Polymorphisms within genes encoding Ikaros family proteins IKZF1 and IKZF3 in multiple myeloma patients treated with thalidomide.

Abstract

Background: Multiple myeloma (MM) is a hematological malignancy characterized by the presence of abnormal plasma cells. It is associated with anemia, bone lesions and renal dysfunction. Immunomodulatory drugs (IMiDs) are commonly used in MM treatment. Recent studies indicate that their therapeutic effect is caused by binding to cereblon (CRBN), which in turn causes the degradation of 2 important immune cell regulatory factors, IKZF1 and IKZF3. These are necessary for the anti-myeloma effect of IMiDs. Their expression level has been shown to affect MM survival and response to treatment. Potentially important single-nucleotide polymorphisms (SNPs) in the genes coding for IKZF1 and IKZF3 have been identified, but they have not been analyzed in MM patients before.

Objectives: The study was designed to establish the relationship between 4 SNPs in the genes coding for IKZF1 (rs61731359, rs4132601 and rs10272724) and IKZF3 (rs907091), and MM survival, response to treatment and other parameters.

Material and methods: The study involved 222 MM patients, as well as 100 control individuals. The IKZF1 and IKZF3 genotypes were determined by the LightSNiP assay. Genotyping was performed in the real-time polymerase chain reaction (PCR) LightCycler 480 device.

Results: No difference was observed between the patients and the controls for any of the SNPs, but the IKZF1 and IKZF3 variants were associated with various clinical parameters. Allele IKZF1 rs4132601 G was more common in the patients with worse response to first-line therapy (p = 0.040), particularly in the patients treated with thalidomide (p = 0.017). The patients tended to have worse overall survival. IKZF3 rs907091 CC was detected more commonly in the patients in stage I than in those in stages II and III, according to the International Staging System (ISS) criteria (p = 0.015). This genotype was also associated with a higher albumin level (p = 0.033), and was less common in the patients with the albumin level below 3.5 g/dL (p = 0.030).

Conclusions: Our results suggest that IKZF1 rs4132601 and IKZF3 rs907091 may affect response to treatment and progression in patients with MM.