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

Division of Hematology, Mayo Clinic, Rochester, MN 55905.
Mayo Clinic Proceedings (Impact Factor: 6.26). 03/2009; 84(2):114-22. DOI: 10.4065/84.2.114
Source: PubMed


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.
Stromal cells were cocultured with IL-1beta-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).
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.
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. Trial Registration: identifier: NCT00635154.

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Available from: Shaji K Kumar, Dec 12, 2014
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    • "Indeed, blocking IL-1 in patients with smoldering or indolent myeloma reduces IL-6 production and prolongs progression-free survival. [11] Proinflammatory cytokines possess several properties that can be considered beneficial to the host when challenged with invasion from bacteria and other microorganisms in the immediate environment. An IL-1-mediated increase in adhesion molecules on the endothelium certainly facilitates the emigration of neutrophils into the tissues, which are an absolute requirement for killing of bacteria. "
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