title: Circulating angiopoietin-1 to angiopoietin-2 ratio is an independent prognostic factor for survival in newly diagnosed patients with multiple myeloma who received therapy with novel antimyeloma agents.
abstract: The circulating levels of several angiogenic cytokines [angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF), angiogenin and basic fibroblast growth factor (bFGF)] were evaluated in 174 consecutive patients with newly diagnosed, symptomatic, multiple myeloma (MM). Circulating levels of Ang-1/Ang-2 were reduced in myeloma patients compared to controls, whereas VEGF and angiogenin levels were increased. Reduced angiopoietin-1/angiopoietin-2 ratio correlated with advanced disease features including international staging system (ISS)-3 stage, renal impairment and extensive bone disease. Based on immunohistochemical results in 20 patients (10 with the higher and 10 with the lower values of circulating angiopoietin-2) we found that angiopoietin-2 is expressed by myeloma cells and correlates with increased microvessel density in subsets of patients. Furthermore, Ang-1/Ang-2 ratio correlated with survival. Patients with circulating Ang-1/Ang-2 below or equal to the median value (6.03) had a median survival of 26.3 months compared to 53 months of all others (p = 0.002). Interestingly, this was mainly observed in patients who received first-line therapy with novel agent-based regimens (65% of our patients). Furthermore, a subset of ISS-3 patients with serum Ang-1/Ang-2 above the median value had favourable prognosis (median survival: 45 months versus 17 months of all others; p = 0.0001). The multivariate analysis revealed that low Ang-1/Ang-2 ratio could independently predict for inferior survival in our cohort of patients (relative risk (RR) 2.07, 95% CI 1.50-2.42; p < 0.001). These results highlight the role of angiopoietins pathway in the biology of MM and reveal novel targets for the development of antimyeloma agents.
authors.affiliation: Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece. eterpos@med.uoa.gr
authors.forename: Evangelos
authors.initials: E
authors.lastname: Terpos
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Anargyrou
authors.forename: Eirini
authors.initials: E
authors.lastname: Katodritou
authors.forename: Efstathios
authors.initials: E
authors.lastname: Kastritis
authors.forename: Athanasios
authors.initials: A
authors.lastname: Papatheodorou
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Christoulas
authors.forename: Anastasia
authors.initials: A
authors.lastname: Pouli
authors.forename: Eurydiki
authors.initials: E
authors.lastname: Michalis
authors.forename: Sosana
authors.initials: S
authors.lastname: Delimpasi
authors.forename: Maria
authors.initials: M
authors.lastname: Gkotzamanidou
authors.forename: Nikitas
authors.initials: N
authors.lastname: Nikitas
authors.forename: Vasilios
authors.initials: V
authors.lastname: Koumoustiotis
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Margaritis
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Tsionos
authors.forename: Ekaterini
authors.initials: E
authors.lastname: Stefanoudaki
authors.forename: John
authors.initials: J
authors.lastname: Meletis
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Zervas
authors.forename: Meletios A
authors.initials: MA
authors.lastname: Dimopoulos
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D042683:Angiopoietin-1 / Q000097:blood*; D042702:Angiopoietin-2 / Q000097:blood*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016207:Cytokines / Q000097:blood; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality*; D011379:Prognosis
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; D000970:Antineoplastic Agents; D016207:Cytokines