# The EMMY longitudinal, cohort study: real-world data to describe multiple myeloma management and outcomes as more therapeutic options emerge

Olivier Decaux, Ronan Garlantézec, Karim Belhadj-Merzoug, Margaret Macro, Laurent Frenzel, Aurore Perrot, Philippe Moreau, Bruno Royer, Denis Caillot, Xavier Leleu, et al.

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## ► To cite this version:

Olivier Decaux, Ronan Garlantézec, Karim Belhadj-Merzoug, Margaret Macro, Laurent Frenzel, et al. The EMMY longitudinal, cohort study: real-world data to describe multiple myeloma management and outcomes as more therapeutic options emerge. Clinical Hematology International, 2024, 6 (3), pp.22-27. 10.46989/001c.121371. hal-04915075

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# THE EMMY LONGITUDINAL, COHORT STUDY: REAL-WORLD DATA TO DESCRIBE MULTIPLE MYELOMA MANAGEMENT AND OUTCOMES AS MORE THERAPEUTIC OPTIONS EMERGE

Olivier Decaux<fnref n="1" />, Ronan Garlantézec²,³, Karim Belhadj-Merzoug³, Margaret Macro⁴, Laurent Frenzel⁵, Aurore Perrot⁶, Philippe Moreau⁷, Bruno Royer⁸, Denis Caillot⁹, Xavier Leleu¹⁰, Mohamad Mohty¹¹, Lionel Karlin¹², Pierre Feugier¹³, Sophie Rigaudeau¹⁴, Jean Fontan¹⁵, Cécile Sonntag¹⁶,¹⁷, Laure Vincent¹⁸, Thomas Chalopin¹⁹, Herve Avet Loiseau²⁰,²¹, Zakaria Maarouf²², Louni Chanaz²², Nathalie Texier²³, Cyrille Hulin²⁴

Keywords: Multiple myeloma, real-world data, therapeutic management

https://doi.org/10.46989/001c.121371

Clinical Hematology International

Vol. 6, Issue 3, 2024

The therapeutic management of patients with multiple myeloma (MM) is complex. Despite substantial advances, MM remains incurable, and management involves cycles of treatment response, disease relapse, and further therapy. Currently, evidence to support the therapeutic decision is limited. Thus, the EMMY longitudinal, real-world study was designed to annually assess therapeutic management of MM in France to provide evidence to support physicians. During an annual prespecified 3-month recruitment period, eligible patients will be identified from their medical records. Adults aged ≥18 years diagnosed with symptomatic MM and requiring systemic treatment will be eligible. The primary objective, the evolution of MM therapeutic management, will be described, as well as the impact on the following outcomes: time-to-next treatment (TTNT), progression-free survival (PFS), and overall survival (OS). The study plans to recruit 5000 patients over 6 years: 700 to 900 patients annually. EMMY is a unique opportunity to collect real-world data to describe the evolving MM therapeutic landscape and record outcomes in France. These data will provide annual snapshots of various aspects of MM management. This knowledge will provide physicians with real-life, evidence-based data for therapeutic decision-making and ultimately improve treatment for MM patients.

INTRODUCTION

Multiple myeloma (MM) is a hematological B-cell malignancy characterized by abnormal proliferation of clonal bone marrow plasma cells, a type of terminally differentiated B-cell.<fnref n="1" />⁻³ This causes overproduction of monoclonal immunoglobulins, including complete IgG, IgA, IgM, or only light chains, which damage end-organs and are associated with immune dysfunction.<fnref n="1" />⁻³ End-organ damage often includes hypercalcemia, renal failure, anemia, and/or bone lesions, the so-called CRAB criteria.<fnref n="1" />,⁴

MM is the second most frequently reported hematological malignancy. In 2020, 176,404 new cases of MM were reported and caused 117,077 deaths.⁵,⁶

Despite the substantial therapeutic advances made over the last two decades, MM remains incurable.² However, recent advances have extended progression-free survival (PFS) and overall survival (OS).⁷ Today, MM management involves reiterative stages of response to treatment, inevitable disease relapse, and initiation of subsequent lines of therapy.²,³

Numerous therapies for treating MM are available, including proteasome inhibitors, alkylating agents, im-

