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
2009; Elsevier BV; Volume: 84; Issue: 2 Linguagem: Inglês
10.4065/84.2.114
ISSN1942-5546
AutoresJohn A. Lust, Martha Q. Lacy, Steven R. Zeldenrust, Angela Dispenzieri, Morie A. Gertz, Thomas E. Witzig, Shaji Kumar, Suzanne R. Hayman, Stephen J. Russell, Francis K. Buadi, Susan Geyer, Megan E. Campbell, Robert A. Kyle, S. Vincent Rajkumar, Philip R. Greipp, Michael Kline, Yuning Xiong, Laurie L. Moon‐Tasson, Kathleen A. Donovan,
Tópico(s)Immunotherapy and Immune Responses
ResumoOBJECTIVE 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 clinicaltrials.gov identifier: NCT00635154
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