Poster Board I-857
IL-1 Antagonists Are More Effective at Inhibiting IL-6 Production than Apoptosis Inducing Agents: Implications for Targeting the Myeloma Proliferative Component. John A. Lust, MD,PhD1, Steven R. Zeldenrust, MD, PhD1, Laurie L. Moon-Tasson1*, and Kathleen A. Donovan, PhD1*. 1Division of Hematology, Mayo Clinic, Rochester, MN, United States, 55905.
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.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.