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1.
Kidney Int ; 99(3): 570-580, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33440212

RESUMO

Symptomatic multiple myeloma is commonly complicated by acute kidney injury through various mechanisms. The most frequent is the precipitation of monoclonal free light chains with uromodulin in the distal tubules, defining light chain cast nephropathy. Early diagnosis and identification of the cause of acute kidney injury are required for optimizing management and avoiding chronic kidney injury that strongly affects quality of life and patient survival. In light chain cast nephropathy, often manifesting with severe acute kidney injury, renal recovery requires urgent intervention based on vigorous rehydration, correction of precipitating factors, and efficient anti-plasma cell chemotherapy to rapidly reduce the secretion of nephrotoxic free light chains. Currently, the association of the proteasome inhibitor bortezomib with high-dose dexamethasone is the standard regimen in newly diagnosed patients. The addition of another drug such as cyclophosphamide or an immunodulatory agent may improve free light chain response but raises tolerance concerns in frail patients. Further studies are warranted to confirm the role of anti-CD38 monoclonal antibodies, whose efficacy and tolerance have been documented in patients without renal impairment. Despite controversial results from randomized studies, recent data suggest that in patients with light chain cast nephropathy and acute kidney injury requiring dialysis, the combination of chemotherapy with free light chain removal through high-cutoff hemodialysis may increase renal response recovery rates. Kidney biopsy may be helpful in guiding management and assessing renal prognosis that appears to depend on the extent of cast formation and interstitial fibrosis/tubular atrophy. Because of continuous improvement in life expectancy of patients with multiple myeloma, renal transplantation is likely to be increasingly considered in selected candidates.


Assuntos
Injúria Renal Aguda , Mieloma Múltiplo , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/terapia , Bortezomib , Humanos , Cadeias Leves de Imunoglobulina , Mieloma Múltiplo/complicações , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/terapia , Qualidade de Vida , Diálise Renal
2.
Kidney Int ; 99(2): 421-430, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32739419

RESUMO

Immunotactoid glomerulopathy is a rare disease defined by glomerular microtubular immunoglobulin deposits. Since management and long-term outcomes remain poorly described, we retrospectively analyzed results of 27 adults from 21 departments of nephrology in France accrued over 19 years. Inclusion criteria were presence of glomerular Congo red-negative monotypic immunoglobulin deposits with ultrastructural microtubular organization, without evidence for cryoglobulinemic glomerulonephritis. Baseline manifestations of this cohort included: proteinuria (median 6.0 g/day), nephrotic syndrome (70%), microscopic hematuria (74%) and hypertension (56%) with a median serum creatinine of 1.5 mg/dL. Nineteen patients had detectable serum and/or urine monoclonal gammopathy. A bone marrow and/or peripheral blood clonal disorder was identified in 18 cases (16 lymphocytic and 2 plasmacytic disorders). Hematologic diagnosis was chronic/small lymphocytic lymphoma in 13, and monoclonal gammopathy of renal significance in 14 cases. Kidney biopsy showed atypical membranous in 16 or membranoproliferative glomerulonephritis in 11 cases, with microtubular monotypic IgG deposits (kappa in 17 of 27 cases), most commonly IgG1. Identical intracytoplasmic microtubules were observed in clonal lymphocytes from 5 of 10 tested patients. Among 21 patients who received alkylating agents, rituximab-based or bortezomib-based chemotherapy, 18 achieved a kidney response. After a median follow-up of 40 months, 16 patients had sustained kidney response, 7 had reached end-stage kidney disease, and 6 died. Chronic/small lymphocytic lymphoma appears as a common underlying condition in immunotactoid glomerulopathy, but clonal detection remains inconstant with routine techniques in patients with monoclonal gammopathy of renal significance. Thus, early diagnosis and hematological response after clone-targeted chemotherapy was associated with favorable outcomes. Hence, thorough pathologic and hematologic workup is key to the management of immunotactoid glomerulopathy.


