Fluorescence in situ hybridization (FISH) has become a powerful technique for prognostic assessment in multiple myeloma (MM). However, the existence of associations between cytogenetic 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 protocol, have been analyzed by FISH in order to ascertain the independent influence on myeloma prognosis of IGH translocations, as well as RB and P53 deletions. Survival analyses showed that patients with t(4;14), RB or P53 deletions had a significantly 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 abnormalities, age >60 years, high proportion of S-phase cells and advanced stage of the disease according to the International Staging System retained their independent prognostic influence. 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.
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 specific characteristics of both the tumor itself and the host.1 The identification 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.2, 3, 4, 5 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.6, 7, 8 These factors are leading to the replacement of classical cytogenetics by interphase fluorescence in situ hybridization (FISH) technology, which allows a rapid and reproducible identification of specific target regions frequently affected in MM and with prognostic influence.
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 prognostic impact. Although RB deletions have been considered as a powerful adverse prognostic factor consistently reported in large series,3, 4, 5, 11, 12 the coexistence of RB deletions and IGH translocations raises the question of whether the adverse prognosis of each abnormality may be influenced by the other. In order to ascertain the individual contribution of each abnormality as well as the influence of associations between abnormalities in MM outcome, we have systematically analyzed by FISH RB and P53 deletions, and IGH translocations in 260 patients uniformly treated according to the GEM 2000 protocol, which includes an induction phase with VBCMP/VBAD followed by autologous cell transplantation (ASCT). In addition, we have explored whether or not these cytogenetic subgroups display distinct clinical and biological disease characteristics.
Patients and methods
Patients under the age of 70 years, with newly diagnosed MM, enrolled in the GEM 2000 Spanish protocol (six alternating cycles of VBCMP/VBAD followed by high-dose therapy – melphalan 200 mg/m2 supported by ASCT) were included in the study. The study was approved by the research ethics committees of all participating centers and written informed consent was obtained from all patients. In order to interpret accurately FISH analysis only those patients with BM PC infiltration by flow cytometry above 10% were eligible for this study (n=260). The main clinical and laboratory characteristics of these patients are shown in Table 1. Forty-seven of 260 patients (18%) did not undergo ASCT because of comorbidity (20 cases), progression of the disease (13 cases), failure in mobilization (11 cases) or withdrawal of informed consent (three cases). The median overall survival (OS) for the whole group was 43 months (95% confidence interval, 36–49), and the median follow-up for survivors was 34 months. At the time of study, 102 patients remained alive.
Interphase FISH studies for the detection of IGH rearrangements were carried out by means of LSI IGH dual color, break apart rearrangement probe (Vysis, Downers Grove, IL, USA). Patients with IGH translocations were explored firstly for t(11;14)(q13;q32) (LSI IGH/CCND1, dual fusion translocation probe) (Vysis), and subsequently analyzed for t(4;14)(p16;q32) (4p – BAC clones L75b9, L190b4, L96a2, PAC 184d6–; 14q32– VH: cosmid yIgH6-9, CH: BAC B158 A2–) and finally for t(14;16)(q32;q23) (16q23 – BAC clones 356D21, 484H2, 10205 and 10206–). The probes corresponding to the last two translocations were kindly provided by Rafael Fonseca from the Mayo Clinic, Scottsdale, AZ, USA. The presence of 13q and 17p deletions were evaluated with a specific probe for RB -LSI 13 (RB1) (Vysis) and for P53 – LSI P53 (17p13.1) (Vysis), respectively. The interphase-FISH procedure has been described previously in detail.13 A total of 500 interphase nuclei were analyzed using the scoring criteria recommended by the manufacturer. Based on the results using these probes in 25 healthy controls, the cutoff point for the identification of alteration was set at more than 8% cells with abnormal signal.
Statistical analysis were performed using SPSS statistical software version 11.5 (SPSS Inc., Chicago, IL, USA). The χ2 and the Fisher's exact test were used to test associations between chromosomal abnormalities as well as between genomic changes and other categoric variables. For continuous variables, the Wilcoxon rank sum test and t-test were used. OS was calculated from the start of the initial treatment to the date of death or last visit. Time to progression (TTP) was estimated from the day of initiation of treatment to the date of relapse or disease progression. Survival curves were plotted by means of the Kaplan–Meier method and the difference in survival curves was tested for statistical significance using the log-rank test. P-values below 0.05 were considered to reflect statistical significance. Multivariate analysis of survival was performed using the Cox proportional hazards model (stepwise regression approach). Factors were retained in the model if they were statistically significant at P⩽0.05.
