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BACKGROUND: Elotuzumab plus lenalidomide and dexamethasone has shown improved progression-free and overall survival versus lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma. We aimed to assess these regimens in patients with newly diagnosed multiple myeloma who are ineligible for haematopoietic stem-cell transplantation (HSCT). METHODS: ELOQUENT-1 is an open-label, multicentre, randomised, phase 3 trial conducted at 185 hospitals, oncology practices, and research centres in 19 countries. Eligible patients were aged 18 years or older with newly diagnosed, untreated, symptomatic myeloma and not candidates for high-dose therapy plus HSCT, and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or lower. Patients were randomly assigned (1:1) to receive elotuzumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone using an interactive voice response system, stratified by the International Staging System (ISS; stage I-II vs III), age (

The value of minimal residual disease (MRD) status by bone marrow and imaging analysis as independent prognostic factors has been well established in multiple myeloma (MM). Nevertheless data about their potential complementarity for a more accurate assessment are limited. With this aim, we retrospectively analyzed the prediction of outcome with the combination of PET-CT and MRD, assessed by multiparameter flow cytometry (MFC) in 103 patients with newly diagnosed MM. We confirmed the benefit in terms of progression-free survival (PFS), linked to the achievement of negativity by MFC (hazard ratio [HR] 0.53; 95% confidence interval [CI]: 0.28-0.98), and PET-CT (HR 0.18; 95% CI: 0.09-0.36) individually. By combining both techniques, patients who became MRD-/PET-, with a median of PFS 92 months, had significant prolonged median PFS (P < .001). This is compared with MRD+/PET- and PET+ patients (median PFS of 45 and 28 months, respectively). We observed a significant difference (P = .003) in overall survival (OS) outcomes between MRD-/PET- and MRD+/PET- patients (4-year OS 94.2% and 100%, respectively), vs PET+ patients (4-year OS 73.8%). All survival results were confirmed in a conditional landmark analysis. These findings support the potential complementarity between PET-CT and MFC, and highlight their better predictive capability when improving sensitivity.

Although light-chain amyloidosis (AL) and multiple myeloma (MM) are characterized by tumor plasma cell (PC) expansion in bone marrow (BM), their clinical presentation differs. Previous attempts to identify unique pathogenic mechanisms behind such differences were unsuccessful, and no studies have investigated the differentiation stage of tumor PCs in patients with AL and MM. We sought to define a transcriptional atlas of normal PC development in secondary lymphoid organs (SLOs), peripheral blood (PB), and BM for comparison with the transcriptional programs (TPs) of tumor PCs in AL, MM, and monoclonal gammopathy of undetermined significance (MGUS). Based on bulk and single-cell RNA sequencing, we observed 13 TPs during transition of normal PCs throughout SLOs, PB, and BM. We further noted the following: CD39 outperforms CD19 to discriminate newborn from long-lived BM-PCs; tumor PCs expressed the most advantageous TPs of normal PC differentiation; AL shares greater similarity to SLO-PCs whereas MM is transcriptionally closer to PB-PCs and newborn BM-PCs; patients with AL and MM enriched in immature TPs had inferior survival; and protein N-linked glycosylation–related TPs are upregulated in AL. Collectively, we provide a novel resource to understand normal PC development and the transcriptional reorganization of AL and other monoclonal gammopathies.

© The Author(s) 2021., Although case-control analyses have suggested an additive value with the association of clarithromycin to continuous lenalidomide and dexamethasone (Rd), there are not phase III trials confirming these results. In this phase III trial, 286 patients with MM ineligible for ASCT received Rd with or without clarithromycin until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). With a median follow-up of 19 months (range, 0–54), no significant differences in the median PFS were observed between the two arms (C-Rd 23 months, Rd 29 months; HR 0.783, p = 0.14), despite a higher rate of complete response (CR) or better in the C-Rd group (22.6% vs 14.4%, p = 0.048). The most common G3–4 adverse events were neutropenia [12% vs 19%] and infections [30% vs 25%], similar between the two arms; however, the percentage of toxic deaths was higher in the C-Rd group (36/50 [72%] vs 22/40 [55%], p = 0.09). The addition of clarithromycin to Rd in untreated transplant ineligible MM patients does not improve PFS despite increasing the ≥CR rate due to the higher number of toxic deaths in the C-Rd arm. Side effects related to overexposure to steroids due to its delayed clearance induced by clarithromycin in this elderly population could explain these results. The trial was registered in clinicaltrials.gov with the name GEM-CLARIDEX: Ld vs BiRd and with the following identifier NCT02575144. The full trial protocol can be accessed from ClinicalTrials.gov. This study received financial support from BMS/Celgene.