Assuntos
Glomerulonefrite , Adulto , Células Clonais , Estudos de Coortes , França/epidemiologia , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/epidemiologia , Humanos , Estudos Retrospectivos
3.
Blood ; 133(6): 576-587, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30578255

RESUMO

Monoclonal immunoglobulin deposition disease (MIDD) is a rare complication of B-cell clonal disorders, defined by Congo red negative-deposits of monoclonal light chain (LCDD), heavy chain (HCDD), or both (LHCDD). MIDD is a systemic disorder with prominent renal involvement, but little attention has been paid to the description of extrarenal manifestations. Moreover, mechanisms of pathogenic immunoglobulin deposition and factors associated with renal and patient survival are ill defined. We retrospectively studied a nationwide cohort of 255 patients, with biopsy-proven LCDD (n = 212) (including pure LCDD [n = 154], LCDD with cast nephropathy (CN) [n = 58]), HCDD (n = 23), or LHCDD (n = 20). Hematological diagnosis was monoclonal gammopathy of renal significance in 64% and symptomatic myeloma in 34%. Renal presentation was acute kidney injury in patients with LCCD and CN, and chronic glomerular disease in the other types, 35% of whom had symptomatic extrarenal (mostly hepatic and cardiac) involvement. Sequencing of 18 pathogenic LC showed high isoelectric point values of variable domain complementarity determining regions, possibly accounting for tissue deposition. Among 169 patients who received chemotherapy (bortezomib-based in 58%), 67% achieved serum free light chain (FLC) response, including very good partial response (VGPR) or above in 52%. Renal response occurred in 62 patients (36%), all of whom had achieved hematological response. FLC response ≥ VGPR and absence of severe interstitial fibrosis were independent predictors of renal response. This study highlights an unexpected frequency of extrarenal manifestations in MIDD. Rapid diagnosis and achievement of deep FLC response are key factors of prognosis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cadeias Pesadas de Imunoglobulinas/imunologia , Cadeias Leves de Imunoglobulina/imunologia , Nefropatias/patologia , Paraproteinemias/patologia , Idoso , Estudos de Coortes , Feminino , Seguimentos , Humanos , Nefropatias/tratamento farmacológico , Nefropatias/imunologia , Masculino , Pessoa de Meia-Idade , Paraproteinemias/tratamento farmacológico , Paraproteinemias/imunologia , Prognóstico , Taxa de Sobrevida
4.
Lancet ; 394(10192): 29-38, 2019 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171419

RESUMO

BACKGROUND: Bortezomib, thalidomide, and dexamethasone (VTd) plus autologous stem-cell transplantation is standard treatment in Europe for transplant-eligible patients with newly diagnosed multiple myeloma. We evaluated whether the addition of daratumumab to VTd before and after autologous stem-cell transplantation would improve stringent complete response rate in patients with newly diagnosed multiple myeloma. METHODS: In this two-part, randomised, open-label, phase 3 CASSIOPEIA trial, we recruited transplant-eligible patients with newly diagnosed multiple myeloma at 111 European sites. Patients were randomly assigned (1:1) to receive four pre-transplant induction and two post-transplant consolidation cycles of VTd alone (VTd group) or in combination with daratumumab (D-VTd group). The primary endpoint of part 1 was stringent complete response assessed 100 days after transplantation. Part 2 (maintenance) is ongoing. The trial is registered with ClinicalTrials.gov, number NCT02541383. FINDINGS: Between Sept 22, 2015, and Aug 1, 2017, 1085 patients were enrolled at 111 European sites and were randomly assigned to the D-VTd group (n=543) or the VTd group (n=542). At day 100 after transplantation, 157 (29%) of 543 patients in the D-VTd group and 110 (20%) of 542 patients in the VTd group in the intention-to-treat population had achieved a stringent complete response (odds ratio 1·60, 95% CI 1·21-2·12, p=0·0010). 211 (39%) patients in the D-VTd group versus 141 (26%) in the VTd group achieved a complete response or better, and 346 (64%) of 543 versus 236 (44%) of 542 achieved minimal residual disease-negativity (10-5 sensitivity threshold, assessed by multiparametric flow cytometry; both p<0·0001). Median progression-free survival from first randomisation was not reached in either group (hazard ratio 0·47, 95% CI 0·33-0·67, p<0·0001). 46 deaths on study were observed (14 vs 32, 0·43, 95% CI 0·23-0·80). The most common grade 3 or 4 adverse events were neutropenia (28% vs 15%), lymphopenia (17% vs 10%), and stomatitis (13% vs 16%). INTERPRETATION: D-VTd before and after autologous stem-cell transplantation improved depth of response and progression-free survival with acceptable safety. CASSIOPEIA is the first study showing the clinical benefit of daratumumab plus standard of care in transplant-eligible patients with newly diagnosed multiple myeloma. FUNDING: The Intergroupe Francophone du Myélome and Dutch-Belgian Cooperative Trial Group for Hematology Oncology.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/terapia , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/administração & dosagem , Bortezomib/uso terapêutico , Quimioterapia Adjuvante , Terapia Combinada , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Talidomida/administração & dosagem , Talidomida/uso terapêutico , Transplante Autólogo , Resultado do Tratamento , Adulto Jovem
5.
Blood ; 132(14): 1478-1485, 2018 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-30012636

