Konstantinos Tsionos

Cystatin-C is an independent prognostic factor for survival in multiple myeloma and is reduced by bortezomib administration

Renal impairment is a common complication of multiple myeloma, and serum cystatin-C is considered an accurate marker of glomerular filtration rate. The findings of this study suggest that serum cystatin-C is not only a sensitive marker of renal impairment, but also reflects tumor burden and is of prognostic value in multiple myeloma. Background Renal impairment is a common complication of multiple myeloma. Cystatin-C is considered an accurate marker of glomerular filtration rate in several renal disorders. Microarray analysis has revealed that cystatin-C is one of the most highly up-regulated genes in multiple myeloma. The aim of this study was to evaluate the serum levels of cystatin-C in myeloma patients, explore possible correlations with clinical data, including survival, and assess the effect of bortezomib on cystatin-C in relapsed multiple myeloma. Design and Methods We measured serum cystatin-C in 157 newly diagnosed, previously untreated myeloma patients, in 28 patients with relapsed disease pre- and post-bortezomib therapy and in 52 healthy controls, using a latex particle-enhanced nephelometric immunoassay. Results In newly diagnosed patients, cystatin-C was elevated and showed strong correlations with advanced ISS stage, extensive bone disease, high β2-microglobulin, high serum creatinine, and low creatinine clearance. Multivariate analysis revealed that only cystatin-C and lactate dehydrogenase had an independent prognostic impact on patients’ survival. The combination of cystatin-C and lactate dehydrogenase revealed three prognostic groups of patients: a high-risk group (both elevated cystatin-C and lactate dehydrogenase) with a median survival of 24 months, an intermediate-risk group (elevated cystatin-C or elevated lactate dehydrogenase) with a median survival of 48 months and a low-risk group (both low cystatin-C and lactate dehydrogenase) in which median survival has not yet been reached (p<0.001). Cystatin-C could also identify a subset of ISS-II patients with worse outcome. Relapsed patients had higher cystatin-C levels even compared to newly diagnosed patients. Treatment with bortezomib produced a significant reduction of cystatin-C, mainly in responders. Conclusions Serum cystatin-C is not only a sensitive marker of renal impairment but also reflects tumor burden and is of prognostic value in myeloma. Its reduction after treatment with bortezomib reflects bortezomib’s anti-myeloma activity and possibly bortezomib’s direct effect on renal function.

Serum concentrations of angiogenic cytokines in Waldenstrom macroglobulinaemia: the ratio of angiopoietin-1 to angiopoietin-2 and angiogenin correlate with disease severity

Angiogenesis represents an essential step of disease progression in several haematological malignancies. Microvessel density is increased in 30% of patients with Waldenstrom macroglobulinaemia (WM), but there is very limited information regarding the role of angiogenic cytokines in this disease. Serum levels of vascular endothelial growth factor (VEGF), VEGF‐A, angiogenin, angiopoietin (Ang)‐1 and ‐2, and basic fibroblast growth factor (bFGF) were evaluated in 56 WM patients at different disease phases (24 untreated, 20 relapsed/refractory and 12 patients at remission) and 11 patients with immunoglobulin M type monoclonal gammopathy of undetermined significance (IgM‐MGUS). All patients had increased levels of angiogenin, VEGF, VEGF‐A, and bFGF compared with controls. The Ang‐1/Ang‐2 ratio was reduced in WM but not in IgM‐MGUS patients. Angiogenin levels correlated with disease status: when compared with healthy subjects, patients with IgM‐MGUS and untreated WM patients had increased angiogenin serum levels, which were higher in untreated WM patients than in MGUS. WM patients at remission had lower angiogenin serum levels compared with untreated patients, but these levels were increased again in active disease post‐therapy. Angiogenin also correlated with albumin levels, while VEGF‐A correlated with β2‐microglobulin (β2M). Ang‐1/Ang‐2 ratio showed a strong, negative correlation with β2M, and positive correlation with albumin, haemoglobin and lymphadenopathy. Our results indicate a potential use of angiogenin levels for follow‐up in WM and angiogenic molecules as targets for the development of novel anti‐WM agents.