Frequency of chromosomal abnormalities
Chromosomal abnormalities explored by FISH were identified in 151 (58%) of the 260 MM patients. IGH translocations and RB deletions were observed in 95 (36%) and 109 (42%) out of the 260 patients, respectively; whereas P53 deletions were present in 8.5% (22/260) of patients. The distribution of IGH translocations according to 14q32 partners were: t(11;14) in 13% (34/260 patients), t(4;14) in 11% (29/260 patients), t(14;16) in 3% (7/260 patients) and IGH rearrangements with other unknown partners in 10% (25/260 patients).
Correlations between chromosomal abnormalities
A significant association between t(4;14) and RB deletions was observed. Thus, 79% of patients with t(4;14) had RB deletions vs 37% of patients without t(4;14) (P<0.001). However, no correlation was found between this translocation and P53 deletions (Table 2). In contrast, t(11;14) was significantly associated with P53 deletions but not with RB deletions (Table 2). Translocations involving 16q and other unknown IGH partners did not correlate with RB or P53 deletions. Finally, a significant association was observed between P53 and RB deletions (P=0.009) (Table 2).
Association between chromosomal abnormalities and clinical and biological parameters
Overall, IGH translocations and RB deletions were significantly more frequent in younger patients (the incidence of IGH translocations was 66% in patients <60 years vs 34% in those >60 years, P=0.006; and for RB deletions, 63% in patients <60 years vs 37% in those >60 years, P=0.02). When clinical and laboratory parameters were correlated with the different subtypes of IGH rearrangements, it was observed that patients with t(4;14) more frequently had lower albumin levels (P=0.02) and advanced International Staging System (ISS)14 (P=0.04); cases with t(14;16) were associated with lower hemoglobin (Hb) levels (P=0.005), and IGH translocations involving unknown partners significantly correlated with lower serum creatinine (P=0.001), β2microglobulin levels (P=0.01) and lower % of S-phase cells (P=0.006). There was no association between t(11;14) and clinical and standard laboratory findings. RB deletions were associated with bone disease (P=0.02) and low Hb levels (P=0.02), whereas no clinical or laboratory correlations were found for P53 deletions.
Prognostic impact of chromosomal abnormalities and other biological parameters
In the univariate analysis, patients with IGH translocations, RB or P53 deletions had a significantly shorter OS and TTP than patients without these abnormalities (Table 3, and Figures 1 and 2). The sub-analysis of the prognostic influence of each IGH translocation showed that only t(4;14) was associated with significantly shorter OS and TTP (Table 3 and Figure 2). Patients with t(14;16) or IGH rearrangements with an unknown partner also showed a shorter survival, although the differences did not reach statistical significance (Table 3). Finally, t(11;14) did not influence the outcome of MM patients (Table 3 and Figure 2).
Given the frequent coexistence of RB deletion and IGH translocations, we performed a survival analysis based on both the influence of RB deletions on patients with IGH translocations, and the other way around, the influence of IGH translocations in patients with RB deletions. We observed that cases with RB deletions negatively influenced the survival of patients with translocations involving other unknown IGH partners (26 vs 49 months, P=0.02). By contrast, RB deletion did not influence the outcome of patients with t(11;14), t(4;14) or t(14;16). On the other hand, when we analyzed the effect of IGH translocations on the patients who had RB deletions, the presence of t(4;14) or IGH translocations affecting another unknown partner added a negative impact in patients with RB deletion (Figure 1). We also analyzed the survival of patients with RB deletion as a single abnormality and it was not different from that of normal patients (46 vs 54 months, P=0.3) (Figure 1). Only t(4;14) showed a significant influence on survival as a single aberration, with patients displaying a shorter OS as compared to normal patients (21 vs 54 months, P=0.008). When both RB and P53 deletions were present, OS was 28 months, a survival which is shorter than that observed in patients without these two deletions (51 months, P<0.0001) (Figure 1). Response to induction treatment was evaluated for each chromosomal abnormality and no correlations were found (Table 3).