RESUMO

Monoclonal gammopathy is a common condition, particularly in the elderly. It can indicate symptomatic multiple myeloma or another overt malignant lymphoid disorder requiring immediate chemotherapy. More frequently, it results from a small and/or quiescent secreting B-cell clone, is completely asymptomatic, and requires regular monitoring only, defining a monoclonal gammopathy of unknown significance (MGUS). Sometimes, although quiescent and not requiring any treatment per se, the clone is associated with potentially severe organ damage due to the toxicity of the monoclonal immunoglobulin or to other mechanisms. The latter situation is increasingly observed but still poorly recognized and frequently undertreated, although it often requires rapid specific intervention to preserve involved organ function. To improve early recognition and management of these small B-cell clone-related disorders, we propose to introduce the concept of monoclonal gammopathy of clinical significance (MGCS). This report identifies the spectrum of MGCSs that are classified according to mechanisms of tissue injury. It highlights the diversity of these disorders for which diagnosis and treatment are often challenging in clinical practice and require a multidisciplinary approach. Principles of management, including main diagnostic and therapeutic procedures, are also described. Importantly, efficient control of the underlying B-cell clone usually results in organ improvement. Currently, it relies mainly on chemotherapy and other anti-B-cell/plasma cell agents, which should aim at rapidly producing the best hematological response.


Assuntos
Paraproteinemias/diagnóstico , Animais , Autoanticorpos/análise , Linfócitos B/patologia , Citocinas/análise , Humanos , Imunoglobulinas/análise , Paraproteinemias/patologia , Paraproteinemias/terapia
6.
Kidney Int ; 96(1): 94-103, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30987838

RESUMO

The clinicopathological characteristics of kidney infiltration in B-cell lymphoproliferative disorders remain poorly described. We retrospectively studied 52 adults with biopsy-proven malignant B-cell kidney infiltration, including Waldenström's macroglobulinemia (n=21), chronic lymphocytic leukemia (n=11), diffuse large B-cell lymphoma (DLBCL) (n=8), other lymphoma (n=11), and multiple myeloma (n=1). Kidney disease varied according to the underlying lymphoproliferative disorder. In DLBCL, malignant kidney infiltration was prominent, resulting in acute kidney injury (AKI, 75%) and kidney enlargement (88%). In the other types, associated immunoglobulin-related nephropathy (most commonly AL amyloidosis) was more common (45%), and chronic kidney disease with proteinuria was the primary presentation. All patients received chemotherapy. Over a median follow-up of 31 months, 20 patients died and 21 reached end-stage kidney disease. Renal response, achieved in 25 patients (48%), was associated with higher overall survival (97 vs. 37 months in non-renal responders). In univariate analysis, percentage of sclerotic glomeruli, kidney enlargement, and complete hematological response at 6 months were predictive of renal response. In multivariate analysis, concomitant immunoglobulin-related nephropathy was the sole independent predictor of poor renal outcome. In conclusion, clinical presentation of renal lymphomatous infiltration depends on the nature of the underlying lymphoproliferative disorder. In DLBCL, massive renal infiltration manifests with enlarged kidneys and AKI, and the diagnosis primarily relies on lymph node biopsy. In other B-cell lymphoproliferative disorders, the clinicopathological spectrum is more heterogeneous, with a high frequency of immunoglobulin-related nephropathy that may affect renal outcome; thus kidney biopsy is required for early diagnosis and prognostic assessment.


Assuntos
Injúria Renal Aguda/epidemiologia , Córtex Renal/patologia , Transtornos Linfoproliferativos/complicações , Proteinúria/epidemiologia , Insuficiência Renal Crônica/epidemiologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Injúria Renal Aguda/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Feminino , Humanos , Incidência , Transtornos Linfoproliferativos/urina , Masculino , Pessoa de Meia-Idade , Proteinúria/etiologia , Proteinúria/patologia , Proteinúria/terapia , Diálise Renal/estatística & dados numéricos , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/terapia , Estudos Retrospectivos , Adulto Jovem
7.
Blood ; 127(21): 2569-74, 2016 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-27002117

