Cytokine involvement in the prediction and prevention of MGUS to multiple myeloma. (2006)

CS14-02 Multiple myeloma (MM) is the model blood disorder for chemoprevention because, in its active form, it is incurable with a median survival of less than 5 years and its asymptomatic precursor conditions are often first recognized with a standard blood test. The precursor conditions consist of monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and indolent multiple myeloma (IMM). Specific criteria exist that serve as useful guidelines to allow clinicians to differentiate between MGUS, MM, SMM/IMM. Patients with MGUS usually have less than 10% marrow plasma cells, a serum monoclonal protein 10%, a serum monoclonal protein of >3 g/dL, a 24 hour urine monoclonal protein of >1 g, anemia, hypercalcemia, renal insufficiency, and lytic bone lesions. Between these two extremes of the disease, two clinically intermediate stages have been described called smoldering multiple myeloma and indolent multiple myeloma. Patients with SMM and IMM are asymptomatic. SMM patients have a marrow plasmacytosis of >10% and/or a serum monoclonal protein of >3 g/dL. Lytic bone lesions are absent and they have stable disease. Patients with IMM are similar to those with SMM except a small number of asymptomatic bone lesions may be present on bone survey studies. The current standard of care for patients with SMM and IMM is observation, however, they are at the greatest risk for progression to active myeloma usually within 1-2 yrs. Comparison of the spectrum of clinical disease between MM and its clinically benign precursor conditions have provided direction into the investigation of those changes that may be important in the pathogenesis of myeloma. For example, interleukin-6 (IL-6) has been shown to be the central growth factor for myeloma cells. Although many cytokines can stimulate IL-6 production, in myeloma we have shown that interleukin-1β (IL-1β) appears to be the major cytokine responsible for the paracrine production of IL-6 by marrow stromal cells. IL-1β is expressed by the plasma cells of virtually all myeloma patients; however, it is not produced by normal plasma cells. The aberrant IL-1β produced by the myeloma cells induces IL-6 by bone marrow stromal cells which in turn supports the growth and survival of the myeloma cells. The above observations are important because it may be possible to predict those patients that will progress to active MM and to delay or prevent this progression with IL-1 antagonists. We investigated whether levels of IL-1β biologic activity might distinguish different groups of patients with SMM. We measured the ability of IL-6 production by bone marrow stromal cells to serve as a surrogate marker for IL-1β biologic activity. Using this IL-1β bioassay, we found that it is sensitive below 1 pg/ml of recombinant IL-1β and that IL-1β biologic activity is detectable with either mature or proIL-1β transduced myeloma cell lines. Patients with active myeloma induced quantitatively higher levels of stromal cell IL-6 production when compared to those with MGUS. The bioassay distinguished two groups of SMM patients, those who were high producers similar to patients with active MM and those who were low producers comparable to MGUS patients. Subsequently, a Kaplan-Meier analysis was performed on 31 patients with SMM/IMM. The time to progression was defined as the time from the date of the bone marrow on which the IL-1β bioassay was performed to the date of progression to active MM. Twelve patients with SMM/IMM had an IL-1 level less than 1.0 by the bioassay and none of these patients have progressed to active disease with a median follow-up of 5 years. In contrast, in the group of 19 SMM/IMM patients that stimulated an IL-1 level > 1.0, 17/19 progressed to active MM with a median time to progression of 12 months. (p 90% in the majority of patients with an elevated IL-6 level. Two clinical studies have been completed at the Mayo Clinic, one in patients with high risk MGUS and one in patients with SMM/IMM, in an attempt to delay or prevent the progression to active myeloma. A Phase II placebo controlled clinical trial of Dehydroepiandrosterone (DHEA) and Clarithromycin was carried out in patients with MGUS. Patients with an IgG or IgA M-spike greater than 1.5 g/dL and bone marrow plasmacytosis 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 IL-1Ra SQ qd for 6 months unless clinical progression occurred. Non-progressors were allowed to continue on therapy with IL-1Ra alone. Low dose Dex (20 mg qweek) was added after 6 months of IL-1Ra or for evidence of clinical progression; the dose was adjusted based on response/toxicity. In the clinical trial, data were available on 47 patients; smoldering (79%) / indolent (21%). All patients received IL-1Ra initially and 20/47 subsequently received IL-1Ra/Dex. Seven patients had a decrease in the plasma cell labeling index (PCLI), a marker of cell proliferation, on IL-1Ra alone which paralleled a decrease in the high sensitivity C-reactive protein (CRP). The IL-1Ra/Dex combination has resulted in stability of disease in the majority of the 47 patients; 28 continue on therapy with a median overall progression-free survival (PFS) of 37.5 months. Four of the 47 pts achieved a minor response (MR) with IL-1Ra alone, and an additional 6 pts achieved a MR/PR after addition of Dex. The continuous measure of % reduction in CRP was significantly associated with time to progression (p=0.02). Patients who had a > 5% increase in the serum M protein (n=20) had a median TTP of 6 months whereas patients who had a 24 months (p