A novel prognostic model in myeloma based on co-segregating adverse FISH lesions and the ISS: analysis of patients treated in the MRC Myeloma IX trial

K D Boyd, F M Ross, L Chiecchio, G P Dagrada, Z J Konn, W J Tapper, B A Walker, C P Wardell, W M Gregory, A J Szubert, S E Bell, J A Child, G H Jackson, F E Davies, G J Morgan, NCRI Haematology Oncology Studies Group, K D Boyd, F M Ross, L Chiecchio, G P Dagrada, Z J Konn, W J Tapper, B A Walker, C P Wardell, W M Gregory, A J Szubert, S E Bell, J A Child, G H Jackson, F E Davies, G J Morgan, NCRI Haematology Oncology Studies Group

Abstract

The association of genetic lesions detected by fluorescence in situ hybridization (FISH) with survival was analyzed in 1069 patients with newly presenting myeloma treated in the Medical Research Council Myeloma IX trial, with the aim of identifying patients associated with the worst prognosis. A comprehensive FISH panel was performed, and the lesions associated with short progression-free survival and overall survival (OS) in multivariate analysis were +1q21, del(17p13) and an adverse immunoglobulin heavy chain gene (IGH) translocation group incorporating t(4;14), t(14;16) and t(14;20). These lesions frequently co-segregated, and there was an association between the accumulation of these adverse FISH lesions and a progressive impairment of survival. This observation was used to define a series of risk groups based on number of adverse lesions. Taking this approach, we defined a favorable risk group by the absence of adverse genetic lesions, an intermediate group with one adverse lesion and a high-risk group defined by the co-segregation of >1 adverse lesion. This genetic grouping was independent of the International Staging System (ISS) and so was integrated with the ISS to identify an ultra-high-risk group defined by ISS II or III and >1 adverse lesion. This group constituted 13.8% of patients and was associated with a median OS of 19.4 months.

Figures

Figure 1
Figure 1
Venn diagram of the relationship of each of the adverse FISH groups (adverse IGH translocations, +1q21 and del(17p13)).
Figure 2
Figure 2
OS of each of the adverse FISH lesions when they occur in isolation compared to samples lacking any adverse lesions.
Figure 3
Figure 3
OS graded by number of adverse lesions, showing the progressive impact of accumulation of adverse lesions.
Figure 4
Figure 4
A – PFS of genetic risk groups defined by the presence of 0, 1 and >1 adverse FISH lesions respectively. B – OS of genetic risk groups defined by the presence of 0, 1 and >1 adverse FISH lesions respectively.
Figure 4
Figure 4
A – PFS of genetic risk groups defined by the presence of 0, 1 and >1 adverse FISH lesions respectively. B – OS of genetic risk groups defined by the presence of 0, 1 and >1 adverse FISH lesions respectively.
Figure 5
Figure 5
Integration of the ISS and FISH groups to identify an ultra-high risk group, defined by ISS II or III with >1 adverse lesion.