RESUMO

The Intergroupe Francophone du Myélome conducted a randomized trial to compare bortezomib-thalidomide-dexamethasone (VTD) with bortezomib-cyclophosphamide-dexamethasone (VCD) as induction before high-dose therapy and autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma. Overall, a total of 340 patients were centrally randomly assigned to receive VTD or VCD. After 4 cycles, on an intent-to-treat basis, 66.3% of the patients in the VTD arm achieved at least a very good partial response (primary end point) vs 56.2% in the VCD arm (P = .05). In addition, the overall response rate was significantly higher in the VTD arm (92.3% vs 83.4% in the VCD arm; P = .01). Hematologic toxicity was higher in the VCD arm, with significantly increased rates of grade 3 and 4 anemia, thrombocytopenia, and neutropenia. On the other hand, the rate of peripheral neuropathy (PN) was significantly higher in the VTD arm. With the exception of hematologic adverse events and PN, other grade 3 or 4 toxicities were rare, with no significant differences between the VTD and VCD arms. Our data support the preferential use of VTD rather than VCD in preparation for ASCT. This trial was registered at www.clinicaltrials.gov as #NCT01564537 and at EudraCT as #2013-003174-27.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Anemia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Estudos Prospectivos , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Trombocitopenia/induzido quimicamente
8.
Ann Hematol ; 97(5): 831-837, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29330561

RESUMO

The combination of pomalidomide and low-dose dexamethasone (Pom-Dex) has proved effective and safe in patients with end-stage relapsed/refractory multiple myeloma (RRMM), otherwise characterized by a very poor outcome. MM remains an incurable disease with unavoidable relapses, and the outcome after pomalidomide is still dismal. However, some patients demonstrate prolonged survival even beyond pomalidomide therapy.We sought to analyze the treatment of RRMM patients following Pom-Dex therapy and the response and survival after this next treatment line.We studied 134 patients treated with Pom-Dex until progression across two IFM studies. Seventy percent of these patients received further therapy after Pom-Dex. Among the treated patients, one third responded and one third maintained stable disease. The median OS for treated patients was 12 months (6.5;17), with 22 and 12.5% of patients surviving beyond 2 and 3 years, respectively. The factors associated with a better outcome were exposure to a triplet-based regimen containing a novel agent, response to therapy, absence of adverse cytogenetic, and a longer time from diagnosis to post pomalidomide therapy.This study suggests that patients relapsing after Pom-Dex therapy can still benefit from a further line of treatment. A subset of these treated patients even displayed a prolonged OS, while the prognosis remained very poor without treatment. An active approach could therefore be recommended even in this adverse situation, however guided by the patients' prognosis factors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Dexametasona/administração & dosagem , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Terapia de Salvação/métodos , Talidomida/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Terapia de Salvação/tendências , Talidomida/administração & dosagem
9.
Rev Prat ; 68(7): 792-796, 2018 Sep.
Artigo em Francês | MEDLINE | ID: mdl-30869335

RESUMO

Monoclonal gammopathy related disorders. The presence of a monoclonal immunoglobulin in serum or urine reflects the existence of an abnormal clone of B cells. In case of large tumor mass, patient need treatment. Sometimes, the clone is nearly undetectable, but gammopathy is associated with complications not directly related to tumor cells but to the presence of the monoclonal immunoglobulin. Most often, lesions result from the deposit of monoclonal immunoglobulin, organized or not. Other mechanisms include autoantibody activity, immune complex formation or deregulation of the complement system. Finally, in some cases, the physiopathology remains to be determined. The downstream complications of gammopathies are protean and can affect various organs, mainly the kidney, the skin and the peripheral nervous system. A delayed diagnosis may be life-threatening or functional. A rigorous clinical examination, and appropriate explorations are therefore necessary in order to put in place a suitable therapy, targeting most often the underlying clone.


Manifestations associées aux gammapathies monoclonales. La présence d'une immunoglobuline monoclonale dans le sérum ou l'urine traduit l'existence d'un clone anormal de cellules B. En cas de forte masse tumorale, le problème est celui du traitement. Parfois, le clone n'est pratiquement pas détectable, mais la gammapathie s'associe à des complications non directement liées aux cellules tumorales mais secondaires à la présence de l'immunoglobuline monoclonale. Le plus souvent, les lésions résultent de dépôts de l'immunoglobuline monoclonale, organisés ou non. Les autres mécanismes incluent une activité auto-anticorps, la formation d'immuns complexes ou une dérégulation du système complémentaire. Enfin, dans certains cas, la physiopathologie reste à déterminer. Les complications d'aval des gammapathies sont protéiformes et peuvent toucher divers organes, principalement le rein, la peau et le système nerveux périphérique. Un retard diagnostique peut mettre en jeu le pronostic vital ou fonctionnel. Un examen clinique rigoureux, et des explorations appropriées face à certaines situations sont donc nécessaires afin de mettre en place un traitement adapté, ciblant le plus souvent le clone sous-jacent.


