Randomized trial experience of the Intergroupe Francophone du Myélome

This article summarizes clinical results of the Intergroupe Francophone du Myélome (IFM) trials: high-dose therapy (HDT) supported with autologous stem cells improves survival, melphalan 200 mg/m(2) is the best preparative regimen, unpurged peripheral blood stem cells (PBSC) are the recommended source of stem cells to support HDT, and tandem transplants significantly improve survival. Although these results are encouraging, the current IFM 99 protocol will evaluate innovative strategies with the goal to improve long-term survival.     

Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome

Acquired genomic aberrations have been shown to significantly impact survival in several hematologic malignancies. We analyzed the prognostic value of the most frequent chromosomal changes in a large series of patients with newly diagnosed symptomatic myeloma prospectively enrolled in homogeneous therapeutic trials. All the 1064 patients enrolled in the IFM99 trials conducted by the Intergroupe Francophone du Myélome benefited from an interphase fluorescence in situ hybridization analysis performed on purified bone marrow plasma cells. They were systematically screened for the following genomic aberrations: del(13), t(11;14), t(4;14), hyperdiploidy, MYC translocations, and del(17p). Chromosomal changes were observed in 90% of the patients. The del(13), t(11;14), t(4;14), hyperdiploidy, MYC translocations, and del(17p) were present in 48%, 21%, 14%, 39%, 13%, and 11% of the patients, respectively. After a median follow-up of 41 months, univariate statistical analyses revealed that del(13), t(4;14), nonhyperdiploidy, and del(17p) negatively impacted both the event-free survival and the overall survival, whereas t(11;14) and MYC translocations did not influence the prognosis. Multivariate analyses on 513 patients annotated for all the parameters showed that only t(4;14) and del(17p) retained prognostic value for both the event-free and overall survivals. When compared with the currently used International Staging System, this prognostic model compares favorably. In myeloma, the genomic aberrations t(4;14) and del(17p), together with ß2-microglobulin level, are important independent predictors of survival. These findings have implications for the design of risk-adapted treatment strategies.      

Thalidomide salvage therapy following allogeneic stem cell transplantation for multiple myeloma: a retrospective study from the Intergroupe Francophone du Myélome (IFM) and the Société Française de Greffe de Moelle et Thérapie Cellulaire (SFGM-TC)

Thalidomide is effective in multiple myeloma (MM), even in patients who have relapsed after high-dose therapy. A potent graft-versus-myeloma (GVM) effect can be induced against MM after allogeneic stem cell transplantation (allo-SCT). In all, 31 MM patients received thalidomide as a salvage therapy after progression following allo-SCT. The median maximum daily dose of thalidomide was 200 mg (range, 50-600). Thalidomide had to be discontinued in six patients (19%) because of toxicity. In all, nine patients (29%; 95% CI, 13-45) achieved an objective response with thalidomide therapy (six partial and three very good partial responses, VGPR). Five patients developed graft-versus-host disease (GVHD) after thalidomide therapy, including the three patients achieving a VGPR. These data demonstrate that thalidomide is potentially effective in MM patients failing allo-SCT.     

Cytogenetic, interphase, and multicolor fluorescence in situ hybridization analyses in primary plasma cell leukemia: a study of 40 patients at diagnosis, on behalf of the Intergroupe Francophone du Myélome and the Groupe Français de Cytogénétique Hématologique

Primary plasma cell leukemia (PCL) is a rare plasma cell malignancy. Consequently, few large reports have been published. Presented is a cytogenetic analysis of 40 patients with primary PCL compared with 247 newly diagnosed patients with stage III multiple myeloma (MM). Cytogenetic abnormalities were observed in 23 of 34 patients, with usually complex hypodiploid or pseudodiploid karyotypes. Analysis of rearrangements of the 14q32 region revealed significant differences with high cell mass MM-a higher incidence of t(11;14) (33% vs 16%; P <.025) and of t(14;16) (13% vs 1%; P <.002) though incidences of t(4;14) were identical and a higher incidence of monosomy 13 (68% vs 42%; P =.005). Hypodiploid karyotypes and monosomy 13 may explain, at least in part, the poorer prognosis of primary PCL. In contrast, significantly longer survival was observed in patients displaying t(11;14) in comparison with those lacking this translocation (P =.001).     

