needs intermittent support for personal 
autonomy. 
o Dependent Grade II: individual needs help to perform ADLs 2 or 3 times a day 
or needs extensive support for personal autonomy, but does not need the 
permanent support of a caregiver. 
o Dependent Grade III: individual needs help to perform ADLs several times a 
day, and due to total loss of physical, mental, intellectual or sensory 
autonomy, needs the indispensable and continuous support of another 
person, or needs generalized support for personal autonomy. 
 
Working situation: 
o Unemployed 
o In active employment 
 
Full time 
 
Part time 
o Temporarily/permanently disabled 
o Retired  
o Student 
o Other 
 
Need for financial assistance 
o Yes 
o No 
 
Healthy habits 
 
Physical activity 
 
High [jogging, walking or climbing briskly up a hill; fast cycling; 
aerobics; fast swimming; competitive sports and games (e.g., 
traditional games, football, volleyball, hockey, basketball); strenuous 
work with a spade or ditch-digging; lifting heavy weights (> 20 kg)] 
 
Moderate/low [fast walking; dancing; gardening; domestic tasks; 
hunting and traditional foraging; active participation in games and 
sports with children and walking pets; general construction work 
(e.g., roofing, painting, etc.); lifting moderate weights (< 20 kg)] 
 
Inactive 
o Current smoking habit (Yes/No) 
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o Alcohol use (yes/no) 
 
7.1.2 Clinical variables on diagnosis and during previous relapses 
 
Age at diagnosis 
 
MM type: heavy chain, light chain, Bence-Jones protein 
 
ISS disease stage at time of diagnosis: 
o Stage I. Low risk. β2-Microglobulin < 3.5 mg/L and albumin ≥ 3.5 g/dL 
o Stage II. Not ISS stage I or III 
o Stage III. High risk. β2-Microglobulin ≥ 5.5 mg/L 
 
CRAB signs at time of diagnosis: 
o Increased blood calcium (serum Ca >0.25 mmol/L (>1 mg/dL) upper limit of 
normal or >2.75 mmol/L (>11 mg/dL).  
o Renal failure: creatinine clearance < 40 mL/min or serum creatinine > 117 
μmol/L (>2 mg/dL). 
o Anemia: reduction of Hb > 2 g/dL below lower limit of normal or Hb < 10 g/dL. 
o Bone lesions: one or more osteolytic lesion on standard radiograph, CT or 
PET-CT. 
 
Cytogenetic abnormalities at time of diagnosis: 
o t (4;14) 
o t (11;14) 
o t (14;16) 
o t (14;20) 
o t (6;14) 
o Trisomies 
o d (17p) 
o g (1q) 
o Others (specify) 
 
Risk according to cytogenetic profile at diagnosis15, 27 
o Standard risk: Trisomies,  t (11;14); t (6;14) 
o Intermediate risk: t (4;14), g (1q) 
o High risk: d (17p), t (14;16), t (14;20) 
 
Previous relapses (before the latest):  
o Number of treatment lines  
o Number of previous relapses  
o For each line of treatment: 
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31/03/2017 
 
 
Treatment(s) used (therapeutic group) 
 
Oral or IV 
 
Refractory to prescribed treatment? (Yes/No)  
 
Response time  
 
Received a stem cell transplant? (Yes/No) (Auto/Alo) 
 
ECOG on diagnosis (ECOG 0 – ECOG 5) 
 
7.1.3 Clinical variables at latest symptomatic relapse and/or refractory 
episode 
 
Date of latest symptomatic relapse and/or refractory episode. 
 
ISS disease stage at latest symptomatic relapse and/or refractory episode:  
o Stage I. Low risk. β2-Microglobulin < 3.5 mg/L and albumin ≥ 3.5 g/dL 
o Stage II. Not ISS stage I or III 
o Stage III. High risk. β2-Microglobulin ≥ 5.5 mg/L 
 
CRAB signs at latest symptomatic relapse and/or refractory episode: 
o Increased blood calcium: serum Ca >0.25 mmol/L (>1 mg/dL) upper limit of 
normal or >2.75 mmol/L (>11 mg/dL).  
o Renal failure: creatinine clearance < 40 mL/min or serum creatinine > 117 
μmol/L (>2 mg/dL). 
o Anemia: reduction of Hb > 2 g/dL below lower limit of normal or Hb <10 g/dL. 
o Bone lesions: one or more osteolytic lesion on standard radiograph, CT or 
PET-CT. 
 
