1 Department of Medicine I, 2 Clinical Division of Oncology, 3 Bone Marrow Transplantation Unit, 5 Division of Hematology and Hemostaseology, University Hospital Vienna, Vienna; 4 3rd Department of Medicine, Hanuschspital, Vienna; 6 1st Department of Internal Medicine with Medical Oncology, Wilhelminenspital, Vienna; 7 Department of Transfusion Medicine, University Hospital Vienna, Vienna, Austria
Received 7 March 2003; revised 30 July 2003; accepted 8 August 2003
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Abstract |
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Key words: ß2-microglobulin, chromosome 13, high-dose chemotherapy, multiple myeloma, prognostic factors, standard-dose chemotherapy
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Introduction |
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Recent studies indicate that chromosomal abnormalities, especially partial or complete deletions of chromosome 13q [del(13q)], provide important prognostic information for patients with MM [917]. It was shown that the combined assessment of chromosome 13q and serum ß2-microglobulin (ß2M) levels at diagnosis provides a powerful prognostic model discriminating groups of MM patients with significantly different survival, and this was true for both SDT [18] and high-dose therapy (HDT) [15]. However, little information is available with respect to the question of which risk-group of MM patients may experience a particular benefit of HDT as compared with SDT [19].
To address this issue, we evaluated the outcome of 77 MM patients enrolled in HDT regimens, according to chromosome 13q status as determined by interphase fluorescence in situ hybridization (FISH) and ß2M. Patients were assigned to a standard-risk group (disomic chromosome 13q14 and ß2M 4 mg/l) or a high-risk group [del(13q14) and/or ß2M >4 mg/l]. Outcome of HDT patients was compared with that of similar patients (age <65 years) who would be eligible for HDT but were treated by SDT.
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Patients and methods |
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Patients treated with SDT. This group consisted of 64 newly diagnosed patients with a median age of 55.3 years (range 3464.9). These patients would be candidates for HDT, but were treated with SDT, mainly because they received treatment prior to routine administration of HDT as up-front therapy. Some patients elected to receive SDT rather than HDT. Twenty-nine patients were male (45.3%) and 35 (54.7%) were female. Seven patients (10.9%) were at stage I, 12 patients (18.8%) were at stage II and 45 patients (70.3%) were at stage III. The paraprotein was IgG in 42 patients (65.6%), IgA in 17 patients (26.6%) and any other subtype in five patients (7.8%). In 55 patients, treatment consisted of an alkylating agent-containing regimen (either melphalanprednisone or vincristinemelphalancyclophosphamideprednisone), and nine patients received VAD. Patients continued to receive SDT also later during the course of their disease, and none of them was salvaged by HDT.
Median time (± SD) between initiation of therapy and date of this analysis was 54 ± 24.1 months for patients treated with HDT and 82.8 ± 27.7 months for patients treated with SDT. Salvage treatment including thalidomide was administered to 14 patients of the HDT group and 13 patients of the SDT group.
Interphase FISH studies
Bone marrow cells, which were obtained during the diagnostic work-up, were used for FISH analyses. To specifically study bone marrow plasma cells, we applied a triple-staining method for the simultaneous detection of cytoplasmatic immunoglobulins with a goat anti-human lambda light chain antibody conjugated with 7-amino-4-methyl-coumarin-3-acetic acid (AMCA; Vector Laboratories, Inc., Burlingame, CA, USA) and interphase FISH signals, as previously described [20]. To determine the status of chromosome 13q, we used a locus-specific DNA probe for 13q14 (RB-1) labeled with Spectrum-orange. The RB-1 probe was simultaneously hybridized with a reference probe (-satellite probes for the pericentromeric regions of chromosomes 7 or 11) conjugated with Spectrum-green. Probes were purchased from Vysis (Downers Grove, IL, USA). Hybridizations were performed according to our previously published protocol [12, 21]. Plasma cells on slides were scored, and 200 cells were evaluated by fluorescence microscopy using a Axioplan-2 immunofluorescence microscope (Zeiss, Jena, Germany), equipped with appropriate filters to visualize green, red and blue immunofluorescence, either separately or simultaneously.
Statistical analysis
To estimate the significance of differences between patient groups, the proportion of patients were compared using Fishers exact test and t-test for independent samples. Progression-free survival (PFS) and overall survival (OS) curves were calculated from the time of initiation of chemotherapy and were plotted according to the KaplanMeier method. Comparisons were made by means of the MantelCox test.
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Results |
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Survival according to chromosome 13q14 status
A del(13q14) by FISH was observed in 58 patients of the entire group of 141 previously untreated MM patients (41.1%): in 31 of the 77 patients of the HDT group (40.3%) and in 27 of the 64 patients of the SDT group (42.4%; P = 0.81). MM patients with a del(13q14) experienced shortened survival: among HDT patients, PFS and OS times were 25.5 and 34.2 months, respectively, for 13q14-deleted patients; median PFS and OS of MM patients with a disomic chromosome 13q14 was 35.6 months and has not yet been reached up to now (P = 0.06 and 0.004, respectively). Similarly, in patients belonging to the SDT group, presence of a del(13q14) was associated with shorter PFS and OS times compared with SDT patients with disomic chromosome 13q14 (median PFS 10.9 versus 27.9 months, P = 0.03; median OS 24.6 versus 74.8 months, P = 0.001). These results are in agreement with previous FISH studies [11, 12, 1416] and confirm the negative impact of del(13q14) on survival, in both HDT- and SDT-treated MM patients.
