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Targeting the pathogenic role of interleukin 1{beta} in the progression of smoldering/indolent myeloma to active disease.

The article by Lust et al1 published in this issue of Mayo Clinic Proceedings is the first study to address a purely cytokine-driven pathogenic mechanism in the progression from a premalignant state of multiple myeloma to active disease. The working hypothesis is that myeloma plasma cell-derived interleukin 1 (IL-1) β induces marrow stromal cells to produce large amounts of interleukin 6 (IL-6), thereby promoting the survival and expansion of the myeloma cells. The 47 patients with smoldering or indolent multiple myeloma (SMM/IMM) enrolled in the study were clearly at high risk of progression to full-blown multiple myeloma on the basis of well-established criteria.2 For reduction of IL-1β activity, the trial used anakinra, a recombinant form of the naturally occurring interleukin 1 receptor antagonist (IL-1Ra) that is used for the treatment of rheumatoid arthritis and autoinflammatory diseases.3 The results of the study by Lust et al suggest that reducing the activity of IL-1β does, in fact, significantly increase progression-free survival (PFS) in these high-risk patients. The trial is thoroughly encouraging because long-term use of anakinra is safe. The combination of anakinra plus a low dose of dexamethasone provided the best outcomes. There may be a hidden benefit of reducing IL-1β activity in these patients; IL-1β is a potent, proangiogenic cytokine,4 and, compared with thalidomide, anakinra is essentially free of toxic adverse effects. A National Institutes of Health trial of anakinra as an antiangiogenic therapy for patients with cutaneous melanoma is ongoing.