Elsevier

Mayo Clinic Proceedings

Volume 84, Issue 2, February 2009, Pages 114-122
Mayo Clinic Proceedings

ORIGINAL ARTICLE
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

https://doi.org/10.4065/84.2.114Get rights and content

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.

Trial Registration

clinicaltrials.gov identifier: NCT00635154

Section snippets

In Vitro Studies

Transduction of Myeloma Cell Lines. KAS-6/1 myeloma cells were retrovirally transduced with a mature IL-1β complementary DNA (cDNA) construct or vector alone using the RetroXpress System available from Clontech (Palo Alto, CA). A human mature IL-1β cDNA was isolated using polymerase chain reaction with appropriate IL-1β oligonucleotide primers and cDNA from normal bone marrow mononuclear cells. An ATG start site was added to the 5′ end of the mature IL-1β construct using polymerase chain

In Vitro Studies

We investigated the effects of dexamethasone and IL-1Ra on stromal cell IL-6 production and myeloma cell apoptosis using an in vitro myeloma cell/stromal cell coculture assay. Control vector-transduced, IL-1β-negative KAS-6/1 cells were cocultured with stromal cells and dexamethasone (10 μM), IL-1Ra (1 μg/mL), or both (or, for controls, with neither) for 48 hours, and the percentage of apoptotic cells was quantified by flow cytometry (Figure 1). Results in Figure 1 are expressed as the percent

DISCUSSION

The results of the clinical trial demonstrated that IL-1Ra in vivo targets the myeloma proliferative component. Interleukin 1 inhibitors can be successfully used in the treatment of patients with SMM or IMM to prevent the progression to active myeloma. In patients with SMM or IMM and an elevated on-study PCLI, IL-1Ra led to a decrease in both the levels of hs-CRP, a surrogate marker for plasma cell IL-6 levels, and correspondingly, the PCLI, a measure of the myeloma cell proliferative rate in

CONCLUSION

Many patients with SMM or IMM are at high risk of progression to active myeloma. We investigated whether the development of active myeloma could be delayed in patients with SMM or IMM by performing in vitro laboratory studies with IL-1β-transduced myeloma cell lines and a phase 2 clinical trial using IL-1Ra and low-dose dexamethasone. The results of the clinical trial showed that IL-1Ra targeted the proliferative myeloma fraction in vivo, resulting in a decrease in hs-CRP levels, a surrogate

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    This work was supported by the Multiple Myeloma Research Foundation, the Robert A. Kyle Hematologic Malignancies Fund, and the National Institutes of Health (P0I CA62242).

    Dr Lust received travel support from Amgen, and Dr Greipp is a member of the Amgen Advisory Board.

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