Stringent complete response (sCR) is used as a deeper response category than complete response (CR) in multiple myeloma (MM) but may be of limited value in the era of minimal residual disease (MRD) testing. Here, we used 4-colour multiparametric flow cytometry (MFC) or next-generation sequencing (NGS) of immunoglobulin genes to analyse and compare the prognostic impact of sCR and MRD monitoring. We included 193 treated patients in two institutions achieving CR, for which both bone marrow aspirates and biopsies were available. We found that neither the serum free light chain ratio, clonality by immunohistochemistry (IHC) nor plasma cell bone marrow infiltration identified CR patients at distinct risk. Patients with sCR had slightly longer progression-free survival. Nevertheless, persistent clonal bone marrow disease was detectable using MFC or NGS and was associated with significantly inferior outcomes compared with MRD-negative cases. Our results confirm that sCR does not predict a different outcome and indicate that more sensitive techniques are able to identify patients with differing prognoses. We suggest that MRD categories should be implemented over sCR for the future classification of MM responses. This study was supported by grants of the Instituto de Salud Carlos III FEDER founds (Ministry of Economy and Competitivity, Madrid, Spain) FIS PI15/01484 and CRIS foundation grants 14/001 to JML. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Sí

Although survival of elderly myeloma patients has significantly improved there is still a subset of patients who, despite being fit and achieving optimal responses, will die within 2 years of diagnosis due to myeloma progression. The objective of this study was to define a scoring prognostic index to identify this group of patients. We have evaluated the outcome of 490 newly diagnosed elderly myeloma patients included in two Spanish trials (GEM2005-GEM2010). Sixty-eight patients (13.8%) died within 2 years of diagnosis (early deaths) due to myeloma progression. Our study shows that the use of simple scoring model based on 4 widely available markers (elevated LDH, ISS 3, high risk CA or >75 years) can contribute to identify up-front these patients. Moreover, unsustained response (, This study was supported by the Cooperative Research Thematic Networkgrants RD12/0036/0058 and RD12/0036/0046 of the Redde Cancer (Cancer Network of Excellence); Instituto deSalud Carlos III, Spain, Instituto de Salud Carlos III/SubdirecciónGeneral de Investigación Sanitaria part-financedby the European Regional Development Fund (FIS: PI12/01761; PI12/02311; PI13/01469; PI14/01867, G03/136;Sara Borrell: CD13/00340); Asociación Española Contra el Cáncer (GCB120981SAN) and FEDER.

A bortezomib-containing regimen followed by high-dose therapy and autologous stem cell transplant (ASCT) is considered the standard of care for front-line therapy in younger patients with newly diagnosed multiple myeloma (MM). We analyzed the results of ASCT with an intravenous busulfan 9.6 mg/kg and melphalan 140 mg/m2 (ivBUMEL) preparative regimen in 47 patients with newly diagnosed MM who had received bortezomib-based combinations as pre-transplant induction. The overall response rate and complete response after transplant were 100% and 49%, respectively. With a median follow-up of 24.5 months, median overall survival and progression-free survival have not been reached. Mucositis and febrile neutropenia were the most frequent toxicities observed. No case of sinusoidal obstruction syndrome was observed and there was no transplant-related mortality. These results suggest that front-line induction therapy with a bortezomib-based combination followed by ASCT with ivBUMEL is an effective and well-tolerated therapeutic approach for transplant eligible patients with MM.

Identification and characterization of genetic alterations are essential for diagnosis of multiple myeloma and may guide therapeutic decisions. Currently, genomic analysis of myeloma to cover the diverse range of alterations with prognostic impact requires fluorescence in situ hybridization (FISH), single nucleotide polymorphism arrays, and sequencing techniques, which are costly and labor intensive and require large numbers of plasma cells. To overcome these limitations, we designed a targeted-capture next-generation sequencing approach for one-step identification of IGH translocations, V(D)J clonal rearrangements, the IgH isotype, and somatic mutations to rapidly identify risk groups and specific targetable molecular lesions. Forty-eight newly diagnosed myeloma patients were tested with the panel, which included IGH and six genes that are recurrently mutated in myeloma: NRAS, KRAS, HRAS, TP53, MYC, and BRAF. We identified 14 of 17 IGH translocations previously detected by FISH and three confirmed translocations not detected by FISH, with the additional advantage of breakpoint identification, which can be used as a target for evaluating minimal residual disease. IgH subclass and V(D)J rearrangements were identified in 77% and 65% of patients, respectively. Mutation analysis revealed the presence of missense protein-coding alterations in at least one of the evaluating genes in 16 of 48 patients (33%). This method may represent a time- and cost-effective diagnostic method for the molecular characterization of multiple myeloma.

