Extramedullary Myeloma.
Authors: Bladé Joan , Cibeira Ma Teresa , Rosiñol Laura , de Larrea Carlos Fernández 
Published: October 2019

Abstract
Abstract SCI-5
Multiple myeloma (MM) is characterized by a proliferation of plasma cells (PC) with strong dependence on the bone marrow (BM) microenvironment. In fact, stromal cells and adhesion molecules play a crucial role in the pathogenesis of MM as well as in the homing of myeloma cells within the bone marrow, in both human myeloma and in murine plasmacytoma models. Virtually, all patients with MM will develop skeletal involvement as result of an imbalanced bone remodelling. This imbalance results in severe osteopenia and/or generalized bone lytic lesions. However, some patients develop large lytic bone lesions, as result of bone replacement by PCs, which can be considered as extramedullary tumors. Importantly, about 15% of patients with MM have soft-tissue extramedullary plasmacytomas (EMP) at diagnosis and an additional 20% develop EMP during the course of the disease. It has been suggested that patients relapsing after Allo-RIC transplantation have even a higher rate of EMP. Although the ultimate mechanisms resulting in extramedullary spread in MM remain unclear, it is likely that in patients with aggressive myeloma or at disease relapse, myeloma cells become stromal independent this favouring their proliferation and survival in the absence of the BM microenvironment. The development of extramedullary disease in MM can show different patterns. First, local soft-tissue growth from adjacent bone lesions. Second, hematogenous spread with: 1) single or multiple large subcutaneous plasmacytomas, 2) metastatic like nodules in the skin or in organs or tissues such as liver, kidney, breast or lymph nodes, and 3) CNS involvement (meningeal myelomatosis). Finally, extramedullary myeloma growth can be triggered by surgical procedures leading to the appearance of plasmacytomas at the sites of catheter insertion, laparotomy or sternotomy scars, and even local dissemination through bone surgery. In our experience, the frequency of high-risk cytogenetics –t/4;14), t(14;16) and 17pdel- by BMPC FISH analysis at diagnosis is similar in patients with or without EMP (22% vs.18%). Despite this fact, patients with extramedullary involvement usually have a more aggressive disease. In many instances, the plasma cells from EMP, particularly at relapse, show an immature or plasmablastic morphology, and highly aberrant phenotypic cell lines have been generated from extramedullary human tumors. Whether or not plasma cells from extramedullary sites have a different phenotype or cytogenetic features than the BMPC has not been reported. Soft-tissue plasmacytomas do not respond to thalidomide and cases of extramedullary progression in patients in serological response have been observed. In contrast, dramatic responses of EMP to bortezomib have been reported. In our experience, patients with extramedullary plasmacytomas show a significantly higher progressive disease rate to the induction pre-transplant regimens compared with those with no extramedullary disease (34% vs. 11%). In summary, up to one third of patients with MM will develop EMP, this being associated with a poor response to therapy and outcome. A better understanding of the mechanisms of myeloma spread and on the biology of extramedullary tumors will hopefully result in better treatment possibilities. In this regard, there is evidence suggesting that plamacytomas in mice and humans exhibit some similarities and the selection of plasmacytomas related to MM subtypes might provide an excellent opportunity for preclinical drug testing.

Disclosures
Bladé: Celgene: Honoraria, Research Funding; Jansen-Cilag: Honoraria, Research Funding. Cibeira:Jansen-Cilag: Honoraria; Celgene: Honoraria. Rosiñol:Jansen-Cilag: Honoraria; Celgene: Honoraria.