HDT versus SDT in patients with del(13q14) and with normal chromosome 13q14
Comparison of HDT with SDT in patients with a del(13q14) indicated that PFS was significantly longer in the HDT-treated group (P = 0.02; Table 2). OS of patients with del(13q14) was also longer in the HDT group than in the SDT group, but the difference was not statistically significant (P = 0.19). The comparison of HDT with SDT in patients with normal chromosome 13q14 suggested a trend towards longer PFS in the HDT group (P = 0.09), but again no statistically significant difference with respect to OS (P = 0.22) (Table 2).
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Discussion |
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The aim of our present investigation was therefore to address the question of whether or not use of prognostic factors could contribute to the identification of a patient population with a particular benefit of HDT. In this analysis, we decided to focus on two major independent prognostic indicators, chromosome 13q and ß2M, based upon the experience of previous studies [15, 18]. The outcome of the patient populations reported here is in agreement with clinical results of published series. HDT and historical SDT patients were not significantly different with respect to standard laboratory and clinical MM parameters, with the exception of age. However, there is no reason to assume that the slightly younger median age of HDT patients (51.8 years as opposed to 55.3 years for the SDT patients) could explain their superior clinical course compared with the SDT group. As shown in Figure 1, MM patients of the present series could be clearly distinguished according to the prognostic factors chromosome 13q14 and ß2M leading to the definition of standard-risk and high-risk groups.
Treatment of MM patients with poor prognostic indicators remains difficult. Administration of HDT, even as tandem autologous transplantation, failed to result in durable PFS and OS, as soon as a del(13q14) was present [9, 1315]. Also, in our present analysis there were only limited survival times of patients assigned to the high-risk group [del(13q14) and/or ß2M >4 mg/l]. However, despite the overall short survival of high-risk patients, comparison of HDT with SDT in this high-risk group revealed significant differences: compared with SDT, HDT led to a significant improvement of both median PFS (26.4 versus 10.7 months) and median OS (40 versus 23 months). From randomized trials evaluating HDT and SDT, information about outcome according to prognostic factors is only available from the preliminary report of the Medical Research Council Myeloma VII trial [22]. In this analysis, HDT was superior to SDT, and there was a trend towards greater survival benefit in the group of patients with poor prognosis defined by high ß2M.
MM patients of the standard-risk group [absence of a del(13q14), ß2M 4 mg/l] had favorable PFS and OS times. This was true for patients not only after HDT, but also after SDT. It is important to note that none of the SDT patients received HDT as salvage treatment, and that a comparable fraction of SDT and HDT patients received thalidomide as salvage treatment; thus, the favorable outcome of standard-risk SDT patients could indeed be attributed to chemotherapy at conventional doses. The results of our SDT patient group are comparable to those previously reported by the PETHEMA group, showing that MM patients at an age of <65 years and with responsive disease to SDT may experience a survival duration similar to that reported in HDT trials [29]. MM patients with del(13q14) are less likely to respond to SDT [12, 16]; thus, it can be assumed that in this Spanish analysis [29] patients with chemosensitive MM may largely correspond to a patient population with absence of adverse prognostic features. On the other hand, these results should not lead to the conclusion that SDT and HDT are equally effective in standard-risk patients. It needs to be considered that the documentation of a potential survival difference between SDT and HDT in younger MM patients with favorable prognostic indicators would certainly require larger patient numbers than those available in our present analysis. In addition, the duration of the observation period of such patient populations could be an important issue. For example, in the IFM 90 randomized trial [6], survival curves of SDT and HDT patients were almost superimposable during the first 3 years, and only thereafter did a survival benefit of the HDT group became apparent. Further intensification of HDT by administration of tandem autologous transplantation can result in PFS beyond 7 years in a fraction of MM patients with favorable prognostic factors [13, 30]. In contrast, this may only occassionally be observed in MM patients after SDT.
In conclusion, although adverse prognostic indicators are associated with shortened survival in MM patients undergoing HDT, intensified treatment is nevertheless able to improve the outcome of such patients as compared with SDT. Thus, in order to further improve the outcome of patients with high-risk MM, it would be worth exploring the role of tandem transplantation, either as tandem autologous transplantation [8] or as sequential autologous/allogeneic transplantation with non-myeloablative conditioning [31]. Incorporation of novel agents (thalidomide and its analogs, proteasome inhibitors) may be an additional strategy to improve the still grim prognosis of MM patients with high-risk disease.
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Acknowledgements |
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Footnotes |
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References |
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