Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
1.
Blood ; 124(12): 1887-93, 2014 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-25102853

RESUMEN

Melphalan (M), in combination with prednisone (MP), has been the backbone of new combinations, including bortezomib plus MP (VMP). However, new alkylator-free schemes, such as lenalidomide plus low-dose dexamethasone, are challenging the role of alkylators in myeloma treatment of elderly patients. Here we have updated, after a long follow-up (median 6 years), the results of the GEM2005 study that addressed this question by comparing VMP with bortezomib plus thalidomide and prednisone (VTP) as induction. Between April 2005 and October 2008, 260 patients were randomized to receive 6 cycles of VMP or VTP as induction. The median progression-free survival was 32 months for the VMP and 23 months for the VTP arms (P 5 .09). VMP significantly prolonged the overall survival (OS) compared with VTP (median of 63 and 43 months, respectively; hazard ratio [HR]: 0.67, P 5 .01). Achieving immunophenotypic complete response was associated with a significantly longer OS, especially in the VMP arm (66%remain alive after 8 years). Melphalan, plus bortezomib, should be maintained as standard care for the treatment of elderly multiple myeloma patients. This trial was registered at www.clinicaltrials.gov as #NCT00443235.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Anciano , Ácidos Borónicos/administración & dosificación , Bortezomib , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Quimioterapia de Inducción , Estimación de Kaplan-Meier , Quimioterapia de Mantención , Masculino , Melfalán/administración & dosificación , Prednisona/administración & dosificación , Pirazinas/administración & dosificación , Talidomida/administración & dosificación
2.
Blood ; 119(3): 687-91, 2012 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-22128143

RESUMEN

The achievement of complete response (CR) after high-dose therapy/autologous stem cell transplantation (HDT/ASCT) is a surrogate for prolonged survival in multiple myeloma; however, patients who lose their CR status within 1 year of HDT/ASCT (unsustained CR) have poor prognosis. Thus, the identification of these patients is highly relevant. Here, we investigate which prognostic markers can predict unsustained CR in a series of 241 patients in CR at day +100 after HDT/ASCT who were enrolled in the Spanish GEM2000 (n = 140) and GEM2005 < 65y (n = 101) trials. Twenty-nine (12%) of the 241 patients showed unsustained CR and a dismal outcome (median overall survival 39 months). The presence of baseline high-risk cytogenetics by FISH (hazard ratio 17.3; P = .002) and persistent minimal residual disease by multiparameter flow cytometry at day +100 after HDT/ASCT (hazard ratio 8.0; P = .005) were the only independent factors that predicted unsustained CR. Thus, these 2 parameters may help to identify patients in CR at risk of early progression after HDT/ASCT in whom novel treatments should be investigated.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Citometría de Flujo , Mieloma Múltiple/terapia , Neoplasia Residual/diagnóstico , Neoplasia Residual/etiología , Trasplante de Células Madre/efectos adversos , Anciano , Terapia Combinada , Análisis Citogenético , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Neoplasia Residual/mortalidad , Inducción de Remisión , Factores de Riesgo , Tasa de Supervivencia , Trasplante Autólogo , Resultado del Tratamiento
3.
Br J Haematol ; 163(5): 581-9, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24117042

RESUMEN

Minimal residual disease monitoring is becoming increasingly important in multiple myeloma (MM), but multiparameter flow cytometry (MFC) and allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) techniques are not routinely available. This study investigated the prognostic influence of achieving molecular response assessed by fluorescent-PCR (F-PCR) in 130 newly diagnosed MM patients from Grupo Español Multidisciplinar de Melanoma (GEM)2000/GEM05 trials (NCT00560053, NCT00443235, NCT00464217) who achieved almost very good partial response after induction therapy. As a reference, we used the results observed with simultaneous MFC. F-PCR at diagnosis was performed on DNA using three different multiplex PCRs: IGH D-J, IGK V-J and KDE rearrangements. The applicability of F-PCR was 91·5%. After induction therapy, 64 patients achieved molecular response and 66 non-molecular response; median progression-free survival (PFS) was 61 versus 36 months, respectively (P = 0·001). Median overall survival (OS) was not reached (NR) in molecular response patients (5-year survival: 75%) versus 66 months in the non-molecular response group (P = 0·03). The corresponding PFS and OS values for patients with immunophenotypic versus non-immunophenotypic response were 67 versus 42 months (P = 0·005) and NR (5-year survival: 95%) versus 69 months (P = 0·004), respectively. F-PCR analysis is a rapid, affordable, and easily performable technique that, in some circumstances, may be a valid approach for minimal residual disease investigations in MM.


