Real-Life Survival Data after Triple-Exposure to Proteasome Inhibitors (PI), Immunomodulators (IMID) and Anti-CD38 in Multiple Myeloma Patients in the Emmy Cohort
Authors: Perrot Aurore , Hulin Cyrille , Macro Margaret , Frenzel Laurent , Araujo Carla , Moreau Philippe , Royer Bruno , Belhadj Karim , Caillot Denis , Leleu Xavier , Vekhoff Anne , Schulmann Samantha , Manier Salomon , Karlin Lionel , Vincent Laure , Rigaudeau Sophie , Chaoui Driss , Garlantezec Ronan , Texier Nathalie , Willaime Marion , Boccaccio Catherine , Decaux Olivier 
Published: November 2021

Abstract
Background
EMMY is a large-scale epidemiological study to assess the epidemiology and real-life management of multiple myeloma (MM). Proteasome inhibitors (PI), immunomodulators (IMID) and anti-CD38, provide broad therapeutic solutions for the management of first-line Multiple Myeloma (MM). At more advanced stages, the therapeutic possibilities in patients already exposed to these 3 therapeutic classes are limited. The EMMY study allows to describe the characteristics and the real-life efficacy of treatments in tri-exposed patients.
Methods
EMMY is a descriptive, multicenter, national, non-interventional study conducted in 72 IFM (Intergroupe Francophone du Myélome, sponsor) centers in France. Any patient initiating treatment for MM over a 3-month observation period, from October to December, is included, since 2017. It is a dynamic cohort with the inclusion of 1000 additional patients each year (2765 patients included at the end of 2019). Data are updated annually from hospital records up to 2020.
Patients with tri-exposure to the 3 classes IMID, IP and anti CD38 were identified, and the index date was defined as the initiation of the next line. The median time to next treatment (mTTNT), median progression-free survival (mPFS), and median overall survival (mOS) were estimated for these patients. Results are focused in patients refractory to the previous line (PL-Ref).
Results
After 3 years of data collection in EMMY, 491 patients (17.8%) were identified as tri-exposed in the cohort. The median age was 69.9 years [62.2-75.8] with 158 patients (32.2%) &lt; 65 years and 63 (12.8%) ≥ 80 years. When available, patients had ECOG 0 or 1 for 59.3% (n=211), high cytogenetic risk for 29.5% (RD) (n=65), an ISS of 1/2/3 for 25.3, 28.5 and 46.2% and at least one comorbidity for 32% (n=157).
The patients were tri-exposed at the end of L2, L3, L4, L5 and L6+ for respectively 2%, 16.9%, 26.9%, 26.3% and 27% of them with a median time from diagnosis to the index date of 54.9 months (mo) [32.9 -89.7]. The proportion of patients early tri-exposed as of L3 or L4 increased over the years with respectively 9.8% (L3) and 15.7% (L4) in 2017 (n=51), 11% and 18.9% in 2018 (n=127), 17.1% and 26.8% in 2019 (n=164) and 24.5% and 37.4% in 2020 (n=147). Time from diagnosis to the index line decreased from 64.6 mo (2017) and 62.8 mo (2018) to 54.5 mo (2019) and 49.5 mo (2020).
Half patients (52.5%) had previously received ASCT. At the index date, patients had previously been treated with bortezomib (98%), carfilzomib (21.2%), ixazomib (10.4%), lenalidomide (90.4%), thalidomide (35.8%), pomalidomide (61,9%), daratumumab (96.5%) and isatuximab (3.5%). In overall, 86% were refractory to anti-CD38, 51% refractory to 3 classes, and 31% to 2 classes. Of them, 89.2% (438) were refractory to the line prior to the index line (PL-Ref).
The mPFS was 5,1 mo 95%CI [4.4 - 6.3] and the mTTNT 6.9 mo 95%CI [6.1 -8.2] for the whole cohort (n=481). In the 438 PL-Ref patients, mPFS was 4.8 mo 95%CI [4.1-6] and mTTNT was 6.6 mo 95%CI [5.5; 7.8] (Figure 1). The mOS was 17.7mo 95%CI [14.2 - 20.2] for the whole cohort with mOS of 16.6 mo 95%CI [13.1 - 19.8] in PL-Ref patients.
Conclusion
Advances in the management of myeloma are leading to the increasingly early use of combination treatments with IMID, PI and anti-CD38 antibodies in the treatment of multiple myeloma. As a result, patients are increasingly early exposed to these 3 major classes. The EMMY cohort confirms that patients are triple exposed to PIs, IMID, and anti CD38 at an increasingly early stage in the management of MM. Most of them were refractory to the last line and to anti-CD38 antibodies. The majority remains healthy with ECOG less than 2 and few comorbidities. Median PFS and TTNTs are approximately six months, lower than those observed with modern anti-BCMA immunotherapies. These results underline the importance of developing new therapeutic strategies in triple-exposed patients such as novel immunotherapy including bi-specific antibody/CART cells.
Figure 1 Figure 1.

Disclosures
Perrot: Abbvie: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hulin: Janssen: Honoraria; abbvie: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Celgene/BMS: Honoraria. Macro: takeda: Honoraria; abbvie: Honoraria; sanofi: Honoraria; celgene bms: Honoraria; janssen: Honoraria. Moreau: Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Celgene BMS: Honoraria; Oncopeptides: Honoraria. Leleu: Roche: Honoraria; Pierre Fabre: Honoraria; Oncopeptides: Honoraria; Novartis: Honoraria; Mundipharma: Honoraria; Merck: Honoraria; Karyopharm Therapeutics: Honoraria; Janssen-Cilag: Honoraria; Gilead Sciences: Honoraria; Celgene: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Bristol-Myers Squibb: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Non-financial support; Amgen: Honoraria; AbbVie: Honoraria. Manier: Novartis: Consultancy, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene - Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Karlin: Takeda: Honoraria, Other: member of advisory board; oncopeptide: Honoraria; Celgene-BMS: Honoraria, Other: member of advisory board; Sanofi: Honoraria; GSK: Honoraria, Other: member of advisory board; Amgen: Honoraria, Other: travel support and advisory board ; Abbvie: Honoraria; Janssen: Honoraria, Other: member of advisory board, travel support. Vincent: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Rigaudeau: Takeda: Membership on an entity's Board of Directors or advisory committees. Boccaccio: celgene: Current holder of individual stocks in a privately-held company. Decaux: Amgen BMS Celgene Janssen Sanofi Takeda: Honoraria.