We evaluated the toxicity and outcome of a conditioning regimen comprising intravenous (iv) busulfan (BU) and melphalan (MEL) in 55 patients (median age, 61 years; range, 34-71) with multiple myeloma (MM) undergoing autologous stem-cell transplantation (ASCT). In 49 patients, this was the first ASCT. At transplant, 3 patients were in complete response (CR), 8 in near CR (nCR) and 30 in partial response (PR). The conditioning regimen comprised ivBU (3.2 mg/kg in a single daily dose, days -5 to -3) and MEL (140 mg/m2, day -2). Mucositis was the most frequent non-hematopoietic toxicity (47 patients). No patient developed sinusoidal occlusive syndrome. Febrile events were observed in 46 patients and were the cause of death in two (3.6%) transplant-related deaths. With a median follow-up of 15 months, 27 patients achieved CR/nCR (11 CR) and 21 a PR. The one-year actuarial overall and progression-free survival rates are 96% and 87%, respectively. This ivBU-containing regimen is associated with an acceptable toxicity and a high-response rate.

Antithymocyte globulin or human Jurkat T-cell-line-derived antilymphocyte globulin is used in allogeneic stem cell transplantation to induce in vivo T-cell depletion to facilitate engraftment and lower graft-versus-host disease. In vitro studies suggest that antithymocyte globulin, besides causing T-cell depletion, has strong anti-myeloma activity.We evaluated the anti-myeloma activity of antilymphocyte globulin in a melphalan/fludarabine-based reduced intensity conditioning regimen as well as the incidence of graft-versus-host disease in 138 multiple myeloma patients who underwent allogeneic stem cell transplantation with (n=79) or without (n=59) antilymphocyte globulin.Leukocyte and platelet engraftment were faster in the group not receiving antilymphocyte globulin (13 vs. 16 days, p0.001 and 11 vs. 19 days, p0.001, respectively). Inclusion of antithymocyte globulin led to a better day 100 overall response rate (93% vs. 78%, p=0.03) and complete response rate (59% vs. 39%, p=0.04), to a lower incidence of both acute grade III/IV graft-versus-host-disease (11% vs. 22%, p=0.10) and chronic graft-versus-host disease (23% vs. 65%, p0.001) and to a trend to improved event-free survival at 3 years (39% vs. 27%, p=0.5). There was no difference in the estimated cumulative incidence of treatment-related mortality at 1 year between the groups receiving or not antilymphocyte globulin (25% vs. 26%). In a multivariate analysis treatment with antilymphocyte globulin was the only significant factor for achievement of a complete remission (RR:2.57, p=0.02).Inclusion of antithymocyte globulin in allogeneic stem cell transplantation protocols for patients with multiple myeloma may increase remission rates and at the same time prevent graft-versus-host disease with no increase of relapses.

Purpose To analyze the prognostic impact of immunophenotyping in patients with multiple myeloma (MM). Patients and Methods We have prospectively analyzed the prognostic impact of antigenic markers, assessed by multiparametric flow cytometry, in a series of 685 newly diagnosed MM patients that were uniformly treated according to the GEM 2000 protocol. Results Our results show that expression of both CD19 and CD28 as well as the absence of CD117 were associated with a significantly shorter progression free-survival (PFS) and overall survival (OS). Interestingly, the CD28 expression correlated with t(14;16) and del(17p), while CD117-negative patients were associated with t(4;14) and del(13q). Simultaneous assessment of CD28 and CD117 antigens allowed stratification of patients with MM into three risk categories: poor risk (CD28 positive CD117 negative), intermediate (either both markers negative or both positive), and good risk (CD28 negative CD117 positive), with PFS rates of 30, 37, and 45 months, respectively (P = .01), and OS rates of 45, 68, and not reached, respectively (P = .0001). Conclusion To the best of our knowledge, this is the first prospective analysis in which the prognostic impact of a relatively high number of antigenic markers has been simultaneously analyzed in a large series of uniformly treated patients, showing that the expression of several antigens (particularly CD28 and CD117) on bone marrow plasma cells from patients with MM can help to identify patients at high risk of progression.

