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

Lust, John A.; Lacy, Martha Q.; Zeldenrust, Steven R.; Dispenzieri, Angela; Gertz, Morie A.; Witzig, Thomas E.; Kumar, Shaji; Hayman, Suzanne R.; Russell, Stephen J.; Buadi, Francis K.; Geyer, Susan M.; Campbell, Megan E.; Kyle, Robert A.; Rajkumar, S. Vincent; Greipp, Philip R.; Kline, Michael P.; Yuning Xiong; Moon-Tasson, Laurie L.; Donovan, Kathleen A.
February 2009
Mayo Clinic Proceedings;Feb2009, Vol. 84 Issue 2, p114
Academic Journal
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-Iβ-expressing myeloma cells In the presence of dexamethasone, IL-1 receptor antagonist (IL-1Ra), or both. Levels of lnterieukin 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.


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