Impact of Extramedullary Disease in Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation: A Study By the EBMT Chronic Malignancies Working Party
Authors: Gagelmann Nico , Iacobelli Simona , Koster Linda , Nahi Hareth , Stoppa Anne-Marie , Masszi Tamás , Caillot Denis , Lenhoff Stig , Udvardy Miklos , Crawley Charles , Arcese William , Mariette Clara , Hunter Ann , Leleu Xavier , Schipperus Martin , Delforge Michel , Pioltelli Pietro , Snowden John A , Itälä-Remes Maija , Musso Maurizio , Garderet Laurent , Kröger Nicolaus 
Published: October 2019

Abstract
Introduction
Multiple myeloma (MM) is characterized by a proliferation of plasma cells with a strong dependence on the bone marrow (BM) microenvironment. However, in some MM patients this proliferation escapes the BM resulting in extramedullary disease (EMD) with two types of involvement: 1) paraskeletal (PS) and 2) extramedullary (EM), involving either skin/lymph nodes (EMS) or organs (EMO). EMD is considered to be associated with poor prognosis. Autologous stem cell transplantation (ASCT) in MM is standard therapy in first line therapy in eligible patients, but only limited reports on outcome of EMD after ASCT exist.
Methods
Within the European Society for Blood and Marrow Transplantation (EBMT) registry, 4658 patients (female n=1898, male n=2760) who received upfront ASCT were reported between January 2005 and December 2014 with available data on EM involvement at time of diagnosis. 3802 patients had no EMD (MM group), while 677 had PS and 179 EM involvement, including EMS (n=68) or EMO (n=111). The median age of the patients was 59 years (range 22 - 77). The stage according ISS at diagnosis was I (n=1229), II (n=1174) and III (n=865). All patients received an upfront single (n=4250) or tandem (n=408) ASCT. Salmon and Durie classification stage B was seen more frequently in EM (31%), than in MM (17%) or PS (16%) (p< 0.001). More EM had ≥ 2 different sites of involvement than PS patients (20% versus 4%, p< 0.001). Tandem ASCT was applied to 15% in the PS group compared to 8% in the MM and 10% in the EM group (p< 0.001). Primary end point was 5 year progression-free survival (PFS).
Results
At ASCT 18% of MM patients achieved a complete remission (CR) compared to 20% of PS and 12% of EM patients (p=0.058). MM and PS patients showed similar 5 year PFS (28% versus 29%, p= 0.74) in the univariate analysis with a median PFS of 31 versus 33 months. In contrast, EM patients had a significant worse median PFS (21.5 months) and 5 year probability (22%) than MM patients (28%) as well as PS patients (29%) (p< 0.001). Five year probability of OS were higher in MM compared to PS (67% versus 63%, p=0.05) and to EM (67% versus 49%, p< 0.001). Furthermore, the difference in 5 year OS between PS and EM involvement reached statistical significance (63% versus 49%, p< 0.001). When analyzing PFS according to the number of sites involved, the median PFS in PS patients was 35 for 1 versus 24 months for ≥ 2 sites and in EM patients 24 versus 17 months (p=0.003). Other significant factors for worse PFS in the univariate analysis were: IgA-type (p< 0.001), Salmon and Durie stage B (p< 0.001), ISS II and III (p< 0.001, respectively), while favorable factors were CR (p< 0.001) and female sex (p< 0.001). In a subanalysis comparing EMS and EMO, the median PFS was significantly worse for EMS than EMO (20 versus 25 months, p=0.024). Cox proportional hazards regression considering independent factors for worse PFS yielded: EM (HR 2.88, 95% CI 1.90 - 4.37), IgA (HR 1.31, 95% CI 1.15 - 1.48) as well as Salmon and Durie stage B (HR 1.26, 95% CI 1.06 - 1.51), while improved PFS was seen for CR (HR 0.47, 95% CI 0.36 - 0.61) and ISS I (HR 0.70, 95% CI 0.60 - 0.83).
Conclusion
This EBMT registry study demonstrates that EMD manifestation in patients with MM is an independent risk factor for worse outcome after ASCT. Within the EMD group, non-paraskeletal extramedullary manifestation, EMS and involvement of 2 or more sites resulted in worse PFS.

Disclosures
Leleu: TEVA: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Delforge:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Kröger:Riemser: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Neovii: Honoraria, Research Funding.