The prognostic significance of 8p21 deletion in multiple myeloma

Multiple myeloma (MM) accounts for approximately 2% of all cancer deaths and 20% of deaths caused by haematological malignancies. Allogeneic stem cell transplantation might be curative for a small group of eligible patients, but the current gold standard for the treatment of patients less than 60–65 years of age is high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT). Factors that predict survival in MM including b2-microglobulin (b2M), creatinine and haemoglobin (Hb) levels have been well defined (Durie et al, 2003; Chng & Fonseca, 2005). Furthermore, the occurrence of various chromosomal abnormalities among the malignant cells, such as del(13), t(4;14), t(11;14) and del(17p) have been shown to have an impact on prognosis (Avet-Loiseau et al, 2007). Nevertheless, better assessment and stratification of prognostic factors are needed in order to comprehend the different responses to therapy. Information gained this way will enhance the understanding about treatment prediction in patients with MM. This study analyzed various previously well-known chromosomal regions and translocations by fluorescent in situ hybridization (FISH) in bone marrow (BM) aspirations from newly diagnosed patients with MM, but with added probes for the 8p21 region. We evaluated the correlations between various chromosomal abnormalities as well as their effects on survival. Statistical analysis was performed using the Statistical Package for the Social Sciences (spss) 15 software (SPSS Inc. Chicago, IL, USA) and P < 0Æ05 was considered as statistically significant. The variables were analyzed by using Log-rank tests on Kaplan–Meier plots to identify their impacts on progression-free survival (PFS) and overall survival (OS). Among the analyzed chromosomal aberrations, the frequency of occurrence was highest for del(13)(q14), at 60%, followed by amp(9)(p21) (53%), amp(15)(q22) (50%), amp(19)(q13) (41%), amp(1)(q21) (38%), del(8)(p21) (24%), del(17)(p13) (22%), t(4;14) (15%), t(11;14) (14%), and lowest for del(6)(q21) (9%). According to univariate analysis del(13)(q14), amp(1)(q21) and del(8)(p21) were significantly associated with PFS while only del(13)(q14) and del(8)(p21) had significant effect on OS. Of the 65 patients evaluated with FISH, 58 had received ASCT and 44 of these patients carried normal 8p21 whereas 14 had del(8)(p21). Survival analysis revealed that loss of 8p21 was significantly associated with poor PFS (Fig 1A) and OS (Fig 1B). Other factors, such as t(4;14) (57 months vs. 34 months, P > 0Æ05), which have been shown to affect survival did not present any significance in this series. This is possibly due to the fact that a larger number of patients is needed to investigate the effect of events with such low incidence (10– 15%) (Avet-Loiseau et al, 2007), whereas del(8)(p21) seems to have a higher incidence (24%) in this series (see Table SI for the results of FISH analysis on all the chromosomal regions as well as PFS and OS values for each group). Bivariate correlations between the occurrences of chromosomal aberrations were analyzed by a two-tailed test of significance using Kendall’s tau-b coefficient. A hierarchical clustering that fits the correlations observed by this method was obtained by using average linkage between groups and the pattern difference as a measure of the distance between factors. Hierarchical clustering analysis of FISH data resulted in three main clusters of chromosomal aberrations (Fig 1C): (i) a ‘chromosomal instability’ branch carrying the closely related aberrations del(13)(q14), t(11;14) and amp(1)(q21), (ii) a ‘hypodiploid’ branch covering losses of 6q21, 17p13, 8p21 as well as the translocation t(4;14), (iii) a ‘hyperdiploid’ branch with extra copies of 15q22, 19q13 and 9p21. Prognostic factors for survival were also subjected to multivariate analysis using the Cox proportional hazards regression model with forward stepwise method. For the multivariate analysis, only FISH results that were significantly associated with PFS or OS in the univariate analysis (13q14, 1q21 and 8p21) were used along with other data that also had a significant effect on survival in this series (percentage of plasma cells in BM at the time of diagnosis, Hb levels, b2M levels) (Table I). This method also identified del(8)(p21) as an independent prognostic factor for both PFS (P = 0Æ033) and OS (P = 0Æ029). Previous studies have linked molecular dysregulations originating from changes in the 8p21 region to various malignancies including leukaemic mantle cell lymphoma (Martinez-Climent et al, 2001), B-cell lymphoma (RubioMoscardo et al, 2005) and prostate cancer (Hornstein et al, 2008). Moreover, the loss of this region has been shown to have a negative effect on survival in head and neck cancers, but has, to our knowledge, previously not been studied in MM. This study presents del(8)(p21) as a novel independent prognostic factor in MM affecting both PFS and OS. Moreover, our data also confirmed the effects of various previously defined prognostic factors, such as del(13)(q14), amp(1)(q21), percentage of plasma cells in BM at the time of diagnosis, Hb levels, b2M levels. The 8p21 region covers a number of genes that could be taking part in the pathogenesis and progression of MM. Correspondence