Other clinical variables at latest symptomatic relapse and/or refractory episode: 
o Plasmacytomas 
 
Medullary (Yes/No, Number) 
 
Extramedullary (Yes/No, Number) 
o Diffuse osteopenia  
 
Yes (Grade) 
 
No 
o Fractures 
 
Yes (Number, Site [Specify]) 
 
No 
 
o Neurological symptoms 
 
Yes 
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o MM related? 
 
Yes 
 
No 
 
No  
o Infections 
 Yes 
 No 
o LDH (IU/L) 
o Paraprotein levels (g/L) (serum and urine)  
o Free light chain levels (g/L) (serum and urine) 
 
Concomitant diseases at time of latest symptomatic relapse and/or refractory 
episode: 
o 
Diabetes 
o 
Neuropathy 
o 
Nephropathy 
o 
Chronic obstructive pulmonary disease 
o 
Cardiovascular disease 
 
Yes (Type [Specify]) 
 
No 
 
o 
Liver failure 
o 
Psychiatric and/or neurological disorders: 
 
Depression/depressive symptoms 
 
Anxiety 
 
Others (specify) 
o 
Other secondary disorders (specify) 
 
Cytogenetic abnormalities at latest relapse and/or refractory episode: 
o t (4;14) 
o t (11;14)  
o t (14;16) 
o t (14;20) 
o t (6;14) 
o Trisomies 
o d (17p) 
o g (1q) 
o Others (specify) 
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 
Risk according to cytogenetic profile at latest symptomatic relapse and/or 
refractory episode15, 27 
o Standard risk: Trisomies,  t (11;14); t (6;14) 
o Intermediate risk: t (4;14), g (1q) 
o High risk: d (17p), t (14;16), t (14;20) 
 
Treatment started after latest symptomatic relapse and/or refractory episode: 
o Treatment line (number) 
o Treatment(s) (therapeutic group) 
 
7.1.4 
Variables in the study visit 
Current treatment 
 
Currently receiving treatment (Yes/No) 
 Costs related with healthcare resources 
 
Distance between home and hospital (km) 
 
Type of transport used: 
o Own vehicle 
o Public transport 
o Ambulance 
 
Hospital visits required for latest treatment (no. visits/month)  
 
Cost of transport to the hospital to receive treatment (Euros/month) 
 
Use of healthcare resources since the latest symptomatic relapse and/or refractory 
episode 
o Where was the patient admitted? 
 
 
UCI  Number of UCI admissions  
 
Hospital  Number of hospital admissions 
 
Emergency room  Number of visits to the emergency room 
 
Others 
o 
Number of days admitted  
o 
Number of visits to specialists 
 
Which specialist? 
 
Oncologist Number of visits 
 
Hematologist Number of visits 
 
GPNumber of visits 
 
PhychologistNumber of visits  
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 
Other. Specify, and number of visits 
o 
Need of some test? 
 
Yes 
 
TAC  Number of tests 
 
RM  Number of tests 
 
XRay Number of tests 
 
Others. Specify, and number of tests 
 
No 
 
For each number of visit: the patient comes to the hospital:  
o Alone 
o Accompanied (Is the accompanying person in active employment? [Yes/No]) 
Evaluation of quality of life 
 
EORTC QLQ-C30 questionnaire20  
 
EORTC QLQ-MY20 questionnaire21.  
 
7.2 Data source 
All study information will be collected during the single study visit, including 
sociodemographic and clinical data corresponding to the time of the visit and clinical data 
from before the study visit (diagnosis, relapses/refractory episodes) taken from the clinical 
records, examinations and tests performed according to the criteria of the physician and in 
line with standard clinical practice. 
This information will be recorded in an electronic CRF created for the purpose. 
 
7.3 QoL questionnaires 
 
EORTC QLQ-C30 questionnaire20. Self-administered QoL questionnaire 
designed for use in cancer patients.  The time frame is the previous week. This 
questionnaire consists of 30 items grouped in 5 functional scales (physical, role, 
emotional, cognitive, and social). The score for each item ranges from 1 to 4 (1: 
not at all, 2: a little, 3: quite a bit, 4: very much), except for items 29 and 30 that 
are scored from 1 to 7 (1: worst possible, 7: excellent). The scores obtained are 
standardized to 0-100. A higher score in the function scale indicates a better 
functional status.  A higher score in the global health scale indicates a better 
global health status. A higher score in the symptom score indicates a higher level 
of problems due to symptoms.  
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 
EORTC 
QLQ-MY20 
questionnaire.21,22 
Self-administered 
questionnaire 
specifically for MM patients. It should be completed alongside the EORTC QLQ-
C30 questionnaire.20 It consists of 20 questions grouped in 3 scales. For each 
item, the lowest possible response is “not at all” and the greatest possible 
response is “very much”, with a score ranging from 1 to 4, respectively. Linear 
transformation will be used to convert the final score to a scale of 0-100. 
 