<footnote n="1">¹ Service d'hématologie clinique, Centre Hospitalier Universitaire de Rennes, ² Santé publique et épidémiologie, Centre Hospitalier Universitaire de Rennes, ³ Unité Fonctionnelle Hémopathies Lymphoïdes, Centre Hospitalier Universitaire Henri-Mondor, ⁴ Service d'hématologie clinique, Centre Hospitalier Universitaire de Caen, ⁵ Service d'hématologie adulte, Hôpital Necker-Enfants Malades, ⁶ Hématologie, Centre Hospitalier Universitaire de Toulouse, ⁷ Hématologie clinique, CHRU - Hôtel Dieu (Nantes), ⁸ Immuno-Hématologie, Hôpital Saint-Louis (Paris), ⁹ Hématologie Clinique, Centre Hospitalier Universitaire Dijon Bourgogne, ¹⁰ Hématologie, Centre Hospitalier Universitaire de Poitiers, ¹¹ Service d'Hématologie et Thérapie cellulaire, Hôpital Saint-Antoine, ¹² Hématologie clinique, Hospices Civils de Lyon, ¹³ Service d'hématologie, CHU de Nancy - Hôpitaux de Brabois, ¹⁴ Service d'Hématologie, CHV André Mignot, ¹⁵ Service Hématologie, CHRU Jean Minjoz (Besançon), ¹⁶ Département d'Hématologie et Oncologie, Hôpitaux Universitaires de Strasbourg, ¹⁷ Département d'Hématologie et Oncologie, Hôpital de Hautepierre et Hôpital Civil, ¹⁸ Département d'hématologie clinique, CHU Montpellier, ¹⁹ Hématologie thérapie cellulaire, CHRU de Tours, ²⁰ IUCT Oncopole Toulouse, ²¹ CHU Toulouse, ²² Intergroupe Francophone du Myélome, ²³ Epidémiologie, Kappa Santé, ²⁴ Hématologie, Hôpital Haut-Lévêque (Pessac)</footnote>
munomodulatory imide drugs, and monoclonal antibod-
ies.<sup>3,8-12</sup> Moreover, therapies targeting B-cell maturation
antigens have been developed, including antibody-drug
conjugates, bispecific antibodies (BiAbs), bispecific T-cell
engagers, and chimeric antigen receptor T (CAR-T) cells.<sup>13</sup>
<sup>14</sup> More recently, therapeutic agents (including BiAbs and
CAR T cells) targeting G protein-coupled receptor class C
group 5 member D have shown efficacy.<sup>15,16</sup> In addition,
autologous stem-cell transplantation (ASCT) is the back-
bone of MM management. In patients eligible for ASCT, in-
duction therapy with bortezomib and dexamethasone com-
bined with daratumumab-thalidomide is recommended.
This is followed by melphalan then ASCT. The recom-
mended frontline therapy for ASCT-eligible patients is
completed by maintenance with lenalidomide. In patients
not eligible for ASCT, various frontline combination thera-
pies are available, but currently, the combination of dara-
tumumab, lenalidomide, and dexamethasone is the most
effective regimen.<sup>17</sup> At inevitable relapse, the choice of
therapy depends on several factors, including age, comor-
bidities, MM symptoms, and prior treatments, as well as the
availability of therapies.<sup>1</sup> The emergence of new treatments
will further complexify the therapeutic decision.

MATERIALS AND METHODS

STUDY DESIGN

EMMY is a multicenter, non-interventional, historical, lon-
gitudinal cohort study. Real-life data will be collected in
centers specialized in MM management and members of
the French myeloma intergroup, "Intergroupe Francophone
du Myélome (IFM)". The study was funded by the IFM with
support from a consortium of pharmaceutical companies.
The Emmy Scientific Committee members, independently
of contributors, defined and conducted the writing of this
EMMY publication. Most patients with MM are managed in
IFM centers. Seventy-three centers have been selected: 34
general hospitals, 26 university hospitals, 11 private hospi-
tals/clinics, 1 military hospital, and 1 comprehensive can-
cer center (Supplemental Table 1). If required, additional
centers can be included. Overall, the average potential pa-
tient population in these centers is 46 patients per day per
center.

Patients are recruited over 6 years (2017-2023) during
annual, pre-defined, 3-month periods (see **Figure 1**), and
data are updated annually.

STUDY POPULATION

Patients will be identified from their medical records at
the centers. Adults aged ≥18 years, diagnosed with symp-
tomatic MM and requiring systemic treatment (irrespective
of the treatment line) will be eligible. Patients with non-se-
cretory, solitary plasmacytoma, or plasma cell leukemia will
be excluded.

STUDY OBJECTIVES

The primary objective of the Emmy study is to describe
the therapeutic management of patients with MM in French
hospitals using real-life data.

