Gains on Chromosome Arm 9q Represent a Novel and Independent Marker of Adverse Prognosis in Multiple Myeloma Patients Receiving Upfront High-Dose Chemotherapy and Autologous Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1559-1559
Author(s):  
Peter Liebisch ◽  
Axel Benner ◽  
Kathrin Tschajka ◽  
Christiane Wendl ◽  
Hartmut Goldschmidt ◽  
...  

Abstract Introduction: Genomic aberrations represent important prognostic markers in many hematological cancers. In multiple myeloma (MM), chromosome 13q and 17p deletions (13q−, 17p−) have emerged as important outcome predictors that indicate a dismal prognosis. Other chromosomal abnormalities have been discussed as prognostic markers in this disease but came not out as independent variables when they were tested in a multivariable fashion. However, the complexity of genomic rearrangements and the clinical heterogeneity seen in malignant plasma cell disorders argue against 13q− and 17p− as the sole genomic change of prognostic relevance. The significance of chromosome arm 1q, 9q, and 11q extra copies - three frequent genomic imbalances in MM - is undetermined. Material and Methods: 90 patients (pts.) treated with one or two cycles of high-dose chemotherapy (HD-CTX) followed by autologous stem cell transplantation (ASCT) at a single center were analyzed by tri-color FISH and five DNA probes mapping to chromosome bands 1q21, 9q34, 11q25, 13q14, and 17p13. A multivariable analysis (Cox proportional hazards regression model) including genetic and clinical variables was performed. Results: The most frequent aberrations in the present series were (in order of decreasing prevalence): +1q (n=39/78, 50.0%), +9q (n=38/78, 48.7%), 13q− (n=42/90, 46.6%), and +11q (n=39/85, 45.9%). 17p− was identified in only 3 out of 88 patients (3.4%), while +17p were present in 13 out of 88 patients (14.8%). The median follow-up time was 37 months (m) and the median event free survival (EFS) and overall survival (OS) time from first ASCT of the entire cohort was 26 m and 71 m, respectively. Multivariable analysis including genetic aberrations, ß2-microblobulin, albumin, LDH, Salmon/Durie stage, and age at time of diagnosis revealed +9q and 13q− as the only independent predictors of EFS (p=0.003 and p=0.01, respectively). The mEFS in patients with 13q− was 19.0 m and 20.7 m in patients with +9q. In patients with concurrent +9q and 13q−, mEFS was only 12.2 m. In patients lacking these two abnormalities, mEFS was not reached. OS was not significantly influenced by any genetic or clinical variable in our series, most likely due to effective salvage treatment after relapse. Conclusions: +9q represents a novel and independent marker of adverse prognosis in MM. A single FISH experiment applying two DNA probes allows easy and rapid assessment of outcome in patients with malignant plasma cell disorders.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1100-1100
Author(s):  
Peter Liebisch ◽  
Hartmut Goldschmidt ◽  
Kathrin Tschajka ◽  
Christiane Wendl ◽  
Axel Benner ◽  
...  

