Increased bone marrow microvessel density in newly diagnosed multiple myeloma carries a poor prognosis

Solid organ tumors associated with neoangiogenesis, as measured by increased microvessel density (MVD), have poorer prognoses. A similar observation of increased MVD has been made in hematologic malignancies; however, its prognostic significance remains unknown. We investigated changes in MVD in 122 newly diagnosed multiple myeloma patients uniformly treated according to the "Total Therapy" protocol (remission induction followed by tandem autotransplants and interferon maintenance) from a set of 231 patients. MVD was measured as mean of 10 fields (MVD) and the single highest field (SHF) on anti-CD34-stained Zenker-fixed paraffin-embedded bone marrow biopsy sections at 400x magnification. MVD was markedly elevated in this population, with a median of 4.4 vessels/field (range, 0.6 to 55.7), and SHF was 13 vessels/field (range, 2 to 80). When compared to 54 patients with less than 4 MVD, 67 patients with mean MVD of greater than 4 had a significantly inferior median duration of event-free survival (EFS) (2.7 v 4.3 years; P =.03), overall survival (OS) (4.3 v 7.9+ years, P =.006), and median complete response (CR) duration (2.2 v 6.8+ years, P=.003). A similarly significant unfavorable relationship to EFS and OS was present for SHF greater than 13. On multivariate analysis of other previously recognized prognostic factors (beta(2)-microglobulin [beta2M], C-reactive protein [CRP], and Bartl grade; and deletion 13), MVD < or = 4 emerged as a major favorable prognostic variable for OS followed by CRP < or = 4, P=.006. Thus, tumor-associated angiogenesis as reflected by MVD is a biologically relevant and important prognostic feature that can be targeted by antiangiogenesis therapy such as thalidomide, which has remarkable antitumor activity in advanced and refractory multiple myeloma.