Assuntos
Paraproteinemias , Humanos
10.
Kidney Int ; 101(5): 1086-1087, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35461602
11.
Kidney Int ; 91(2): 423-434, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27773425

RESUMO

Randall-type heavy chain deposition disease (HCDD) is a rare disorder characterized by tissue deposition of a truncated monoclonal immunoglobulin heavy chain lacking the first constant domain. Pathophysiological mechanisms are unclear and management remains to be defined. Here we retrospectively studied 15 patients with biopsy-proven HCDD of whom 14 presented with stage 3 or higher chronic kidney disease, with nephrotic syndrome in 9. Renal lesions were characterized by nodular glomerulosclerosis, with linear peritubular and glomerular deposits of γ-heavy chain in 12 patients or α-heavy chain in 3 patients, without concurrent light chain staining. Only 2 patients had symptomatic myeloma. By serum protein electrophoresis/immunofixation, 13 patients had detectable monoclonal gammopathy. However, none of these techniques allowed detection of the nephrotoxic truncated heavy chain, which was achieved by immunoblot and/or bone marrow heavy chain sequencing in 14 of 15 patients. Serum-free kappa to lambda light chain ratio was abnormal in 11 of 11 patients so examined. Immunofluorescence studies of bone marrow plasma cells showed coexpression of the pathogenic heavy chain with light chain matching the abnormal serum-free light chain in all 3 tested patients. Heavy chain sequencing showed first constant domain deletion in 11 of 11 patients, with high isoelectric point values of the variable domain in 10 of 11 patients. All patients received chemotherapy, including bortezomib in 10 cases. Renal parameters improved in 11 patients who achieved a hematological response, as assessed by normalization of the free light chain ratio in 8 cases. Tissue deposition in HCDD relates to physicochemical peculiarities of both variable and constant heavy chain domains. Early diagnosis and treatment with bortezomib-based combinations appear important to preserve renal prognosis. Thus, monitoring of serum-free light chain is an indirect but useful method to evaluate the hematological response.


Assuntos
Doença das Cadeias Pesadas/imunologia , Doença das Cadeias Pesadas/patologia , Cadeias gama de Imunoglobulina/análise , Nefropatias/imunologia , Rim/imunologia , Rim/patologia , Idoso , Idoso de 80 Anos ou mais , Biópsia , Bortezomib/uso terapêutico , Quimioterapia Combinada , Feminino , Imunofluorescência , França , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Doença das Cadeias Pesadas/tratamento farmacológico , Doença das Cadeias Pesadas/genética , Humanos , Cadeias alfa de Imunoglobulina/análise , Cadeias gama de Imunoglobulina/genética , Cadeias kappa de Imunoglobulina/análise , Cadeias lambda de Imunoglobulina/análise , Rim/efeitos dos fármacos , Nefropatias/tratamento farmacológico , Nefropatias/patologia , Masculino , Pessoa de Meia-Idade , Síndrome Nefrótica/tratamento farmacológico , Síndrome Nefrótica/imunologia , Síndrome Nefrótica/patologia , Paraproteinemias/tratamento farmacológico , Paraproteinemias/imunologia , Reação em Cadeia da Polimerase , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/imunologia , Insuficiência Renal Crônica/patologia , Estudos Retrospectivos , Resultado do Tratamento
12.
N Engl J Med ; 371(10): 906-17, 2014 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-25184863

RESUMO

BACKGROUND: The combination melphalan-prednisone-thalidomide (MPT) is considered a standard therapy for patients with myeloma who are ineligible for stem-cell transplantation. However, emerging data on the use of lenalidomide and low-dose dexamethasone warrant a prospective comparison of the two approaches. METHODS: We randomly assigned 1623 patients to lenalidomide and dexamethasone in 28-day cycles until disease progression (535 patients), to the same combination for 72 weeks (18 cycles; 541 patients), or to MPT for 72 weeks (547 patients). The primary end point was progression-free survival with continuous lenalidomide-dexamethasone versus MPT. RESULTS: The median progression-free survival was 25.5 months with continuous lenalidomide-dexamethasone, 20.7 months with 18 cycles of lenalidomide-dexamethasone, and 21.2 months with MPT (hazard ratio for the risk of progression or death, 0.72 for continuous lenalidomide-dexamethasone vs. MPT and 0.70 for continuous lenalidomide-dexamethasone vs. 18 cycles of lenalidomide-dexamethasone; P<0.001 for both comparisons). Continuous lenalidomide-dexamethasone was superior to MPT for all secondary efficacy end points, including overall survival (at the interim analysis). Overall survival at 4 years was 59% with continuous lenalidomide-dexamethasone, 56% with 18 cycles of lenalidomide-dexamethasone, and 51% with MPT. Grade 3 or 4 adverse events were somewhat less frequent with continuous lenalidomide-dexamethasone than with MPT (70% vs. 78%). As compared with MPT, continuous lenalidomide-dexamethasone was associated with fewer hematologic and neurologic toxic events, a moderate increase in infections, and fewer second primary hematologic cancers. CONCLUSIONS: As compared with MPT, continuous lenalidomide-dexamethasone given until disease progression was associated with a significant improvement in progression-free survival, with an overall survival benefit at the interim analysis, among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. (Funded by Intergroupe, Francophone du Myélome and Celgene; FIRST ClinicalTrials.gov number, NCT00689936; European Union Drug Regulating Authorities Clinical Trials number, 2007-004823-39.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Talidomida/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Lenalidomida , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Prednisona/administração & dosagem , Talidomida/administração & dosagem , Talidomida/efeitos adversos
13.
Blood ; 125(9): 1411-7, 2015 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-25575538

