Genetic risk identifies multiple myeloma patients who do not benefit from autologous stem cell transplantation

Abstract

Summary:Genetic aberrations have emerged as major prognostic factors for patients with multiple myeloma (MM). We evaluated 126 MM patients for t(4;14) or t(11;14), 13q or p53 deletions and correlated the number of genetic aberrations with patient's clinical outcome following undergoing autologous stem cell transplantation. We demonstrate the significance of genetic-based risk classification that clearly segregate patients into low (no genetic abnormalities or only t(11;14)), intermediate (any one of the genetic abnormalities other than t(11;14)) and highrisk groups (any two or more of the genetic abnormalities other than t(11;14)). High-risk patients do not benefit from stem cell transplant and should be offered alternative therapies. deletions; p53 deletions; fluorescence in situ hybridization; autologous stem cell transplantation Multiple myeloma (MM) is a clonal plasma cell malignancy characterized by recurrent genetic changes that include chromosome 13q14 deletions and translocations involving the immunoglobulin heavy chain switch region (IgH) with various partner genes, most commonly t(11;14) and t(4;14).1,2 We and others have found that t(4;14) but not t(11;14) detected by cytoplasmic fluorescence in situ hybridization (cIg-FISH), is an adverse risk factor for MM patients receiving high-dose therapy and autologous stem cell transplantation (ASCT). 3,4 In addition, we found that p53 deletions are an independent adverse prognostic factor in MM patients undergoing ASCT. 5 We now extend our analysis by studying MM patients evaluated by cIg-FISH for each of these four genetic abnormalities and propose a new genetic-based risk stratification model for MM patients treated with high-dose chemotherapy and ASCT. Specifically, we suggest that genetically high-risk patients do not benefit from high dose melphalan and should be offered alternative therapies. Patients and methodsA total of 126 MM patients who received melphalan-based high-dose chemotherapy and ASCT were studied. The major clinical and biological features are summarized in Table 1. After institutional ethics review board approval, bone marrow aspirates were obtained, mononuclear cells enriched for by Ficoll separation and cytospin slides prepared and stored at À701C. To improve FISH scoring specificity, we combined interphase FISH with immunofluorescent detection of the cytoplasmic light chain as previously described. 6 The FISH probes for detection of 13q deletions, t(11;14), t(4;14) and p53 deletions were previously described by us. 6 A total of 100 cells were scored for each abnormality and the percentages of cells with abnormal patterns recorded.Progression-free survival (PFS) and overall survival (OS) were calculated from the transplant date by the KaplanMeier method. Survival curves between risk groups were compared by log-rank tests. Multivariate analysis of PFS and PS was performed using the COX proportional hazards regression model. P-values o0.05 were considered significant. ResultsChromosome 13q deletions were detected by cIg-FISH in 39 of 104...

1p21 deletions are strongly associated with 1q21 gains and are an independent adverse prognostic factor for the outcome of high-dose chemotherapy in patients with multiple myeloma

“…It is evident that genetic aberrations have become a major prognostic factor for MM patients treated with conventional chemotherapy or autologous SCT. 7,9 With a larger sample size and longer follow-up, here, we confirm that 1p21 deletions are associated with a poor prognosis in MM. Importantly, after adjusting for myeloma-associated genetic risk factors including deletions in 13q and 17p, t(4;14) and CKS1B amplification, 1p21 deletion remains an independent marker predicting shorter PFS and shorter OS in MM.…”

“…The cIg-FISH methods with appropriate probes for evaluating deletions of 13q and TP53, t(11;14), t(4;14) and CKS1B amplification were described previously. 7,8 Statistical analysis Statistical evaluation was conducted using the Fisher's exact test, w 2 -test and nonparametric Wilcoxon test. Progression-free survival (PFS) and overall survival (OS) were calculated from the transplantation date by the Kaplan-Meier method.…”

“…Cytoplasmic Ig light chain immunofluorescence with simultaneous FISH analysis (cIg-FISH) was performed on fixed mononuclear BM cells on cytospin slides as previously described. 7 To investigate the 1p21 status, we identified a bacterial artificial chromosome (BAC) clone . This clone was labeled with SpectrumOrange-dUTP using a nick translation kit (Vysis, Downers Grove, IL, USA) and used as a FISH probe.…”

“…The cIg-FISH methods with appropriate probes for evaluating deletions of 13q and TP53, t(11;14), t(4;14) and CKS1B amplification were described previously. 7,8 …”

Bortezomib in relapsed multiple myeloma: response rates and duration of response are independent of a chromosome 13q-deletion

“…Together with the observation of marked responses in patients with a translocation t(4;14), another recognized poor prognostic parameter even with high-dose therapy, 16,[22][23][24][25] these results suggest that bortezomib is an active agent for MM patients with high-risk cytogenetic features. Moreover, high serum levels of b 2 -M, a dominantnegative prognostic indicator in MM patients treated with chemotherapy [10][11][12] or thalidomide, 26 were not correlated with adverse outcome after bortezomib in our investigation.…”