Soluble urokinase-type plasminogen activator receptor (suPAR) as an independent factor predicting worse prognosis and extra-bone marrow involvement in multiple myeloma patients Gian Matteo Rigolin, 1 Alessia Tieghi, 1 Maria Ciccone, 1 Letizia Zenone Bragotti, 1 Francesco Cavazzini, 1 Matteo Della Porta, 1 Barbara Castagnari, 1 Rosanna Carroccia, 2 Giovanni Guerra, 2 Antonio Cuneo 1 and Gianluigi Castoldi 1 1 Section of Haematology, Department of Biomedical Sciences, University of Ferrara, Ferrara, and 2 Laboratorio Analisi Chimico-Cliniche Azienda Ospedaliera Universitaria, Arcispedale S Anna Ferrara, Italy Received 15 August 2002; accepted for publication 29 October 2002 Summary. The urokinase-type plasminogen activator (uPA) system, which consists of a proteinase (uPA), a receptor (uPAR or CD87) and inhibitors, is involved in proteolysis, cell migration, tissue remodelling, angiogenesis and cell adhesion. Recent findings suggest that malignant plasma cells express uPA and uPAR. The expression of these factors could represent a process by which myeloma plasma cells interact with the bone marrow (BM) environment and influence important biological events such as bone matrix degradation, plasma cell invasion and homing and, possibly, clinical evolution. We evaluated uPAR (CD87) and its sol- uble form (suPAR) in 49 multiple myeloma (MM) patients and correlated their expression and levels with clinico- biological characteristics of the disease. Flow cytometric analysis demonstrated that CD87 was expressed in all MM patients. High CD87 expression was associated with higher intensity of expression of CD56 (P ¼ 0®038), CD38 (P ¼ 0®058) and CD138 (P ¼ 0®054) and CD45 bright positivity (P ¼ 0®014). suPAR levels correlated positively with soluble serum CD138 (P ¼ 0®001), creatinine (P ¼ 0®001), beta 2 -microglobulin (P <0®001), disease stage (P ¼ 0®017) and extra-BM involvement (P ¼ 0®002). In the 46 evaluable patients, multivariate analysis showed that high levels of suPAR (P ¼ 0®0214) and disease stage (P ¼ 0®0064) were predictive of extra-BM involvement. In multivariate Cox analysis, 13q deletion (P ¼ 0®0278), high soluble serum CD138 (P ¼ 0®0201) and high suPAR (P ¼ 0®0229) were the only parameters that independently affected survival. We conclude that CD87 is expressed on myeloma plasma cells and that suPAR, which predicts ex- tra-BM involvement and poor prognosis, possibly represents a molecule with a relevant role in the biology of MM. Keywords: multiple myeloma, CD87, soluble urokinase- type plasminogen activator receptor (suPAR), prognosis. The urokinase-type plasminogen activator system, which consists of a proteinase (the urokinase-type plasminogen activator, uPA), a receptor (the urokinase-type plasminogen activator receptor, uPAR or CD87) and inhibitors, is involved in proteolysis, cell migration and adhesion (Wei et al, 1996; Chapman, 1997; May et al, 1998), tissue remodelling and chemokine-like activities (Plesner et al, 1997). uPA is a specific serine protease, which converts plasminogen into its active form, plasmin, a broad-spectrum protease involved in the digestion of various protein substrates in the extracellular matrix. uPAR is a glycosyl- phosphatidylinositol (GPI)-anchored cell surface receptor that binds endogenously produced uPA as well as uPA released from surrounding cells, and focuses plasmin proteolytic activity on the cell surface. The uPA system has been shown to be involved in tumour cell invasion and metastasis. The invasive proper- ties of tumour cells depend on the direct proteolytic action of plasmin on extracellular matrix proteins and on its indirect activating action on latent matrix metalloproteases (MMPs; Ossowsky, 1988; Andreasen et al, 1997). Correspondence: Gian Matteo Rigolin, MD, Section of Haematology, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca, 203, 44100 Ferrara, Italy. E-mail: sse@dns.unife.it British Journal of Haematology, 2003, 120, 953–959 Ó 2003 Blackwell Publishing Ltd 953