Chromosome Abnormalities in Multiple Myeloma Patients: Impact on Prognosis and Survival.

The importance of genetic alterations and their prognostic impact is of growing interest in multiple myeloma (MM). Chromosome 13 abnormalities (del 13q and monosomy) have been associated with lower response rate and shorter survival in patients affected by MM, indipendently from the type of detection (karyotype versus FISH) and the type of treatment (standard versus high-dose chemotherapy). The presence of these abnormalities also in monoclonal gammopathy of uncertain significance (MGUS), suggests that they are an early genetic event, even thought it is not clear if they have a role in disease progression or represent only an initiation event.

Alterations involving the immunoglobuline heavy chain locus on 14q32 are also frequent events in plasma cell dyscrasias. The variety of partner genes suggests that it may contribute to tumor progression. The most frequent translocation is t(11;14) (30%) and t(4;14) (25%), both of high prognostic impact.

In our Institution, 40 MM patients (29 at diagnosis, 8 at relapse and 3 during post CHT follow-up) were studied by conventional cytogenetics and FISH analysis. The mean age was 63.4 (range 32–80), with male prevalence. The serum monoclonal component was IgG and IgA in 26 and 8 patients respectively; 4 patients had light chain only, 1 patient had IgD and one IgG+IgM. At the time of analysis, the stages were: I/II (n=14), IIIA (n=15) and IIIB (n=11).

At the time of cytogenetic analysis, the mean bone marrow plasma cell percentage was 47.5% (range 6–100 %). Cytogenetics and FISH analysis were performed simultaneously.

An abnormal karyotype was detected in 11/19 successful cultures: 2 patients showed del (13q), one patient monosomy 13, 4 patients had hypodiploid karyotype, 2 patients showed chromosome 1 abnormalities in a hyperdiploid karyotype, 1 patient revealed del 1q in a normal karyotype, 1 patient had hyperdiploid karyotype with +iso11q.

FISH analysis, performed with LSI D13S19 (13q14.3) and LSI IgH/CCND1-XT

(VYSIS) probes, was informative in all 40 patients: all 3 patients with chromosome 13 abnormalities had del(13q); in addition, 11/40 patients with normal or non informative karyotype showed del(13q) by FISH analysis. The mean of cells carrying del(13q) was 34% (range 15–80%); the highest values were found in patients who showed hypodiploid karyotype or del(13q) or chromosome 13 monosomy by conventional cytogenetic analysis.

FISH analysis with a t(11;14) translocation probe showed 1/40 positive patient; in addition, 5 patient showed an extra signal of 11q13, and 5 others showed an extra signal of the IgH gene, suggesting the first over expression of the CCND1 gene and the second a translocation with a different partner chromosome.

The impact of chromosome 13 deletion on time to progression and overall survival was analyzed only considering the most sensitive technique used (FISH). The time to progression analysis showed a significantly worse prognosis in del(13q) patients (p=0.0260); overall survival tended to be shorter in patients carrying del (13q), without reaching statistical significance.

Our data, even thought in a small series, confirm the negative impact of chromosome 13 deletion on prognosis and survival of MM patients. We would like to emphasize the usefulness of a very sensitive technique such as the FISH analysis, for the assessment of genetic alterations in the context of clinical trials specifically designed for MM patients with adverse prognostic features.