 
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8 
Pharmacovigilance 
8.1 Definitions 
Adverse event (AE) 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a 
causal relationship with that treatment.  
An adverse event (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 product, whether or not related to that medicinal product. 
Adverse reaction (AR)  
Any response to a medication that is harmful and unintended, occurring at doses that are 
normally applied in humans for the prophylaxis, diagnosis or treatment of diseases, or the 
restoration, correction or modification of physiological functions. Unlike an AE, in the case of 
an AR, there is a suspected causal relationship between the study medication and that AR. 
This term also includes all the harmful clinical consequences derived from dependence, 
abuse and inappropriate use of medications, including those caused by use not included in 
the approved conditions and those caused by medication errors.  
Special Situation Report (SSR)  
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 
 
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Product Complaint 
A Product Quality Issue 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. 
 
8.2 Classification 
Seriousness 
A serious adverse event (SAE) or a serious adverse reaction (SAR) is any AE or AR that 
at any dose:  
 
results in death. 
 
is life-threatening, understood as any reaction or event in which the patient was at 
risk of death at the time of the event; it does not refer to an event which might have 
caused death if it had been more severe. 
 
requires hospitalization of the patient or prolongs existing hospitalization. 
 
results in persistent or significant disability/incapacity, or  
 
causes a congenital abnormality or defect. 
For reporting purposes, any suspected AEs or ARs that are considered significant from a 
medical point of view will also be handled as serious, even if they do not meet the above-
mentioned criteria, including significant medical events that require intervention to prevent 
one of the above-mentioned outcomes (e.g., intensive treatment for bronchospasm, blood 
dyscrasias, or convulsions, even if they do not result in hospitalization, or development of 
dependence or abuse). Additionally, all suspected transmission of an infectious agent via a 
medication will also be reported as serious. 
 
Severity 
 
Mild: Transient symptoms that do not interfere with the patient's activities of daily living.  
 
Moderate: More pronounced symptoms that interfere moderately with the patient's 
activities of daily living.  
 
Severe: Symptoms that interfere considerably with the patient's activities of daily living. 
 
Causality  
 
Related: There is a reasonable temporal relationship between the administration of the 
medication and the appearance of the event, and no obvious alternative explanation is 
available.  
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 
Unrelated: There is at least one alternative explanations for the event that occurred; for 
example, the event may be explained by any of the following: a) the patient's clinical 
condition (according to clinical history, disease progression, indication), b) concomitant 
medication for which this event is listed in the product information, or c) the event 
occurred before administration of the medication.  
 
Outcome  
 
Fatal: The patient dies as a result of the event. If the patient dies from causes other than 
the event, the outcome should be classified as “not recovered” or “recovering”.  
 
Recovered/Resolved: The patient has recovered completely from the event or his/her 
condition has returned to the same situation as before the event.  
 
Recovering/resolving: The event is improving but the patient has still not fully recovered.  
 
Not recovered/Not resolved: The event persists at the time of the communication and the 
patient has not yet recovered.  
 
Recovered with sequelae/Resolved with sequelae: As a result of the event, the patient 
has persistent and significant disability or incapacity (e.g., blindness, deafness or 
paralysis).  
 
Unknown: The outcome is unknown. 
 
8.3 
Notification of adverse events and adverse reactions 
In this study, standard clinical practice will not be modified and no investigational drugs will 
be used. Investigators will be responsible for complying with Order SAS/3470/2009, 16 
December 2009, which publishes the regulations on post-approval observational studies in 
medications for human use, in which it is stated that suspected serious adverse reactions 
that are detected must be reported to the point of contact designated by the responsible 
authorities in the matter of pharmacovigilance of the autonomous community in which the 
healthcare professional who reports the case is practicing, within a maximum period of 15 
calendar days after becoming aware of the suspected adverse reaction, including a 
reference to the study code. 
Investigators in the participating sites must send to Takeda adverse reaction reports or any 
other relevant safety information/special situation associated with any product marketed by 
Takeda, whether initial or follow-up, severe or mild, using the Takeda adverse reaction 
notification form (see ANNEX 8) within 24 hours of becoming aware of the event, using the 
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electronic mail address farmacovigilancia@takeda.com. Product complaint information 
should also be reported to the same mailbox. 
 
