Abstract
Immunomodulatory drugs (IMIDs) are very effective in the treatment of multiple myeloma (MM). The description of their cereblon-mediated mechanism of action was a hallmark in MM research. Although the importance of IMID-induced degradation of cereblon-binding proteins is well described in vitro, the prognostic value of their expression levels in MM cells is less clear. Based on recently published data showing somewhat conflicting RNA levels, we analyzed the association between the levels of the Ikaros family zinc finger protein 1 (IKZF1), IKZF3, and karyopherin subunit alpha 2 (KPNA2) proteins measured by flow cytometry and prognostic parameters in 214 newly diagnosed MM patients who were randomized in the GMMG HD6 trial. No statistically significant associations between the expression levels and age, gender, light chain type, International Staging System (ISS) stage or cytogenetic high- and normal risk groups could be identified. Hyperdiploid MM cells expressed significantly higher levels of IKZF1, IKZF3 and KPNA2 than nonhyperdiploid cells. In contrast, translocation t(11;14) was associated with significantly lower expression levels. In conclusion, the observed overexpression of cereblon-binding proteins in MM cells with gain of chromosomes 5, 9, 11, 15, and 19 is consistent with the previously proposed positive regulation of MYC by IKZF1 and IKZF3, as well as MYC activation in hyperdiploid MM cells.
Highlights
IntroductionLenalidomide, an immunomodulatory drug (IMID), is a highly effective treatment option for patients with newly diagnosed and relapsed multiple myeloma (MM) and achieves response rates of up to 70% in combination with dexamethasone
Lenalidomide, an immunomodulatory drug (IMID), is a highly effective treatment option for patients with newly diagnosed and relapsed multiple myeloma (MM) and achieves response rates of up to 70% in combination with dexamethasone1–3.In terms of its mechanism of action, lenalidomide binds to cereblon (CRBN), the substrate adaptor of the CRL4CRBN E3 ubiquitin ligase complex4
Patient selection and data matching An analysis of 214 patients who were newly diagnosed with MM and randomized to participate in the multicenter prospective phase III trial GMMG-HD6 on the “Effect of Elotuzumab in VRD (Velcade, Revlimid, and Dexamethasone) Induction/Consolidation and Lenalidomide Maintenance” conducted by the German-Speaking Myeloma Multicenter Group (GMMG) was performed
Summary
Lenalidomide, an immunomodulatory drug (IMID), is a highly effective treatment option for patients with newly diagnosed and relapsed multiple myeloma (MM) and achieves response rates of up to 70% in combination with dexamethasone. In terms of its mechanism of action, lenalidomide binds to cereblon (CRBN), the substrate adaptor of the CRL4CRBN E3 ubiquitin ligase complex. By modulating the substrate specificity of the CRL4CRBN E3 ubiquitin ligase, lenalidomide induces the selective ubiquitination and subsequent degradation of Ikaros family zinc finger protein (IKZF) 1 and IKZF3 in MM cells. The expression levels of several CRBN-binding proteins, including IKZF1, IKZF3, and karyopherin subunit alpha 2 (KPNA2), are associated with clinical variables and cytogenetic aberrations and have predictive and prognostic relevance in IMID-treated patients with relapsed or newly diagnosed MM8–10. In the study by Krönke et al., Kriegsmann et al Blood Cancer Journal (2019)9:13
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