IL-1 Antagonists Are More Effective at Inhibiting IL-6 Production Than Apoptosis Inducing Agents: Implications for Targeting the Myeloma Proliferative Component.

Multiple myeloma patients with an elevated growth rate have a shortened duration of response and survival. IL-6 is a central myeloma growth factor and we have shown that abnormal production of IL-1beta in the myeloma microenvironment stimulates the generation of paracrine IL-6 and myeloma cell growth in vivo. Dexamethasone and IL-1Ra both have the ability to inhibit IL-1 induced IL-6 production in vitro however their ability to inhibit IL-6 production and myeloma cell growth have not been investigated in a comparative fashion.

In vitro, IL-1 (100, 10, 1 pg/ml) was added to stromal cell cultures in the presence or absence of IL-1Ra (1 and 0.1 μg/ml) or dexamethasone (100 and 10 μM). IL-6 levels were quantitated by ELISA. In vivo, a patient with smoldering myeloma (≥ 10% bone marrow plasma cells) received 100 mg of IL-1Ra SQ qd for 6 months, low dose dexamethasone (20 mg qweek) for 6 months, followed by the combination of IL-1Ra and dexamethasone for 6 months. The bone marrow plasma cell percentage (BMPC), serum IgG, the plasma cell labeling index (marker of myeloma cell proliferation) and the C-reactive protein (marker of IL-6 production) were monitored serially.

The effects of IL-1Ra and dexamethasone on IL-1 induced IL-6 production by marrow stromal cells are detailed in Figure 1. The results showed that IL-1Ra at 1 μg/ml was able to inhibit IL-1 induced IL-6 production back to baseline at all IL-1 concentrations tested. The inhibitory effect was less pronounced at 0.1 μg/ml IL-1Ra but still superior to dexamethasone. Dexamethasone was less effective at IL-6 inhibition compared to IL-1Ra using 100 and 10 pg/ml of IL-1 but similar at 1 pg/ml of IL-1. Of interest, the patient treated with IL-1Ra alone, dexamethasone alone, and the combination appeared to mimic these results in vivo. Anakinra alone induced a reduction of the PCLI and CRP. Dexamethasone alone decreased the M-protein; however the PCLI and CRP values increased. The PCLI increased from 0% to 0.8% and the CRP increased from 0.18 up to 1.48 indicating increased levels of IL-6 and a more active proliferative component of the disease. Subsequently, the combination of dexamethasone and IL-1Ra led to a further decrease in the IgG and the PCLI and CRP decreased again; PCLI decreased from 0.8% to 0.2% and CRP decreased from 1.48 down to 0.40.

The above results suggest that agents such as IL-1Ra are more effective at IL-6 inhibition and targeting the proliferative myeloma component than apoptosis inducing agents such as dexamethasone. Combination therapy with IL-1 inhibitors and apoptosis inducing agents may be useful in patients with active myeloma that have an elevated PCLI at diagnosis.

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No relevant conflicts of interest to declare.