Interplay Between IL-1, IL-6 and IL-17 in IL-1 Receptor Antagonist (IL-1Ra) Treated Multiple Myeloma Patients

Abstract 1874

In early stage myeloma, IL-6 is a central myeloma growth factor and we have shown that abnormal production of IL-1 in the myeloma microenvironment stimulates the generation of IL-6 in a paracrine fashion. IL-1 has also been shown to be a crucial factor in the induction of IL-17 producing T-cells in vivo. IL-1Ra is a specific blocker of IL-1 activity. We have previously reported on a Phase II trial using IL-1Ra and dexamethasone, in patients with smoldering/indolent MM (SMM/IMM), showing that IL-1Ra targets the myeloma proliferative component which parallels a decrease in the C-reactive protein (CRP), a surrogate for IL-6 production. These patients are the individuals most likely to benefit from anti-cytokine therapy in an attempt to delay/prevent the development of active myeloma. Patients that had > 10% bone marrow plasma cells and/or an IgG or IgA M-spike > 3 g/dL and did not require immediate chemotherapy were eligible. All patients received 100 mg of Anakinra (IL-1Ra) SQ qd for 6 months. Patients with evidence of reduction in M-protein levels continued receiving IL-1Ra alone. Patients with stable disease at 6 months or those with a rising M-protein before 6 months received low dose dexamethasone (20 mg qweek) in addition; the dose was adjusted based on response/toxicity. Data were available on 47 patients based on intent to treat, and patients were classified as smoldering (72%) vs. indolent (28%). All 47 patients received IL-1Ra initially and 25/47 subsequently received IL-1Ra/Dex. Myeloma cell growth rate (PCLI), C-reactive protein (an in vivo marker of IL-6 levels) and IL-17 were measured in patients on trial. Seven patients had a decrease in the plasma cell labeling index (PCLI) on IL-1Ra alone which paralleled a decrease in the C-reactive protein in all cases. Three patients achieved a minor response to IL-1Ra alone and 9 patients achieved a PR/MR after addition of dexamethasone. When patients were grouped into whether they exhibited a reduction in the C-reactive protein from baseline after 6 months of therapy, the median PFS for patients without (21 patients) or with (26 patients) a greater than one-third reduction in baseline CRP was 1 year vs more than 8 years (p<.01). Analyses of biomarkers suggest that patients with elevated IL-17 levels may be less likely to respond to IL-1Ra treatment. Only 25% of the responders with a decrease in CRP had IL-17 levels > 10 pg/ml versus 60% of those without a CRP decrease. Although not statistically significant do to the small sample size, the median PFS in the IL-17 < 10 pg/ml group was 2047days vs 1367 days in the IL-17 > 10 pg/ml group. In conclusion, the above results suggest that agents such as IL-1Ra that specifically inhibit IL-1 induced paracrine IL-6 production are effective at targeting the proliferative myeloma component and warrant further investigation in combination with standard myeloma therapies. Elevated IL-17 levels may suggest that the inflammatory process is too far advanced in some individuals to respond to IL-1 blockade. Biomarkers such as CRP and IL-17 may be useful to predict those patients that are most likely to benefit from IL-1 treatment.