RESUMO

The combination of pomalidomide and low-dose dexamethasone (Pom-Dex) can be safely administered to patients with end-stage relapsed/refractory multiple myeloma (RRMM). However, we observed a shorter median progression-free survival (PFS) and overall survival (OS) in these patients when characterized with adverse cytogenetics (deletion 17p and translocation [4;14]) in the Intergroupe Francophone Myélome (IFM) 2009-02 trial. We then sought to determine whether MM with adverse cytogenetics would benefit more from Pom-Dex if exposed earlier in the multicenter IFM 2010-02 trial. The intention-to-treat population included 50 patients, with a median age of 63 years (38% were ≥65 years). Interestingly, there was a striking difference in time to progression (TTP), duration of response, and overall response rate (ORR) according to the presence of del(17p) compared with t(4;14) (TTP, 7.3 vs 2.8 months; duration of response, 8.3 vs 2.4 months; and ORR, 32% vs 15%). OS was prolonged after Pom-Dex, particularly in t(4;14), given the short TTP, suggesting that patients were rescued at relapse with further lines of therapy. Pom-Dex, a doublet immunomodulatory drug-based regimen, is active and well tolerated in adverse cytogenetic patients with early RRMM, particularly in those with del(17p), who are characterized by a high and rapid development of a refractoriness state and known for their poor prognosis. Future studies will determine the underlying mechanisms of Pom-Dex activity in del(17p). This trial is registered at www.clinicaltrials.gov as #NCT01745640.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 4/genética , Deleção de Genes , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Translocação Genética/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Dexametasona/administração & dosagem , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida , Talidomida/administração & dosagem , Talidomida/análogos & derivados
14.
JAMA ; 318(21): 2099-2110, 2017 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-29209721

RESUMO

Importance: Cast nephropathy is the main cause of acute kidney injury in multiple myeloma and persistent reduction in kidney function strongly affects prognosis. Strategies to rapidly remove nephrotoxic serum-free light chains combined with novel antimyeloma agents have not been evaluated prospectively. Objective: To compare the hemodialysis independence rate among patients newly diagnosed with myeloma cast nephropathy treated with hemodialysis using a high-cutoff dialyzer (with very large membrane pores and high permeability to immunoglobulin light chains) or a conventional high-flux dialyzer (with small pores and lower permeability). Design, Setting, and Participants: Randomized clinical trial involving 98 patients with biopsy-proven myeloma cast nephropathy requiring hemodialysis treated at 48 French centers between July 2011 and June 2016; the final date of follow-up was June 29, 2016. Interventions: Intensive hemodialysis (eight 5-hour sessions over 10 days) with either a high-cutoff dialyzer (46 patients) or a conventional high-flux dialyzer (48 patients). All patients received the same chemotherapy regimen of bortezomib and dexamethasone. Main Outcomes and Measures: Primary end point was hemodialysis independence at 3 months; secondary end points: hemodialysis independence rates at 6 and 12 months, hemodialysis- and chemotherapy-related adverse events, and death. Results: Among 98 randomized patients, 94 (96%) (median age, 68.8 years [interquartile range, 61.2-75.3 years]; 45% women) were included in the modified intent-to-treat analysis. The hemodialysis independence rate at 3 months was 41.3% (n = 19) in the high-cutoff hemodialysis group vs 33.3% (n = 16) in the conventional hemodialysis group (between-group difference, 8.0% [95% CI, -12.0% to 27.9%], P = .42); at 6 months, the rate was 56.5% (n = 26) vs 35.4% (n = 17), respectively (between-group difference, 21.1% [95% CI, 0.9% to 41.3%], P = .04); and at 12 months, the rate was 60.9% (n = 28) vs 37.5% (n = 18) (between-group difference, 23.4% [95% CI, 3.2% to 43.5%], P = .02). The incidence of hemodialysis-related adverse events was 43% in the high-cutoff hemodialysis group vs 39% in the conventional hemodialysis group; chemotherapy-related serious adverse events, 39% vs 37%, respectively; and at 12 months, 9 patients vs 10 patients died. Conclusions and Relevance: Among patients with myeloma cast nephropathy treated with a bortezomib-based chemotherapy regimen, the use of high-cutoff hemodialysis compared with conventional hemodialysis did not result in a statistically significant difference in hemodialysis independence at 3 months. However, the study may have been underpowered to identify an early clinically important difference. Trial Registration: clinicaltrials.gov Identifier: NCT01208818.


