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Targeting the Pathogenic Role of Interleukin 1β in the Progression of Smoldering/Indolent Myeloma to Active Disease

  • Charles A. Dinarello
    Correspondence
    Address correspondence to Charles A. Dinarello, MD, Department of Medicine, Division of Infectious Diseases, University of Colorado Denver, 12700 E 19th Ave, B168, Aurora, CO 80045
    Affiliations
    Department of Medicine, Division of Infectious Diseases, University of Colorado Denver Aurora
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      The article by Lust et al
      • Lust JA
      • Lacy MQ
      • Zeldenrust SR
      • et al.
      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.
      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.
      • Kyle RA
      • Remstein ED
      • Therneau TM
      • et al.
      Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma.
      For reduction of IL-1β activity, the trial used anakinra, a recombinant form of the naturally occurring interleukin 1 receptor antagonist (IL-1Ra) that is used for the treatment of rheumatoid arthritis and autoinflammatory diseases.
      • Dinarello CA
      Immunological and inflammatory functions of the interleukin-1 family.
      The results of the study by Lust et al suggest that reducing the activity of IL-1β does, in fact, significantly increase progression-free survival (PFS) in these high-risk patients. The trial is thoroughly encouraging because long-term use of anakinra is safe. The combination of anakinra plus a low dose of dexamethasone provided the best outcomes. There may be a hidden benefit of reducing IL-1β activity in these patients; IL-1β is a potent, proangiogenic cytokine,
      • Voronov E
      • Shouval DS
      • Krelin Y
      • et al.
      IL-1 is required for tumor invasiveness and angiogenesis.
      and, compared with thalidomide, anakinra is essentially free of toxic adverse effects. A National Institutes of Health trial of anakinra as an antiangiogenic therapy for patients with cutaneous melanoma is ongoing.
      In a 1999 article, Lust and Donvoan
      • Lust JA
      • Donovan KA
      The role of interleukin-1 beta in the pathogenesis of multiple myeloma.
      reported their in vitro observations on IL-1β in multiple myeloma, which led to the design of a clinical trial that would test their hypothesis. The findings of the current trial
      • Lust JA
      • Lacy MQ
      • Zeldenrust SR
      • et al.
      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.
      represent the culmination of these investigators' lifelong pursuit of a better understanding of multiple myeloma. Moreover, it was from their studies of myeloma cells from patients with various monoclonal gammopathies that the importance of IL-1β-driven IL-6 emerged.
      • Donovan KA
      • Lacy MQ
      • Kline MP
      • et al.
      Contrast in cytokine expression between patients with monoclonal gammopathy of undetermined significance or multiple myeloma.
      Most medical advances result from years of laboratory investigation, often using cells and tissue samples from patients with a particular disease. The aim is to develop or use drugs that target the pathogenic mechanism of the disease in question. Thus, the current clinical study by Lust et al
      • Lust JA
      • Lacy MQ
      • Zeldenrust SR
      • et al.
      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.
      is a triumph of translational research. Because blocking IL-1β reduces IL-6 as well as the proangiogenic chemokine IL-8, the use of IL-1β-blocking strategies may result in new standards of therapy for high-risk patients with SMM/IMM.
      The story starts more than 25 years ago with work on soluble products, then called lymphokines but now termed cytokines. Although many of these cytokines stimulated B-lymphocyte proliferation and antibody production, several laboratories focused on a cytokine that is now called IL-6. Interleukin 6 is a versatile cytokine. Although it is a B-lymphocyte growth factor, it is of interest today primarily for its ability to stimulate the liver to synthesize several acute phase proteins, most notably C-reactive protein (CRP). Measurement of CRP levels serves as a sensitive and reliable biomarker for many inflammatory diseases, both local and systemic, including risk of cardiovascular disease. In the Framingham cohort, increasing levels of serum IL-6 correlated significantly with sarcopenia and death.
      • Payette H
      • Roubenoff R
      • Jacques PF
      • et al.
      Insulin-like growth factor-1 and interleukin 6 predict sarcopenia in very old community-living men and women: the Framingham Heart Study.
      When IL-6 was tested in humans as an inducer of platelets, it was shown to increase platelets in patients with chemotherapy-induced bone marrow suppression. When injected into humans, IL-6 induced high levels of CRP.