Asunto(s)
Reordenamiento Génico de Cadena Pesada de Linfocito B , Reordenamiento Génico de Cadena Ligera de Linfocito B , Genes de Inmunoglobulinas , Mieloma Múltiple/genética , Reacción en Cadena de la Polimerasa/métodos , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos Clínicos Fase III como Asunto/estadística & datos numéricos , ADN de Neoplasias/genética , Pruebas Diagnósticas de Rutina/economía , Femenino , Citometría de Flujo/economía , Fluorometría/economía , Fluorometría/métodos , Trasplante de Células Madre Hematopoyéticas , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto/estadística & datos numéricos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Mieloma Múltiple/cirugía , Neoplasia Residual , Reacción en Cadena de la Polimerasa/economía , Pronóstico , Sensibilidad y Especificidad , Trasplante Autólogo
4.
Am J Pathol ; 181(5): 1870-8, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22974582

RESUMEN

The incorporation of high-dose therapy/autologous stem cell transplantation (HDT/ASCT) and novel agents has significantly improved survival in patients with multiple myeloma (MM), but whether this improvement also benefits patients harboring poor prognostic features, such as nonhyperdiploid MM (NH-MM) and a high proliferation index, remains largely unknown. We analyzed the DNA content and proliferation index of bone marrow plasma cells (PCs) by multiparameter flow cytometry in 595 newly diagnosed transplant-eligible patients with MM included in two consecutive PETHEMA/GEM trials: GEM2000 [VBMCP/VBAD (vincristine, carmustine, melphalan, cyclophosphamide, prednisone/vincristine, bischloroethylnitrosourea, adriamycin, and dexamethasone) followed by HDT/ASCT; n = 319] and GEM2005<65y (randomized induction with VBMCP/VBAD/bortezomib or thalidomide/dexamethasone or bortezomib/thalidomide/dexamethasone followed by HDT/ASCT; n = 276). Of the 595 patients, 295 were classified as NH-MM (49.6%) and 336 (56.5%) as high-proliferative MM (≥1% PCs in S-phase). Detection of NH-MM DNA content and ≥1% PCs in S-phase were of independent prognostic value for overall survival. Treatment with bortezomib-based regimens abrogated the inferior overall survival of patients with ≥1% PCs in S-phase but not of patients with NH-MM. Finally, a comparative analysis of PC proliferation index at diagnosis versus disease progression showed a twofold increase at relapse in 44 of 52 patients (85%) analyzed at both time points. NH-MM and a high proliferation index assessed by multiparameter flow cytometry remain as independent prognostic factors in MM, but the latter may be overcome by incorporating novel agents in the HDT/ASCT setting.


Asunto(s)
ADN de Neoplasias/metabolismo , Citometría de Flujo/métodos , Mieloma Múltiple/patología , Mieloma Múltiple/terapia , Células Plasmáticas/metabolismo , Trasplante de Células Madre , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Células Clonales , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Análisis Multivariante , Células Plasmáticas/efectos de los fármacos , España
5.
Blood ; 118(17): 4547-53, 2011 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-21900193

