Abstract 2802

Poster Board II-778

Introduction:

Bone marrow angiogenesis has been shown to correlate with growth, disease progression and survival in multiple myeloma (MM). The angiogenic stimulus in the bone marrow microenvironment is mediated by various angiogenic factors. Serum levels of the angiogenic cytokines basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) can be elevated in MM patients in different disease stages.

Patients and methods:

In the present study we investigated the prognostic value of circulating levels of serum-bFGF, serum-HGF and plasma-VEGF by enzyme-immunoassays in 100 newly diagnosed MM patients, 24 with smoldering MM and 76 patients with symptomatic MM. In addition, the parameters of the recently introduced International Staging System (ISS), beta-2-microglobulin (β2M) and albumin were evaluated in comparison to the angiogenic cytokines in a multivariate prognostic model.

Results:

Circulating levels of serum bFGF, serum HGF and plasma VEGF were significantly elevated in symptomatic versus smoldering MM (P= 0.015, P= 0.005 and P=0.015 respectively). In a univariate survival analysis, all angiogenic factors and a combined angiogenic cytokine score (0-1 versus 2-3 angiogenic factors elevated) were identified as significant prognostic factors for overall survival in the total cohort of MM patients (P= 0.046, P= 0.005 and P< 0.009, respectively) and in symptomatic MM (P= 0.025, P< 0.001 and P= 0.018, respectively). In addition to angiogenic cytokine levels, beta-2-microglobulin (β2M) and albumin as parameters of the ISS were also entered in a multivariate analysis. In this model, bFGF, HGF and VEGF were found to be independent prognostic factors (hazard ratio: 2.5, 3.6 and 2.6, respectively) in symptomatic MM (Table 1). A combined angiogenic risk score (0-1 or 2-3 angiogenic factors elevated) was also a significant prognosticator for overall survival in symptomatic MM (P< 0.001) and clearly separated two subgroups with a good and a worse prognosis within ISS stage III (P= 0.003). In patients with a high angiogenic risk score (2 or 3 factors elevated) there was no significant survival benefit of high-dose therapy, in contrast to patients with a low risk score (0-1 factors elevated).

Conclusions:

Our data show that elevated angiogenic cytokines predict poor prognosis and gives additional prognostic information in comparison to the ISS parameters β2M and albumin in symptomatic MM. Since a variety of drugs with anti-angiogenic properties are currently in use or under investigation in MM, our data support the idea of using angiogenic cytokines as risk factors to identify poor prognosis groups, which may be considered for novel anti-angiogenic treatment strategies.

Table 1.

Univariate and multivariate prognostic value of angiogenic cytokines in comparison to β2-microglobulin and albumin in symptomatic MM.

Prognostic parameterlog rank†P = *Cox regression††P = *Hazard ratio(95% CI)
bFGF (> median) 0.03 0.02 2.5 (1.2 – 5.6) 
HGF (> median) < 0.001 < 0.001 3.6 (1.6 – 8.0) 
VEGF (> median) 0.02 0.01 2.6 (1.2 – 5.7) 
albumin (≥ 3.5 g/dl) 0.05 0.02 0.4** (0.2 – 0.8) 
β2M (μ 5.5 mg/l) 0.05 n.s. 1.2 (0.5 – 3.3) 
angiogenic score (0-1 vs 2-3) < 0.001 < 0.001 1.6 (1.2 – 2.0) 
Prognostic parameterlog rank†P = *Cox regression††P = *Hazard ratio(95% CI)
bFGF (> median) 0.03 0.02 2.5 (1.2 – 5.6) 
HGF (> median) < 0.001 < 0.001 3.6 (1.6 – 8.0) 
VEGF (> median) 0.02 0.01 2.6 (1.2 – 5.7) 
albumin (≥ 3.5 g/dl) 0.05 0.02 0.4** (0.2 – 0.8) 
β2M (μ 5.5 mg/l) 0.05 n.s. 1.2 (0.5 – 3.3) 
angiogenic score (0-1 vs 2-3) < 0.001 < 0.001 1.6 (1.2 – 2.0) 
†

, univariate model, cut-off value for bFGF, HGF and VEGF: median values

††

, adjusted multivariate model including β2M, albumin and bFGF, HGF or VEGF

*

,P < 0.05 = statistically significant;

**

, hazard ratio < 1 = risk reduction; n.s., not significant

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Disclosures:

No relevant conflicts of interest to declare.

Topics:
angiogenesis, multiple myeloma, fibroblast growth factor 2, vascular endothelial growth factor a, cytokine, albumins, angiogenesis factor, beta 2-microglobulin, prognostic factors, disease progression

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2009 by The American Society of Hematology
2009
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