Abstract
We analyzed the prognostic impact of the most frequent genetic abnormalities detected by fluorescence in situ hybridization in 101 patients with multiple myeloma, who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after melphalan/fludarabine-based reduced conditioning. The incidences of abnormalities in the present analysis were as follows: del(13q14) (61%), t(11;14)(q13;q32) (14%), t(4;14)(p16.3;q32) (19%), MYC-gain gains (8q24) (21%), del(17p13) (16%) and t(14;16)(q32;q23) (5%). None of the patients had t(6;14)(p25;q32). The overall complete remission (CR) rate was 50% with no differences between the genetic abnormalities except for patients with del(17p13) who achieved less CR (7 vs 56%; P=0.001). Univariate analysis revealed a higher relapse rate in patients aged >50 years (P=0.002), patients with del(13q14) (P=0.006) and patients with del(17p13) (P=0.003). In multivariate analyses, only del(13q14) (HR: 2.34, P=0.03) and del(17p13) (HR: 2.24; P=0.04) significantly influenced the incidence of relapse, whereas for event-free survival, only age (HR 2.8; P=0.01) and del(17p13) (HR: 2.05; P=0.03) retained their negative prognostic value. These data show that del(17p13) is a negative prognostic factor for achieving CR as well as for event-free survival after HSCT. Translocation t(4;14) might be overcome by allogeneic HSCT, which will have implication for risk-adapted strategies.
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References
Desikan R, Barlogie B, Sawyer J, Ayers D, Tricot G, Badros A et al. Results of high-dose therapy for 1000 patients with multiple myeloma: durable complete remissions and superior survival in the absence of chromosome 13 abnormalities. Blood 2000; 95: 4008–4010.
Shaughnessy Jr J, Tian E, Sawyer J, McCoy J, Tricot G, Jacobson J et al. Prognostic impact of cytogenetic and interphase fluorescence in situ hybridization-defined chromosome 13 deletion in multiple myeloma: early results of total therapy II. Br J Haematol 2003; 120: 44–52.
Tricot G, Barlogie B, Jagannath S, Bracy D, Mattox S, Vesole DH et al. Poor prognosis in multiple myeloma is associated only with partial or complete deletions of chromosome 13 or abnormalities involving 11q and not with other karyotype abnormalities. Blood 1995; 86: 4250–4256.
Avet-Loiseau H, Attal M, Moreau P, Charbonnel C, Garban F, Hulin C et al. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myelome. Blood 2007; 109: 3489–3495.
Avet-Loiseau H, Facon T, Grosbois B, Magrangeas F, Rapp MJ, Harousseau JL et al. Oncogenesis of multiple myeloma: 14q32 and 13q chromosomal abnormalities are not randomly distributed, but correlate with natural history, immunological features, and clinical presentation. Blood 2002; 99: 2185–2191.
Avet-Loiseau H, Gerson F, Magrangeas F, Minvielle S, Harousseau JL, Bataille R . Intergroupe Francophone du Myelome. Rearrangements of the c-myc oncogene are present in 15% of primary human multiple myeloma tumors. Blood 2001; 98: 3082–3086.
Chang H, Qi C, Yi QL, Reece D, Stewart AK . p53 gene deletion detected by fluorescence in situ hybridization is an adverse prognostic factor for patients with multiple myeloma following autologous stem cell transplantation. Blood 2005; 105: 358–360.
Chang H, Sloan S, Li DL, Yi QL, Chen CI, Reece D et al. The t(4;14) is associated with poor prognosis in myeloma patients undergoing autologous stem cell transplant. Br J Haematol 2004; 125: 64–68.
Facon T, Avet-Loiseau H, Guillerm G, Moreau P, Genevieve F, Zandecki M et al. Chromosome 13 abnormalities identified by FISH analysis and serum beta2-microglobulin produce a powerful myeloma staging system for patients receiving high-dose therapy. Blood 2001; 97: 1566–1571.
Fonseca R, Blood E, Rue M, Harrington D, Oken MM, Kyle RA et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 2003; 101: 4569–4575.
Fonseca R, Harrington D, Oken MM, Dewald GW, Bailey RJ, Van Wier SA et al. Biological and prognostic significance of interphase fluorescence in situ hybridization detection of chromosome 13 abnormalities (delta13) in multiple myeloma: an eastern cooperative oncology group study. Cancer Res 2002; 62: 715–720.
Gertz MA, Lacy MQ, Dispenzieri A, Greipp PR, Litzow MR, Henderson KJ et al. Clinical implications of t(11;14)(q13;q32), t(4;14)(p16.3;q32), and −17p13 in myeloma patients treated with high-dose therapy. Blood 2005; 106: 2837–2840.
Gutierrez NC, Castellanos MV, Martin ML, Mateos MV, Hernandez JM, Fernandez M et al. Prognostic and biological implications of genetic abnormalities in multiple myeloma undergoing autologous stem cell transplantation: t(4;14) is the most relevant adverse prognostic factor, whereas RB deletion as a unique abnormality is not associated with adverse prognosis. Leukemia 2007; 21: 143–150.