RESUMEN

Cytogenetic abnormalities (CAs) such as t(4;14), t(14;16) or del(17p), and nonhyperdiploidy are associated with poor prognosis in multiple myeloma. We evaluated the influence of CAs by FISH and DNA ploidy by flow cytometry on response and survival in 232 elderly, newly diagnosed multiple myeloma patients receiving an induction with weekly bortezomib followed by maintenance therapy with bortezomib-based combinations. Response was similar in the high-risk and standard-risk CA groups, both after induction (21% vs 27% complete responses [CRs]) and maintenance (39% vs 45% CR). However, high-risk patients showed shorter progression-free survival (PFS) than standard-risk patients, both from the first (24 vs 33 months; P = .04) and second randomization (17 vs 27 months; P = .01). This also translated into shorter overall survival (OS) for high-risk patients (3-year OS: 55% vs 77%; P = .001). This adverse prognosis applied to either t(4;14) or del(17p). Concerning DNA ploidy, hyperdiploid patients showed longer OS than nonhyperdiploid patients (77% vs 63% at 3 years; P = .04), and this was more evident in patients treated with bortezomib, thalidomide, and prednisone (77% vs 53% at 3 years; P = .02). The present schema does not overcome the negative prognosis of high-risk CAs and nonhyperdiploidy. This trial was registered with www.ClinicalTrials.gov as NCT00443235.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Ácidos Borónicos/administración & dosificación , Aberraciones Cromosómicas , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/tratamiento farmacológico , Ploidias , Pirazinas/administración & dosificación , Anciano , Anciano de 80 o más Años , Algoritmos , Bortezomib , ADN de Neoplasias/genética , Esquema de Medicación , Humanos , Quimioterapia de Inducción/métodos , Quimioterapia de Mantención/métodos , Mieloma Múltiple/genética , Pronóstico , Factores de Tiempo , Resultado del Tratamiento
6.
Blood ; 114(20): 4369-72, 2009 Nov 12.
Artículo en Inglés | MEDLINE | ID: mdl-19755674

RESUMEN

Multiparameter flow cytometry immunophenotyping allows discrimination between normal (N-) and myelomatous (MM-) plasma cells (PCs) within the bone marrow plasma cell compartment (BMPCs). Here we report on the prognostic relevance of detecting more than 5% residual normal plasma cells from all bone marrow plasma cells (N-PCs/BMPCs) by multiparameter flow cytometry in a series of 594 newly diagnosed symptomatic MM patients, uniformly treated according to the Grupo Español de MM 2000 (GEM2000) protocol. Our results show that symptomatic MM patients with more than 5% N-PCs/BMPCs (n = 80 of 594; 14%) have a favorable baseline clinical prospect, together with a significantly lower frequency of high-risk cytogenetic abnormalities and higher response rates. Moreover, this group of patients had a significantly longer progression-free survival (median, 54 vs 42 months, P = .001) and overall survival (median, not reached vs 89 months, P = .04) than patients with less than or equal to 5% N-PCs/BMPCs. Our findings support the clinical value of detecting residual normal PCs in MM patients at diagnosis because this reveals a good prognostic category that could benefit from specific therapeutic approaches. This trial was registered at www.clinicaltrials.gov as NCT00560053.


Asunto(s)
Células de la Médula Ósea/patología , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Células Plasmáticas/patología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica , Supervivencia sin Enfermedad , Femenino , Citometría de Flujo , Trasplante de Células Madre Hematopoyéticas , Humanos , Inmunofenotipificación , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mieloma Múltiple/terapia , Pronóstico
7.
Lancet Oncol ; 11(10): 934-41, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20739218