Secondary objectives aim to assess PFS, TTNT, OS and
treatment response rates, as well as to assess therapy dis-
continuations and the evolution of MM practices. The study
will also assess the impact of MM on healthcare resources
and on patients' professional activity, as well as the evolu-
tion of healthcare resource utilization, using the study data
and data retrieved from the French healthcare database, the
"Système National des Donnes de Santé" (SNDS).

STUDY ENDPOINTS

The study aims to describe the evolution of MM therapeutic
management and its impact on the following outcomes:
time-to-next treatment (TTNT), PFS, and OS.

Secondary endpoints will be therapy administered ac-
cording to age, gender, body mass index, Eastern Coop-
erative Oncology Group (ECOG) performance status, co-
morbidities, medical history, clinical and biochemical
parameters, as well as MM symptoms and characteristics.
MM treatment modalities will be described according to the
time interval between diagnosis and treatment initiation,
prior treatments and refractoriness to these, reason for ini-
tiation, treatment dosage at initiation and during follow up.

DATA COLLECTION

Once patients have been informed and do not oppose to
participating, they will be enrolled in the study and data
will be retrieved from their medical files. No additional data
nor study specific visits are planned. Each year, selected
data on treatment response and medical history will be ret-
rospectively updated (Figure 1) The data to be collected
and the collection process are shown in Table 1.

In addition to patient information, data on the investi-
gators and the healthcare institutions will be collected to
assess study representativeness. Investigator data include
their specialty (hematologist, oncologist, rheumatologist,
internal medicine physician, etc.) and sociodemographic
values (gender, age, medical experience). The institution
data include the type of healthcare institution and the
number of MM patients treated.

Furthermore, data will be retrieved from the SNDS and
associated with the ancillary study's clinical data. The
SNDS and clinical data will be linked by probabilistic chain-
ing using indirect nominative variables for each patient.
The data collected from the SNDS will include details on
hospitalizations, visits to the emergency department with-
out hospitalizations, medical consultations, medical proce-
dures and examinations (such as imagery and laboratory
tests), paramedical procedures, treatments, and medical
transport.
<figure><img src="image_4.png" /><figcaption>**Figure 1. Overall study design**</figcaption></figure>

DATA MANAGEMENT

Patient data will be collected at each center using an elec-
tronic case report form (e-CRF) and centralized in the study
database. Critical data will be mandatory in the e-CRF. Data
coherence and consistency will be verified throughout the
study. Data quality control will be performed at least an-
nually by the scientific committee during a review meeting
before the database locks. The steering, scientific, and op-
erational committees will oversee the study.

SAMPLE SIZE AND STATISTICAL ANALYSIS

Overall, we plan to recruit approximately 5,000 patients
with symptomatic MM, ranging from 700 to 900 patients
annually.

The data will be analyzed annually to obtain a “snapshot” of MM management during the previous year. Data will be summarized using descriptive statistics (numbers with percentages, means with standard deviations, or medians with 95% CI) and presented graphically to highlight trends. The number of missing data points will be indicated. Time-to-event analyses (OS and PFS) will be performed using the Kaplan-Meier method, which will be reported as medians with 95% CIs and presented as plots. The

analysis's significance level is set at 5% unless otherwise
specified.

PFS is the interval between treatment initiation and disease progression or death, whichever occurs first. TTNT is the interval between the treatment initiation of a given treatment line and the subsequent treatment line or death. OS is the time interval between treatment initiation and death of any cause. Response rates will be the proportion of patients in each response category at the time point of interest. The best response for each line of treatment will be retained for the analyses. PFS and response will be assessed using the International Myeloma Working Group definitions.¹⁸ Treatment discontinuation will include the time interval from treatment initiation to discontinuation and the reason(s) for discontinuation. The outcomes will be described according to the line of treatment, patient profiles, and other criteria of interest (defined by the scientific committee). Lastly, the evolution of MM management practices will be assessed and described, including therapy choice, use of grafts, hospitalizations, follow-up, and examinations performed.