If the sponsor requires additional information for the evaluation of an adverse reaction, and 
sends queries to the investigator of the corresponding site, the information provided by that 
investigator will be considered as follow-up information on the adverse reaction and thus 
must be reported to the point of contact designated by the responsible authorities in the 
matter of pharmacovigilance in the autonomous community in which the healthcare 
professional who reports the case is practicing, at the same time as to the sponsor who 
requested the information, including a reference to the initially reported adverse reaction. 
This notification to the responsible authorities and to the sponsor will be made as described 
in this section. 
If the CRO becomes aware of any adverse reaction or any other relevant safety information 
associated with any product marketed by Takeda, the CRO will be obliged to report it to the 
pharmacovigilance department of Takeda within 24 hours of receipt, using the Takeda 
adverse 
reaction 
notification 
form 
and 
the 
electronic 
mail 
address 
farmacovigilancia@takeda.  
 
Every three months, Takeda Pharmacovigilance will send the CRO a list of adverse events 
received for reconciliation purposes. The CRO will then send any discrepancies to Takeda 
Pharmacovigilance for resolution. 
 
Only one AE/AR should be reported in each form. A diagnosis should be established, if 
possible. If this is impossible, the investigator should record each sign or symptom in 
separate forms. The seriousness, intensity, and causality of the AE/AR should be evaluated.  
Notifications regarding Takeda medications will be followed up until outcome by the 
Pharmacovigilance Unit, in accordance with the established protocols and the applicable 
regulations, for which the collaboration of the investigator will be required. 
All safety data collected or reported to Takeda during the conduct of the study according to 
the standard procedure for marketed drugs must be included in the final study report. 
  
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9 
Data quality control and assurance 
9.1 
Quality control 
All data will be verified, and electronic database entries will be reviewed against the source 
documents and a quality control check will be performed to ensure that the investigator 
complies with the protocol and applicable regulations, in accordance with the specific study 
data management plan. Regulations applicable to observational studies do not specify 
monitoring requirements for this type of study.  
An electronic database will be created in which all data from each clinical record will be 
recorded. Access to the database will be restricted, for security reasons, to the investigator, 
the data manager and personnel responsible for data review. The database will contain 
internal consistency rules and filters to minimize possible errors in data entry.  
Logic controls will be run to check for inconsistent study data and laboratory values outside 
normal limits. During the data entry period, consistency of the inclusion/exclusion criteria 
values and clinical evaluations will be checked. 
 
9.2 
Quality Assurance Unit Audits   
The Quality Assurance Unit may audit the study to ensure that study procedures comply with 
the provisions of the protocol and standard operating procedures, and that the data collected 
are correct and complete.  
 
9.3 
CREC and health authority inspections  
Representatives of the CREC or the health authorities may request an on-site data 
inspection. If the responsible investigator in the site receives notification of an inspection, 
he/she must immediately contact Takeda Farmacéutica España S.A. and must provide 
access to the requested files.   
 
9.4 
Data management 
The Data Management Plan must be approved by the sponsor before the database design 
and study CRFs are complete. The Data Manager will be the CRO. If the IC of a patient is 
missing, the data from that patient will not be entered in the database, and only the 
inclusion/exclusion criteria and the visit date will be recorded. If it is subsequently found that 
no IC is available for a patient, the data entered in the system will be maintained as 
recorded, but these data will not be used for the statistical analysis and the patient will be 
considered a screening failure. If a patient is mistakenly included more than once in the 
study, the information for the initial inclusion will be retained. The statisticians will be 
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informed of the duplicate inclusion of a patient, so that those data are not taken into account 
in the analysis.  
The method of coding clinical data will be documented in the Data Management Plan, 
indicating the dictionaries used and variables to be coded.  
In the database, patients will be coded according to the site code and patient number; no 
identifying or identifiable personal data will appear. 
 
9.4.1 
Tools for data collection and flow 
The participating site will receive tools for data collection (electronic CRF) from the Sponsor 
or the CRO. All attempts should be made in every case to enter the complete data set.  
The responsible investigator in the site must sign the data set for each patient, thus 
confirming the information collected just before the database closure. AE/ARs will be 
collected as specified in Section 7 of this protocol, and SARs will also be reported as 
described in Section 8 of this protocol.  
 
