Semra Paydaş, Arbil Açıkalın, Emine Kılıç Bağır, Perihan Alsancak

Multiple myelom’da kromozomal aberasyonlar: klinik sonuçlar ve bortezomib’ e yanıt

Amaç: Mutltiple myelom heterojen bir hastalık olup, en etkin tedavinin planlanlanabilmesi için kromozomal aberasyonların prognostik ve prediktif değerlerinin anlaşılması önemlidir. Bu çalışmada kurumumuzda tanı almış hastaların kromozomal aberasyonlarının sıklığını ve tedavi seçenekleri ile arasındaki ilişkiyi araştırmayı amaçladık. Gereç ve Yöntem: Ocak 2010 ve Aralık 2015 tarihleri arasında kurumumuzda tanı almış multiple myelomlu hastalarda, interfaz-floresan in situ hibridizasyon yöntemi ile del(17p13), del(13q14), t(11;14), and t(4;14) kromozomal aberasyonlarının sıklığını araştırdık. Bu sonuçların, konvansiyonel kemoterapi alan hastalar ile bortezomib tabanlı kemoterapi alan hastalardaki yanıtlarını karşılaştırdık. Bulgular: Seksen hastada (%72.7) en az bir adet kromozomal aberasyon saptandı. En sık saptanan aberasyon del(17p13) (%48.2) idi. Bunu sırasıyla del(13q14) (%40.9), t(11;14) (%16.4), ve t(4;14) (%11.8) takip etmekteydi. Klinik bulgularına ulaşılabilen 67 hastalık grupta, Bortezomib tabanlı kemoterapi alan 36 hastanın tedaviye yanıt oranı (%55.6) konvansiyonel kemoterapi alan gruba oranla (%48.4) daha yüksek idi. Kromozomal aberasyonlar ile karşılaştırıldığında; del (17p13) saptanan hastaların Bortezomib tabanlı kemoterapiye yanıtları (%63.2), konvansiyonel kemoterapi alanlardan (%50) daha yüksek saptandı. Benzer şonuç; del (13q14) saptanan hastalarda da gözlendi (Bortezomib alanlarda %61.5, konvansiyonel kemoterapi alanlarda %50). Sonuç: Bortezomib içeren tedaviler özellikle del (17p13) ve del (13q14) aberasyonu saptanan hastalarda daha iyi sonuç vermektedir.

Chromosomal aberrations in multiple myeloma: clinical outcome and response to bortezomib

Purpose: Multiple myeloma is a heterogeneous disease,for which an understanding of the prognostic andpredictive value of chromosomal aberrations is necessaryto prescribe the most appropriate therapy. We aimed todocument the frequencies of chromosomal aberrations inour institute and searched the relationships betweentherapy regimens and chromosomal aberrations.Materials and Methods: We analyzed the frequency ofdel(17p13), del(13q14), t(11;14), and t(4;14) in patients withMM by interphase-fluorescent in situ hybridization whowere diagnosed between January 2010 and December 2015in our institute. We researched the relationship betweenresponse to conventional chemotherapy and Bortezomibbased chemotherapy.Results: Eighty patients (72.7%) had at least onechromosomal aberration. The most frequently observedaberration was del(17p13) (48.2%), followed by del(13q14)(40.9%), t(11;14) (16.4%), and t(4;14) (11.8%). In clinicallyanalyzed subgroup (n=67), 36 patients who receivedBortezomib based chemotherapy showed a higherresponse rate (55.6%) than conventional chemotherapygroup (48.4%). With respect to chromosomal aberrations,response rates were higher in Bortezomib based therapygroup (63.2%) than conventional chemotherapy group(50%) in del (17p13) positive patients as well as in del(13q14) positive patients (61.5% in Bortezomib based,50% in conventional chemotherapy group).Conclusion: Bortezomib-containing regimens may havebeneficial effects on the clinical outcome of patients withdel (17p13) and del (13q14).