Data management and statistical analysis will be per-
formed using SAS (version 9.1, SAS Institute, North Car-
olina, USA).
<table><caption>Table 1. Patient data collected during the EMMY study</caption><thead><tr><th>Data collected</th><th></th><th>Newly recruited patients</th><th>Annual update of data</th></tr></thead><tbody><tr><td>Sociodemographic</td><td>Age, gender, height, weight, and ECOG PS</td><td>X</td><td>X</td></tr><tr><td rowspan="4">Multiple myeloma diagnosis</td><td>Date of diagnosis</td><td>X</td><td></td></tr><tr><td>Type of myeloma (at diagnosis)</td><td>X</td><td></td></tr><tr><td>Immunoglobulin type</td><td>X</td><td></td></tr><tr><td>ISS stage (at diagnosis)</td><td>X</td><td></td></tr><tr><td rowspan="2">Multiple myeloma diagnostic criteria</td><td>CRAB criteria</td><td>X</td><td></td></tr><tr><td>Malignancy biomarkers</td><td>X</td><td></td></tr><tr><td rowspan="6">Multiple myeloma treatment(s) and response(s)</td><td>Radiotherapy</td><td>X</td><td>X</td></tr><tr><td>Corticosteroid therapy</td><td>X</td><td>X</td></tr><tr><td>Autograft(s) and allograft(s)</td><td>X</td><td>X</td></tr><tr><td>Multiple myeloma treatment(s)</td><td>X</td><td>X</td></tr><tr><td>Response(s) to treatment(s)</td><td>X</td><td>X</td></tr><tr><td>Date of discontinuation for each line of treatment with reason</td><td>X</td><td>X</td></tr><tr><td>Cytogenetics</td><td>Del13q, t(4;16), t(4;14), Del17p, and others</td><td>X</td><td></td></tr><tr><td rowspan="3">Medical history and comorbidities</td><td>History of myeloma (familial immunoglobulin G, MGUS, SMM etc.)</td><td>X</td><td></td></tr><tr><td>History of cancer (including leukaemia, solid cancers, lymphoma etc.)</td><td>X</td><td></td></tr><tr><td>Other relevant medical history</td><td>X</td><td>X</td></tr><tr><td rowspan="4">Biological data</td><td>Concomitant diseases (including diabetes, HIV, and cardiovascular, renal, liver, and pulmonary diseases)</td><td>X</td><td>X</td></tr><tr><td>Full blood count</td><td>X</td><td>X</td></tr><tr><td>Biochemistry</td><td>X</td><td>X</td></tr><tr><td>Immunoglobulin assays</td><td>X</td><td>X</td></tr><tr><td rowspan="2">Imaging data</td><td>Immunofixation</td><td>X</td><td>X</td></tr><tr><td>Type of imaging (X-rays, scans, MRIs, PET-CT)</td><td>X</td><td>X</td></tr><tr><td rowspan="2">Study withdrawal</td><td>Lesions identified (including plasmacytomas)</td><td>X</td><td>X</td></tr><tr><td>Date and reason for study withdrawal (termination of data collection for the given patient)</td><td></td><td>X</td></tr></tbody></table>

CRAB: hypercalcaemia, renal failure, anaemia, and/or bone lesions, ECOG PS: Eastern Cooperative Oncology Group Performance Status, HIV: human immunodeficiency virus, ISS: international staging system, MGUS: monoclonal gammopathy of undetermined significance, MM: multiple myeloma, SMM: smoldering multiple myeloma, MRI: magnetic resonance imaging, PET-CT: positron emission tomography-computed tomography.

The study is sponsored by the IFM group and financed and overseen by a consortium of partners that represent key role players in MM management in France.

## DISCUSSION

Over the last few decades, therapeutic advances have improved outcomes for patients with MM. However, the extensive arsenal of new treatments approved and in clinical development has complexified therapeutic decision-making for physicians. Indeed, physicians lack data to make and support these decisions.

EMMY is a unique opportunity to collect real-world data to describe and evaluate France's evolving MM therapeutic management. The study will collect real-world data annually from a representative sample of MM patients.

The EMMY study design, with an annual 3-month recruitment period over 6 years, will collect patient data, MM

diagnosis and disease evolution, therapeutic management, and survival outcomes. The analyses will provide annual “snapshots” of MM prevalence and therapeutic management. This will detect treatment strategies that depend on age, disease severity, prior treatments, and the availability of new treatments. In addition, the clinical data will be associated with SNDS data to access healthcare resource utilization and obtain a more complete overview of MM management.

Two international observational studies have assessed aspects of MM management. The CoMMpass study (NCT01454297) predominantly focused on identifying the clinical characteristics and molecular profiles of patients with MM, while the INSIGHT MM cohort (NCT02761187) collected data on various aspects of MM, as in our study. However, the latter study was completed in 2021,¹⁸ and the EMMY study will provide more recent data concerning the therapeutic management of patients with MM.
As with all real-world studies, this study is limited by
data quality. The data quality in the medical files will de-
pend on its completeness and accuracy.

Overall, the Emmy study is a unique and important col-
laboration between various key players in MM management
in France. Our common objective is to provide physicians
with evidence-based data for therapeutic decisions and, ul-
timately, to improve treatment for MM patients.