10 Statistical methods and calculation of the sample size 
This section describes the statistical analysis foreseen at the time of planning the study. 
Possible modifications and reasons for any changes, as well as any additional analysis and 
the final statistical analysis will be described in detail in the revised Statistical Analysis Plan 
before database closure. All modifications or subsequent deviations will be explained in the 
study clinical report.  
 
10.1 Statistical analysis plan 
The principal objective of this study is to characterize the profile of the relapsing/refractory 
MM patient in Spain. To this end, sociodemographic data, current clinical and therapeutic 
data, clinical data relative to the latest relapse and clinical data at diagnosis and previous 
relapses will be collected.   
A descriptive analysis of all variables will be used to characterize the profile of MM patients 
with symptomatic relapse and/or refractory episode: 
 
For qualitative variables, the number and percentage of patients in each category will 
be used. 
 
For quantitative variables, central tendency and dispersion measurements will be 
presented. 
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To evaluate which clinical and sociodemographic findings are related with the selection of 
treatment after relapse, the relationship between the clinical and sociodemographic variables 
collected before starting treatment with the prescribed treatment will be evaluated. 
 
For qualitative variables, numbers and percentages of the variable categories for 
each treatment will be presented. To evaluate the relationship with treatment, Chi-
squared or Fisher exact tests will be performed and the resulting p-value will be 
presented. 
 
For quantitative variables, central tendency and dispersion descriptions will be 
presented for each treatment. To evaluate the relationship with treatment, ANOVA or 
non-parametric Kruskal-Wallis tests will be performed and the resulting p-value will 
be presented. 
 
No type of data imputation will be performed. Only patients observed will be analyzed, and 
the number of missing data will be described in each analysis. 
 
Validation of the EORTC QLQ-MY20 questionnaire.  
 
To validate the psychometric properties of the EORTC QLQ-MY20 questionnaire, feasibility, 
reliability and validity will be evaluated using the following constructs: 
 
Questionnaire feasibility: 
o Percentage of non-responses in the questionnaire. 
o Floor and ceiling effects for each questionnaire item. 
 
Internal consistency will be evaluated using Cronbach’s . A result of 0.7 or higher is 
considered acceptable for psychometric scales.21  
 
Temporal stability will be evaluated in a test-retest analysis, and the intraclass 
correlation coefficient will be presented. 
 
Construct validity will be evaluated using a factor analysis.21  
 
Clinical validity will be evaluated by the comparison of results in pre-defined groups 
(ISS stage, presence/absence of fractures, and 2-microglobulin levels) that will 
indicate the capacity of discrimination between patients in different clinical 
situations.21 The groups will be defined as follows: 
o ISS Stage I-II vs III 
o Fractures: fractures currently present vs. absent 
o 2-microglobulin: <4 mg/L vs. 4 mg/L. 
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 
Convergent validity will be evaluated by calculating the correlation between the 
EORTC QLQ-MY20 questionnaire scores with the global health scores from the 
EORTC QLQ-C30 questionnaire. 
 
A two-tailed level of significance of 0.05 will be used for all tests. 
All statistical analyses will be carried out using the statistical package SAS© system, version 
9.3 or higher. 
 
10.2 Interim analyses 
An interim analysis will be evaluated during the enrollment process. .  
 
10.3 Sample size calculation 
The aim of this study is to describe the epidemiological profile of the MM patient with 
symptomatic relapse and/or refractory disease in Spain, and to identify thereby potential 
differences that may be relevant for making clinical and therapeutic decisions. The sample 
was calculated on the basis of the estimation of a proportion in case of maximum 
indetermination (proportion of 50%). 
To estimate a proportion of the MM population with symptomatic relapse and/or refractory 
disease, approximately 3,4807 patients in Spain in 2016, with a 95% confidence interval and 
a precision of 5%, a total of 346 patients will have to be included. To facilitate the distribution 
of patients between the different participating sites, and taking into account the cross-
sectional design of the study and the need to have all the information needed for the study 
as listed in the screening criteria available in the patient records, the risk of patient attrition is 
high, so the final sample size for the study was established at 350 patients. With this sample 
size, the psychometric properties of the EORTC QLQ-MY30 questionnaire can be 
validated.21, 22, 26 
Moreover, for the test-retest analysis to validate the EORTC QLQ-MY20 questionnaire, a 
second questionnaire will be provided to 40 patients to complete 7 days after the visit, which 
should be returned to the site by post, in a pre-paid envelope. According to previous 
publications on questionnaire validation in other languages22, 20 patients are sufficient for a 
test-retest analysis. Taking into account the possibility of questionnaires with invalid data or 
those that are not returned after 7 days, we decided to ask 40 patients to complete the 
second questionnaire. 
 