RESUMEN

BACKGROUND: Bortezomib plus melphalan and prednisone (VMP) is significantly better than melphalan plus prednisone alone for elderly patients with untreated multiple myeloma; however, toxic effects are high. We investigated a novel and less intensive bortezomib-based regimen to maintain efficacy and to reduce toxic effects. METHODS: Between March, 2006, and October, 2008, 260 patients with untreated multiple myeloma, 65 years and older, from 63 Spanish centres, were randomly assigned to receive six cycles of VMP (n=130) or bortezomib plus thalidomide and prednisone (VTP; n=130) as induction therapy, consisting of one cycle of bortezomib twice per week for 6 weeks (1·3 mg/m² on days 1, 4, 8, 11, 22, 25, 29, and 32), plus either melphalan (9 mg/m² on days 1-4) or daily thalidomide (100 mg), and prednisone (60 mg/m² on days 1-4). The first cycle was followed by five cycles of bortezomib once per week for 5 weeks (1·3 mg/m² on days 1, 8, 15, and 22) plus the same doses of melphalan plus prednisone and thalidomide plus prednisone. 178 patients completed the six induction cycles and were randomly assigned to maintenance therapy with bortezomib plus prednisone (n=87) or bortezomib plus thalidomide (n=91), consisting of one conventional cycle of bortezomib for 3 weeks (1·3 mg/m² on days 1, 4, 8, and 11) every 3 months, plus either prednisone (50 mg every other day) or thalidomide (50 mg per day), for up to 3 years. Treatment codes were generated with a computerised random number generator, and neither participants nor study personnel were masked to treatment. The primary endpoint was response rate in induction and maintenance phases. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00443235. FINDINGS: In the induction phase, 105 (81%) patients in the VTP group and 104 (80%) in the VMP group achieved partial responses or better (p=0·9), including 36 (28%) and 26 (20%) complete remissions, respectively (p=0·2). Treatment with VTP resulted in more serious adverse events (40 [31%] vs 20 [15%], p=0·01) and discontinuations (22 [17%] vs 15 [12%], p=0·03) than did treatment with VMP. The most common toxicities (grade 3 or worse) were infections (one [1%] in the VTP group vs nine [7%] in the VMP group), cardiac events (11 [8%] vs 0), and peripheral neuropathy (nine [7%] vs 12 [9%]). After maintenance therapy, the complete remission rate was 42% (40 [44%] patients in complete remission in the bortezomib plus thalidomide group, 34 [39%] in the bortezomib plus prednisone group). No grade 3 or worse haematological toxicities were recorded during maintenance therapy; two (2%) patients in the bortezomib plus prednisone group and six (7%) in the bortezomib plus thalidomide group developed peripheral neuropathy. INTERPRETATION: Reduced-intensity induction with a bortezomib-based regimen, followed by maintenance, is a safe and effective treatment for elderly patients with multiple myeloma. FUNDING: Pethema (Spanish Program for the Treatment of Hematologic Diseases).


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Factores de Edad , Anciano , Inhibidores de la Angiogénesis/administración & dosificación , Antineoplásicos Alquilantes/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ácidos Borónicos/administración & dosificación , Bortezomib , Esquema de Medicación , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Melfalán/administración & dosificación , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/mortalidad , Prednisona/administración & dosificación , Modelos de Riesgos Proporcionales , Inhibidores de Proteasas/administración & dosificación , Pirazinas/administración & dosificación , Medición de Riesgo , Factores de Riesgo , España , Talidomida/administración & dosificación , Factores de Tiempo , Resultado del Tratamiento
8.
Haematologica ; 94(11): 1599-602, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19880781

RESUMEN

Quantification of bone marrow plasma cells in multiple myeloma patients using conventional morphology is of limited prognostic value, while the merit of multiparameter flow cytometry immunophenotyping is still considered unproven. Here we compare the bone marrow plasma cell counts obtained by morphology and multiparameter flow cytometry and explore the potential prognostic impact of both techniques in 765 newly diagnosed, uniformly treated multiple myeloma patients. Although multiparameter flow cytometry generally yields lower plasma cell counts (median percentage of 11% vs. 40%, respectively; p<0.001), there is a significant positive correlation between the two techniques (R =0.46, p<0.001). Regarding prognosis, multivariate analysis selected the bone marrow plasma cell counts obtained by multiparameter flow cytometry as an independent prognostic factor for overall survival (p=0.007), supporting the incorporation of multiparameter flow cytometry immunophenotyping into the routine diagnostic evaluation of multiple myeloma patients and validating the clinical utility of bone marrow plasma cell counting by multiparameter flow cytometry approaches. (clinicaltrials.gov identifier: NCT00560053).