Regarding the influence of other clinical and biological parameters in disease outcome, the following factors were significantly associated with a shorter OS: age >60 years (P=0.002), ISS=3 (P=0.002), Eastern Cooperative Oncology Group (ECOG) ⩾2 (P=0.02), percentage of S-phase PC >2.5% (P=0.004), β2-microglobulin >3 mg/l (P=0.03), Hb <9 g/dl (P=0.02) and albumin <2.5 mg/dl (P=0.007). For multivariate analysis, all parameters with a P<0.1 in the univariate analysis for OS were included in the Cox proportional hazards model. In this model five variables retained independent prognostic influence: t(4;14) (P<0.001), RB deletions (P<0.001), stage according to ISS (P=0.001), age (P=0.001) and proportion of S-phase cells (P=0.002) (Table 4). In order to clarify whether the prognostic influence of RB deletion was attributable to this genetic change by itself or whether it was owing to its association with other cytogentic abnormalities, a second multivariate analysis was carried out. For that purpose, the variable corresponding to RB deletion was re-codified into two new variables for defining RB status: one, which distinguishes the patients with RB as a single abnormality, and another, which identifies patients with RB plus other abnormalities. In this second analysis the former variable was not selected as an independent prognostic factor (Table 4).
In the present study, the prognostic influence of chromosomal abnormalities detected by FISH was assessed in a large series of myeloma patients uniformly treated with high-dose therapy and autologous stem cell support. The most relevant finding of this study is the lack of prognostic influence of RB deletion when it is the only abnormality, whereas t(4;14) by itself is associated with a dismal outcome.
The incidence of chromosomal abnormalities detected in the present series by FISH (58%), is notably higher than that usually obtained by conventional cytogentetics.15, 16, 17 The global incidence of IGH translocations detected in our study was lower than that described by the Mayo Clinic group (55%),18 and the French group (70%),3 which could be explained by the lack of PC selection. Regarding each particular IGH translocation,3, 4, 9 as well as RB and P53 deletions,3, 4, 9, 19, 20, 21, 22 the frequency observed was consistent with that described by other groups.
This study demonstrates the important prognostic impact of the t(4;14) in the survival of MM patients treated with high-dose chemotherapy. Moreover, the presence of t(4;14) on its own was sufficient for shortening MM patient survival. This reinforces previous results from other series of patients treated with conventional chemotherapy,4 as well as two series of stem cell transplantation,3, 9 illustrating that this is probably the most relevant cytogenetic prognostic factor for MM patients, independently of the therapeutic strategies used. Whether or not this adverse influence could be overcome by novel agents remains to be elucidated. Recent reports indicate that the response rate to Bortezomib is independent of cytogenetic abnormalities.23 In the present study, response was not affected by cytogenetic changes either, and the poor outcome mainly derived from rapid relapse. Initial cytogenetic studies by FISH in MM revealed that t(11;14) was associated with an adverse outcome in MM.24 However, this translocation has recently been associated with good prognosis in large series of patients,3 or with a similar outcome to that of patients without IGH translocations.4 In the present study we failed to observe a significant longer survival for patients with t(11;14) compared to patients without IGH translocations. Finally, regarding patients with t(14;16) and translocations involving other IGH partners, these abnormalities tended to be associated with shorter survival, although the differences did not reach statistical significance.3, 4, 25
