Mayo Clinic Proceedings Home

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


      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-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).


      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

      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)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Mayo Clinic Proceedings
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Kyle RA
        • Rajkumar SV
        Treatment of multiple myeloma: an emphasis on new developments.
        Ann Med. 2006; 38: 111-115
        • Kyle RA
        • Rajkumar SV
        Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma.
        Hematol Oncol Clin North Am. 2007; 21: 1093-1113
        • International Myeloma Working Group
        Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group.
        Br J Haematol. 2003; 121: 749-757
        • Kyle RA
        • Remstein ED
        • Therneau TM
        • et al.
        Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma.
        N Engl J Med. 2007; 356: 2582-2590
        • Weber DM
        • Dimopoulos MA
        • Moulopoulos LA
        • Delasalle KB
        • Smith T
        • Alexanian R
        Prognostic features of asymptomatic multiple myeloma.
        Br J Haematol. 1997; 97: 810-814
        • Dimopoulos MA
        • Moulopoulos A
        • Smith T
        • Delasalle KB
        • Alexanian R
        Risk of disease progression in asymptomatic multiple myeloma.
        Am J Med. 1993; 94: 57-61
        • Facon T
        • Menard JF
        • Michaux JL
        • Groupe d'Etudes et de Recherche sur le Myelome (GERM)
        • et al.
        Prognostic factors in low tumour mass asymptomatic multiple myeloma: a report on 91 patients.
        Am J Hematol. 1995; 48: 71-75
        • Wisloff F
        • Andersen P
        • Andersson TR
        • et al.
        Incidence and follow-up of asymptomatic multiple myeloma: the myeloma project of health region I in Norway. II.
        Eur J Haematol. 1991; 47: 338-341
        • Kawano M
        • Hirano T
        • Matsuda T
        • et al.
        Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas.
        Nature. 1988; 332: 83-85
        • Schwab G
        • Siegall CB
        • Aarden LA
        • Neckers LM
        • Nordan RP
        Characterization of an interleukin-6-mediated autocrine growth loop in the human multiple myeloma cell line, U266.
        Blood. 1991; 77: 587-593
        • Klein B
        • Zhang XG
        • Jourdan M
        • et al.
        Paracrine rather than autocrine regulation of myeloma-cell growth and differentiation by interleukin-6.
        Blood. 1989; 73: 517-526
        • Portier M
        • Rajzbaum G
        • Zhang XG
        • et al.
        In vivo interleukin 6 gene expression in the tumoral environment in multiple myeloma.
        Eur J Immunol. 1991; 21: 1759-1762
        • Hilbert DM
        • Kopf M
        • Mock BA
        • Köhler G
        • Rudikoff S
        Interleukin 6 is essential for in vivo development of B lineage neoplasms.
        J Exp Med. 1995; 182: 243-248
        • Xiong Y
        • Donovan KA
        • Kline MP
        • et al.
        Identification of two groups of smoldering multiple myeloma patients who are either high or low producers of interleukin-1.
        J Interferon Cytokine Res. 2006; 26: 83-95
        • Donovan KA
        • Lacy MQ
        • Kline MP
        • et al.
        Contrast in cytokine expression between patients with monoclonal gammopathy of undetermined significance or multiple myeloma.
        Leukemia. 1998; 12: 593-600
        • Lust JA
        • Donovan KA
        The role of interleukin-1 beta in the pathogenesis of multiple myeloma.
        Hematol Oncol Clin North Am. 1999; 13: 1117-1125
        • Lacy MQ
        • Donovan KA
        • Heimbach JK
        • Ahmann GJ
        • Lust JA
        Comparison of interleukin-β1 expression by in situ hybridization in monoclonal gammopathy of undetermined significance and multiple myeloma.
        Blood. 1999; 93: 300-305
        • Horton RM
        • Hunt HD
        • Ho SN
        • Pullen JK
        • Pease LR