PDF

___

1. McKenna RW, Kyle RA, Kuehl WM, Harris NL, Coupland RW, Fend F. Plasma cell neoplasms. In texbook of WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (Eds Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H et al) . France: IARC press. 2017.
2. Gmidene A, Avet-Loiseau H, Sennana H, Ben Abdallah I, Khlif A, Meddeb B et al. Molecular cytogenetic aberrations in Tunisian patients with multiple myeloma identified by cIg-FISH in fixed bone marrow cells. Cytogenet Genome Res. 2012;136:44-9.
3. Gao X, Li C, Zhang R, Yang R, Qu X, Qiu H, et al.Fluorescence in situ hybridization analysis of chromosome aberrations in 60 Chinese patients with multiple myeloma. Med Oncol. 2012; 29:2200-6.
4. Seidl S, Kaufmann H, Drach J.New insights into the pathophysiology of multiple myeloma. Lancet Oncology. 2003;4:557-64.
5. 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;117:2009-11.
6. Soverini S, Cavo M, Cellini C, Terragna C, Zamagni E, Ruggeri D et al. Cyclin D1 overexpression is a favorable prognostic variable for newly diagnosed multiple myeloma patients treated with high-dose chemotherapy and single or double autologous transplantation. Blood. 2003;102:1588-94.
7. 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;106:2837-40.
8. Segges P, Braggio E. Genetic markers used for risk stratification in multiple myeloma. Genet Res Int. 2011;798089.
9. Terpos E, Eleutherakis-Papaiakovou V, Dimopoulos MA. Clinical implications of chromosomal abnormalities in multiple myeloma. Leukemia & Lymphoma. 2006;47:803-14.
10. 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;100:1579-83.
11. 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;101:1520-9.
12. 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;23:2210- 21.
13. Hu Y, Chen L, Sun CY, She XM, Ai LS, Qin. Clinical significance of chromosomal abnormalities detected by interphase fluorescence in situ hybridization in newly diagnosed multiple myeloma patients. Chin Med J (Engl). 2011;124:2981-5.
14. He J, Yang L, Meng X, Wei G, Wu W, Han X et al: A retrospective analysis of cytogenetic and clinical characteristics in patients with multiple myeloma. Am J Med Sci. 2013;345:88-93.
15. Durak BA, Akay OM, Sungar G, Bademci G, Aslan V, Caferler J et al. Conventional and molecular cytogenetic analyses in Turkish patients with multiple myeloma. Turk J Haematol. 2012;29:135-42.
16. 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;28:4630-4.
17. Chang H, Yeung J, Qi C, Xu W. Aberrant nuclear p53 protein expression detected by immunohistochemistry is associated with hemizygous P53 deletion and poor survival for multiple myeloma. Br J Haematol. 2007;138:324-9.
18. Kroger 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;103:4056-61.
19. Shaughnessy J, Jr., Tian E, Sawyer J, McCoy J, Tricot G, Jacobson J, et al: Prognostic impact of cytogenetic and interphase fluorescence in situ hybridizationdefined chromosome 13 deletion in multiple myeloma: early results of total therapy II. Br J Haematol. 2003;120:44-52.
20. Yuregir OO, Sahin FI, Yilmaz Z, Kizilkilic E, Karakus S, Ozdogu H. Fluorescent in situ hybridization studies in multiple myeloma. Hematology. 2009;14:90-4.
21. 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;95:1925-30.
22. 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;359:906-17.
23. Romano A, Conticello C, Di Raimondo F. Bortezomib for the treatment of previously untreated multiple myeloma. Immunotherapy. 2013;5:327-52.
24. Sonneveld P, Goldschmidt H, Rosinol L, Blade J, Lahuerta JJ, Cavo M et al. Bortezomib-based versus nonbortezomib-based induction treatment before autologous stem-cell transplantation in patients with previously untreated multiple myeloma: a metaanalysis of phase III randomized, controlled trials. J Clin Oncol. 2013;31:3279-87.
25. Yang G, Chen W, Wu Y: Bortezomib, dexamethasone plus thalidomide for treatment of newly diagnosed multiple myeloma patients with or without renal impairment. Chin J Cancer Res. 2013;25:155-60.
26. Zeng Z, Lin J, Chen J: Bortezomib for patients with previously untreated multiple myeloma: a systematic review and meta-analysis of randomized controlled trials. Ann Hematol. 2013;92:935-43.
27. Zou Y, Lin M, Sheng Z, Niu S: Bortezomib and lenalidomide as front-line therapy for multiple myeloma. Leuk Lymphoma. 2014;55:2024-31.
28. Jiang A, Reece D, Chang H. Genomic stratification of multiple myeloma treated with novel agents. Leuk Lymphoma. 2012;53:202-7.
29. Richardson PG, Xie WL, Mitsiades C, Chanan-Khan AA, Lonial S, Hassoun H et al. Single-agent bortezomib in previously untreated multiple myeloma: efficacy, characterization of peripheral neuropathy, and molecular correlations with response and neuropathy. J Clin Oncol. 2009;27:3518-25.
30. Shaughnessy JD, Zhou YM, Haessler J, van Rhee F, Anaissie E, Nair B et al. TP53 deletion is not an adverse feature in multiple myeloma treated with total therapy 3. Br J Haematol. 2009;147:347-51.