Normalization of the serum angiopoietin-1 to angiopoietin-2 ratio reflects response in refractory/resistant multiple myeloma patients treated with bortezomib

Bortezomib is a proteasome inhibitor producing high response rates in patients with relapsed/resistant multiple myeloma patients. This study investigates the effect of bortezomib on circulating angiopoietins levels, and shows that the normalization of the angiopoietin-1/angiopoietin-2 ratio reflects the response to treatment. Neoangiogenesis is involved in the pathophysiology of multiple myeloma and angiopoietins possibly contribute to myeloma-induced neovascularization. Bortezomib’s antineoplastic potential includes an anti-angiogenic effect. We determined serum levels of angiopoietin-1 and angiopoietin-2 with ELISA pre- and post-bortezomib administration in 35 patients with relapsed/refractory multiple myeloma. Pre-bortezomib, serum angiopoietin-1 levels did not differ in patients and in healthy individuals, while serum angiopoietin-2 levels were elevated. Corresponding serum angiopoietin-1/angiopoietin-2 ratio was reduced in patients compared with controls. After treatment, serum angiopoietin-1 levels increased, while serum angiopoietin-2 levels decreased, therefore the angiopoietin-1/angiopoietin-2 ratio increased and normalized. This increase was significant in patients who responded to treatment. In conclusion, angiopoietin-1/angiopoietin-2 ratio normalization reflected response to bortezomib.

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

The circulating levels of several angiogenic cytokines [angiopoietin‐1 (Ang‐1), angiopoietin‐2 (Ang‐2), vascular endothelial growth factor (VEGF), angiogenin and basic fibroblast growth factor (bFGF)] were evaluated in 174 consecutive patients with newly diagnosed, symptomatic, multiple myeloma (MM). Circulating levels of Ang‐1/Ang‐2 were reduced in myeloma patients compared to controls, whereas VEGF and angiogenin levels were increased. Reduced angiopoietin‐1/angiopoietin‐2 ratio correlated with advanced disease features including international staging system (ISS)‐3 stage, renal impairment and extensive bone disease. Based on immunohistochemical results in 20 patients (10 with the higher and 10 with the lower values of circulating angiopoietin‐2) we found that angiopoietin‐2 is expressed by myeloma cells and correlates with increased microvessel density in subsets of patients. Furthermore, Ang‐1/Ang‐2 ratio correlated with survival. Patients with circulating Ang‐1/Ang‐2 below or equal to the median value (6.03) had a median survival of 26.3 months compared to 53 months of all others (p = 0.002). Interestingly, this was mainly observed in patients who received first‐line therapy with novel agent‐based regimens (65% of our patients). Furthermore, a subset of ISS‐3 patients with serum Ang‐1/Ang‐2 above the median value had favourable prognosis (median survival: 45 months versus 17 months of all others; p = 0.0001). The multivariate analysis revealed that low Ang‐1/Ang‐2 ratio could independently predict for inferior survival in our cohort of patients (relative risk (RR) 2.07, 95% CI 1.50–2.42; p < 0.001). These results highlight the role of angiopoietins pathway in the biology of MM and reveal novel targets for the development of antimyeloma agents.

Abnormal bone remodelling and increased levels of macrophage inflammatory protein-1 alpha (MIP-1α) in Waldenström macroglobulinaemia

Serum levels of macrophage inflammatory protein‐1 alpha (MIP‐1α) and bone remodelling markers were evaluated in 38 patients with Waldenström macroglobulinaemia (WM) and correlated with clinical and laboratory variables. MIP‐1α was elevated in WM; untreated patients had higher MIP‐1α levels than patients in remission or with active disease after treatment. MIP‐1α correlated with increased bone resorption, β2‐microglobulin and splenomegaly. Receptor activator of nuclear factor‐κB ligand serum levels were elevated in WM patients; the subsequent increased bone resorption was balanced by a comparable elevation of osteoprotegerin production and bone formation. These findings may explain the absence of lytic lesions in WM patients and suggest a potential role of MIP‐1α in WM.