        Engineering hybrid genes without the use of restriction enzymes: gene splicing by overlap extension.
        Gene. 1989; 77: 61-68
        • Westendorf JJ
        • Ahmann GJ
        • Greipp PR
        • Witzig TE
        • Lust JA
        • Jelinek DF
        Establishment and characterization of three myeloma cell lines that demonstrate variable cytokine responses and abilities to produce autocrine interleukin-6.
        Leukemia. 1996; 10: 866-876
        • Feinman R
        • Koury J
        • Thames M
        • Barlogie B
        • Epstein J
        • Siegel DS
        Role of NF-κB in the rescue of multiple myeloma cells from glucocorticoid-induced apoptosis by bcl-2.
        Blood. 1999; 93: 3044-3052
        • Witzig TE
        • Timm M
        • Larson D
        • Therneau T
        • Greipp PR
        Measurement of apoptosis and proliferation of bone marrow plasma cells in patients with plasma cell proliferative disorders.
        Br J Haematol. 1999; 104: 131-137
        • Greipp PR
        • Witzig TE
        • Gonchoroff NJ
        • et al.
        Immunofluorescence labeling indices in myeloma and related monoclonal gammopathies.
        Mayo Clin Proc. 1987; 62: 969-977
        • Bataille R
        • Boccadoro M
        • Klein B
        • Durie B
        • Pileri A
        C-reactive protein and β-2 microglobulin produce a simple and powerful myeloma staging system.
        Blood. 1992; 80: 733-737
        • Dinarello CA
        Biologic basis for interleukin-1 in disease.
        Blood. 1996; 87: 2095-2147
        • Hjorth M
        • Hellquist L
        • Holmberg E
        • Magnusson B
        • Rödjer S
        • Westin J
        • Myeloma Group of Western Sweden
        Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I—a randomized study.
        Eur J Haematol. 1993; 50: 95-102
        • Rajkumar SV
        • Gertz MA
        • Lacy MQ
        • et al.
        Thalidomide as initial therapy for early-stage myeloma.
        Leukemia. 2003; 17: 775-779
        • Musto P
        • Petrucci MT
        • Bringhen S
        • et al.
        Final analysis of a multicenter, randomised study comparing zoledronate vs observation in patients with asymptomatic myeloma [abstract 534].
        Blood. 2007; 110: 164a
        • Greipp PR
        • Kyle RA
        Clinical, morphological, and cell kinetic differences among multiple myeloma, monoclonal gammopathy of undetermined significance, and smoldering multiple myeloma.
        Blood. 1983; 62: 166-171
        • Witzig TE
        • Kyle RA
        • O'Fallon WM
        • Greipp PR
        Detection of peripheral blood plasma cells as a predictor of disease course in patients with smouldering multiple myeloma.
        Br J Haematol. 1994; 87: 266-272
        • Dispenzieri A
        • Kyle RA
        • Katzmann JA
        • et al.
        Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering multiple myeloma [abstract 1487].
        Blood. 2007; 110: 445a
        • Greipp PR
        • Katzmann JA
        • O'Fallon WM
        • Kyle RA
        Value of β2-microglobulin level and plasma cell labeling indices as prognostic factors in patients with newly diagnosed myeloma.
        Blood. 1988; 72: 219-223
        • Greipp PR
        • Lust JA
        • O'Fallon WM
        • Katzmann JA
        • Witzig TE
        • Kyle RA
        Plasma cell labeling index and β2-microglobulin predict survival independent of thymidine kinase and C-reactive protein in multiple myeloma.
        Blood. 1993; 81: 3382-3387
        • Greipp PR
        • Lust JA
        Pathogenetic relation between monoclonal gammopathies of undetermined significance and multiple myeloma.
        Stem Cells. 1995; 13: 10-21
        • Huff CA
        • Matsui W
        • Smith BD
        • Jones RJ
        The paradox of response and survival in cancer therapeutics.
        Blood. 2006 Jan; 107 (Epub 2005 Sep 8.): 431-434

      Linked Article

      • Targeting the Pathogenic Role of Interleukin 1β in the Progression of Smoldering/Indolent Myeloma to Active Disease
        Mayo Clinic ProceedingsVol. 84Issue 2
        • Preview
          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.
        • Full-Text
        • PDF