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

John A. Lust, Martha Lacy, Steven R. Zeldenrust, Angela Dispenzieri, Morie Gertz, Thomas Elmer Witzig, Shaji K Kumar, Suzanne R. Hayman, Stephen J Russell, Francis K. Buadi, Susan M. Geyer, Megan E. Campbell, Robert A. Kyle, S Vincent Rajkumar, Philip R. Greipp, Michael P. Kline, Yuning Xiong, Laurie L. Moon-Tasson, Kathleen A. Donovan

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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. 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.

Original languageEnglish (US)
Pages (from-to)114-122
Number of pages9
JournalMayo Clinic Proceedings
Volume84
Issue number2
DOIs
StatePublished - 2009

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Multiple Myeloma
Interleukin-1
Interleukin-6
Chronic Disease
Interleukin-1 Receptors
Dexamethasone
Disease-Free Survival
C-Reactive Protein
Clinical Trials
Apoptosis
Stromal Cells
Plasma Cells
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

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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; Zeldenrust, Steven R.; Dispenzieri, Angela; Gertz, Morie; Witzig, Thomas Elmer; Kumar, Shaji K; 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.; Xiong, Yuning; Moon-Tasson, Laurie L.; Donovan, Kathleen A.

In: Mayo Clinic Proceedings, Vol. 84, No. 2, 2009, p. 114-122.

Research output: Contribution to journalArticle

Lust, John A. ; Lacy, Martha ; Zeldenrust, Steven R. ; Dispenzieri, Angela ; Gertz, Morie ; Witzig, Thomas Elmer ; Kumar, Shaji K ; 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. ; Xiong, Yuning ; Moon-Tasson, Laurie L. ; Donovan, Kathleen A. / 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. In: Mayo Clinic Proceedings. 2009 ; Vol. 84, No. 2. pp. 114-122.
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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. 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.",
author = "Lust, {John A.} and Martha Lacy and Zeldenrust, {Steven R.} and Angela Dispenzieri and Morie Gertz and Witzig, {Thomas Elmer} and Kumar, {Shaji K} and Hayman, {Suzanne R.} and Russell, {Stephen J} and Buadi, {Francis K.} and Geyer, {Susan M.} and Campbell, {Megan E.} and Kyle, {Robert A.} and Rajkumar, {S Vincent} and Greipp, {Philip R.} and Kline, {Michael P.} and Yuning Xiong and Moon-Tasson, {Laurie L.} and Donovan, {Kathleen A.}",
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T1 - 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

AU - Lust, John A.

AU - Lacy, Martha

AU - Zeldenrust, Steven R.

AU - Dispenzieri, Angela

AU - Gertz, Morie

AU - Witzig, Thomas Elmer

AU - Kumar, Shaji K

AU - Hayman, Suzanne R.

AU - Russell, Stephen J

AU - Buadi, Francis K.

AU - Geyer, Susan M.

AU - Campbell, Megan E.

AU - Kyle, Robert A.

AU - Rajkumar, S Vincent

AU - Greipp, Philip R.

AU - Kline, Michael P.

AU - Xiong, Yuning

AU - Moon-Tasson, Laurie L.

AU - Donovan, Kathleen A.

PY - 2009

Y1 - 2009

N2 - 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-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.

AB - 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-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.

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