NUMBER OF ADVERSE CYTOGENETIC LESIONS DETECTED BY FISH IS ASSOCIATED WITH PROGNOSIS IN NEWLY DIAGNOSED MULTIPLE MYELOMA PATIENTS TREATED WITH THALIDOMIDE-BASED REGIMENS

Background:

Cytogenetic abnormalities are considered the major prognostic factors in multiple myeloma (MM). The most important chromosomal aberrations associated with unfavourable prognosis are translocations involving immunoglobulin heavy chain gene located in chromosome 14q32, like t(4,14)(p16;q32), t(14;16)(q32;q23) or t(14;20)(q32;q12), amp(1q21), del(17p13) and del(13q14).

Aims:

In this study we assessed the prognostic value of t(4,14)(p16;q32), amp(1q21), del(17p13) and del(13q14) as well as the combination of these lesion in newly diagnosed MM patients treated with thalidomide-based regimens.

Methods:

The study group consisted of 128 patients treated with cyclophosphamide, thalidomide and dexamethasone(CTD, n=96) or melphalan, prednisone and thalidomide (MPT, n=32). Responding patients from CTD group were given high-dose melphalan with autologous stem cell support (HDT/ASCT, n=65). Bone marrow aspirates obtained from patients at diagnosis were analyzed for the presence of t(4,14)(p16;q32), amp(1q21), del(17p13) and del(13q14) using fluorescence in situ hybridization (FISH). The cut-off level for all abnormalities was 20% according to the recommendations of the European Myeloma Network.

Results:

FISH analysis detected t(4,14)(p16;q32) in 20%, amp(1q21) in 45%, del(17p13) in 17% and del(13q14) in 44% of patients; 30% had 1 lesion, 24% 2 lesions and 17% 3 or more. On univariate analysis the presence of all analyzed abnormalities was associated with shorter progression-free survival (PFS) and overall survival (OS): for t(4,14)(p16;q32) PFS was 7.0 versus 18.9 months (p=0.003) and OS 23.6 versus 44.3 months (p=0.026); for amp(1q21) PFS 8.0 versus 29.0 months (p<0.001) and OS 24.0 versus 55.3 months (p<0.001); for del(17p13) PFS 5.5 versus 17.0 months (p=0.048) and OS 12.0 versus 45.0 months (p=0.016); for del(13q14) PFS 8.0 versus 28.0 months (p=0.003) and OS 23.8 versus 52.9 months (p<0.001). Multivariate analysis was performed for six covariates: age, HDT/ASCT and four examined genetic lesions. It confirmed amp(1q21), del(17p13) and del(13q14) as being independently associated with shorter PFS (p<0.001, p<0.001 and p=0.042 accordingly) and OS (p<0.001, p<0.001 and p=0.007 accordingly) and HDT/ASCT with longer PFS (p<0.001) and OS (p<0.001). The number of genetic abnormalities detected in patients significantly influenced both PFS and OS. The median PFS was 38.9 months in patients with no lesions, 18.4 months in patients with 1 lesion, 11.5 months in patients with 2 lesions and 5.0 months in patients with 3 or more lesion (p<0.001). The median OS was 79.6 months, 39.6 months, 25.0 months and 12.0 months accordingly (p<0.001). Adverse prognosis associated with multiple genetic changes was also seen in the subgroup of patients undergoing HDT/ASCT (median PFS 46.3 months, 31.8 months, 12.0 months and 5.0 months accordingly, p<0.001; median OS 98.6 months, 39.7 months, 26.9 months and 12.0 months accordingly, p<0.001).

Summary / Conclusion:

The results of the study showed that the presence of amp(1q21), del(17p13) and del(13q14) is associated with significantly shortened PFS and OS in newly diagnosed MM patients treated with thalidomide-based regimens. Accumulation of adverse cytogenetic abnormalities resulted in further reduction of survival and the number of coexisting genetic lesions defined risk groups with different PFS and OS. Impact of cytogenetic changes on survival was also seen in patients undergoing HDT/ASCT suggesting that this procedure is not able to change poor prognosis associated with high-risk genetic abnormalities.

Email address: norbertgrzasko@gmail.com

Abstrakta v časopise Haematologica 2013, Suppl1

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