ORIGINAL ARTICLEInduction 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
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.