ASCT constitutes a therapeutic option for HL patients after a first relapse. Promising results are observed in patients with low tumour burden at diagnosis, autografted after a long CR and without detectable disease at ASCT. Innovative approaches should be pursued for patients with risk factors at relapse.
Summary. We have retrospectively analysed 344 multiple myeloma (MM) patients (202 de novo patients) treated in a non-uniform way in whom high-dose therapy and autologous stem cell transplantation (ASCT) response was simultaneously measured by both electrophoresis (EP) and immunofixation (IF). Patients in complete remission (CR) by EP were further subclassified as CR1 when IF was negative and CR2 when it remained positive. Partial responders (PR) were also subclassified as PR1 (very good PR, . 90% reduction in M-component) or PR2 (50±90% reduction). CR1 patients showed a significantly better event-free survival (EFS) [35% at 5 years, 95% confidence interval (CI) 17±53, median 46 months] and overall survival (OS) (72% at 5 years, CI 57±86, median not reached) compared with any other response group (univariate comparison P , 0´00000 to P 0´004). In contrast, comparison of CR2 with PR1 and with PR2 did not define different prognostic subgroups (median EFS 30, 30 and 26 months respectively, P 0´6; median survival 56, 44 and 42 months respectively, P 0´5). The non-responding patients had the worst outcome (5-year OS 8%, median 7 months). Multivariate analysis confirmed both the absence of differences among CR2, PR1 and PR2 and the highly discriminatory prognostic capacity of a threecategory classification: (i) CR1 (ii) CR2 1 PR1 1 PR2, and (iii) non-response (EFS P , 0´00000; OS P , 0´00000; both Cox models P , 0´00000). In the logistic regression analysis, the factors significantly associated with failure to achieve CR1 were the use of two or more up-front chemotherapy lines, status of non-response pre-ASCT and inclusion of total body irradiation (TBI) in the preparative regimen. Tandem transplants or the use of multiple agents (busulphan and melphalan) in the preparative regimen resulted in a higher CR1 level; none of the biological factors explored influenced the possibility of achieving CR1. These results confirm that, in MM patients undergoing ASCT, achieving a negative IF identifies the patient subset with the best prognosis; accordingly, therapeutic strategies should be specifically designed to achieve negative IF.
We investigated the prognostic impact and clinical utility of serum free light chains (sFLC) and serum heavy-light chains (sHLC) in patients with multiple myeloma treated according to the GEM2005MENOS65, GEM2005MAS65, and GEM2010MAS65 PETHEMA/GEM phase III clinical trials. Serum samples collected at diagnosis were retrospectively analyzed for sFLC (n = 623) and sHLC (n = 183). After induction or autologous transplantation, 309 and 89 samples respectively were available for sFLC and sHLC assays. At diagnosis, a highly abnormal (HA) sFLC ratio (sFLCr) (<0.03 or >32) was not associated with higher risk of progression. After therapy, persistence of involved-sFLC levels >100 mg/L implied worse survival (overall survival [OS], P = 0.03; progression-free survival [PFS], P = 0.007). Among patients that achieved a complete response, sFLCr normalization did not necessarily indicate a higher quality response. We conducted sHLC investigations for IgG and IgA MM. Absolute sHLC values were correlated with monoclonal protein levels measured with serum protein electrophoresis. At diagnosis, HA-sHLCrs (<0.29 or >73) showed a higher risk of progression (P = 0.006). Additionally, involved-sHLC levels >5 g/L after treatment were associated with shorter survival (OS, P = 0.001; PFS, P = 0.018). The HA-sHLCr could have prognostic value at diagnosis; absolute values of involved-sFLC >100 mg/L and involved-sHLC >5 g/L could have prognostic value after treatment.
