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VEGF and prognosis in multiple myeloma

VEGF and progression

Clinical outcomes in multiple myeloma have been correlated with VEGF expression and increased vascularity.¹ In fact, multiple myeloma was the first hematological malignancy in which a prognostic relevance of angiogenesis was found.²

In multiple studies, increased plasma or serum VEGF was associated with more advanced disease stages in multiple myeloma.² By analyzing plasma blood in 34 patients, Di Raimondo and colleagues found that mean VEGF concentrations were significantly lower in patients with stage I multiple myeloma vs stages II-III (43 pg/mL vs 125 pg/mL, respectively; P=0.01); bone marrow VEGF concentrations were also lower (94 pg/mL vs 278 pg/mL, respectively; P=0.2).³ Through an analysis of 20 representative biopsies, Swelam and Tamimi showed a direct correlation between upregulation of inducible nitrous oxide and VEGF with high-grade tumors in multiple myeloma. They showed a similar direct correlation between MVD and high-grade tumors in multiple myeloma.⁴

In a preclinical study, Podar and colleagues found that VEGF caused increased proliferation of multiple myeloma cells, and in a dose-dependent manner. In this study, they cultured multiple myeloma cells from 5 patients and then treated them with VEGF. Radioactive thymidine labeling ([3H] thymidine [3H (dT)]) was then used to measure cell proliferation, which showed a 1.3- to 1.4-fold increase for VEGF concentrations of 1000 ng/mL vs control. Results are shown in the graph below.⁵

Effect of VEGF on multiple myeloma cell proliferation⁵

Adapted from Podar K, Tai YT, Davies FE, et al. Blood. 2001;98:428-435. Figure 2.

VEGF and MVD

Multiple studies have shown that VEGF is significantly and directly correlated with MVD in patients with multiple myeloma.^6,7

Through immunohistochemical bone marrow analysis in 75 patients with multiple myeloma, Choi and colleagues found that VEGF was significantly correlated with MVD. The increased levels of MVD indicated that angiogenesis may play a role in multiple myeloma.⁶ Gianelli and colleagues also noted that high VEGF levels were directly linked to increased MVD in multiple myeloma.⁷

MVD and progression

Through analysis of bone biopsies in 59 patients with multiple myeloma, Marković and colleagues showed that MVD is significantly correlated with overall survival in multiple myeloma (46 months for "low" MVD [<15 microvessels per 3 "hot spots" at 400x magnification] vs 22 months for "high" MVD [≥15 microvessels per 3 "hot spots" at 400x magnification]; P=0.009).⁸ Studies have found that increased MVD and bone marrow angiogenesis are powerful, adverse prognostic factors in multiple myeloma.^9,10 Furthermore, MVD was found to be 5 to 6 times higher in active multiple myeloma vs nonactive multiple myeloma.¹⁰

Sezer and colleagues showed that patients with a reduction in MVD (after chemotherapy) had significantly longer progression-free survival in multiple myeloma vs those without a decrease in MVD (P=0.006).¹¹

References:

1.

Podar K, Anderson KC. Blood. 2005;105:1383-1395.

2.

Jakob C, Sterz J, Zavrski I, et al. Eur J Cancer. 2006;42:1581-1590.

3.

Di Raimondo F, Azzaro MP, Palumbo G, et al. Haematologica. 2000;85:800-805.

4.

Swelam WM, Tamimi DM. Pathol Res Pract. 2010;206:753-759.

5.

Podar K, Tai YT, Davies FE, et al. Blood. 2001;98:428-435.

6.

Choi JH, Ahn MJ, Jang SJ, et al. Int J Hematol. 2002;76:460-464.

7.

Gianelli U, Vener C, Raviele P, et al. Am J Clin Pathol. 2007;128:966-973.

8.

Marković O, Marisavljević D, Cemerikić V, et al. Med Oncol. 2008;25:451-457.

9.

Kumar S, Witzig TE, Timm M, et al. Leukemia. 2003;17:2025-2031.

10.

Ria R, Roccaro AM, Merchionne F, et al. Leukemia. 2003;17:1961-1966.

11.

Sezer O, Niemöller K, Kaufmann O, et al. Eur J Haematol. 2001;66:238-244.