Circulating Angiogenic Cytokines Are Elevated in Patients with Smoldering Myeloma; Implications Into Disease Biology

Abstract 5059

Angiogenesis is a critical step in the evolution of carcinogenesis in solid tumors and hematologic malignancies and is considered to be an early event in tumorigenesis. Multiple myeloma (MM) is a hematologic malignancy in which a preceding monoclonal gammopathy (MGUS) is considered a precursor. Asymptomatic/smoldering MM (SMM) is associated with a substantial risk of progression to MM and according to current recommendations these patients should be followed without therapy. Thus evolution from MGUS to SMM and to symptomatic myeloma is now considered as the model describing the natural history of the disease. In order to study the role and evolution of circulating angiogenesis related cytokines, we studied their levels in patients with MGUS, asymptomatic MM and symptomatic MM, before the initiation of first line therapy. We also studied possible associations of these cytokines with features of the disease in patients with SMM that could help identify possible markers of early evolution.

We measured serum levels of vascular endothelial growth factor (VEGF), angiogenin, angiopoietin (angp)-1 and -2, using standard ELISA methodology (R&D Systems, Minneapolis, MN, USA). The definition of MGUS, SMM and symptomatic MM was based on the published IMWG criteria. All above cytokines were also measured in 21 individuals with MGUS, in 174 newly diagnosed, untreated MM patients (31 with SMM) and in 44 age- and gender-matched healthy controls.

We focused our analysis on patients with SMM. The median age was 63.5 years (range 40–83 years) and 55% were males. The median bone marrow infiltration in trephine biopsy was 20% (range: 12%-75%). Sixty-one per cent had IgG, 29% had IgA isotype while 3% had light chain only myeloma and 6% had biclonal myeloma.

The median (range) serum levels for VEGF were 406.5 pg/ml (186.3–797.6 pg/ml), for angp-1 were 31064 pg/ml (18220–50856 pg/ml), for angp-2 were 1434 pg/ml (486.1–4004.5 pg/ml), for angp-1 to angp-2 ratio were 20.8 (6.5–78.1), for angiogenin were 262732.6 pg/ml (138670–1003040 pg/ml) and for bFGF were 12.082 pg/ml (non-detected to 123.37 pg/ml). There were no significant correlations of the levels of angiogenesis related cytokines with serum beta-2 microglobulin levels, the levels of the monoclonal protein, IgA versus IgG isotype, serum LDH levels or age. Patients with extensive bone marrow infiltration (≥60%) had significantly higher levels of ang-2 (p=0.017) and significantly lower angp-1/angp-2 ratio (p=0.004) compared to all others. Compared to healthy controls, patients with SMM had higher levels of angp-1 (p=0.05) and angp-2 (p=0.03) but their respective ratio was not significantly different (p=0.272). Serum levels of VEGF were significantly higher in SMM patients than in controls (mean 429 pg/ml vs. 196 pg/ml, p<0.001). Similarly serum levels of angiogenin were significantly higher in SMM (mean 304028 pg/ml vs 190245 pg/ml, p<0.001). When patients with SMM compared to MGUS patients, there were no significant differences for any of the studied angiogenesis related cytokines. Compared to patients with symptomatic MM, patients with SMM had higher levels of angp-1 (p<0.001) and lower level of angp-2 (p<0.001) resulting in a significantly lower angp-1/angp-2 ratio, indicating a switch to increased vessel-formation activity, while the levels of VEGF were similar.

The above results indicate that early in the evolution of the disease (MGUS to SMM to Symptomatic MM) there is an angiogenic switch which is manifested by an increase in the levels of angiogenic cytokines that promote neovasculogenesis (such as VEGF, angp-2 and angiogenin) and a gradual suppression of cytokines that balance their effects (such as angp-1). A possible prognostic significance of the circulating levels of angiogenic cytokines in patients with SMM that could help identify patients at higher risk for progression to symptomatic MM needs further study.