      The concept that antibodies to IL-6 could be used to suppress IL-6 grew out of many studies of bone marrow cultures from patients with multiple myeloma.
      • Gu ZJ
      • De Vos J
      • Rebouissou C
      • et al.
      Agonist anti-gp130 transducer monoclonal antibodies are human myeloma cell survival and growth factors.
      There was no dearth of reports that IL-6 stimulated the growth and survival of myeloma-associated plasma cells in vitro and that antibodies to IL-6 added to bone marrow cultures in vitro inhibited the proliferation of these cells. The next step was testing neutralizing anti-IL-6 antibodies in patients with active multiple myeloma. However, when trials failed, interest in treating multiple myeloma by blocking a growth factor waned.
      • Bataille R
      • Barlogie B
      • Lu ZY
      • et al.
      Biologic effects of anti-interleukin-6 murine monoclonal antibody in advanced multiple myeloma.
      Although IL-1β was known to stimulate IL-6 in vitro as well as in several animal models of inflammatory diseases, not until the clinical trials of anakinra in patients with sepsis was it revealed that blocking IL-1 activity reduced IL-6 levels in a dose-dependent manner, suggesting a pivotal role for IL-1 in controlling the production of IL-6 in humans.
      • Fisher Jr, CJ
      • Slotman GJ
      • Opal SM
      • IL-1RA Sepsis Syndrome Study Group
      • et al.
      Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial.
      In nearly all patients with rheumatoid arthritis or autoinflammatory diseases treated with anakinra, serum IL-6 levels decreased within days.
      • Goldbach-Mansky R
      • Dailey NJ
      • Canna SW
      • et al.
      Neonatal-onset multisystem inflammatory disease responsive to interleukin-1β inhibition.
      Not unexpectedly, levels of CRP also decreased. In fact, a decrease in IL-6 and CRP levels heralds the amelioration of disease severity in systemic inflammation treated with any therapeutic agent that specifically targets IL-1. In autoinflammatory diseases, IL-1β rather than IL-1α appears to be the agonist because treatment with soluble IL-1 receptors (known as the IL-1 Trap or rilonacept) and with monoclonal antibodies to IL-1β is effective.
      • Hoffman HM
      • Throne ML
      • Amar NJ
      • et al.
      Efficacy and safety of rilonacept (interleukin-1 trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies.
      • Donath M
      • Weder C
      • Whitemore J
      • et al.
      XOMA 052, an anti-IL-1β antibody, in a double-blind, placebo controlled, dose escalation study of the safety and pharmacokinetics in patients with type 2 diabetes mellitus—a new approach to therapy [abstract 1].
      Because quantifying the low levels of circulating IL-1β levels in human disease is difficult, circulating levels of IL-6 are commonly used as a reliable marker of IL-1β activity. By default, CRP levels are also a biomarker for IL-1β activity.
      Given this background, Lust et al
      • Lust JA
      • Lacy MQ
      • Zeldenrust SR
      • et al.
      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 JA
      • Donovan KA
      The role of interleukin-1 beta in the pathogenesis of multiple myeloma.
      reasoned that a better control of IL-6 activity for proliferation and survival of myeloma plasma cells was to block IL-1β activity. They found that relatively low amounts of IL-1β induced large amounts of IL-6 from bone marrow stem cells cocultured with a myeloma cell line secreting active IL-1β. This paracrine in vitro assay served as a model for the bone marrow microenvironment in multiple myeloma. Although the presence of dexamethasone in these cocultures reduced some stromal cell IL-6, the amount of IL-6 remained sufficiently high to protect the plasma cells against dexamethasone-induced apoptosis. The presence of anakinra in the cocultures greatly reduced IL-6 levels, but myeloma cell death did not increase. However, the combination of anakinra plus dexamethasone induced myeloma cell death.
      However encouraging the results of in vitro studies, a clinical trial was needed to truly test the hypothesis that myeloma cell-derived IL-1β induces large amounts of stromal cell IL-6 and that, in turn, IL-6 promotes the survival and expansion of myeloma cells. The aim of the Lust et al
      • Lust JA
      • Lacy MQ
      • Zeldenrust SR
      • et al.
