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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-1β-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.

      Trial Registration

      cDNA (complementary DNA), FI (fold increase), hs-CRP (high-sensitivity C-reactive protein), IL-1 (interleukin 1), IL-6 (interleukin 6), IL-1Ra (IL-1 receptor antagonist), IMM (indolent multiple myeloma), ISR (injection site reaction), MGUS (monoclonal gammopathy of undetermined significance), MR (minor response), PCLI (plasma cell labeling index), PFS (progression-free survival), PR (partial response), SMM (smoldering multiple myeloma)
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      Linked Article

      • Targeting the Pathogenic Role of Interleukin 1β in the Progression of Smoldering/Indolent Myeloma to Active Disease
        Mayo Clinic ProceedingsVol. 84Issue 2
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          The article by Lust et al1 published in this issue of Mayo Clinic Proceedings is the first study to address a purely cytokine-driven pathogenic mechanism in the progression from a premalignant state of multiple myeloma to active disease. The working hypothesis is that myeloma plasma cell-derived interleukin 1 (IL-1) β induces marrow stromal cells to produce large amounts of interleukin 6 (IL-6), thereby promoting the survival and expansion of the myeloma cells. The 47 patients with smoldering or indolent multiple myeloma (SMM/IMM) enrolled in the study were clearly at high risk of progression to full-blown multiple myeloma on the basis of well-established criteria.
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