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11 Reports 
A final clinical report will be prepared containing the study results and sent to Takeda 
Farmacéutica España S.A. for distribution. This form must be made available within one year 
following the date of the collection of the last study data point, and all participating sites and 
patients must be informed accordingly. 
 
12 Publication of results 
Takeda Farmacéutica S.A. agrees to disseminate the results obtained from this study. 
Takeda Farmacéutica S.A. reserves the right to use the data and results for regulatory 
purposes and to make internal presentations within the company or with commercial 
partners.  
 
13 Study documentation archives 
During the study conduct, the responsible investigator at the site must file at least the 
essential documents (section 3.5), the protocol, any amendment, the list of participants, the 
ICs, CRFs, and study progress reports in the site file. After database closure, the 
responsible investigator in the site must keep at least the list of participants and the IC 
documents in the site for at least 5 years. The responsible investigator in the site will in all 
cases comply with legal obligations with regard to archiving and retention of study 
documentation. 
 
14 Funding 
The study will be funded by the Sponsor  (Takeda Farmacéutica España S.A.). 
The study financial schedule is attached in Annex 7. 
 
 
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15 References 
 
 
 
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Research Involving Human Subjects, Helsinki 1964, amended in Tokyo 1975, Venice 
1983, Hong Kong 1989, South Africa 1996, Edinburgh 2000, Seoul 2008 and Fortaleza 
2013. Fortaleza 2013. 
 2.  Conferencia Internacional de Armonización. Guía de Buenas Prácticas Clínicas (ICH 
E6). (ICH E6) 2016. 
 3.  Epstein 
M. 
Guidelines 
for 
good 
pharmacoepidemiology 
practices 
(GPP). 
Pharmacoepidemiol Drug Saf 2005;14(8):589-595. 
 4.  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-e548. 
 5.  Multiple 
Myeloma 
Research 
Foundation. 
About 
Multiple 
Myeloma. 
https://www.themmrf.org/multiple-myeloma/. (Acceso 8 Jul 2016) 2016. 
 6.  Moreau P, San MJ, Ludwig H, Schouten H, Mohty M, Dimopoulos M et al. Multiple 
myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 
Ann Oncol 2013;24 Suppl 6:vi133-vi137. 
 7.  Decision Resources Group. Biopharma Report. https://decisionresourcesgroup.com/. 
(Acceso 8 Jul2016) 2016. 
 8.  Palumbo A, Anderson K. Multiple myeloma. N Engl J Med 2011;364(11):1046-1060. 
 9.  Van VE, Schouppe E, Movahedi K, De BE, Menu E, De BP et al. Multiple myeloma 
induces the immunosuppressive capacity of distinct myeloid-derived suppressor cell 
subpopulations in the bone marrow. Leukemia 2012;26(11):2424-2428. 
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 11.  Kumar SK, Lee JH, Lahuerta JJ, Morgan G, Richardson PG, Crowley J et al. Risk of 
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International Myeloma Working Group recommendations for the treatment of multiple 
myeloma-related bone disease. J Clin Oncol 2013;31(18):2347-2357. 
 18.  Ludwig H, Miguel JS, Dimopoulos MA, Palumbo A, Garcia SR, Powles R et al. 
International Myeloma Working Group recommendations for global myeloma care. 
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 19.  Dimopoulos MA, Sonneveld P, Leung N, Merlini G, Ludwig H, Kastritis E et al. 
International Myeloma Working Group Recommendations for the Diagnosis and 
Management of Myeloma-Related Renal Impairment. J Clin Oncol 2016;34(13):1544-
1557. 
 20.  Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ et al. The 
European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-
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1993;85(5):365-376. 
 21.  Cocks K, Cohen D, Wisloff F, Sezer O, Lee S, Hippe E et al. An international field 
study of the reliability and validity of a disease-specific questionnaire module (the QLQ-
MY20) in assessing the quality of life of patients with multiple myeloma. Eur J Cancer 
2007;43(11):1670-1678. 
 22.  Espinoza-Zamora JR, Portilla-Espinosa CM, Labardini-Mendez JR, Cervera E, 
Niesvisky R, Onate-Ocana LF. Quality of life in multiple myeloma: clinical validation of 
the Mexican-Spanish version of the QLQ-MY20 instrument. Ann Hematol 
2015;94(6):1017-1024. 
 23.  Rondeau V, Cornet E, Moreau P, Troussard X. Prediction of patients with multiple 
myeloma eligible for second- or third-line treatment in France. Ann Hematol 
2016;95(8):1307-1313. 
 24.  Levin KA. Study design III: Cross-sectional studies. Evid Based Dent 2006;7(1):24-25. 
 25.  Mann CJ. Observational research methods. Research design II: cohort, cross 
sectional, and case-control studies. Emerg Med J 2003;20(1):54-60. 
 26.  Ahmadzadeh A, Yekaninejad MS, Saffari M, Pakpour AH, Aaronson NK. Reliability and 
Validity of an Iranian Version of the European Organisation for Research and 
Treatment of Cancer Quality of Life Questionnaire for Patients with Multiple Myeloma: 
the EORTC QLQ-MY20. Asian Pac J Cancer Prev 2016;17(1):255-259. 
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CharisMMa Study 
 