The benefit of ASCT in MM is associated with the degree of tumour decrease with the initial induction chemotherapy. In April 2006, the Spanish Myeloma Group (PETHEMA/GEM) activated a randomized phase III trial comparing TD vs. VTD vs. VBMCP/VBAD/Velcade® in patients 65 years-old or younger with newly diagnosed symptomatic MM, followed by ASCT with MEL-200. The primary end points were response rate after induction and after ASCT and time to progression. TD consisted of thalidomide 200 mg daily (escalating doses in the first cycle) and dexamethasone 40 mg on days 1–4 and 9–12 at 4-week intervals for 6 cycles. The VTD regimen was identical to TD plus Velcade 1.3 mg/m2 on days 1,4,8,11 of each cycle. Combination chemotherapy plus Velcade® consisted of 4 cycles of VBMCP/VBAD on an alternating basis followed by 2 cycles of Velcade® (1.3 mg/m2 on days 1,4,8, and 11 every 3 weeks). The duration of the induction therapy was 24 weeks in all arms. Two-hundred and seventy-five out of the 390 planned patients have been included so far. As of February 15, 2008, 190 patients (median age: 57 yrs., M:96, F:94; IgG:107, IgA:50, light chain:25, others:9) entered the study. 32 (17%) patients had soft-tissue extramedullary plasmacytomas (EMP) and the stage according to the ISS classification was I in 38%, II in 41%, III in 20% and unknown in 1%. The prognostic factors, including cytogenetics, were similar in the 3 arms. The prognostic factors, including cytogenetics, were similar in the three arms. 173 patients (TD:61, VTD:54 and VBMCP/VBAD/Velcade:58) were already evaluable for response and toxicity to induction therapy. Efficacy and toxicity were assessed on an intention-to-treat basis. The ≥PR rate was 62%, 77% and 70% with TD, VTD and VBMCP/VBAD/Velcade®, respectively (p=NS). The IF negative CR rate was significantly higher with VTD (31%) and with VBMCP/VBAD/Velcade® (22%) compared to TD (6%) (p< 0.01). Progressive disease was significantly higher in patients with EMP (31% vs. 12%, p=0.01). This higher PD rate in patients with EMP was similar in the three arms. The incidence of grade 3 and 4 adverse events (AEs) was 38%, 54% and 50% with TD, VTD, and VBMCP/VBAD/Velcade® respectively. The total number of AEs for TD, VTD and VBMCP/VBAD/Velcade® were 37, 36 and 44, respectively. 13% of patients receiving TD developed ≥ grade 3 thrombotic events while 16% of patients in the VTD arm had grade ≥3 peripheral neuropathy. Treatment discontinuation due to toxicity was required in 8 patients (TD: 1; VTD: 5, VBMCP/VBAD: 2). 5 patients died during the induction phase (TD:3, VTD:0, VBMCP/VBAD/Velcade:2). 72 patients were evaluable for response after ASCT. The post-ASCT CR rate were higher with VTD (50%) and with VBMCP/VBAD/Velcade® (39%) compared to the TD arm (26%), although the difference did not reach statistical significance. Our preliminary analysis shows that VTD and VBCMP/VBAD plus Velcade® result in a higher CR rate than TD both before and after ASCT and that the toxicity in the three arms is not significantly different. Longer follow-up is needed to establish whether or not this higher tumour reduction is translated into a significant better long-term outcome. Updated results will be presented at the meeting.
The current treatment of hereditary hemochromatosis (HH) consists of performing periodic manual whole blood phlebotomies. Erythroapheresis (EPH) is considered to be an alternative procedure if the classic treatment is contra-indicated. A prospective study of 13 consecutive cases of HH were included in a periodic EPH program with the aim of assessing the efficacy, feasibility, and tolerability of EPH in the treatment of HH by induction and maintenance. Iron depletion (ferritin <20 microg/l) was achieved in all patients after a mean of 6.7 +/- 2.9 months of treatment and a mean of 13.5 +/- 7.2 EPH sessions. The procedure was well tolerated and there were no complications. After a follow-up period of 10.5 +/- 6.6 months, only four patients have required further maintenance sessions beyond 6 months after completing the induction therapy. The efficacy, speed, tolerability, and more favorable schedule of an EPH program facilitate treatment of HH.
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