Cytokines Behaviour in Multiple Myeloma during Zoledronic Acid Treatment.

Abstract

The main pathological feature underlying the bone disease in multiple myeloma is an uncoupling of bone resorption from bone formation so that resorption predominates. In the bone marrow (BM), MM plasmacells are in close contact with stromal elements and induce the release of several cytokines which modify the BM microenviroment, upregulating RANKL expression and secretion by both stroma and osteoblasts. Destruction of bone matrix induced by MM and its cellular interactions is accompanied by further release of cytokines. Bisphosphonates are chemical compounds which selectively concentrate at the interface of the active osteoclasts and the bone resorption surface where they inhibit osteoclast activity.Recently, in solid tumors, Santini et al have demostred that zoledronic acid could have an in vivo antiangiogenic property through a significant and long-lasting reduction in serum VEGF levels (Clin Cancer Res 2003; 9:2893–7). Taking into account that angiogenesis plays an important role in MM progression, we have investigated the behaviour of IL6, PDGF, IGF, TNFα and VEGF in a cohort of 28 (16 males and 13 females) consecutive MM pts with lytic bone lesions treated with 4 mg of zoledronic acid. Venous blood samples were drawn just before the beginning of drug infusion and at 1,2,7,21 (before the subsequent infusion) days after the zoledronic acid infusion. Serum samples were then tested for PDGF, VEGF, IL6, TNFα , and IGF with the R & D quantitative kits (R & D Systems, Minneapolis, USA), according to the manufacturer's instructions. Basal cytokine levels were compared with the values observed at 1, 2, 7 and 21 days using the Wilcoxon's test for nonparametric-dependent continuous variables. Differently from what observed by Santini et al in solid tumors, serum VEGF median levels did not decrease;on the contrary, it significantly increased at days 7 (P=0.0047). Moreover, IL 6 and TNFα levels significantly increased after 1 (P=0.0000 and 0.0001 respectively) and 2, ( P=0.0000 and 0.0021 respectively) days. Furthermore, PDGF significantly decreased (P=0.005) after 2 days following zoledronic acid infusion. Among these pts, 8 (28.5%) were receiving also Interferon; no statistically significant differences in the levels of VEGF, IL6, TNFa and IGF between the two groups were observed. Only the PDGF levels have shown a statistically significant decrease in the interferon group at 0, 1, 2, 7, 21 days (P<0.05). In conclusion, the cytokines' behaviour after the administration of zoledronic acid in MM is different from that observed in solid tumors; in particular, we did not observe a decrease in VEGF levels. This behaviour may partially explain why zoledronic acid has no effect on MM progression as originally postulated.