Assuntos
Injúria Renal Aguda/terapia , Mieloma Múltiplo/complicações , Diálise Renal/métodos , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/mortalidade , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/administração & dosagem , Dexametasona/administração & dosagem , Feminino , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Diálise Renal/instrumentação , Diálise Renal/estatística & dados numéricos , Análise de Sobrevida
15.
Blood ; 124(16): 2498-506, 2014 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-25202139

RESUMO

CAN2007 was a phase 1/2 study of once- and twice-weekly single-agent bortezomib in relapsed primary systemic amyloid light chain amyloidosis (AL) amyloidosis. Seventy patients were treated, including 18 and 34 patients at the maximum planned doses on the once- and twice-weekly schedules. This prespecified final analysis provides mature response and long-term outcomes data after 3-year additional follow-up since the last report. In the once-weekly 1.6 mg/m(2) and twice-weekly 1.3 mg/m(2) bortezomib groups, final hematologic response rates were 68.8% and 66.7%; 80% of patients in each group sustained their response for ≥1 year. One-year progression-free rates were 72.2% and 76.8%. Median overall survival (OS) was 62.1 months and not reached; 4-year OS rates were 75.0% and 63.0%. Low baseline difference in κ/λ free light-chain level was associated with higher hematologic complete response rates and longer OS. At data cutoff, 40 (57%) patients had received subsequent therapy, including 19 (27%) retreated with bortezomib, 11 (58%) of whom achieved complete or partial hematologic responses. Four patients received prolonged bortezomib for between 3.5 and 5.6 years, with no new safety concerns, highlighting the feasibility of long-term therapy. Single-agent bortezomib produced durable hematologic responses and promising long-term OS in relapsed AL amyloidosis. This trial was registered at www.clinicaltrials.gov as #NCT00298766.


Assuntos
Amiloidose/tratamento farmacológico , Antineoplásicos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Pirazinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Ácidos Borônicos/efeitos adversos , Bortezomib , Feminino , Seguimentos , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina , Masculino , Pessoa de Meia-Idade , Pirazinas/efeitos adversos , Recidiva , Análise de Sobrevida
17.
Nephrol Dial Transplant ; 31(1): 64-72, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26289418

RESUMO

BACKGROUND: Light chain myeloma cast nephropathy (MCN) is the major cause of renal failure in multiple myeloma and strongly impacts patient survival. The role of kidney biopsy in the management of MCN is unclear. METHODS: Renal pathological findings were retrospectively studied in 70 patients with multiple myeloma and MCN. Patients were categorized according to the achievement or not of renal response, as defined by estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m(2) and/or dialysis independence at 3 months. RESULTS: Thirty-two patients (46%) achieved a renal response. In the whole study population, the following parameters differed significantly between patients with and without renal response, respectively: baseline median eGFR (13.3 versus 9.3 mL/min/1.73 m(2), P = 0.017), Acute Kidney Injury Network Stage 3 (68.8 versus 92.1%, P = 0.019), haematological response rate (94 versus 34%, P < 0.0001), median percentage of free light chain (FLC) reduction at Day 21 (92 versus 24%, P = 0.006) and median number of casts/10 fields (14 versus 25, P = 0.005). The extent of interstitial fibrosis and tubular atrophy was similar. In multivariate analysis, only FLC reduction at Day 21 was significantly associated with renal response. However, when considering only the subgroup of haematological responders, both median number of casts [odds ratio (OR) = 0.93, 95% confidence interval (95% CI): 0.88-0.98, P = 0.01] and extent of tubular atrophy (OR = 0.03, 95% CI: 0.00-0.52, P = 0.02) were independent predictors of renal response. CONCLUSIONS: In MCN, the presence of numerous casts and diffuse tubular atrophy is associated with poor renal prognosis. These data suggest that additional strategies to reduce FLC burden should be considered in patients with extensive cast formation.