New treatment options offering enhanced activity in elderly, newly diagnosed patients with multiple myeloma are required. One strategy is to combine melphalan and prednisone with novel agents. We previously reported an 89% response rate, including 32% complete responses and 11% near complete responses, in our phase 1/2 study of bortezomib plus melphalan and prednisone (VMP) in 60 newly diagnosed multiple myeloma patients with a median age of 75 years. Here, we report updated time-to-events data and the impact of poor prognosis factors on outcome.Updated analyses of time to biochemical progression and overall survival with VMP were conducted, and compared with those of historical controls treated with melphalan and prednisone. A univariate analysis was performed to evaluate the influence of known prognostic factors on the time to progression.After a median follow-up of 26 months, the median time to progression with VMP was 27.2 months, compared with 20.0 months with melphalan plus prednisone. The median overall survival with VMP was not reached versus 26 months with melphalan and prednisone; the survival rate at 38 months was 85% versus 38%, respectively. Time to progression was not significantly affected by elevated beta(2)-microglobulin or lactate dehydrogenase levels, advanced age, or cytogenetic abnormalities, but was shorter in patients with albumin3 g/dL, Karnofsky performance statusor =70%, bone marrow plasma cell infiltrationor =40%, and, particularly, high plasma cell proliferative activity (or = 2.5% S-phase cells).VMP is highly active and well tolerated in elderly patients with newly diagnosed multiple myeloma, with 85% of patients alive at 3 years. Moreover, VMP may overcome the poor prognostic impact of various factors, particularly cytogenetic abnormalities.

A 64-year-old woman with IgA kappa multiple myeloma was treated with thalidomide-dexa- methasone. Due to progression of the disease, bortezomib, doxorubicin and dexamethasone were administered, followed by autologous stem cell transplantation. Although near-complete remission was achieved, 5 months later, neuro- logical symptoms appeared and the patient was diagnosed with multiple myeloma with cells in- filtrating the spinal cord. Bis-chloronitrosourea, bortezomib and lenalidomide were then admin- istered and although the patient remained neu- rologically asymptomatic, she died 3 months later becausee of disease progression. Lena- lidomide entered into the cerebrospinal fluid (confirmed by ultrasensitive high-performance liquid chromatography), although did not im- prove the poor prognosis of multiple myeloma involving the central nervous system.

Immunomodulatory drugs have been shown to be of benefit in relapsed/refractory immunoglobulin light-chain (AL) amyloidosis. We designed a prospective, multicentre phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with AL amyloidosis not eligible for autologous stem-cell transplantation. Twenty-eight patients were included in the study. Cardiac involvement was present in 23 patients; 14 of them had cardiac stage III. The overall haematological response rate was 46%, including complete and very good partial responses in 25% and 18% of patients respectively. Haematological response was mainly associated with absence of cardiac stage III and lower tumour burden. Organ response was observed in 46% of patients. After a median follow-up of 24 months, median progression-free and overall survival have not been reached, both being significantly longer in responders (P < 0·001 and P = 0·001 respectively). Seventeen patients have discontinued treatment, mostly due to amyloid-related death, disease progression or lack of response. Only 14% of the patients discontinued treatment due to therapy-related adverse events. Our results support the efficacy of this regimen, with high quality responses and prolonged survival, as well as its tolerability, in patients with AL amyloidosis not eligible for stem cell transplant and without advanced cardiac involvement (clinicaltrials.gov identifier: NCT01194791).

Purpose The aim of International Myeloma Working Group was to develop practical recommendations for the use of magnetic resonance imaging (MRI) in multiple myeloma (MM). Methods An interdisciplinary panel of clinical experts on MM and myeloma bone disease developed recommendations for the value of MRI based on data published through March 2014. Recommendations MRI has high sensitivity for the early detection of marrow infiltration by myeloma cells compared with other radiographic methods. Thus, MRI detects bone involvement in patients with myeloma much earlier than the myeloma-related bone destruction, with no radiation exposure. It is the gold standard for the imaging of axial skeleton, for the evaluation of painful lesions, and for distinguishing benign versus malignant osteoporotic vertebral fractures. MRI has the ability to detect spinal cord or nerve compression and presence of soft tissue masses, and it is recommended for the workup of solitary bone plasmacytoma. Regarding smoldering or asymptomatic myeloma, all patients should undergo whole-body MRI (WB-MRI; or spine and pelvic MRI if WB-MRI is not available), and if they have > one focal lesion of a diameter > 5 mm, they should be considered to have symptomatic disease that requires therapy. In cases of equivocal small lesions, a second MRI should be performed after 3 to 6 months, and if there is progression on MRI, the patient should be treated as having symptomatic myeloma. MRI at diagnosis of symptomatic patients and after treatment (mainly after autologous stem-cell transplantation) provides prognostic information; however, to date, this does not change treatment selection.