Asunto(s)
Citometría de Flujo/métodos , Mieloma Múltiple/patología , Adulto , Anciano , Células de la Médula Ósea/patología , Recuento de Células , Técnicas y Procedimientos Diagnósticos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Pronóstico
9.
Br J Haematol ; 142(5): 766-74, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18637804

RESUMEN

This study aimed to standardize a simple molecular method for evaluating the response to treatment in multiple myeloma (MM) patients after high dose chemotherapy. Fifty three patients enrolled in the GEM2000 protocol were studied for minimal residual disease (MRD) using both fluorescent-polymerase chain reaction (F-PCR) and flow cytometry. Most patients had achieved complete remission or very good response after autologous stem cell transplantation. The molecular analysis of immunoglobulin gene rearrangements at diagnosis and during the follow-up was carried out by F-PCR according to the Biomed-2 protocols. F-PCR could be used in 91% of the patients and the results were similar to flow cytometry. F-PCR was able to identify a group of patients with a better prognosis [progression-free survival (PFS) 67.86% in patients with negative F-PCR vs. 28%; P = 0.001], even amongst patients who achieved a complete response with negative immunofixation (PFS 75% vs. 25%; P = 0.002). Multivariate analysis identified the F-PCR result as the only variable to show a prognostic value when PFS was analysed. F-PCR of DHJ and light chain rearrangements of immunoglobulin genes is a feasible method for evaluating MRD in MM patients after intensive therapy. Achieving molecular response by F-PCR shows prognostic value.


Asunto(s)
Mieloma Múltiple/diagnóstico , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Citometría de Flujo , Trasplante de Células Madre Hematopoyéticas , Humanos , Cadenas Pesadas de Inmunoglobulina , Cadenas Ligeras de Inmunoglobulina , Masculino , Persona de Mediana Edad , Mieloma Múltiple/terapia , Neoplasia Residual , Reacción en Cadena de la Polimerasa/métodos , Pronóstico , Sensibilidad y Especificidad
10.
J Clin Oncol ; 29(12): 1627-33, 2011 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-21402611

RESUMEN

PURPOSE: To investigate the impact of immunophenotypic response (IR) versus complete response (CR) and CR plus normal serum free light chain (sFLC) ratio (stringent CR) in elderly patients with multiple myeloma (MM) treated with novel agents. PATIENTS AND METHODS: From a total of 260 elderly patients newly diagnosed with MM included in the GEM05>65y trial, 102 patients achieving at least a partial response with ≥ 70% reduction in M-component after the six planned induction cycles were simultaneously analyzed by immunofixation, sFLC, and multiparameter flow cytometry (MFC) immunophenotyping; this population is the focus of this study. RESULTS: Forty-three percent of patients achieved CR, 30% achieved stringent CR, and 30% achieved IR. Patients in stringent CR showed no significant survival advantage compared with those in CR, whereas patients in IR showed significantly increased progression-free survival (PFS) and time to progression (TTP) compared with those in stringent CR or CR; this was confirmed by multivariate analysis (hazard ratio, 4.1; P = .01 for PFS). Discrepancies between the three techniques were relatively common. Notably, in all seven patients achieving IR but remaining immunofixation positive, the M-component disappeared in follow-up analysis. In contrast, MFC-positive patients who were immunofixation negative (n = 20) showed a tendency toward early reappearance of the M-component (median, 3 months). Similarly, in five of 11 stringent CR but MFC-positive patients, symptomatic disease progression was recorded at a median of 13 months after induction. CONCLUSION: Achieving an IR translates into superior PFS and TTP compared with conventional CR or stringent CR. These techniques provide complementary information and thus, an effort should be made to refine response criteria in MM.


Asunto(s)
Biomarcadores de Tumor/sangre , Cadenas Ligeras de Inmunoglobulina/sangre , Técnicas Inmunológicas , Inmunofenotipificación , Mieloma Múltiple/inmunología , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Humanos , Estimación de Kaplan-Meier , Masculino , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Nefelometría y Turbidimetría , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , España , Tasa de Supervivencia , Factores de Tiempo , Resultado del Tratamiento
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA