Elevated Level of Plasma Basic Fibroblast Growth Factor in Multiple Myeloma Correlates with Increased Disease Activity

Abstract

Recent reports that bone marrow angiogenesis is increased in multiple myeloma prompted us to examine plasma concentrations of angiogenic growth factors and to elucidate their clinical and biological significance. In 45 cases including 36 cases of multiple myeloma and 9 cases of monoclonal gammopathies of undetermined significance (MGUS), plasma concentrations of basic fibroblast growth factor (FGF-2) and vascular endothelial growth factor (VEGF) were evaluated. FGF-2 was significantly elevated in 25 out of 45 (56%) of the patients with multiple myeloma compared with control subjects (median 9.01 pg/ml vs. 1.58 pg/ml, P < < < <0.0001). The 25 cases were all active multiple myeloma, and none of the non-active myeloma and MGUS patients showed a high FGF-2 level. VEGF level was also elevated in 26 out of 45 patients (58%) compared with control subjects (median 42.0 pg/ml vs. 15.8 pg/ml, P < < < <0.0001 for VEGF). VEGF concentration was high in 20 active myelomas, but also in one non-active myeloma and five MGUS. Elevation of FGF-2 level was associated with β β β β2-microglobulin level, anemia and bone marrow plasma cell percentage, which represent disease activity. Interestingly, none of five Bence-Jones type myelomas, including four clinically active cases, revealed a high plasma FGF-2 level, while all of them showed a high VEGF level. In all five responders, the plasma FGF-2 levels were significantly decreased after chemotherapy. FGF-2 was immunohistochemically detected in the bone marrow myeloma cells of the patients with high plasma FGF-2 level. We conclude that plasma concentration of FGF-2 can be a useful indicator of disease activity.

Pre‐diagnostic blood immune markers, incidence and progression of B‐cell lymphoma and multiple myeloma: Univariate and functionally informed multivariate analyses

“…Several clinical studies have reported that the plasma concentrations of FGF‐2 were elevated in patients with active MM compared to patients with inactive disease, and this correlates with increased bone marrow angiogenesis and lymphangiogenesis 36, 37, 38, 39. MM patients who respond to chemotherapy (an immunosuppressed condition) show a significant decrease in serum FGF‐2 levels, whereas non‐responders do not 39.…”

Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma

“…This explains why FGF-2 concentrations in marrow aspirates and peripheral blood correlate with MM activity (Di Raimondo et al, 2000;Sezer et al, 2001;Sato et al, 2002). Bisping et al (2003) have illustrated the expression of highaffinity FGFR-1 through R-4 in RPMI-8226 and U266 MM cell lines and patients' plasma cells, as well as in BMSC, and hence the likelihood of both autocrine and paracrine loops of growth and angiogenesis.…”

Thalidomide for the Treatment of Refractory Multiple Myeloma: Association of Plasma Concentrations of Thalidomide and Angiogenic Growth Factors with Clinical Outcome

“…Previously we also reported that elevated plasma concentrations of FGF-2 and VEGF were observed in 55% of myeloma patients, and correlated with disease activity. 16) This growth factor paradigm may play an important role in the progression of myeloma cells, and reduction of plasma concentration of growth factors by thalidomide may induce tumor regression. Our results indicate that plasma VEGF level may correlate with clinical response to thalidomide in responders (Fig.…”

“…Those for HGF and IL-8 were all below 0.3 ng/ml and below 10 pg/ml, respectively. 16) In all patients, plasma concentrations were measured before and 4 weeks after the start of thalidomide. Additional sampling and measurement were conducted in several patients.…”

“…[12][13][14][15] We also found significant elevation of plasma concentrations of FGF-2 and vascular endothelial growth factor (VEGF) in patients with active MM. 16) Recently, several reports have demonstrated the efficacy of thalidomide in 25-58% of refractory multiple myeloma with only minor complications such as somnolence, constipation, peripheral neuropathy or skin rash. 11,[17][18][19][20] However, measurement of microvascular density of the bone marrow in MM failed to demonstrate a significant anti-angiogenic effect, and the precise mechanism of the anti-myeloma effect of this drug remains to be elucidated.…”