IKZF1 mRNA Expression Linked To Multiple Myeloma Lenalidomide Regimen PFS

Messenger RNA levels of the transcription factor IKZF1 may be linked to multiple myeloma progression-free survival in some patients given a lenalidomide-based regimen

medwireNews: Pretreatment plasma cell messenger (m)RNA concentrations of the lymphoid transcription factor Ikaros (IKZF1) predict progression-free survival (PFS) in lenalidomide-treated multiple myeloma (MM) patients, research suggests.

Analysis of 60 patients receiving the German Myeloma Study Group lenalidomide-based treatment protocol for newly diagnosed, symptomatic MM showed that those with IKZF1 expression levels in the lowest quartile (Q1) had significantly better PFS than patients with higher levels.

Three-year PFS was achieved by 86% of those in IKZF1 mRNA Q1 versus 51% of those in Q2–4. And this translated into a 3-year overall survival (OS) gain for Q1 patients, with an estimated rate of 100% versus 74% for Q2–4 patients.

The researchers explain in Leukemia that the immunomodulator lenalidomide interacts with the E3 ubiquitin ligase cereblon, increasing the rate of IKZF1 and IKZF3 degradation. “As MM cells depend on IKZF1 and IKZF3, depletion of both proteins results in growth inhibition”, say Jan Krönke, from Ulm University Hospital in Germany, and co-workers.

In addition, the transcription factor cereblon is also required for a ubiquitin-independent BSG pathway that promotes MM cell proliferation, giving a second lenalidomide mechanism, they write.

Multivariate analysis confirmed that poor PFS was predicted by both a high-risk cytogenetic profile, defined as the presence of del17p13, t(4;14) and/or t(14;16), with a hazard ratio (HR) of 5.06, and high pretreatment IKZF1 mRNA expression (HR=1.91).

The high-risk cytogenetic profile was also associated with a significantly increased risk of death, with a HR for OS of 7.31.

When participants were stratified by their cytogenetic risk profile, however, the team found that high levels of IKZF1, IKZF3 and BSG were associated with poor PFS in the 41 standard-risk patients. By contrast, the transcription factor expression levels did not impact the PFS of the high-risk patients.

“These observations imply that MM cells with high IKZF1, IKZF3 and/or BSG expression levels are less sensitive to a lenalidomide-comprising therapy”, the researchers write, hypothesising that high pretreatment levels may “prevent degradation of these proteins to critical low levels by the lenalidomide concentrations achieved in patients.”

Nevertheless, they observe: “Given that all our patients received lenalidomide within an intensive upfront protocol, these conclusions cannot be generalized to other commonly used anti-myeloma regimens.

“Future studies need to elucidate whether IKZF1, IKZF3 and BSG expression levels are predictive for lenalidomide-based therapies or are general prognostic markers in multiple myeloma.”

Reference

Krönke J, Kuchenbauer F, Kull M, et al. IKZF1 expression is a prognostic marker in newly diagnosed standard-risk multiple myeloma treated with lenalidomide and intensive chemotherapy: a study of the German Myeloma Study Group (DSMM). Leukemia; Advance online publication 20 January 2017. doi: 10.1038/leu.2016.384

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