Background: Standard therapy for suspected infections in patients with profound neutropenia is the combination of a beta-lactam antibiotic plus an aminoglycoside. Cefepime's broad-spectrum activity makes it an option for initial empirical therapy in neutropenic patients. The aim of this study is to evaluate the efficacy and safety of cefepime plus amikacin compared with piperacillin-tazobactam plus amikacin for initial empirical treatment of fever in adult haematology patients with severe neutropenia. Methods: In this prospective multicentre trial, 969 patients with 984 febrile neutropenic episodes were randomized to receive iv amikacin (20 mg/kg every 24 h) combined with either cefepime (2 g every 8 h) or piperacillin-tazobactam (4 g/500 mg every 6 h). Clinical response was determined at 72 h and at completion of therapy. Results: Eight hundred and sixty-seven episodes were assessable for efficacy (432 cefepime, 435 piperacillin-tazobactam). The frequency of success without modification of the empirical therapy was nearly identical for cefepime plus amikacin (49%) compared with piperacillin-tazobactam plus amikacin (51%). Similar rates of success were found for microbiologically documented infection: 40% versus 39%, respectively. Antibiotic modification was necessary in 49% of cefepime and 44% of piperacillin-tazobactam patients. The overall response rate, with or without modification of the assigned treatment, was 94% in both groups. Drug-related adverse events were reported in 10% of cefepime plus amikacin versus 11% of piperacillin-tazobactam plus amikacin patients. Mortality due to infection occurred in a total of 10 patients (two cefepime, eight piperacillin-tazobactam). Conclusion: The empirical regimen of cefepime plus amikacin is equivalent to piperacillin-tazobactam plus amikacin in febrile adult haematology patients with severe neutropenia.

We assessed the prognostic value of minimal residual disease (MRD) detection in multiple myeloma(MM) patients using a sequencing-based platform in bone marrow samples from 133 MM patients in at least very good partial response (VGPR) after front-line therapy. Deep sequencing was carried out in patients in whom a high-frequency myeloma clone was identified and MRD was assessed using the IGH-VDJH, IGH-DJH, and IGK assays. The results were contrasted with those of multiparametric flow cytometry (MFC) and allelespecific oligonucleotide polymerase chain reaction (ASO-PCR). The applicability of deep sequencing was 91%. Concordance between sequencing and MFC and ASO-PCR was 83% and 85%, respectively. Patients who were MRD- by sequencing had a significantly longer time to tumor progression (TTP) (median 80 vs 31 months; P, This research project was supported by grants PS09/01370, PS09/1450, PI12/01761, and PI12/023121 from the Fondo de Investigaciones Sanitarias; RD12/10 Red de Cáncer (Cancer Network of Excellence) from the Instituto de Salud Carlos III, Spain, and from the Fondo de Investigaciones Sanitarias, Asociación Española Contra el Cáncer (AECC, GCB120981SAN) and the CRIS foundation. This study was supported in part by research funding from Sequenta, Inc. (F.P., L.W., M.M., M.F.).

TO THEEDITOR:Recently,Regelinketal 1 reportedthelong-term results of a series of 90 patients with multiple myeloma (MM) who underwent either single or tandem autologous stem-cell transplantation. Conditioning regimens that were administered for the first and second transplantation were high-dose melphalan (MEL) and the combination of busulfan (BU) and cyclophosphamide, respectively. The authors reported a significantly higher 10-year overall survival and event-free survival for patients in the tandem transplantation group. According to their hypothesis, the better outcomes that were observed in patients who underwent tandem transplantation were only a result of the greater amount of chemotherapy administered in this group of patients; this suggests that these results would have been achieved regardless of the conditioning regimen that was administered in the second transplantation. However, and in contrast to the opinion of Regelink et al, we believe that the use of a preparative regimenthatcombinedtwoalkylatingagentsinthesecondtransplantation could have played a key role in the encouraging long-term results that were reported by the authors. In this regard, when two conditioning regimens (MEL v BU MEL, or BUMEL) were pro

