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IntroductionTreatment of patients with multiple myeloma (MM) is disappointing. In this regard, the Southwest Oncology Group (SWOG) experience on standard dose therapy in 7 consecutive, large phase 3 studies has shown median survival times of less than 3 years, irrespective of the treatment given. 1 In addition, the Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) group found that increased doses of conventional chemotherapy did not result in significant prolongation of survival. 2 Finally, meta-analysis of 6633 patients from 27 randomized trials failed to show any superiority of combination chemotherapy over melphalan/ prednisone in terms of duration of response and survival. 3 Furthermore, the Nordic Myeloma Study Group reported no survival improvement in conventionally treated younger patients with myeloma in the past 2 decades. 4 These limitations led to the current tendency to offer high-dose therapy (HDT)/stem cell support to MM patients as part of the frontline treatment. 5 Two randomized trials conducted by the Intergroup Français du Myeloma (IFM) and the Medical Research Council (MRC) showed that HDT significantly increased complete remission (CR), event-free survival (EFS), and overall survival (OS) compared with conventional chemotherapy. 5,6 However, 2 other randomized trials, reported in abstract form, failed to show any superiority of autologous J.B. and J.S.M. created the initial concept/design of the trial, analyzed and interpreted the data, wrote the manuscript, modified subsequent drafts, and finalized the manuscript; L.R. and A. Sureda contributed to analysis and interpretation of the data and to drafting the manuscript; J.B., J.S.M., L.R., and A. Sureda brought a significant number of patients to the study; M.F. participated in the analysis of the data and in the updating process throughout the study period; and J.M.R., J.D.-M., J.G.-L., M.V.M., L.P., J.F.-C, J.M.M., P.G., F.C., M.C., J.T., S.G., M.J.M., A.B., A. Soler, and L.F. participated in the conception/design of the study, included patients, provided the PETHEMA database with the patient data and periodic updating, and actively discussed the progress of the trial at the annual PETHEMA meetings. All the authors are members of PETHEMA and reviewed and approval the final version of the manuscript.An Inside Blood analysis of this article appears in the front of this issue.Reprints: Joan Bladé , Hematology Department, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain; e-mail: jblade@clinic.ub.es.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 U.S.C. section 1734. For personal use only. on March 22, 2019. by guest www.bloodjournal.org From transplantation. 7,8 The objective of the present study was to investigate, in a prospective randomized trial, the efficacy of HDT intensification therapy compared with continuation with conventional chemotherapy in patients wit...

Summary Recombinant human erythropoietin (rHuEPO) is an effective treatment for the anaemia that occurs secondary to various conditions, but its role in myelofibrosis with myeloid metaplasia (MMM) is not well established. rHuEPO, at an initial dose of 10 000 U thrice a week, was given to 20 patients with MMM and anaemia. Complete response (CR) was defined as transfusion cessation with normal haemoglobin (Hb) levels and partial response (PR) as a transfusion decrease ≥50% and Hb > 10 g/dl maintained for at least 8 weeks. Nine patients (45%) showed a favourable response to treatment, including four CR and five PR, four of whom have maintained their response at a median follow‐up of 12·5 months (range: 4–21 months) from the start of treatment. The pretreatment factors associated with a favourable response were lack of transfusion requirement (P = 0·002) and higher Hb at start treatment of (P = 0·01). An analysis of the present series (n = 20) and 31 patients from the literature identified 28 (55%) favourable responses to rHuEPO, including 16 CR and 12 PR. In the multivariate analysis, serum erythropoietin level <125 U/l was found to be associated with a favourable response to rHuEPO, whereas lack of transfusional support had borderline significance.

Summary. The outcome of 29 multiple myeloma patients receiving fludarabine and melphalan-based non-myeloablative allogeneic transplant (NMT) was evaluated. Eventfree survival (EFS) at 24 months was 33%, being significantly higher for patients who developed chronic graft-versus-host disease (cGVHD) when compared with those who did not [51% vs 0% respectively, P ¼ 0AE02; hazard rate ¼ 3AE16 (95% confidence interval ¼ 1AE09-9AE15, P ¼ 0AE03)] as well as for patients transplanted in complete remission/partial response (CR/PR) or stable disease (SD), compared with those with refractory/progressive disease (43% vs 0% respectively, P ¼ 0AE02). Overall survival (OS) at 24 months was 60% [72% vs 42% for patients who did and did not develop cGVHD respectively (P ¼ 0AE1); 63% vs 41% for patients in CR/PR or SD vs refractory/progressive disease at transplant respectively (P ¼ 0AE013)]. At a median follow-up of 366 d, 13 patients remained in CR/PR (45% overall response rate). Nine patients have died, three of them as a result of disease progression and six (21%) as a result of transplant-related mortality (TRM). Actuarial incidence of TRM was 37% for patients who developed acute GVHD vs 13% for those who did not (log rank, P ¼ 0AE04). The present study suggests that graft-versus-myeloma effect is the main weapon for disease control after NMT in MM patients and the efficacy of this immune effect depends on tumour burden before transplant.

Background: In this work, we assessed the efficacy and safety of brentuximab vedotin (BV) plus ESHAP (BRESHAP) as secondline therapy for Relapsed/Refractory Hodgkin lymphoma (RRHL) to improve the results before autologous stem-cell transplantation (ASCT).Patients and methods: This was a multicenter, open-label, phase I-II trial of patients with RRHL after first-line chemotherapy. Treatment had three 21-day cycles of etoposide, solumedrol, high-dose AraC, and cisplatin. BV was administered at three dose levels (0.9, 1.2, and 1.8 mg/kg) intravenous on day -1 to 3 þ 3 cohorts of patients. Final BV dose was 1.8 mg/kg. Responding patients proceeded to ASCT, followed by three BV courses (1.8 mg/kg, every 21 days). Main end points for evaluation were maximum tolerable dose and overall and complete response (CR) before ASCT.Results: A total of 66 patients were recruited (median age 36 years; range 18-66): 40 were primary refractory, 16 early relapse and 10 late relapse. There were 39 severe adverse events were reported in 22 patients, most frequently fever (n ¼ 25, 35% neutropenic), including 3 deaths. Grade 3-4 hematological toxicity presented in 28 cases: neutropenia (n ¼ 21), thrombocytopenia (n ¼ 14), and anemia (n ¼ 7). Grade !3-4 extrahematological adverse events (!5%) were non-neutropenic fever (n ¼ 13) and hypomagnesaemia (n ¼ 3). Sixty-four patients underwent stem-cell mobilization; all collected >2Â10e6/kg CD34þ cells (median 5.75; range 2.12-33.4). Overall response before transplant was 91% (CI 84% to 98%), including 70% (CRs 95% CI 59% to 81%). 60 patients were transplanted with no failure engraftments. Post-transplant response was CR in 49 patients (82% CI 73% to 91%) and partial responses in six (10% CI 5% to 15%). After a mean follow-up of 27 months, the 30-month time to treatment to failure was 74% (95% CI 68% to 80%), progression-free survival 71% (95% CI 65% to 77%), and overall survival 91% (CI 84% to 98%). Conclusion:BRESHAP looks a safe and effective pre-transplant induction regimen, does not jeopardize transplant and allows long-term remissions and survival.

BackgroundThe aim of this study was to compare the long-term safety and efficacy of oral busulfan 12 mg/kg plus melphalan 140 mg/m 2 and melphalan 200 mg/m 2 as conditioning regimens for autologous stem cell transplantation in newly diagnosed patients with multiple myeloma in the GEM2000 study. Design and MethodsThe first 225 patients received oral busulfan 12 mg/kg plus melphalan 140 mg/m 2 ; because of a high frequency of veno-occlusive disease, the protocol was amended and a further 542 patients received melphalan 200 mg/m 2 . ResultsEngraftment and hospitalization times were similar in both groups. Oral busulfan 12 mg/kg plus melphalan 140 mg/m 2 resulted in higher transplant-related mortality (8.4% versus 3.5%; P=0.002) due to the increased frequency of veno-occlusive disease in this group. Response rates were similar in both arms. With respective median follow-ups of 72 and 47 months, the median progression-free survival was significantly longer with busulfan plus melphalan (41 versus 31 months; P=0.009), although survival was similar to that in the melphalan 200 mg/m 2 group. However, access to novel agents as salvage therapy after relapse/progression was significantly lower for patients receiving busulfan plus melphalan (43%) than for those receiving melphalan 200 mg/m 2 (58%; P=0.01). ConclusionsConditioning with oral busulfan 12 mg/kg plus melphalan 140 mg/m 2 was associated with longer progression-free survival but equivalent survival to that achieved with melphalan 200 mg/m 2 but this should be counterbalanced against the higher frequency of veno-occlusive disease-related deaths. This latter fact together with the limited access to novel salvage therapies in patients conditioned with oral busulfan 12 mg/kg plus melphalan 140 mg/m 2 may explain the absence of a survival difference. Oral busulfan was used in the present study; use of the intravenous formulation may reduce toxicity and result in greater efficacy, and warrants further investigation in myeloma patients. (Clinicaltrials.gov identifier: NCT00560053).Key words: multiple myeloma, melphalan, oral busulfan, conditioning regimens, autologous stem cell transplantation, survival, progression-free survival. . Haematologica 2010;95(11):1913-1920. doi:10.3324/haematol.2010 Citation

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.