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 27.  Mikhael JR, Dingli D, Roy V, Reeder CB, Buadi FK, Hayman SR et al. Management of 
newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of 
Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines 2013. Mayo 
Clin Proc 2013;88(4):360-376. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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ANNEX: 
 
1. Sample patient information sheet  
 
INFORMATION SHEET FOR ADULT PATIENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
We would like to inform you about a research study in which we are inviting you to 
participate. The study has been approved by the Clinical Research Ethics Committee of 
_________________________________________, 
in 
accordance 
with 
applicable 
legislation. 
This information sheet contains the relevant information about the study, and you should 
read it and understand it before you decide if you want or do not want to participate in this 
study. Your doctor will also explain to you verbally about what is involved and you will be 
able to ask them about anything that occurs to you at any time. 
 
INTRODUCTION 
You have been invited to participate in a research study in multiple myeloma (MM) patients 
who have received at least one previous line of treatment and who have developed 
refractory disease and/or relapse. Our aim is to expand the existing knowledge base of this 
disease.  
STUDY OBJECTIVE 
The general objective of this study is to evaluate the clinical and epidemiological 
characteristics of MM patients who are experiencing symptomatic relapse and/or refractory 
disease after a previous treatment. Specifically, the aim is to describe the clinical profile of 
Study title: “CLINICAL AND SOCIODEMOGRAPHIC CHARACTERIZATION OF 
MYELOMA MULTIPLE PATIENTS WITH SYMPTOMATIC RELAPSE AND/OR 
REFRACTORY DISEASE IN SPAIN” CharisMMa Study  
Sponsor: Takeda Farmacéutica España S.A. 
Protocol Number:  
PIS Version: v1 
Principal investigator at the site: _____________________________________________ 
Site: ___________________________________________________________________ 
Address: _________________________________________________________________  
Telephone: ________________________________ 
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these patients and to determine, on the basis of these characteristics, the optimal regimen 
for the patients.  
A second objective of this study is to test the feasibility, reliability and validity of a 
questionnaire designed to evaluate quality of life (QoL) in MM patients.  
An important issue in MM patients is how both the disease and the treatments administered 
can affect QoL. In medicine, QoL is evaluated by using scales and questionnaires. There is 
a specific questionnaire for evaluating QoL in MM called the EORTC QLQ-MY20. In this 
study, we want to test the feasibility, reliability and validity of this questionnaire. 
STUDY INFORMATION 
This observational cross-sectional (single-visit) study will include approximately 350 adult 
patients with a diagnosis of MM who, after being treated already, have experienced a 
relapse of their disease (either after having been in remission for some time or because they 
are resistant to the treatment administered). 
As this is an observational cross-sectional study, participation in this study means that your 
doctor will only consult and record information from your clinical records and tests performed 
in this visit for the follow-up and/or treatment of your disease. Moreover, two QoL 
questionnaires will be completed. 
Some of the patients (40 in all) will be asked to submit a second questionnaire after 7 days 
by post, in a pre-paid envelope. This is necessary to check the reliability of the EORTC 
QLQ-MY20 questionnaire, although you can decide if you want to participate in this specific 
part of the study or not.  
In order for patients to keep themselves informed about the study progress and when study 
milestones are reached, Takeda has made available the following open access website, 
which will be updated as milestones are achieved during the course of the study. This site 
will contain public information only and in no case will any information on the patient or any 
confidential information be disclosed. www.charismmastudy.com  
 