<figure><img src="image_5.png" /></figure>

ACKNOWLEDGMENTS

The authors thank Trevor Stanbury (Pro-Pens) for medical
writing services.

AUTHORS’ CONTRIBUTION

Conceptualization: Olivier Decaux (Equal), Ronan Garlan-
tézec (Equal), Karim Belhadj-Merzoug (Equal), Margaret
Macro (Equal), Laurent Frenzel (Equal), Aurore Perrot
(Qual), Philippe Moreau (Equal), Bruno Royer (Equal),
Laure Vincent (Equal), Thomas Chalopin (Equal), Herve
Avet Loiseau (Equal), Cyrille Hulin (Equal). Writing - review
& editing: Olivier Decaux (Equal), Ronan Garlantézec
(Qual), Karim Belhadj-Merzoug, Margaret Macro (Equal),
Laurent Frenzel (Equal), Aurore Perrot (Equal), Philippe
Moreau (Equal), Bruno Royer (Equal), Denis Caillot (Equal),
Xavier Leleu (Equal), Mohamad Mohty (Equal), Lionel Kar-
lin (Equal), Pierre Feugier (Equal), Sophie Rigaudeau
(Qual), Jean Fontan (Equal), Cécile Sonntag (Equal), Laure
Vincent (Equal), Thomas Chalopin (Equal), Herve Avet
Loiseau (Equal), Zakaria Maarouf (Equal), Louni Chanaz
(Qual), Nathalie Texier (Equal), Cyrille Hulin (Equal).
Methodology: Ronan Garlantézec (Lead).

COMPETING OF INTEREST

Olivier Decaux declares receiving honoraria from Bristol Myers Squib (BMS), Gilead, GlaxoSmithKline (GSK), Janssen, Roche, Sanofi, and Takeda. Karim Belhadj-Merzoug received honoraria, research funding, and traveling expenses from Amgen, BMS, Janssen, Pfizer, Sanofi, and Takeda. Margaret Macro received honoraria and research funding from Amgen, BMS, GSK, Janssen, Sanofi, and Takeda. Laurent Frenzel received consulting fees and research funding from BioMarin, CSL Behring, Pfizer, Sobi, and Roche. Aurore Perrot received honoraria from AbbVie,

Adaptive, Amgen, BMS, Janssen, Pfizer, Sanofi, and Takeda. Philippe Moreau received honoraria and payment for advisory boards from AbbVie, Amgen, BMS-Celgene, Janssen, Pfizer, Sanofi, and Takeda. Xavier Leleu received consultancy fees from AbbVie, Amgen, BMS, Gilead, GSK, Hарpoon Therapeutic, iTeos therapeutics, Janssen, Merck, Novartis, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, and Takeda. Mohamad Mohty received honoraria, consultancy fees, and research funding from Amgen, BMS, Gilead, GSK, Janssen, Jazz Pharmaceuticals, Novartis, Pfizer, Sanofi, Stemline Therapeutics, and Takeda. Lionel Karlin received honoraria, payment for advisory boards, as well as logistical and financial assistance for attending conferences from AbbVie, Amgen, BMS-Celgene, GSK, Janssen, Pfizer, Sanofi, Stemline Therapeutics, and Takeda. Cécile Sonntag is a member of the board of directors or on the advisory committee of BMS, Janssen, Sanofi, and Takeda. Laurent Vincent declares being a board member for BMS and Takeda. He also declares that he is receiving honoraria from Janssen and Pfizer. Cyrille Hulin received honoraria from AbbVie, Amgen, BMS, Janssen, Pfizer, and Sanofi. The other authors have no competing interests to declare.

ETHICAL CONDUCT APPROVAL

The EMMY study is classified as research not involving hu-
man subjects, as defined in article L. 1121-1 of the French
Public Health Code. This retrospective and prospective per-
sonal data study is being conducted following the Decla-
ration of Helsinki and has been submitted to the French
Health Data (N° F20220518161845) https://www.health-
data-hub.fr/projets/emmy-epidemiologie-de-laprise-en-
charge-therapeutique-du-myelome-multiple-en-france No
ethical approval for this study was required. All patients
were informed about the processing of their data before en-
rolment in the study.

INFORMED CONSENT STATEMENT

All authors and institutions have confirmed this manuscript
for publication.

DATA AVAILABILITY STATEMENT

Not applicable.

Submitted: April 04, 2024 BST, Accepted: May 02, 2024 BST

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