We have explored the potential role of genetics in the development of osteonecrosis of the jaw (ONJ) in multiple myeloma (MM) patients under bisphosphonate therapy. A genome-wide association study was performed using 500 568 single nucleotide polymorphisms (SNPs) in 2 series of homogeneously treated MM patients, one with ONJ (22 MM cases) and another without ONJ (65 matched MM controls). Four SNPs (rs1934951. rs1934980, rs1341162. and rs17110453) mapped within the cytochrome P450-2C gene (CYP2C8) showed a different distribution between cases and controls with statistically significant differences (P=1.07 × 10-6, P= 4.231 × 10-6, P= 6.22 × 10-6, and P=2.15 × 10-6, respectively). SNP rs1934951 was significantly associated with a higher risk of ONJ development even after Bonferroni correction (P corrected value=.02). Genotyping results displayed an overrepresentation of the T allele in cases compared with controls (48% vs 12%). Thus, individuals homozygous for the T allele had an increased likelihood of developing ONJ (odds ratio 12.75, 95% confidence interval 3.7-43.5) © 2008 by The American Society of Hematology., This work has been partially supported by grants PI06-1354 from the Spanish Fondo de Investigaciones Sanitarias de la Seguridad Social, Red Española de Cancer RD06/0020/0006, and with the support of the Hemato-Oncology Institut, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Spain.

8 páginas, 3 figuras, 2 tablas.-- GEM (Grupo Español de MM)/PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatías Malignas) cooperative study groups: et al., Minimal residual disease (MRD) assessment is standard in many hematologic malignancies but is considered investigational in multiple myeloma (MM). We report a prospective analysis of the prognostic importance of MRD detection by multiparameter flow cytometry (MFC) in 295 newly diagnosed MM patients uniformly treated in the GEM2000 protocol VBMCP/VBAD induction plus autologous stem cell transplantation [ASCT]). MRD status by MFC was determined at day 100 after ASCT. Progression-free survival (PFS; median 71 vs 37 months, P < .001) and overall survival (OS; median not reached vs 89 months, P = .002) were longer in patients who were MRD negative versus MRD positive at day 100 after ASCT. Similar prognostic differentiation was seen in 147 patients who achieved immunofixation-negative complete response after ASCT. Moreover, MRD- immunofixation-negative (IFx-) patients and MRD- IFx + patients had significantly longer PFS than MRD- IFx + patients. Multivariate analysis identified MRDstatus byMFCat day 100 afterASCTas the most important independent prognostic factor for PFS (HR = 3.64, P = .002) and OS (HR = 2.02, P = .02). Our findings demonstrate the clinical importance of MRD evaluation by MFC, and illustrate the need for further refinement of MM response criteria. This trial is registered at http://clinicaltrials.gov under identifier NCT00560053., This work was supported by the Cooperative Research Thematic Network (RTICs; RD06/0020/0006), MM Jevitt, SL firm, and Instituto de Salud Carlos III/Subdirección General de Investigación Sanitaria (FIS: PI060339; 02/0905; 01/0089/01-02; and PI060339; Madrid, Spain).

Objectives: The role of high-dose therapy and autologous stem-cell transplantation (HDT/ASCT) in the up-front treatment of poor-risk aggressive lymphoma is still unknown. We conducted a prospective multi-centre trial with dose-escalated CHOP (MegaCHOP) and tailored intensification prior to HDT/ASCT according to early response assessed by CT and gallium scan (Ga67S). Patients and methods: Eighty-six patients with newly diagnosed and Ga-67 avid aggressive B-cell lymphoma received MegaCHOP for three courses and were evaluated for response by CT and Ga67S. Patients with CT response and negative Ga67S received another MegaCHOP cycle followed by BEAM and ASCT. Those patients with positive Ga67S or without CT response received salvage treatment with two courses of ifosfamide and etoposide (IFE) followed, whenever response had been achieved, by BEAM and ASCT. Results: Response rate before HDT/ASCT was 85% and, with 34 months of median follow-up, progression-free survival (PFS), overall survival (OS) and treatment-related mortality were 56%, 64% and 7%, respectively. For transplanted patients (81% of the whole series), PFS and OS were 67% and 74%, respectively. No different outcomes were observed between patients achieving an early negative Ga67S response treated with MegaCHOP and BEAM/ASCT and patients with mid-treatment positive Ga67S who received IFE prior BEAM/ASCT. Conclusions: This response-adapted strategy including early treatment modifications prior HDT/ASCT have yielded encouraging PFS and OS in patients with poor-risk B aggressive non-Hodgkin’s lymphoma.