Risks derived from participation in the study 
You will not be exposed to any additional risk derived from participation in this study. 
Except for the completion of the QoL questionnaires, all examinations, tests and treatment 
will be exactly the same as if you did not participate in the study. 
Benefits obtained from participation in the study 
You will not obtain any additional medical benefit from participation in this study.  
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The information which is obtained may be scientifically important, and as such, may be 
useful in the future for other people who have the same disease as you. 
 
ALTERNATIVES TO PARTICIPATION 
If you decide not to participate, you will receive exactly the same treatment and care from 
your doctor.  
Your medical care will not be affected in any way if you decide not to participate. 
 
VOLUNTARY PARTICIPATION AND WITHDRAWAL 
You should know that your participation in this study is totally voluntary. 
You have the right not to participate in this study and if you decide to participate, you have 
the right to change your mind and to withdraw your consent and to discontinue your 
participation at any time, without this affecting your medical care in any way. 
 
CONFIDENTIALITY 
The information collected in the study will be confidential and will comply with the provisions 
of the Personal Data Protection Act 15/1999, 13 December 1999, and the Royal Decree 
1720/2007, 21 December 2007, approving the Regulations developing this law.  
The documents and information that may be collected about you during the performance of 
this study will not contain either your name, nor your initials, nor any other identifying data; 
instead only a code will be shown, so that only your study doctor and co-workers can link 
those data with you and your clinical records. 
The study results, after the information collected is analyzed, may be presented at medical 
meetings or published in scientific journals, but your name will never appear, nor will any 
personal information from which you could be identified. 
Access to their personal information will be limited to the study doctor and co-workers, the 
health authorities, the Research Ethics Committee and representatives of the sponsor, who 
will be bound by professional secrecy, when they need to check the data and study 
procedures, but the confidentiality of your data will always be maintained according to 
current legislation. 
In accordance with the current regulations regarding data protection, all the data in your 
clinical records, and the results from your participation in the study are included in a personal 
data file, under the responsibility of the hospital 
 ______________________________________________________. 
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3. Case report form 
Enclosed separately 
 
4. Coordinating Investigator Commitment (sample) 
Enclosed separately 
 
5. Participating Investigator Commitment (sample) 
Enclosed separately 
 
6. Approval of Clinical research ethics committee 
Enclosed separately 
7. Financial agreement 
Enclosed separately 
 
 
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9. EORTC QLQ-MY20 questionnaire, MM module  
Enclosed separately 
 
10. EORTC QLQ-C30 questionnaire 
Enclosed separately 
 
 
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11. ECOG scale 
 
ECOG 0 
The  patient is completely asymptomatic and able to carry on all work 
and daily living activities. 
ECOG 1 
The patient has symptoms that prevent him/her performing strenuous 
tasks, but is able to carry out daily living activities and light work. The 
patient only stays in bed during night-time sleeping hours. 
ECOG 2 
The patient is unable to carry out any work activities, he/she has 
symptoms that mean he/she has to stay in bed several hours a day, in 
addition to night-time sleeping hours, but not than 50% of the day. The 
individual can perform most of their self-care alone. 
ECOG 3 
The patient is confined to bed more than 50% of the day due to 
symptoms. Requires help for most activities of daily living, for example, 
getting dressed. 
ECOG 4 
The patient confined to bed 100% of the day and needs help for all 
activities of daily living, such as personal hygiene, turning over in bed 
and even feeding. 
ECOG 5 
Dead 
 
 
 
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12. Principal investigators by site: 
 
NAME 
SITE 
ADDRESS 
1. 
 
 
2. 
 
 
3. 
 
 
4. 
 
 
5. 
 
 
6. 
 
 
7. 
 
 
8. 
 
 
9. 
 
 
10. 
 
 
11. 
 
 
12. 
 
 
13. 
 
 
14. 
 
 
15. 
 
 
16. 
 
 
17. 
 
 
18. 
 
 
19. 
 
 
20. 
 
 
21. 
 
 
22. 
 
 
23. 
 
 
24. 
 
 
25. 
 
 
26. 
 
 
27. 
 
 
28. 
 
 
29. 
 
 
30. 
 
 
 
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