High-dose chemotherapy with autologous stem cell transplantation for multiple myeloma: what predicts the outcome? Experience from a developing country

We analyzed the results of 108 patients (78 males and 30 females) with multiple myeloma who underwent autologous stem cell transplantation (ASCT). The median age of patients was 52 years (range, 26-68 years). High-dose melphalan (200 mg/m(2)) was used for conditioning. In all, 66 (61%) patients had evidence of chemo-sensitive disease before transplant. After ASCT 79.6% of patients responded: complete response 36%, very good partial response 29.6%, and partial response 13.9%. Complete response rate was higher for patients with chemo-sensitive disease; 33 of 66 (50.0%) patients achieved complete response compared with 7 of 42 (14.3%) patients with progressive disease, P<0.01. Response rates to ASCT were significantly low for patients with Hb 5.5 mg/l, International Staging System stage III at diagnosis and >12 months interval from diagnosis to transplant. Grade III-IV mucositis was the major regimen-related toxicity. At a median follow-up of 70 months, the median overall survival and event free survival (EFS) were 71 and 42 months, respectively. Estimated overall survival and EFS at 60 months were 54.4+/-0.05% (s.e.) and 49.3+/-0.05% (s.e.), respectively. Survival was significantly better for patients with pre-transplant chemo-sensitive disease and for those who achieved complete response following transplant.     

Endoscopic ultrasonography is an independent predictive factor of prognosis in locally advanced esophageal cancer. Results from the randomized FFCD 9102 study from the Fédération Francophone de Cancérologie Digestive

BACKGROUND: No multivariate study has assessed the independent prognostic role of endoscopic ultrasonography (EUS) in esophageal cancer, even when considering computed tomography (CT). OBJECTIVE: To evaluate the prognostic value of EUS in esophageal cancer before exclusive or preoperative radiochemotherapy. METHODS: From 1993 to 1999, the FFCD 9102 study enrolled 444 patients who had cancer of the thoracic esophagus, stages T3-4, N0-1 and M0 on CT. The patients received two sessions of chemotherapy in addition to radiotherapy. The 259 patients with objective response and no contraindications for further treatment were randomized to undergo surgery or to continue with radiochemotherapy. EUS was performed in 174 patients enrolled in the trial (mean age: 59 years). Tumor characteristics and lymph node status were prospectively recorded. A Cox statistical model was used to identify any predictive prognostic factors among the clinical, EUS and CT data. RESULTS: In the multivariate analysis, three factors were associated with a poor prognosis: inability to ingest solid food (OR: 1.98; P=0.0008); more than three neoplastic subdiaphragmatic lymph nodes (LN) on EUS (OR: 2.41; P<0.0045) and age>65 (OR: 1.53; P<0.056). Their prognostic value persisted after adjustment for type of treatment given. Two- and five- year survival rates were 21.5 and 10.5%, respectively, in the presence of three neoplastic subdiaphragmatic LN, and 43 and 30%, respectively, in all other cases. CONCLUSION: Degree of dysphagia, age and presence of neoplastic subdiaphragmatic LN on EUS were independently predictive of the prognosis for locally advanced esophageal cancer. EUS results should be taken into account in future trials.     

A non-randomised dose-escalating phase II study of thalidomide for the treatment of patients with low-risk myelodysplastic syndromes: the Thal-SMD-2000 trial of the Groupe Français des Myélodysplasies

Patients (n=47) with low-risk myelodysplastic syndrome were treated with thalidomide [200 mg/d, increased by 200 mg/d/4 weeks up to week 16]. Responses were evaluated according to the International Working Group criteria at week 16 for 39 patients who received at least 8 weeks of treatment. Twenty-three (59%) patients showed haematological improvement (HI): four major erythroid response (HI-EM), 15 minor erythroid response, six major neutrophil response, two major platelet response. Side effects caused 22/39 to stop thalidomide before week 16. Nine of 23 responders continued thalidomide after week 16 [19% of trial patients] with sustained response in eight of nine. Six reached week 56, including the four HI-EM patients [13% of trial patients]. Nineteen of 36 red blood cell transfusion-dependent patients (53%) showed erythroid response, but only four became transfusion-independent. Among the 23 responders, the median duration of response was 260 d (range 30-650). Responses were sustained in all patients except one, and were observed between week 4 and week 8 in 85% of patients, at doses ranging from 200 to 400 mg. Only two patients responded at 600 mg/d and none at 800 mg/d. No clinical characteristics of responding versus non-responding patients were identified. The erythroid response rate was identical in all cytogenetic subgroups, including 5q31.1 deletions. Pretreatment vascular endothelial growth factor levels were lower in responders compared with non-responders (P=0.004). Microvessel density (MVD) increased and apoptosis decreased in four of six and in all six responders studied respectively whereas MVD and apoptosis were unchanged in three non-responders.     