The adverse prognosis of RB, as it was also observed in our patients, has almost become an axiom in MM, independently of the detection method used (karyotype vs FISH) and the treatment approaches (conventional chemotherapy vs high-dose chemotherapy).3, 5, 11, 22, 26, 27, 28 Our results also confirm that P53 deletions confer an adverse outcome even though they are present in a low proportion of patients. Similar observations have been described for patients who received conventional chemotherapy or high-dose therapy.4, 9, 20, 29 However, the strong association observed between chromosomal abnormalities raises two important questions: (1) what is the prognostic impact of each single abnormality? and (2) to what extent does the coexistence of another change modify its prognosis? The results obtained in the present study showed that the presence of t(4;14) by itself significantly reduces survival in MM. However, patients with RB deletions as a sole abnormality displayed the same prognosis than patients without any abnormalities (46 vs 54 months, P=0.3). Therefore, the RB deletion on its own would not represent a negative prognostic characteristic in contrast to what has previously been widely assumed.22, 27 Although the low number of patients with deletions on P53 prevents us from reaching a similar conclusion, it should be noted that the only five patients with P53 deletion, as a single abnormality had the same OS than cytogenetically normal patients, whereas patients with concomitant RB and P53 deletions had a significantly shorter survival. When the effect of the RB deletion on the survival of patients with IGH translocations was explored, it was observed that RB deletion did not modify the survival of patients with t(11;14) and t(4;14). This latter finding could be explained by the fact that t(4;14) is associated with a very poor outcome by itself, and therefore RB deletion does not make the prognosis of the patients with these abnormalities any worse. Patients in whom the t(11;14) translocation coexisted with RB deletion displayed a similar survival to those without the RB deletion. In contrast to these results, RB deletion did negatively influence the prognosis of patients with IGH translocations in other unknown partners as reported in a previous study.3
In our multivariate analysis, t(4;14) and RB deletions when associated with other abnormalities, but not as a single change, were the only chromosomal abnormalities that retained independent prognostic influence, and therefore, they could be considered the most important cytogenetic prognostic factors in MM patients treated with high-dose chemotherapy. Regarding non-chromosomal prognostic features, age >60 years, stage according to ISS=3 and proportion of S-phase cells >2.5% retained statistical significance in the multivariate model.
In summary, our study illustrates the importance of performing a systematic FISH analysis on all newly diagnosed myeloma patients. This should include the investigation of IGH translocations plus RB and P53 deletions, in order to detect the simultaneous presence of some of the changes, as the prognostic value of each one of them greatly depends on its coexistence with one of the others.
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We thank Arturo Touchard and Manuel Delgado for data managing; Belén González, M Ángeles Hernández and Isabel Isidro for technical assistance; and Mark Anderson from the University Technology Transfer Office. This study was partially supported by Spanish Myeloma Network Program (G03/136) and ‘Ministerio de Ciencia y Tecnologia’ grant (SAF 04/06587).
List of the members of GEM 2000 group: Hospital General de Albacete (Ángela Ibáñez, Félix Manso, Juan Carlos Gómez García); Hospital General Universitario de Alicante (Concepción Rivas González, Pascual Fernández Abellán); Hospital General Universitario Marina Alta Alicante (Rosa Ferrer Marco); Hospital Nuestra Señora de Sonsoles Ávila (Abelardo Bárez García); Complejo Asistencial Son Dureta Palma de Mallorca (Joan Besalduch Vidal, Mariana Canaro); Hospital Verge del Toro Mahon (Pilar Galán Alvarez); Hospital Son Llatzer Palma de Mallorca (Joan Bargay LLeonart); Hospital del Mar Barcelona (Eugenia Abella Monreal); Hospital Clínic Universitari Barcelona (Joan Bladé Creixenti, Laura Rosiñol Dach); Hospital Sant Pau Barcelona (Anna Sureda Balari); Clínica Corachan Barcelona (Alfons Modolell Roig); Hospital de Badalona Germans Trias i Pujol Barcelona (Josep María Ribera Santasusana); Hospital General de Manresa (Maricel Subirá); Complejo Hospitalario del Parc Tauli Barcelona (Juan Alfonso Soler Campos); Hospital del Espíritu Santo (Albert Altes); Hospital