Paradoxical effect of lenalidomide on cytokine/growth factor profiles in multiple myeloma.

Multiple myeloma (MM) is a presently incurable plasma cell malignancy with a high degree of heterogeneity at presentation and a great variability with regard to the clinical outcome of patients following chemotherapy treatment. Recently, new therapies, such as proteasome inhibitors and immunomodulatory drugs, have been introduced, expanding the options for the treatment of MM. Lenalidomide (LEN) (Revlimid; Celgene, Summit, NJ, USA), a derivative of thalidomide, is a second-generation oral immunomodulatory drug with proven activity against MM in clinical studies and with a toxicity profile that differs from that of thalidomide. The use of IMiDs alone or as part of combinations plays an increasingly important role in the management of MM patients in all phases of treatment, as induction, consolidation or maintenance. Lenalidomide targets both MM cells and their microenvironment, while also modulating the immune system through the activation of natural killer, CD4+ and CD8+ cells, the inhibition of regulatory T cells and the augmentation of humoral immunity (Raje et al, 2006; Palumbo et al, 2008). The direct anti-MM effect of LEN was shown to occur through the induction of a G1 growth arrest of myeloma cells (Escoubet-Lozach et al, 2009) and was consistently associated with a decrease in interferon regulatory factor 4 (Lopez-Girona et al, 2011). However, it was shown that the inhibitory effect of LEN on myeloma cell proliferation differed from one cell line to another (Lopez-Girona et al, 2011), raising the question of whether there is a correlation with the molecular heterogeneity of MM. Beside the well-known direct effect of LEN on myeloma proliferation, both the anti-inflammatory and antiangiogenic effects of LEN in the bone marrow environment have previously been shown to contribute significantly to the antimyeloma activity of the agent (Raje et al, 2006). Particularly, LEN was selected for its increased capacity to inhibit strongly tumour necrosis factor-α (TNF-α) secretion by peripheral blood cells compared with thalidomide (Muller et al, 1999). However, the direct anti-inflammatory effect of LEN on myeloma cells has not been evaluated previously. Finally, because insulin-like growth factor-1 (IGF-1) has an important role in the pathogenesis of MM, acting not only as a growth, clonogenic and survival factor but also by favouring the homing of myeloma cells to the bone environment and the angiogenesis process (Collette et al, 2007; Menu et al, 2009; Sprinski et al, 2009), we explored the effect of LEN on IGF-1 mRNA synthesis.