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ORIGINAL ARTICLE 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 NC Gutie ?rrez1,13 , MV Castellanos1,13 , ML Mart? ?n2 , MV Mateos1 , JM Herna ?ndez1 , M Ferna ?ndez2 , D Carrera3 , L Rosin ?ol4 , JM Ribera5 , JM Ojanguren6 , L Palomera7 , S Gardella8 , L Escoda9 , JC Herna ?ndez-Boluda10 , JL Bello11 , J de la Rubia12 , JJ Lahuerta2 and JF San Miguel1 , on behalf of GEM/PETHEMA Spanish Group

1 Servicios de Hematolog? ?a: Hospital Universitario de Salamanca and Centro de Investigacio ?n del Ca ?ncer (CIC), Universidad de Salamanca-CSIC, Spain;

2 Hospital

12 de Octubre, Madrid, Spain;

3 Hospital Central de Asturias, Oviedo, Spain;

4 Hospital Cl? ?nic Universitari, IDIBAPS, Barcelona, Spain;

5 Hospital German Trias i Pujol, Badalona, Spain;

6 Hospital de Galdakao, Bilbao, Spain;

7 Hospital Cl? ?nico, Zaragoza, Spain;

8 Hospital Dr Josep Trueta, Gerona, Spain;

9 Hospital Joan XXIII, Tarragona, Spain;

10 Hospital Cl? ?nico Universitario, Valencia, Spain;

11 Hospital Universitario, Santiago de Compostela and

12 Hospital Universitario La Fe, Valencia, Spain Fluorescence in situ hybridization (FISH) has become a power- ful technique for prognostic assessment in multiple myeloma (MM).

However, the existence of associations between cytoge- netic abnormalities compels us to re-assess the value of each abnormality. A total of

260 patients with MM at the time of diagnosis, enrolled in the GEM-2000 Spanish transplant proto- col, have been analyzed by FISH in order to ascertain the independent in?uence on myeloma prognosis of IGH transloca- tions, as well as RB and P53 deletions. Survival analyses showed that patients with t(4;

14), RB or P53 deletions had a signi?cantly shorter survival than patients without these abnormalities. However, patients with RB deletions without other abnormalities in FISH analysis, displayed a similar outcome to those patients without genetic changes by FISH (46 vs

54 months, P ? 0.3). In the multivariate analysis the presence of t(4;

14), RB deletion associated with other abnorm- alities, age

460 years, high proportion of S-phase cells and advanced stage of the disease according to the International Staging System retained their independent prognostic in?u- ence. In summary, RB deletion as a sole abnormality does not lead to a shortening in the survival of MM patients, whereas t(4;

14) confers the worst prognosis in MM patients treated with high-dose chemotherapy. Leukemia (2007) 21, 143C150. doi:10.1038/sj.leu.2404413;

published online

5 October

2006 Keywords: multiple myeloma;

genetic abnormalities;

FISH;

RB deletion Introduction Multiple myeloma (MM) is a clonal plasma cell (PC) disorder that remains as an incurable disease. Nevertheless, the survival of myeloma patients is highly variable, ranging from a few months to more than

10 years. This heterogeneity relates mainly to prognostic factors associated with speci?c characteristics of both the tumor itself and the host.1 The identi?cation of those characteristics associated with either a good or poor prognosis is most important in order to obtain individualized information about disease outcome and to design risk-adapted therapeutic strategies. The cytogenetic status have emerged as the most relevant prognostic factor in MM.2C5 However, the low proliferative activity of PC, as well as the limited extent of bone marrow (BM) involvement, reduce the number of analyzable metaphases and hamper cytogenetic studies. In addition, the resolution of conventional cytogenetics makes it impossible to recognize cryptic translocations.6C8 These factors are leading to the replacement of classical cytogenetics by interphase ?uores- cence in situ hybridization (FISH) technology, which allows a rapid and reproducible identi?cation of speci?c target regions frequently affected in MM and with prognostic in?uence. Several groups, including our own, have investigated by FISH the cytogenetic abnormalities most frequently involved in MM.3,4,9,10 Immunoglobulin heavy-chain (IGH ) translocations, as well as retinoblastoma (RB) and P53 deletions represent chromosomal abnormalities with a widely recognized prognos- tic impact. Although RB deletions have been considered as a powerful adverse prognostic factor consistently reported in large series,3C5,11,12 the coexistence of RB deletions and IGH translocations raises the question of whether the adverse prognosis of each abnormality may be in?uenced by the other. In order to ascertain the individual contribution of each abnormality as well as the in?uence of associations between abnormalities in MM outcome, we have systematically analyzed by FISH RB and P53 deletions, and IGH translocations in