General de Mataró (Luis Rodríguez Fernández); Hospital Val D’Hebron Barcelona (Manuel Callis de Nadal); Hospital San Pedro de Alcántara Cáceres (Juan Miguel Bergua Burgués, Maria Luz Amigo Lozano); Hospital Punta de Europa Algeciras (Rosario Butrón Vila); Hospital General de Jerez de la Frontera (Ángel León Lara, José Luís Guzmán Zamudio, Patricio Leiva); Hospital General de Castellón (Maria Guinot Martinez, Raimundo García Boyero); Hospital Nuestra Señora de Alarcos Ciudad Real(Belén Hernández Ruiz); Hospital Clínico Universitario de Santiago de Compostela (José Luís Bello López, Natalia Alonso Vicente); Hospital Virgen de la Luz Cuenca (José Luís Guerra Moyano, María José Busto Medina); Hospital de Girona Josep Trueta (Santiago Gardella Company, Yolanda González Montes); Hospital General de Guadalajara (Félix Fuentes Galván, Miguel Díaz Morfa); Hospital de San Jorge Huesca (Fernando Puente Mangirón); Complejo Hospitalario de Jaén (Antonio Alcalá Muñoz); Hospital de Jaén (Pilar Mesa Valle); Hospital del Bierzo Ponferrada (Josefina Galende del Canto); Hospital Ramón y Cajal Madrid (José García Laraña); Hospital 12 de Octubre Madrid (Carlos Grande García, Juan José Lahuerta); Complejo Universitario San Carlos Madrid (Rafael Martínez Martínez); Hospital Universitario La Princesa Madrid (Adrián Alegre Amor, Beatriz Aguado Bueno, Flor Lara García-Escribano); Fundación Jiménez Díaz Madrid (Elena Prieto Pareja); Hospital Príncipe de Asturias Madrid (Carmen Burgaleta, Gemma Moreno Jiménez); Hospital Severo Ochoa Madrid (Pedro Sánchez Godoy); Hospital de Fuenlabrada Madrid (José Ángel Hernández Rivas); Hospital Universitario de Getafe (María del Carmen Monteserín); Hospital Universitario Virgen de la Victoria Málaga (Inmaculada Pérez Fernández, María José Moreno); Hospital General Morales Messeguer Murcia (Felipe de Arriba de la Fuente, José María Moraleda Jiménez); Hospital Nuestra señora del Rosell Cartagena (Jerónima Ibáñez García); Clínica Universitaria de Navarra Pamplona (Elena Carrascal, Felipe Prosper Cardoso, José Rifon); Hospital de Jarrio Oviedo (Ana Díaz Trapiella, Manuel Vargas Pabón); Hospital Central de Asturias Gijón (Consuelo Rayón Suárez, Dolores Carrera); Hospital Río Carrión Palencia (Fernando Ortega Rivas, José María Alonso Alonso); Complejo Hospitalario Materno-insular Las Palmas (José David González San Miguel ); Complejo Hospitalario Xeral-Cies Vigo (Carmen Albo López, Concha Poderos Baeta); Hospital Clínico de Salamanca (Jesús San Miguel Izquierdo); Hospital Universitario de Canarias Santa Cruz de Tenerife (Miguel Hernández García); Hospital Universitario Marques de Valdecilla Santander (Eulogio Conde García); Hospital General de Segovia (José Mariano Hernández Martín); Hospital Joan XXIII Tarragona (Andrés Llorente, Lourdes Escoda Teigell); Hospital Virgen de la Cinta Tortosa (Llorenç Font Ferré ); Hospital Nuestra Señora del Prado Talavera de la Reina (Fernando Solano Ramos); Hospital Virgen de la Salud Toledo (Felipe Casado Montero); Hospital Universitario La Fe Valencia (Isidro Jarque, Javier de la Rubia Comos); Hospital Doctor Peset Valencia (María José Sayas LLoris, Paz Ribas García); Hospital Arnau de Vilanova Valencia (Aurelio López Martínez, Encarna Monzó Castellano, José Mayans Ferrer); Hospital Clínico Universitario de Valencia (Inmaculada Blasco Blasco, Juan Carlos Hernández Boluda, Mará José Terol Casterá); Hospital General Universitario de Valencia (Félix Carbonell Ramón, Maite Otero Castelló); Fundación Instituto Valenciano de Oncología Valencia (Pablo Llorente Alegre); Hospital Francesc de Borja Gandia (María José Fernández, María Ángeles Ruiz Guinaldo); Hospital de Sagunto (Ana Carral Tatay, Isabel Navarro Gonzalo); Hospital Río Hortera Valladolid (Javier García Frade, María Jesús Peñarrubia); Hospital Clínico Universitario de Valladolid (Francisco Javier Fernández Calvo, Rebeca Cuello García); Hospital de Cruces Barakaldo (Elena Amutio Díez, Juan Carlos García Ruiz); Hospital de Galdakao (Jesús María Ojanguren Bergaz., Koldo Atutxa Aresti); Hospital Virgen de la Concha Zamora (Alejandro Martín García); Hospital Clínico Universitario Lozano Blesa Zaragoza (Luís Palomera Bernal); Hospital Miguel Server Zaragoza (Pilar Giraldo).
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