Tandem transplants with different high-dose regimens improve the complete remission rates in multiple myeloma. Results of a Grupo Español de Síndromes Linfoproliferativos/Trasplante Autólogo de Médula Osea phase II trial

Between 1994 and 1999, 88 multiple myeloma (MM) patients were included in a phase II study to evaluate a tandem autologous stem cell transplantation (ASCT) programme. The first was conditioned with melphalan 200 mg/m2 (MEL200-ASCT1), and the second with cyclophosphamide, etoposide and BCNU (CBV-ASCT2). All patients were in response after MEL200-ASCT1. A control group of MM patients with response to a single ASCT was selected to compare outcomes. After MEL200-ASCT1, 26 patients (30%) achieved complete remission (CR). Of the remaining 48 evaluable patients, 16 (33%) achieved CR with CBV-ASCT2. The final CR rate was 48%. The 5-year survival (OS) was 55%[95% confidence interval (CI) 43-67%] while the event-free survival (EFS) was 28% (95% CI 15-39%). CR status after CBV-ASCT2 was the most important prognostic factor for OS and EFS (P = 0.00001), although no differences in outcomes were detected when the patients in CR after MEL200-ASCT1 were compared with those who obtained CR after CBV-ASCT2. Univariate and multivariate analyses showed improved OS and EFS for the tandem series as compared with the control series treated with a single MEL200-ASCT. However, in a stratified comparison by response, there were no prognostic differences between tandem patients and control patients treated with a single ASCT. In summary, our study suggests that the benefit of a second high-dose therapy course depends on its capacity to result in CR for MM patients who have not attained CR after ASCT1.     

Does chemical shift imaging offer a biomarker for the diagnosis and assessment of disease severity in multiple myeloma?: A cross-sectional study

To investigate whether chemical shift imaging (CSI) is useful for differentiating myelomatous infiltration from hematopoietic bone marrow (BM) and for quantitatively assessing disease severity.In this retrospective study, spinal MRI, including a sagittal iterative decomposition of water and fat with echo asymmetry and least-squares estimation T2 fast spin-echo sequence, was performed on 76 myeloma patients (45 men, 67.0 ± 11.4 years; 31 women, 66.5 ± 11.0 years) and 30 control subjects (20 men, 67.0 ± 8.4 years; 10 women, 67.0 ± 9.2 years). The fat-signal fraction (FF) and mean signal dropout ratio (DR) were calculated from lumbar BM that contained no focal lesions. The BM plasma cell percentage (BMPC%) and serological data were obtained. As DR is highest when FF = 50%, the patients were divided into 2 groups: a water-dominant group (FF < 50%) and a fat-dominant group (FF > 50%).Serum monoclonal protein (M protein), β2-microglobulin, and BMPC% were significantly higher in the water-dominant group than in the fat-dominant group. In the water-dominant group, DR correlated significantly with BMPC% and M protein, whereas in the control group, DR showed a weak correlation with age but no correlation with other clinical factors. No significant differences in any clinical data were seen between high and low DR.CSI proved ineffective for differentiating myelomatous infiltration from hematopoietic BM. For myeloma patients with relatively high BM cellularity, a small signal drop on opposed-phase images indicated a higher tumor burden. For BM with relatively low cellularity, disease severity was not reflected by CSI.     

Daily practice management of myelodysplastic syndromes in France: data from 907 patients in a one-week cross-sectional study by the Groupe Francophone des My��lodysplasies

Background

There is little published information on the everyday clinical management of myelodysplastic syndromes in real world practice.

Design and Methods

We conducted a cross-sectional study of all patients with myelodysplastic syndromes attending 74 French centers in a 1-week period for inpatient admission, day-hospital care or outpatient visits.

Results

Nine hundred and seven patients were included; 67.3% had lower-risk myelodysplastic syndromes (International Prognostic Scoring System: low or intermediate-1). Karyotype had been analyzed in 82.5% of the cases and was more often of intermediate or poor risk in patients under 65 years old compared with those who were older. Red blood cell transfusions accounted for as many as 31.4% of the admissions. Endogenous erythropoietin level was less than 500 IU/L in 88% of the patients tested. Erythroid stimulating agents had been or were being used in 36.8% of the lower risk patients, iron chelation in 31% of lower risk patients requiring red blood cell transfusions and lenalidomide in 41% of lower risk patients with del 5q. High-dose chemotherapy, hypomethylating agents, low dose cytarabine and allogeneic stem cell transplantation had been or were being used in 14.8%, 31.1%, 8.8% and 5.1%, respectively, of higher-risk patients.

Conclusions

Karyotype is now assessed in most patients with myelodysplastic syndromes, and patients under 65 years old may have more aggressive disease. Apart from erythroid-stimulating agents and, in higher-risk myelodysplastic syndromes, hypomethylating agents, specific treatments are used in a minority of patients with myelodysplastic syndromes and red blood cell transfusions still represent the major reason for hospital admission.     

Successful autologous peripheral blood stem cell transplantation in a Jehovah’s Witness with multiple myeloma: review of literature and recommendations for high-dose chemotherapy without support of allogeneic blood products

We present a case report of a successful high-dose melphalan therapy and autologous stem cell transplantation without the use of allogeneic blood product support in a 70-year-old patient suffering from multiple myeloma. Based on the experience in this case and thorough evaluation of the literature, we consider pre-transplant Hb level of 11–12 g/dl, platelet count higher than 70/nl, good WHO performance status of two and lower and informed consent as important eligibility criteria. During cytopenia recommended supportive measures include growth factor support with erythropoietin and G-CSF, p.o. iron treatment as well as prophylactic use of anti-fibrinloytic agents. Furthermore we discuss additional options that might be considered depending on the individual factors as e.g. pre-transplant collection and cryoconservation of autologous platelet concentrates. Moreover, an analysis of socio-economic issues regarding this procedure is presented. We conclude that allogeneic blood product free transplantation is a feasible procedure that can be offered to the patients belonging to distinct religious groups refusing allogeneic blood products as Jehova′s Witnesses and patients presenting other contraindications for transfusions.     

Epidemiology of NIV for Acute Respiratory Failure in COPD Patients: Results from the International Surveys vs. the “Real World”

Non-invasive ventilation (NIV) has been recommended as the first-line ventilation modality for acute respiratory failure (ARF) due to acute exacerbation of chronic obstructive pulmonary disease (AECOPD) based on strong evidence. However, everyday clinical practice may differ from findings of multiple randomized controlled trials. Physicians and respiratory therapists involved in NIV management have been queried about its utilization and effectiveness. In addition to these estimates, cohort studies and analysis of large inpatient dataset of patients with AECOPD and ARF managed with NIV have been extensively published over the last two decades. This review summarizes the perception of medical staff vs. the “real life” data about NIV use for ARF in AECOPD patients.     

Adverse effects of a multicentre system for ethics approval on the progress of a prospective multicentre trial of cancer treatment: how many patients die waiting?

Background: As cancer survival is improving approximately by 1–2% per year, delays in the clinical trials that lead to that improvement could cost lives.
Aims: To review the process of ethics committee approval for a multicentre clinical trial of cancer treatment and to estimate the delay it will cause in obtaining the results and the effects of such delays on survival for all cancers in Australia.
Methods: A survey was sent to each of the 15 centres participating in the study to obtain details about submissions they had made to their ethics committees and the replies received from them.
Results: The survey response rate was 100%. The average time required to complete an ethics submission was 12 h, and the average length of time for a final reply was 70 days. Wide variation was noted in the replies, 40% were considered constructive. Most centres said the effort in ethics submissions is sufficient to limit participation in other clinical trials that are available.
Conclusion: The multicentre system of ethics approval has significantly delayed this multicentre trial and may delay advances in cancer care. Extrapolating this delay to determine an influence on improvements in cancer survival suggests that it may be responsible for 60 cancer deaths per year. A method for measuring the effect on the shape of the accrual curve is defined, and the term DIABOLECAL ( D elays in A ccrual B rought O n L argely by E thics C ommittee A ctivity L ag-time) is proposed to describe it. Attempts to overcome this problem have been introduced overseas.     

Tamponnade cardiaque : première manifestation du Myélome Multiple : à propos d'un cas et revue de la littérature: Cardiac tamponade as first manifestation of multiple myeloma : A case report with literature review

Multiple myeloma is a hematologic malignancy characterized by clonal proliferation of plasma cells, mainly in bone marrow. Extramedullary disease is reported in many cases and may occur at diagnosis, at progression, or during relapse phase. Pericardial involvement is a rare condition that usually occurs with advanced-stage disease.We report a rare case of 76-year-old women with plasma cell-based pericardial effusion with cardiac tamponade as a form of presentation of multiple myeloma and discuss it in the light of literature.Diagnosis was established by pericardial fluid cytology. The patient received systemic chemotherapy, according to MPT protocol.