Induction of a Chronic Disease State in Patients With Smoldering or Indolent Multiple Myeloma by Targeting Interleukin 1β-Induced Interleukin 6 Production and the Myeloma Proliferative Component

OBJECTIVE: To conduct In vitro studies as well as a phase 2 clinical trial In patients with smoldering or Indolent multiple myeloma to determine if Interleukin 1 (IL-1) inhibitors can delay or prevent active myeloma. PATIENTS AND METHODS: Stromal cells were cocultured with IL-1 beta-expressing myeloma cells In the presence of dexamethasone, IL-1 receptor antagonist (IL-1Ra), or both. Levels of Interleukin 6 (IL-6) and of apoptosis were also quantified. Between November 19, 2002, and May 24, 2007, 47 patients were enrolled In the study and subsequently treated with IL-1Ra. In 25 (53%) of the 47 study patients, low-dose dexamethasone (20 mg/wk) was added. The primary end point was progression-free survival (PFS). RESULTS: In vitro, IL-1Ra was superior to dexamethasone at inhibiting IL-6 production; maximal IL-6 inhibition and apoptosis Induction were achieved by addition of both IL-1Ra and dexamethasone. In the clinical trial, 3 patients achieved a minor response to IL-1Ra alone; 5 patients achieved a partial response and 4 patients a minor response after addition of dexamethasone. Seven patients showed a decrease in the plasma cell labeling Index that paralleled a decrease In high-sensitivity C-reactive protein (hs-CRP) levels. The median overall PFS was 37.5 months. The median PFS for patients without (n=12) or with (n=35) a greater than 15% decrease In 6-month vs baseline hs-CRP levels was 6 months and more than 3 years, respectively (P=.002). Disease stability was maintained In 8 patients who received therapy for more than 4 years. CONCLUSION: In patients with smoldering or indolent multiple myeloma who were at risk of progression to active myeloma, treatment with IL-1 Inhibitors decreased the myeloma proliferative rate and hs-CRP levels in those who responded, leading to a chronic disease state and an Improved PFS.