      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.
      study reported in this issue was to reduce IL-1β activity in vivo and show that IL-1β had a pathogenic role in patients with myeloma. Patients with SMM or IMM were selected with the clinical objective of slowing or preventing progression to active disease. Anakinra is readily available and has been used for the past 7 years in more than 100,000 patients with rheumatoid arthritis and autoinflammatory diseases without evidence of increased opportunistic infections, including Mycobacterium tuberculosis reactivation.
      In the Lust et al
      • Lust JA
      • Lacy MQ
      • Zeldenrust SR
      • et al.
      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.
      study, all patients received 100 mg/d of anakinra subcutaneously for 6 months. Serum CRP levels were used to monitor the IL-6 activity. As with IL-1β determinations, the activity of the cytokine is important, not the measure of its immunoreactivity; therefore, a decrease in the serum CRP level becomes the measure of the efficacy of reducing IL-1β activity with anakinra. Indeed, during the 6 months of anakinra therapy, CRP levels decreased in some patients, paralleling a decrease in the plasma cell labeling index, a measure of myeloma cell proliferation in unfractionated bone marrow cells. Thus, reducing IL-1β activity alone was effective in some patients. After 6 months of anakinra, a low dose of dexamethasone (20 mg/wk) was added.
      During the trial, the effectiveness of reducing IL-1β production was monitored. First synthesized as an inactive precursor, IL-1β requires processing by the intracellular enzyme caspase-1, followed by secretion of the active cytokine by the cell. Because common epitopes are shared by the inactive IL-1β and the processed active IL-1β, no enzyme-linked immunosorbent assay or other immunoassay accurately measures active IL-1β. More often than not, reports of IL-1β levels represent both the inactive and the active cytokine. Therefore, the investigators developed a bioassay for determining the activity of IL-1β in cultured bone marrow from patients with myeloma; this bioassay was able to determine the amount of IL-6 that was attributable to IL-1β. Using this bioassay system, investigators could monitor the biological activity of IL-1β during the trial.
      The overall PFS for the 47 study patients who received anakinra (25 of whom also received dexamethasone) was greater than 3 years; in 8 patients, it was greater than 4 years. Compared with historical experience, the findings indicate a significant failure to progress to active disease. Two patients are used to illustrate the effects of blocking IL-1β activity in combination with the proapoptotic effect of dexamethasone. Unexpectedly, stable disease was maintained in the 2 cases for more than 3 and even 4 years; at the time of this writing, progression to active disease has not yet occurred in these patients. The parameters used to determine the predictive value of the responses were established in the study. Patients with a decrease of greater than 15% from baseline CRP levels after 6 months of anakinra monotherapy had more than 3 years of PFS, whereas patients with a 15% decrease or less in CRP levels during anakinra therapy had a PFS of 6 months (P<.002). In the study, patients with a decrease in CRP levels were more likely to have stable disease, confirming that effectively blocking IL-1β (using CRP levels as the marker for IL-1β activity) can halt progression to active myeloma. Other markers for lack of disease progression are reported in the study.
      Where do we go from here? The methods for reducing IL-1β activity are relatively straightforward, including treatment with the IL-1 Trap, neutralizing antibodies to IL-1β, or recombinant IL-1Ra (anakinra). For patient comfort, antibodies are given monthly, every 6 weeks, or even less frequently if possible. The amount of IL-1β that induces IL-6 is low and thus easily amenable to strategies that neutralize IL-1β. In contrast, with the sole exception of red blood cells, IL-1 receptors are present on all cells, and the IL-1Ra anakinra does not distinguish between an IL-1 receptor on a hair follicle and that on a myeloma plasma cell. In many ways, the study by Lust et al
      • Lust JA
      • Lacy MQ
      • Zeldenrust SR
      • et al.
      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.
      suggests that responders may benefit more from a neutralization-based strategy to reduce IL-1β activity than from receptor blockade. Continued treatment with an IL-1β-blocking strategy in combination with low-dose dexamethasone may eliminate the monoclonal clones. The methods described by Lust et al
      • Lust JA
      • Lacy MQ
      • Zeldenrust SR
      • et al.
      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.
      provide the hematologist with a bioassay for making that determination. However, for now, offering IL-1β-blocking strategies to high-risk patients with SMM/IMM is safe and nontoxic and could prevent progression to active myeloma.

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