Abstract
Cereblon is a primary molecular target for immunomodulatory drugs. The aim of this study was to evaluate the influence of selected clinical and molecular factors including single nucleotide polymorphisms (SNPs) in CRBN gene on the efficacy of first line CTD (cyclophosphamide, thalidomide, dexamethasone) chemotherapy in patients with multiple myeloma. Study group consisted of 68 patients. Analysis of CRBN gene SNPs (rs6768972, rs1672753) was performed using Real-Time PCR genotyping technique. Median progression free survival (PFS) was 15 months and overall survival (OS) 79 months. Factors associated with significantly shorter OS included ISS 3, kidney disease, weight loss, anemia, thrombocytopenia, hypoalbuminemia, elevated β2-microglobuline and CRP. The presence of t(4;14) was associated with significantly shorter PFS and OS. Both examined SNPs proved to be statistically significant, independent predictive factors of efficacy of the CTD chemotherapy. The presence of AA genotype (rs6768972) correlated with longer median PFS (18 vs 9 months; HR=0.49,95% CI: 0.26-0.91, p=0.0062). Conversely, in the carriers of CC genotype (rs1672753) significantly shorter median PFS was observed (4 vs 16 months; HR=3.93, 95% CI: 0.26-59.64, p=0.0321). In conclusion, SNPs of the CRBN gene may be useful in qualifying patients for treatment with regimens containing thalidomide.
Highlights
Multiple myeloma (MM) is a malignant disease characterized by clonal proliferation of atypical plasma cells, which is usually accompanied by the expression of an abnormal monoclonal protein
Genotypes AA, AC and CC of the CRBN gene occurred respectively in 50%, 42.6% and 7.4% of subjects, whereas genotypes CC, CT and TT occurred in 7.4%, 35.3% and 57.3% of patients (Table 1). Genotypes of both examined single nucleotide polymorphisms (SNPs) were within the Hardy-Weinberg equilibrium
CTD chemotherapy was a standard in newly diagnosed MM patients who qualify for high-dose chemotherapy supported by auto-HSCT
Summary
Multiple myeloma (MM) is a malignant disease characterized by clonal proliferation of atypical plasma cells, which is usually accompanied by the expression of an abnormal monoclonal protein. It constitutes about 0.8% of all malignant neoplasms and is the third most prevalent cancer of the hematopoietic system. Thalidomide, a drug with multidirectional activity towards bone marrow microenvironment and against myeloma cells was the first of IMiDs used in the therapy of MM It directly affects the neoplastic plasma cells, stopping the cells in G1 phase and causing apoptosis. It exhibits immunomodulatory activity associated with the induction of helper Th1 lymphocytes, excretion of interferon γ (IFN−γ) and interleukin 2 (IL−2) [3, 4]
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