References

    1. Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Blade J, et al. International staging system for multiple myeloma. J Clin Oncol. 2005 May 20;23(15):3412–3420.
    1. Shaughnessy JD, Jr., 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 Mar 15;109(6):2276–2284.
    1. DecauxO LL, Magrangeas F, et al. Prediction of survival in multiple myeloma based on gene expression profiles reveals cell cycle and chromosomal instability signatures in high-risk patients and hyperdiplod signatures in low risk patients: A study of the Intergroupe Francophone dy Myelome. J Clin Oncol. 2008;26(24)
    1. Dickens NJ, Walker BA, Leone PE, Johnson DC, Brito JL, Zeisig A, et al. Homozygous deletion mapping in myeloma samples identifies genes and an expression signature relevant to pathogenesis and outcome. Clin Cancer Res. 2010 Mar 15;16(6):1856–1864.
    1. Keats JJ, Reiman T, Maxwell CA, Taylor BJ, Larratt LM, Mant MJ, et al. In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression. Blood. 2003 Feb 15;101(4):1520–1529.
    1. 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 Jun 1;101(11):4569–4575.
    1. Chang H, Sloan S, Li D, Zhuang L, Yi QL, Chen CI, et al. The t(4;14) is associated with poor prognosis in myeloma patients undergoing autologous stem cell transplant. Br J Haematol. 2004 Apr;125(1):64–68.
    1. 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 Oct 15;106(8):2837–2840.
    1. Zhan F, Huang Y, Colla S, Stewart JP, Hanamura I, Gupta S, et al. The molecular classification of multiple myeloma. Blood. 2006 Sep 15;108(6):2020–2028.
    1. 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 Apr 15;109(8):3489–3495.
    1. Neben K, Jauch A, Bertsch U, Heiss C, Hielscher T, Seckinger A, et al. Combining information regarding chromosomal aberrations t(4;14) and del(17p13) with the International Staging System classification allows stratification of myeloma patients undergoing autologous stem cell transplantation. Haematologica. 2010 Jul;95(7):1150–1157.
    1. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008 Aug 28;359(9):906–917.
    1. Pineda-Roman M, Zangari M, Haessler J, Anaissie E, Tricot G, van Rhee F, et al. Sustained complete remissions in multiple myeloma linked to bortezomib in total therapy 3: comparison with total therapy 2. Br J Haematol. 2008 Mar;140(6):625–634.
    1. Avet-Loiseau H, Leleu X, Roussel M, Moreau P, Guerin-Charbonnel C, Caillot D, et al. Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p) J Clin Oncol. 2010 Oct 20;28(30):4630–4634.
    1. Ross FM, Ibrahim AH, Vilain-Holmes A, Winfield MO, Chiecchio L, Protheroe RK, et al. Age has a profound effect on the incidence and significance of chromosome abnormalities in myeloma. Leukemia. 2005 Sep;19(9):1634–1642.
    1. Avet-Loiseau H, Malard F, Campion L, Magrangeas F, Sebban C, Lioure B, et al. Translocation t(14;16) and multiple myeloma: is it really an independent prognostic factor? Blood. 2011 Feb 10;117(6):2009–2011.
    1. Drach J, Ackermann J, Fritz E, Kromer E, Schuster R, Gisslinger H, et al. Presence of a p53 gene deletion in patients with multiple myeloma predicts for short survival after conventional-dose chemotherapy. Blood. 1998 Aug 1;92(3):802–809.
    1. Chang HQC, Yi QL, Reece D, Stewart AK. p53 gene deletion detected by fluorescent in situ hybridization is an adverse prognostic factor for patients with multiple myeloma following autologous stem cell transplantation. Blood. 2005;105:358–360.
    1. Harousseau JL, Avet-Loiseau H, Attal M, Charbonnel C, Garban F, Hulin C, et al. Achievement of at least very good partial response is a simple and robust prognostic factor in patients with multiple myeloma treated with high-dose therapy: long-term analysis of the IFM 99-02 and 99-04 Trials. J Clin Oncol. 2009 Dec 1;27(34):5720–5726.
    1. 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 Dec 1;86(11):4250–4256.
    1. 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 May 1;91(9):3366–3371.
    1. 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 Mar 15;95(6):1925–1930.
    1. Chiecchio L, Protheroe RK, Ibrahim AH, Cheung KL, Rudduck C, Dagrada GP, et al. Deletion of chromosome 13 detected by conventional cytogenetics is a critical prognostic factor in myeloma. Leukemia. 2006 Sep;20(9):1610–1617.
    1. 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 Jan;21(1):143–150.
    1. Hanamura I, Stewart JP, Huang Y, Zhan F, Santra M, Sawyer JR, et al. Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantation. Blood. 2006 Sep 1;108(5):1724–1732.
    1. Fonseca R, Van Wier SA, Chng WJ, Ketterling R, Lacy MQ, Dispenzieri A, et al. Prognostic value of chromosome 1q21 gain by fluorescent in situ hybridization and increase CKS1B expression in myeloma. Leukemia. 2006 Nov;20(11):2034–2040.
    1. Fonseca R, Bergsagel PL, Drach J, Shaughnessy J, Gutierrez N, Stewart AK, et al. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia. 2009 Dec;23(12):2210–2221.
    1. Morgan GJ, Davies FE, Gregory WM, Cocks K, Bell SE, Szubert AJ, et al. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet. 2010 Dec 11;376(9757):1989–1999.
    1. Nair B, van Rhee F, Shaughnessy JD, Jr., Anaissie E, Szymonifka J, Hoering A, et al. Superior results of Total Therapy 3 (2003-33) in gene expression profiling-defined low-risk multiple myeloma confirmed in subsequent trial 2006-66 with VRD maintenance. Blood. 2010 May 27;115(21):4168–4173.
    1. Ross FM, Chiecchio L, Dagrada G, Protheroe RK, Stockley DM, Harrison CJ, et al. The t(14;20) is a poor prognostic factor in myeloma but is associated with long-term stable disease in monoclonal gammopathies of undetermined significance. Haematologica. 2010 Jul;95(7):1221–1225.

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