Abstract Introduction: Genomic aberrations represent important prognostic markers in many hematological cancers. In multiple myeloma (MM), chromosome 13q deletion (13q-) has emerged as one of the most important outcome predictors and indicates a dismal prognosis. Other chromosomal abnormalities have been discussed as prognostic markers in this disease but came not out as independent variables when they were tested in a multivariate fashion. However, the complexity of genomic rearrangements and the clinical heterogeneity seen in malignant plasma cell disorders argue against 13q- as the sole genomic change of prognostic relevance. Material and Methods: In a retrospective analysis, 109 patients (pts.) treated with one or two cycles of high-dose chemotherapy (HD-CTX) followed by autologous stem cell transplantation (ASCT) at a single center were analyzed by tri-color FISH and four DNA probes mapping to chromosome bands 1q21, 9q34, 11q25, and 13q14. The selection of DNA probes based upon previous data from a comprehensive molecular cytogenetic study that revealed a high incidence of chromosomal gains (+) and losses (−) involving these four loci. The Cox proportional hazards regression model was applied to correlate molecular cytogenetic markers with clinical data. Results: The most frequent chromosomal abnormalities in the present series were +9q (49%), +1q (48%), +11q (47%), and 13q- (42%). The median follow-up time was 30 months (m) and the median event free survival (EFS) and overall survival (OS) time (calculated from first ASCT) of the entire cohort was 30 m and 71 m, respectively. There were 52 events (31 deaths). In a multivariable analysis including the four most frequent chromosomal abnormalities, +9q (hazard ratio 2.49, 95% CI 1.20-5.18; p=.01) and 13q- (2.34, 1.17–4.68; p=.02) were statistically significant risk factors for shorter EFS. The median EFS in pts. lacking both genomic changes was 3.6 years , while it was 2.5 years in pts. with either +9q or 13q- and only 1.5 years in pts. that exhibited both chromosomal abnormalities. Of note, when other potential prognostic factors ß2-microglobulin, albumin, number of chemotherapy cycles prior to first ASCT) were included in the multivariable analysis, +9q and 13q- remained independent risk factors for shorter EFS (p=.008 and p=.03, respectively). Due to the diversity of salvage treatment protocols applied after relapse, OS was not analyzed in this study. Conclusions: +9q34 could represent a novel independent marker of adverse prognosis in MM pts. receiving HD-CTX with ASCT. The prognostic significance of +9q34 and other molecular cytogenetic aberrations is currently investigated within large multicenter trials on more homogenously treated cohorts of pts.


Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2868-2868 ◽  
Author(s):  
Ingmar Bruns ◽  
Ulrich Steidl ◽  
Christof Scheid ◽  
Kai Hübel ◽  
Roland Fenk ◽  
...  

Abstract To date the most effective treatment for patients (pts) with multiple myeloma consists of conventional induction chemotherapy followed by either single or tandem high-dose chemotherapy and autologous blood stem cell transplantation. Collection of sufficient numbers of hematopoietic stem cells is essential for high-dose chemotherapy. Current regimens for stem cell mobilization are based on daily subcutaneous injections of human recombinant G-CSF starting shortly after cytotoxic therapy. Here we examined the use of polyethyenglycole (PEG)-conjugated G-CSF (pegfilgrastim) at two different doses in patients with stage II or III multiple myeloma. Patients received induction therapy with 2–4 cycles ID or VAD. Following cytotoxic therapy with cyclophosphamide (4g/m2) we administered either a single dose of 6 mg pegfilgrastim (n=10 pts; median age: 55 years), 12 mg pegfilgrastim (n=12 pts; median age: 51 years) or daily doses of 8,5 μg/kg unconjugated G-CSF (filgrastim) (n=12 pts; median age: 51 years). The growth factor was given on day 4 (range 2–5 days) in the “6 mg pegfilgrastim group”, on day 5 (range 2–7 days) in the “12 mg pegfilgrastim group” and on day 4 (range 3–6 days) in the “filgrastim group” after cyclophosphamide. Numbers of CD34+ cells were determined during leukocyte recovery and harvested by large volume apheresis using a cobe spectra blood cell separator. Pegfilgratim was associated with an earlier leukocyte recovery both at the 6mg dose (median 12 days, range 8–16 days) and the 12mg dose (median 12 days, range 7–16 days) as compared to filgrastim (median 14 days, range 11–15 days, p=0.04). Similarily, the peripheral blood CD34+ cell peak occurred earlier in patients who received pegfilgrastim (median 12 days, range 11–18 days versus median 15 days, range 12–18). On the other hand the peripheral blood CD 34+ peak did not differ significantly between the three groups (median 129/μl with 6 mg pegfilgrastim, range 30–433, median 78/μl with 12 mg pegfilgrastim, range 20– 1055 and median 111/μl with filgrastim, range 28–760, p=0.95). With a median of 1.0x10E7 CD34+ cells per kg (range 5.8x10E6-1.9x10E7) in the “6 mg pegfilgrastim group”, 7.4x10E6 CD34+ cells per kg (median, range 4.9x10E6- 3.8x10E7) in the “12 mg pegfilgrastim group” and 10.8x10E6 CD34+ cells per kg (median, range 5.0x10E6-8.7x10E7) in the “filgrastim group” there were no significant differences in the total number of harvested CD34+ cells. Following high-dose therapy with melphalan (200 mg/m2) and autografting leukocyte and platelet reconstitution was similar within all groups. In summary, a single dose of pegfilgrastim after high dose cyclophosphamide is capable of mobilizing a sufficient number of CD 34+ cells for succesful autografting and sustained hematological reconstitution in patients with multiple myeloma. No difference could be observed between 6 mg and 12 mg of pegfilgrastim. Our data provide the basis for randomized studies evaluating the optimal dose and timing of pegfilgrastim as well as long-term outcome in larger cohorts of patients.


Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 945-945
Author(s):  
Roland Fenk ◽  
Peter Schneider ◽  
Martin Kropff ◽  
Ali-Nuri Huenerlituerkoglu ◽  
Ulrich Steidl ◽  
...  

Abstract High-dose chemotherapy (HDT) improves the outcome of patients with multiple myeloma (MM) in comparison to conventional chemotherapy. Dose-escalating strategies including tandem HDT are currently evaluated to further improve remission rates and survival of patients. Therefore we conducted a randomized multicenter trial to compare an intensified conditioning regimen with the current standard high-dose melphalan. The primary study endpoint was response rate, with overall survival (OS), event-free survival (EFS) and toxicity analysed as secondary endpoints. Between 1997 and 1999 a total of 56 patients with stage II and III disease, who were matched for age (median 56 years), number of previous therapies (median time from diagnosis to transplant 7 months) and different risk factors (beta2-microglobulin, LDH, CRP, cytogentic abnormalities, chemoresistant disease, IgA-subtype, renal impairment), were randomized. All patients received 2 courses of oral idarubicine/dexamethasone and 2 courses of intravenous cyclophosphamide/adriamycine in combination with G-CSF followed by peripheral stem cell collection. Thirty patients were treated with melphalan 200mg/m2 (HD-M) whereas 26 patients received idarubicine 42mg/m2, melphalan 200mg/m2 and cyclophosphamide 120mg/kg (HD-IMC) followed by autologous blood stem cell transplantation. Acute toxicity was higher with HD-IMC, including 5 (20%) treatment-related deaths due to infections versus none (0%) in the HD-M group. This lead to early termination of the study. Severity of mucositis (grade III-IV 19 vs. 8 pts., p=0.001), CRP (20 vs. 7 mg/dl, p<0.001), days of fever (11 vs. 3, p<0.001), days with iv-antibiotics (13 vs. 4, p<0.001), number of erythrocyte-transfusions (6 vs. 2, p<0.001), number of platelet-transfusions (16 vs. 4, p<0.001) and days to granulocyte engraftment (18 vs. 11, p=0.007) were significantly higher after HD-IMC. After a follow-up of 5 years analysis restricted to patients surviving the first 30 days after HDT showed a trend to higher response rates (CR+vgPR: 47% (95%CI 24–72%) vs. 35% (95%CI 18–56%), PR 37% (95%CI 17–63%) vs. 48% (95%CI 29–68%) and time-to-progression (median 31 vs. 15 months, p=0.1) in the HD-IMC treatment arm in comparison to HD-M, but there was no significant difference in EFS and OS (median 22 vs. 30, p= 0.31 and 66 vs. 66 months, p=0.8, respectively). Univariate analysis demonstrated that LDH levels > 200 U/L (p=0.04) and chemoresistant disease (p=0.05) were a bad prognostic factor for EFS. Beta2-Microglobulin levels > 5mg/dl (p=0.01), abnormal conventional cytogenetics (p=0.02) and LDH levels > 200 U/L (p=0.03) were predictive for an inferior OS. In conclusion intensified conditioning for HDT had an intolerable high treatment-related mortality and did not improve EFS and OS in patients with multiple myeloma.


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