PurposeThere is a need for a simple, reliable staging system for multiple myeloma that can be applied internationally for patient classification and stratification.Patients and MethodsClinical and laboratory data were gathered on 10,750 previously untreated symptomatic myeloma patients from 17 institutions, including sites in North America, Europe, and Asia. Potential prognostic factors were evaluated by univariate and multivariate techniques. Three modeling approaches were then explored to develop a staging system including two nontree and one tree survival assessment methodologies.ResultsSerum beta2-microglobulin (Sβ2M), serum albumin, platelet count, serum creatinine, and age emerged as powerful predictors of survival and were then used in the tree analysis approach. A combination of Sβ2M and serum albumin provided the simplest, most powerful and reproducible three-stage classification. This new International Staging System (ISS) was validated in the remaining patients and consists of the following stages: stage I, Sβ2M less than 3.5 mg/L plus serum albumin ≥ 3.5 g/dL (median survival, 62 months); stage II, neither stage I nor III (median survival, 44 months); and stage III, Sβ2M ≥ 5.5 mg/L (median survival, 29 months). The ISS system was further validated by demonstrating effectiveness in patients in North America, Europe, and Asia; in patients less than and ≥ 65 years of age; in patients with standard therapy or autotransplantation; and in comparison with the Durie/Salmon staging system.ConclusionThe new ISS is simple, based on easy to use variables (Sβ2M and serum albumin), and recommended for early adoption and widespread use.

Introduction: Conditioning regimen with oral busulfan (BU) and melphalan (MEL) for patients with multiple myeloma (MM) undergoing autologous transplant (ASCT) has been associated with a high incidence of liver complications, especially severe sinusoidal occlusive syndrome (SOS). Material and methods: We conducted the current study to assess the toxicity profile and outcomes associated with ASCT after intravenous (iv) BU-based conditioning in 45 patients (24 M/21 F; median age 60 years, range 34–71) with MM. Front-line chemotherapy consisted of VBMCP/VBAD (31cases), VAD (8 cases), and other regimens (6 cases). At transplant, 8 patients were in complete response (2 with negative immunofixation) 24 in partial response, 13 with other responses (6 with minor response, 5 had progressive disease, 1 stable disease, and 1 patient no evaluated). Median interval from diagnosis to transplant was 11 months (range 5–80). Conditioning regimen consisted of iv BU (3.2 mg/kg in a single daily dose, days −5 to −3) and MEL (140 mg/m2, day −2). In 39 patients this was the first ASCT and the remaining 6 had relapsed after a previous ASCT conditioned with MEL-based regimens. Results: Median number of CD34+ cells administered was 2.9 x10^6/kg (range 1–5.8). Hematopoietic recovery was fast with median (range) time to 0.5 PMN and 20 platelets x10^9/L of 12 (11–46) and 13 (9–64) days, respectively. The toxicity profile was favourable. Particularly, no case of SOS, commonly seen with the oral BU, has been reported. Mucositis was the non-hematopoietic toxicity most frequently seen (42 cases). Other toxicities observed were uncommon (gastrointestinal toxicity, 6 cases, increase of liver enzymes, 3 cases and mild cardiac failure, 1 case). Fever was observed in 38 patients: fever of unknown origin in 21 cases, microbiologically documented infection in 13 cases and clinically documented infection in the remaining 4 cases. Only 2 patients (4%) died due to transplant-related toxicity (one patient to pneumonia, day 51; the other patient to sepsis to Acinetobacter baumani, day 54). With a median follow-up of 18 months, 41 patients had been evaluated for response: 19 are in complete response (9 with negative immunofixation), 16 in partial response, 2 with minor response, 2 had progressive disease, and 2 transplant-related deaths. The 18 months actuarial overall and progression-free survival rates are 95±3% and 70±10%, respectively. Interestingly, in 19 patients significant improvement response was observed after transplant. Conclusions: These preliminary results show that iv BU-containing regimen for MM is associated with an acceptable toxicity profile and with a high anti-myeloma effect.

An ultrastructural and immunohistochemical study was performed on three malignant lymphomas of follicular center cell origin with signet-ring cells. The first case corresponded to a diffuse lymphoma with follicular center cells and plasmacytic features; the other two cases corresponded to the nodular centrocytic-centroblastic category. The neoplastic lymphocytes contained Russell bodylike inclusions, clear vacuoles, and ill-defined eosinophilic masses, respectively, which produced a displacement of the nuclei to the periphery. Ultrastructurally, there were three different morphologic types because of the following cytoplasmic changes: the accumulation of electron-dense granular material in the cisternae of the rough endoplasmic reticulum; the formation of clear vacuoles with a smooth limiting membrane; and, the presence of granular-fibrillar and crystalline material in the hyaloplasm without a limiting membrane. The first type of signet-ring cell contained monoclonal immunoglobulin (IgM-K). No immunoglobulins were found in the clear cytoplasmic vacuoles of the second type; however, the rim of cytoplasm stained for IgG, kappa and lambda. Finally, the third type showed IgG and kappa light chain in the hyaloplasmic inclusions. It is concluded that the signet-ring cell appearance is due to an abnormal production and secretion of immunoglobulins.

We analyzed the efficacy of imipenem/cilastatin alone (group I, 197 patients) or in combination with a glycopeptide (group I + G, 231 patients) as first-line antibiotic therapy for 2 consecutive cohorts of autologous stem cell transplantation (ASCT) recipients with febrile neutropenia. From June 2001 to June 2002, patients received imipenem/cilastatin (500 mg/6 hours), and from July 2002 to December 2003, they received imipenem/cilastatin as for group I plus a glycopeptide (vancomycin, 1 g/12 hours or teicoplanin, 400 mg/day). Fever of unknown origin accounted for 33.5% of episodes (66 patients) in group I and 50% of episodes (116 patients) in group I + G (P = .005). Bacteremia occurred in 55 patients (28%) in group I and in 51 patients (22%) in group I + G (P = .16). Resolution of fever without modification of the therapy regimen was observed in 108 patients (55%) and 159 patients (69%) in groups I and I + G, respectively (P = .003). The median interval to defervescence (4 days) and overall mortality were similar between groups. Inclusion of a glycopeptide in the initial antibiotic regimen for febrile neutropenia results in a higher success rate without modifying the regimen. However, glycopeptide inclusion does not improve the interval to defervescence or mortality rate.

Under a Creative Commons license.-- et al., Melphalan 200 mg/m2 (MEL200) is the standard conditioning regimen administered to newly diagnosed patients with multiple myeloma (MM) undergoing autologous stem cell transplantation (ASCT). Few alternatives have been explored in order to improve the antimyeloma activity of this conditioning. We compare i.v. busulfan (BU) 9.6 mg/kg and MEL 140 mg/m2 (MEL140) versus MEL200 mg/m2 as a conditioning regimen before ASCT for newly diagnosed patients with MM. For this purpose, 51 patients receiving i.v. BU plus MEL were compared to 102 patients receiving MEL200 mg/m2 in a 1:2 matched control analysis. Matching criteria included age, clinical stage at diagnosis, and response to induction therapy. No differences in the overall and complete response (CR) rates were observed after ASCT between both groups. After a median follow-up of 63 and 50 months in control and BU plus MEL groups, progression-free survival (PFS) was 24 and 33 months, respectively (P = .10). Most frequent toxicities included mucositis and febrile neutropenia in both groups. No case of sinusoidal obstruction syndrome was observed. Transplant-related mortality was 4% and 2% in BU plus MEL and control groups, respectively. ASCT conditioned with i.v. BU plus MEL may be considered an effective and well-tolerated alternative to a MEL-only approach as a conditioning regimen for patients with MM who are candidates for ASCT. (Clinicaltrials.gov identifier: NCT00560053 and NCT00804947.)., This study was supported in part by research funding from grants “Red Temática de Investigación Cooperativa en Cancer”RD06/0020/0031 and RD06/0020/0005 and “Red de Biobancos Hospitalarios”RD09/0076/00021, research project PS09/01882 from the “Instituto de Salud Carlos III”, research grant CA08/00141, CM10/00321 and CM09/00038 from the “Instituto de Salud Carlos III”, and “Ministerio de Ciencia e Innovación” grant BES2008-008053.

Analysis of the antigenic profile of malignant cells has shown to be a valuable tool for the diagnosis and the identification of prognostic markers in haematological malignancies. By contrast, in multiple myeloma (MM), immunophenotyping is rarely used in clinical practice. Moreover, conflicting results have been reported probably because they were based on short series of heterogeneously treated MM patients. In the present study, we have prospectively analysed the prognostic impact of antigenic markers, assessed by multiparametric flow cytometry, in a series of 685 newly diagnosed MM patients that were uniformly treated according to the GEM-2000 protocol. The results show that three antigenic markers (CD19, CD28 and CD117) afford prognostic information. The expression of both CD19 and CD28 as well as the absence of CD117 were associated with a significantly shorter progression free-survival (PFS) and overall survival (OS). Interestingly, the CD28 expression correlated with t(14;16) and Del(17p), while CD117 negative cases were associated with t(4;14) and Del(13q) as well as several other disease characteristics. The simultaneous assessment of CD28 and CD117 antigens, allowed stratification of myeloma patients into three risk categories: poor risk (CD28+CD117−), intermediate (either both markers negative or both positive), and good risk (CD28−CD117+), with PFS rates of 30, 37 and 45 months, respectively (p=0.01), and OS of 45, 68 and not reached, respectively (p=0.0001). To the best of our knowledge, this is the first prospective analysis in which the prognostic impact of a relatively high number of antigenic markers has been simultaneously analysed in a large series of uniformly treated patients.