Moreau P, Facon T, Leleu X, Morineau N, Huyghe P, Harousseau JL et al. Recurrent 14q32 translocations determine the prognosis of multiple myeloma, especially in patients receiving intensive chemotherapy. Blood 2002; 100: 1579–1583.
Perez-Simon JA, Garcia-Sanz R, Tabernero MD, Almeida J, Gonzalez M, Fernandez-Calvo J et al. Prognostic value of numerical chromosome aberrations in multiple myeloma: a FISH analysis of 15 different chromosomes. Blood 1998; 91: 3366–3371.
Stewart AK, Fonseca R . Prognostic and therapeutic significance of myeloma genetics and gene expression profiling. J Clin Oncol 2005; 23: 6339–6344.
Zojer N, Konigsberg R, Ackermann J, Fritz E, Dallinger S, Kromer E et al. Deletion of 13q14 remains an independent adverse prognostic variable in multiple myeloma despite its frequent detection by interphase fluorescence in situ hybridization. Blood 2000; 95: 1925–1930.
Drach J, Schuster J, Nowotny H, Angerler J, Rosenthal F, Fiegl M et al. Multiple myeloma: high incidence of chromosomal aneuploidy as detected by interphase fluorescence in situ hybridization. Cancer Res 1995; 55: 3854–3859.
Kröger N, Schilling G, Einsele H, Liebisch P, Shimoni A, Nagler A et al. Deletion of chromosome band 13q14 as detected by fluorescence in situ hybridization is a prognostic factor in patients with multiple myeloma who are receiving allogeneic dose-reduced stem cell transplantation. Blood 2004; 103: 4056–4061.
Kröger N, Schwerdtfeger R, Kiehl M, Sayer HG, Renges H, Zabelina T et al. Autologous stem cell transplantation followed by a dose-reduced allograft induces high complete remission rate in multiple myeloma. Blood 2002; 100: 755–760.
Badros A, Barlogie B, Siegel E, Cottler-Fox M, Zangari M, Fassas A et al. Improved outcome of allogeneic transplantation in high-risk multiple myeloma patients after nonmyeloablative conditioning. J Clin Oncol 2002; 20: 1295–1303.
Bruno B, Rotta M, Patriarca F, Mordini N, Allione B, Carnevale-Schianca F et al. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med 2007; 356: 1110–1120.
Maloney DG, Molina AJ, Sahebi F, Stockerl-Goldstein KE, Sandmaier BM, Bensinger W et al. Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 2003; 102: 3447–3454.
Garban F, Attal M, Michallet M, Hulin C, Bourhis JH, Yakoub-Agha I et al. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood 2006; 107: 3474–3480.
Perez-Simon JA, Sureda A, Fernandez-Aviles F . Reduced intensity conditioning allogeneic transplantation is associated with a high incidence of extramedullary relapses in multiple myeloma patients. Leukemia 2006; 20: 542–545.
Hardan I, Rothman R, Gelibter A, Cohen N, Shimoni A, Sokolovsky M et al. Determination of chromosome 13 status in bone marrow cells of patients with multiple myeloma using combined morphologic and fluorescence in situ hybridization analysis. Exp Hematol 2004; 32: 254–260.
Bladé J, Samson D, Reece D, Apperley J, Bjoerkstrand B, Gahrton G et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. B J Haematol 1998; 102: 1115–1123.
Kröger N, Perez-Simon JA, Myint H, Klingemann H, Shimoni A, Nagler A et al. Relapse to prior autograft and chronic graft-versus-host disease are the strongest prognostic factors for outcome of melphalan/fludarabine-based dose-reduced allogeneic stem cell transplantation in patients with multiple myeloma. Biol Blood Marrow Transplant 2004; 10: 698–708.
Chesi M, Nardini E, Brents LA, Schrock E, Ried T, Kuehl WM et al. Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3. Nat Genet 1997; 16: 260–264.
Shaughnessy JD, Zhan F, Burington BE, Huang Y, Colla S, Hanamura I et al. A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood 2007; 109: 2276–2284.
Moreau P, Attal M, Garban F, Hulin C, Facon T, Marit G et al. Heterogeneity of t (4 ;14) in multiple myeloma. Long term follow-up of 100 case treated with tandem transplantation in IFM 99 trial. Leukemia 2007; 21: 2020–2024.
Acknowledgements
We thank the staff of the BMT unit for providing excellent care of our patients and the medical technicians for their excellent work in the laboratories. This work was supported by a grant of the German José Carreras Leukemia-Foundation to NK (DJCCS R 05/04v), and from the Erich and Gertrud Roggenbuck-Foundation eV to GS. GS performed designed research and wrote the paper; TH performed research and collected data; JAS, NCG and PL performed research; AS, WB, RS, MB, FA, DA, UB, CB, AZ and JSM contributed patients for the study, SO, EMP and JD performed research, TZ performed statistical analysis, NK designed the study and wrote the paper.
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Schilling, G., Hansen, T., Shimoni, A. et al. Impact of genetic abnormalities on survival after allogeneic hematopoietic stem cell transplantation in multiple myeloma. Leukemia 22, 1250–1255 (2008). https://doi.org/10.1038/leu.2008.88
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DOI: https://doi.org/10.1038/leu.2008.88
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