Interleukin-1 Receptor Antagonist (IL-1Ra) Targets the Proliferative Component in Early Stage Myeloma. (2004)

Abstract Background: It has been hypothesized that multiple myeloma (MM) remains incurable due to a stemcell/proliferative component that responds only partially to standard treatment regimens. We have shown that abnormal production of IL-1beta in the myeloma microenvironment stimulates the generation of paracrine IL-6, the central myeloma growth factor, and that IL-1Ra will inhibit paracrine IL-6 production in vitro. Based on these preclinical studies, we have developed a Phase II trial using IL-1Ra. Purpose: To determine the biologic and clinical activity of IL-1Ra (Anakinra) in a subgroup of smoldering MM (SMM) patients that present with an elevated plasma cell labeling index (PCLI; a measure of myeloma cell proliferation). Methods: 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. Patients received 100 mg of Anakinra (IL-1Ra) SQ qd for a total duration of 6 months. Results: Eleven of 29 patients enrolled on the protocol had an on-study PCLI &gt; 0 and have completed six months of therapy with IL-1Ra. Seven of the 11 patients had a decrease in the PCLI of 75–100% (see Table), three had only modest changes (≤ 50%), and one had an increase. The decrease in the PCLI paralleled a decrease in the high sensitivity C-reactive protein (CRP) in all cases (43–90% decrease). The above results suggested that IL-1Ra inhibited IL-6 production in the myeloma microenvironment, as evidenced by a reduction in the CRP, resulting in suppression of myeloma cell growth. However, there was little effect on the M-protein. To investigate these clinical observations, we co-cultured IL-1beta transduced +/− myeloma cells with stromal cells +/− dexamethasone (DEX), IL-1Ra, or both for 48 hours and quantitated the percent apoptotic cells by flow cytometry and IL-6 production by ELISA. The results showed: 1) IL-1Ra was superior at inhibition of IL-6 but caused no increase in apoptosis; 2) the DEX apoptotic effect was eliminated by IL-6 3) DEX and IL-1Ra combined induced maximal IL-6 inhibition and apoptosis of myeloma cells. Based on these in vitro results, 5 of the 11 patients have been advanced to IL-1Ra + low dose DEX (20 mg/week) resulting in 4/5 minor responses (25–50% decrease M-spike) and 1/5 with stable disease. Conclusion: The use of IL-1Ra is a novel targeted therapeutic strategy that interferes with myeloma cell growth. By inhibiting IL-1beta induced IL-6 production, IL-1Ra specifically targets the proliferative myeloma fraction and also complements DEX induced apoptosis. Preliminary studies on the use of IL-1 inhibitors in SMM patients to delay/prevent progression to active MM and to minimize toxicity appear encouraging, however, more patients need to be studied. Patient # On Study 6 months % Change 1 PCLI 0.8% 0% −100% CRP (mg/L) 2.01 0.58 − 71% M-spike (g/dL) 2.5 2.4 − 4% 2 PCLI 0.2% 0% − 100% CRP 0.89 0.51 − 43% M-spike 2.8 2.7 − 3% 3 PCLI 0.2% 0% − 100% CRP 5.7 1.02 − 82% M-spike 2.9 2.9 0% 4 PCLI 4.1% 1% − 75% CRP 3.39 1.51 − 55% M-spike 3.8 3.6 − 5% 5 PCLI 0.4% 0% − 100% CRP 3.46 0.34 − 90% M-spike 2.7 3.1 15% 6 PCLI 0.3% 0% − 100% CRP 17 5.35 − 68% M-spike 4.4 3.9 − 11% 7 PCLI 1.2% 0% − 100% CRP 1.06 0.32 − 70% M-spike 3.1 2.9 − 6%