title: Induction of a chronic disease state in patients with smoldering or indolent multiple myeloma by targeting interleukin 1{beta}-induced interleukin 6 production and the myeloma proliferative component.
abstract: 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.
  
  
  METHODS
  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).
  
  
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  clinicaltrials.gov identifier: NCT00635154.
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, MN 55905. lust.john@mayo.edu
authors.forename: John A
authors.initials: JA
authors.lastname: Lust
authors.forename: Martha Q
authors.initials: MQ
authors.lastname: Lacy
authors.forename: Steven R
authors.initials: SR
authors.lastname: Zeldenrust
authors.forename: Angela
authors.initials: A
authors.lastname: Dispenzieri
authors.forename: Morie A
authors.initials: MA
authors.lastname: Gertz
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Witzig
authors.forename: Shaji
authors.initials: S
authors.lastname: Kumar
authors.forename: Suzanne R
authors.initials: SR
authors.lastname: Hayman
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Russell
authors.forename: Francis K
authors.initials: FK
authors.lastname: Buadi
authors.forename: Susan M
authors.initials: SM
authors.lastname: Geyer
authors.forename: Megan E
authors.initials: ME
authors.lastname: Campbell
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kyle
authors.forename: S Vincent
authors.initials: SV
authors.lastname: Rajkumar
authors.forename: Philip R
authors.initials: PR
authors.lastname: Greipp
authors.forename: Michael P
authors.initials: MP
authors.lastname: Kline
authors.forename: Yuning
authors.initials: Y
authors.lastname: Xiong
authors.forename: Laurie L
authors.initials: LL
authors.lastname: Moon-Tasson
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Donovan
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000473:pathology; D002097:C-Reactive Protein / Q000032:analysis; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D066298:In Vitro Techniques; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology / Q000627:therapeutic use*; D007375:Interleukin-1 / Q000097:blood; D015850:Interleukin-6 / Q000032:analysis / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000401:mortality; D010950:Plasma Cells / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D005938:Glucocorticoids; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D003907:Dexamethasone; D002097:C-Reactive Protein