p53 gene deletion detected by fluorescence in situ hybridization is an adverse prognostic factor for patients with multiple myeloma following autologous stem cell transplantation

Abstract

We investigated the relevance of p53 deletions to the clinical outcome of patients with multiple myeloma (MM) treated with highdose chemotherapy and autologous stem cell transplantation. Hemizygous p53 gene deletions were detected by fluorescence in situ hybridization in 10 of 105 (9.5%) patients studied. p53 deletions were associated with higher serum calcium (P ‫؍‬ .0062) and creatinine (P ‫؍‬ .013) levels, but there were no association with patient age, gender, ␤ 2 -microglobulin, C-reactive protein, hemoglobin, albumin or bone lytic lesions, or immunoglobulin isotype. There were no associations of p53 deletions with 13q deletions or translocations t(11;14) or t(4;14). Patients with p53 deletions had significantly shorter progression-free (median, 7.9 versus 25.7 months, P ‫؍‬ .0324) and overall survival (median, 14.7 versus 48.1 months, P ‫؍‬ .0008) than patients without a p53 deletion. A multivariate analysis confirmed p53 deletion was an independent prognostic factor predicting shortened progression-free (P ‫؍‬ .0009) or overall survival (P ‫؍‬ . Introductionp53, a tumor suppressor gene, is implicated in the regulation of cell proliferation, differentiation, and apoptosis. 1 Inactivation of p53 inactivation by mutation or allelic loss has been observed in various human neoplasms and associated with tumor progression. 2,3 In multiple myeloma (MM), p53 mutations are rare and may represent late events in myeloma progression. [4][5][6] The frequency of p53 deletions detected by fluorescence in situ hybridization (FISH) is reported to range from 9% to 34% of MMs. [7][8][9][10] The p53 gene deletions are associated with poor survival in patients with MM treated with conventional chemotherapy regimens, 7,8,10 but there is little information on the relevance of p53 deletions to survival of patients with MM treated with autologous stem cell transplantation (ASCT).We recently reported that t(4;14) but not t(11;14) is an adverse prognostic factor in patients with MM undergoing ASCT. 11 The current study extends our experience of cytoplasmic light-chain immunofluorescence combined with FISH (cIg-FISH) to investigate the frequency and prognostic significance of p53 deletions in a single institutional cohort of patients with MM treated with high-dose chemotherapy followed by autologous stem cell support. Study design PatientsBetween January 1998 and December 2001, 128 consecutive patients were diagnosed and treated for MM with high-dose chemotherapy followed by ASCT at the Princess Margaret Hospital/University Health Network. Informed consent was provided by the patients in this study. The clinical and biologic features were previously reported. 11 Karyotypic analysis was not routinely performed during this study period. All patients received 4 to 5 cycles of the VAD regimen (vincristine, Adriamycin [doxorubicin], and dexamethasone) followed by stem cell mobilization with cyclophosphamide 2.5 g/m 2 and granulocyte colony-stimulating factor (G-CSF; 10 g/kg) and 1 course of melphalan 200 mg/m 2 immediately prior to ASCT. ...

A practical guide to defining high-risk myeloma for clinical trials, patient counseling and choice of therapy

“…25,32 Again, a number of series have confirmed the very poor prognosis of MM patients with deletion of p53. 6,26,27,29,63 Interestingly, this deletion is not specifically correlated with other high-risk groups particularly t(4;14) that seems almost mutually exclusive. 46 …”

“…25,26,28,46,63,64 This deletion is generally considered to be a progression event and is prevalent in plasma cell leukemia and central nervous system MM. 25,32 Again, a number of series have confirmed the very poor prognosis of MM patients with deletion of p53.…”

“…[30][31][32] Each of these genetic events (IgH translocation and hyperdiploidy) is then unified by the downstream upregulation of either cyclin D1, D2 or D3. 18 This seminal phase of chromosome rearrangement or duplication and disease initiation is followed by further karyotypic instability that often includes deletions/monosomy at chromosome 13q14 [32][33][34] or chromosome 17p13 (p53) 26,28 or amplifications of chromosome 1 35,36 or chromosome 8 (MYC). 37 Somatic activating mutation in genes such as P53, FGFR3, NRAS and KRAS2 may arise, or secondary translocation may occur by a non-B-cell-mediated mechanisms.…”

“…6,[15][16][17][18][19][20][21][22][23][24][25][26][27][28] In contrast, the SEER database also demonstrates that 15% of MM patients were alive 10 years after diagnosis. We will show here that the primary determinant of these heterogeneous patient outcomes are the underlying genetics of the malignant plasma cell and propose that this finding is sufficiently important as to warrant a formal definition of 'high risk disease'.…”

Prognostic factors for hyperdiploid-myeloma: effects of chromosome 13 deletions and IgH translocations

“…Levels of prognostic Table 5 Cox proportional hazard regression model for overall survival within hyperdiploid myeloma when only immunoglobulin heavy chain translocations are considered 37,38 are associated with poorer prognosis regardless of treatment modalities. On the other hand, t(11;14) has been associated with better prognosis in patients treated with high dose chemotherapy and stem cell support in some series 13,16 but not others.…”