Prognostic Value of Bone Marrow Angiogenesis in Newly Diagnosed Multiple Myeloma: A Comparison with Conventional Prognostic Factors.

Abstract

Background: Abnormally increased tumor associated neovasculature plays an important role in tumor progression in solid tumors and hematological malignancies. In multiple myeloma (MM) bone marrow angiogenesis, measured in terms of microvessel density (MVD), has prognostic value, and appear to increase with disease progression from monoclonal gammopathy of undetermined significance to relapsed MM. We have shown that MVD has prognostic value in patients with newly diagnosed MM including patients undergoing upfront high dose therapy and stem cell transplantation, but comparison with other known prognostic factors has been limited by sample size. It is also not known whether the MVD adds prognostic value once the recently described International Staging System (ISS) is applied. The goal of this study was to determine the prognostic effect of bone marrow MVD in newly diagnosed MM relative to the ISS and other known prognostic factors.Methods: We studied 400 patients with newly diagnosed MM seen at the Mayo Clinic between March of 1988 and December 2001. Sections from bone marrow biopsy blocks from the time of initial diagnosis were studied by immunohistochemistry using antibodies against CD34 antigen to high light the endothelial cells. Under low power (100X); three areas with maximum number of microvessels (hotspots) were identified. Each of these areas was further studied at 400X magnification and the number of microvessels per high power field counted. The average of the three readings was taken as the MVD for the sample. In addition, the samples were graded as low, intermediate or high by using a visual estimate as previously described. Additional clinical data was extracted from medical records. Some of the patients have been included in previous studies related to angiogenesis.Results: A total of 400 patients in whom a bone marrow biopsy from within 30 days of diagnosis was available were studied. The pts were followed for a median of 37 months (Range: 1 month to 16.5 years) and 318 pts (80%) had died at the time of this analysis. The median MVD for the entire group was 14.7 (Range 0–168). The median overall survival for the three groups according to the MVD grade was lower for the high grade group (31.9 months) compared to the intermediate grade group (37.2 months) and the low grade group (not reached); P <0.029, log rank test. We examined this group of patients for other factors prognostic for overall survival. Factors significant on univariate analysis included ISS stage, platelet count (<150 vs. >= 150 X 106/L), and plasma cell labeling index (<1 vs >=1). In a multivariate analysis using these variables and MVD as a continuous variable, high MVD and the ISS staging system were significantly associated with poorer survival (Table).Conclusion: In this large group of pts with newly diagnosed MM, we confirm the prognostic value of increased bone marrow angiogenesis. We examined the MVD as a continuous variable in the multivariate analysis for a closer evaluation of this measure in this comparison. More importantly, the prognostic value appears to be independent of the ISS and other major prognostic factors. The resultsof this study reinforces the biological relevance of this finding in MM.HR95% CIP valueMVD1.006(1.001, 1.011)0.0279ISS Stage I0.37(0.25, 0.56)<0.001ISS Stage II0.58(0.41, 0.83)0.0025