The combination of intermediate doses of thalidomide and dexamethasone reduces bone marrow micro‐vessel density but not serum levels of angiogenic cytokines in patients with refractory/relapsed multiple myeloma

Abstract

The aim of the study was the evaluation of anti-angiogenic activity of the combination of intermediate doses of thalidomide and dexamethasone in patients with refractory/relapsed myeloma. Twenty-five patients were included in the study. Microvessel density (MVD) was evaluated in marrow biopsies before and after treatment. Serum levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (b-FGF), tumor necrosis factor-alpha (TNF-alpha), which have angiogenic potential and interleukin-6 (IL-6), IL-1beta, soluble IL-6 receptor (sIL-6R), and transforming growth factor-beta (TGF-beta) which are involved in the disease biology, were measured before treatment and then every 2 weeks for 8 weeks. Pretreatment levels of MVD, VEGF, b-FGF, IL-6, sIL-6R were increased in the patients compared to controls. The overall response rate to therapy was 72%. The administration of the combined regimen produced a significant reduction in MVD in responders. However, an increase in serum levels of VEGF, b-FGF, IL-6, sIL-6R was observed post-treatment in responders. In contrast, serum levels of TNF-alpha, TGF-beta, IL-1beta did not differ between patients and controls and remained unchanged during the study. These results suggest that the combination of thalidomide plus dexamethasone is an effective treatment for myeloma reducing MVD marrow levels but not serum levels of angiogenic cytokines or cytokines implicated in myeloma biology.

Circulating angiopoietin‐1 to angiopoietin‐2 ratio is an independent prognostic factor for survival in newly diagnosed patients with multiple myeloma who received therapy with novel antimyeloma agents

“…Increased circulating levels of VEGF and of angiogenin have been previously described in patients with MM [20][21][22] and our results confirm these observations. The effect of circulating VEGF on survival of myeloma patients who received CC was previously reported but the results were conflicting.…”

“…The effect of circulating VEGF on survival of myeloma patients who received CC was previously reported but the results were conflicting. 20,23 In our study, circulating VEGF had no prognostic value; this may be due to the reduction of VEGF by novel agent-based therapies, 11,22,24,25 which may override a possible adverse effect of VEGF on prognosis.…”

Patients with multiple myeloma treated with thalidomide: evaluation of clinical parameters, cytokines, angiogenic markers, mast cells and marrow CD57+ cytotoxic T cells as predictors of outcome

“…Thirdly, MVD and VEGF tended to decline in responding patients, confirming observations by some, but not all, investigators. [24][25][26] In support of our observation, Du et al and Hatjuharissi et al both reported a significant decline in MVD in patients with myeloma who responded to thalidomide and Kumar et al demonstrated a similar degree of MVD reduction to that seen in our study.…”

“…24,25,[28][29][30][31] One study correlating responses to chemotherapy with VEGF levels demonstrated results different from ours -with lower VEGF levels associated with higher complete or partial responses to chemotherapy and longer survival times.…”

“…However, the pitfalls of assessing angiogenesis in a tumor by MVD have been described elsewhere and we and others have demonstrated that MVD does not necessarily correlate with the degree of plasmacytosis in the marrow. 25,27 MVD in a tumor that is regressing under antiangiogenic treatment is related to the ratio between tumor cell death and endothelial cell apoptosis. Therefore the timing of measurement of MVD will affect the results seen, as microvessels may decline initially and then decrease more slowly or even increase as tumor cells drop out.…”