Negative prognostic significance of two or more cytogenetic abnormalities in multiple myeloma patients treated with autologous stem cell transplantation

Abstract

Multiple myeloma (MM) is the second most common haematological malignancy. It is characterized by malignant transformation and clonal proliferation of B-lymphocytes with the accumulation of malignant plasma cells in the bone marrow. The incidence of MM increases with age. The average age at presentation is 62 years in men and 61 years in women [1]. Patients below 40 years of age represent less than 3% of all cases. For many years, conventional chemotherapy with combination of melphalan and prednisone was the standard treatment, resulting in overall survival (OS) of approximately 3 years [2]. Currently, high-dose chemotherapy followed by autologous haematopoietic stem cell transplantation is recommended for patients below the age of 65 [3,4]. This treatment extends the OS to 4-5 years [5], with approximately 28% of patients surviving 5 or more years [6]. Despite this relative treatment success, MM remains an incurable disease. Many prognostic factors for MM have been identified. The presence of numerical and/or structural chromosomal aberrations is one of the most important indicators for the prognostic assessments.Due to low proliferation activity of MM cells, conventional cytogenetics detects chromosomal changes in as few as 26-40% of cases [7,8]. In contrast, the technique of interphase fluorescent in situ hybridization (I-FISH) in combination with cytoplasm immunoglobulin staining or immunomagnetic separation of plasma cells enables detection of specific abnormalities in up to 86-98% of patients [9,10,11] Received April 8, 2009Malignant plasma cells in multiple myeloma (MM) are frequently characterized by complex karyotypes and chromosome instability. These cytogenetic changes are considered important prognostic indicators in MM patients. We have studied samples from 68 patients with newly diagnosed MM who were treated with high-dose chemotherapy and autologous stem cell transplantation. G-banding revealed abnormal karyotypes in 14 of 55 patients (25%) who had informative conventional cytogenetics. The combination of cytoplasmic immunoglobulin light chain labeling and interphase fluorescent in situ hybridization (cIg-FISH) revealed the presence of genetic aberrations in 53 of 68 patients (78%). Chromosome 13 abnormalities were found in 33 patients (50%) and IgH rearrangements in 36 patients (56.25%). In IgH positive patients we performed subsequent examinations of IgH affecting translocations t(4;14) and t(11;14) and we found translocation t(11;14) in 8 patients (12.5%) and t(4;14) in 10 patients (15.5%). The occurrences of others chromosomal abnormalities with known prognostic impact in MM were as follows: del(17)(p13) was present in 5 patients (9.8%) and gain 1q21 in 14 patients (36%). Analysis of survival of patients with different cytogenetic abnormalities revealed shorter overall survival (OS) in patients with IgH rearrangements (p=0.020) and trend to shorter OS in patients with gain 1q21 (p=0.064), respectively. Remarkably, patients with two or more aberrations had significantly shorter overall surviva...

Soft-tissue extramedullary multiple myeloma prognosis is significantly worse in comparison to bone-related extramedullary relapse

“…The following chromosomal abnormalities with presumed impact on the prognosis of MM 16,17 were studied: RB1 deletion, p53 deletion, IgH gene disruption, translocation t(4;14), amplification 1q21 and hyperploidy. No differences were shown in the incidence of any of these chromosomal abnormalities between EM patients and those without EM (Table 5).…”

Uncovering the biology of multiple myeloma among African Americans: a comprehensive genomics approach

“…Indeed our results are indirectly supported by the finding of improved overall survival of AA patients with MM, something likely in subsets of patients with a lower prevalence of IgH translocations. 36,37 Aside from translocation events, other factors may be considered that account for the differences in MM between AA and EA patients. Distinctions in the frequency of somatic activating mutations such as those previously reported in KRAS, 38 NRAS, 38 TP53, 39 and NFkB signaling pathway members, 40 and the more novel mutations recently found by Chapman et al, 17 in FAM46C, DIS3, and the kinase, BRAF by whole genome sequencing, may reveal clues to the increased incidence seen in AA patients.…”

Nestin expression throughout multistep pathogenesis of multiple myeloma

“…The purity of PC was >90%. Interphase fluorescent in situ hybridization (iFISH) was used for detection of chromosomal abnormalities: del(13)(q14), del(17)(p13), gain 1q21, IGH rearrangements and hyperdiploidy, in CD138 + PC as described (Greslikova et al , ). One hundred PC per slide were counted, and 20% cut‐off for positivity was set according to the recommendations of the European Myeloma Network (Fonseca et al , ).…”