Assuntos
Injúria Renal Aguda/diagnóstico , Mieloma Múltiplo/patologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/mortalidade , Injúria Renal Aguda/terapia , Idoso , Biópsia/efeitos adversos , Feminino , Taxa de Filtração Glomerular , Humanos , Estimativa de Kaplan-Meier , Rim/patologia , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Análise Multivariada , Prognóstico , Diálise Renal , Estudos Retrospectivos , Resultado do Tratamento
18.
Kidney Int ; 88(5): 1135-43, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26176826

RESUMO

Monoclonal immunoglobulin deposition disease (MIDD) is a rare complication of plasma cell disorders, defined by linear Congo red-negative deposits of monoclonal light chain, heavy chain, or both along basement membranes. While renal involvement is prominent, treatment strategies, such as the impact of novel anti-myeloma agents, remain poorly defined. Here we retrospectively studied 49 patients with MIDD who received a median of 4.5 cycles of intravenous bortezomib plus dexamethasone. Of these, 25 received no additional treatment, 18 also received cyclophosphamide, while 6 also received thalidomide or lenalidomide. The hematological diagnoses identified 38 patients with monoclonal gammopathy of renal significance, 10 with symptomatic multiple myeloma, and 1 with Waldenstrom macroglobulinemia. The overall hematologic response rate, based on the difference between involved and uninvolved serum-free light chains (dFLCs), was 91%. After median follow-up of 54 months, 5 patients died and 10 had reached end-stage renal disease. Renal response was achieved in 26 patients, with a 35% increase in median eGFR and an 86% decrease in median 24-h proteinuria. Predictive factors were pre-treatment eGFR over 30 ml/min per 1.73 m(2) and post-treatment dFLC under 40 mg/l; the latter was the sole predictive factor of renal response by multivariable analysis. Thus, bortezomib-based therapy is a promising treatment strategy in MIDD, mainly when used early in the disease course. dFLC response is a favorable prognostic factor for renal survival.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/uso terapêutico , Nefropatias/fisiopatologia , Mieloma Múltiplo/tratamento farmacológico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Idoso , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Progressão da Doença , Feminino , Seguimentos , Membrana Basal Glomerular/metabolismo , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Cadeias Pesadas de Imunoglobulinas/metabolismo , Cadeias Leves de Imunoglobulina/metabolismo , Nefropatias/imunologia , Nefropatias/patologia , Lenalidomida , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/complicações , Proteinúria/tratamento farmacológico , Estudos Retrospectivos , Taxa de Sobrevida , Talidomida/administração & dosagem , Talidomida/análogos & derivados , Macroglobulinemia de Waldenstrom/sangue , Macroglobulinemia de Waldenstrom/complicações
19.
Kidney Int ; 87(4): 698-711, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25607108

RESUMO

Monoclonal gammopathy of renal significance (MGRS) regroups all renal disorders caused by a monoclonal immunoglobulin (MIg) secreted by a nonmalignant B-cell clone. By definition, patients with MGRS do not meet the criteria for overt multiple myeloma/B-cell proliferation, and the hematologic disorder is generally consistent with monoclonal gammopathy of undetermined significance (MGUS). However, MGRS is associated with high morbidity due to the severity of renal and sometimes systemic lesions induced by the MIg. Early recognition is crucial, as suppression of MIg secretion by chemotherapy often improves outcomes. The spectrum of renal diseases in MGRS is wide, including old entities such as AL amyloidosis and newly described lesions, particularly proliferative glomerulonephritis with monoclonal Ig deposits and C3 glomerulopathy with monoclonal gammopathy. Kidney biopsy is indicated in most cases to determine the exact lesion associated with MGRS and evaluate its severity. Diagnosis requires integration of morphologic alterations by light microscopy, immunofluorescence (IF), electron microscopy, and in some cases by IF staining for Ig isotypes, immunoelectron microscopy, and proteomic analysis. Complete hematologic workup with serum and urine protein electrophoresis, immunofixation, and serum-free light-chain assay is required. This review addresses the pathologic and clinical features of MGRS lesions, indications of renal biopsy, and a proposed algorithm for the hematologic workup.


Assuntos
Imunoglobulinas/sangue , Nefropatias/patologia , Rim/patologia , Gamopatia Monoclonal de Significância Indeterminada/complicações , Gamopatia Monoclonal de Significância Indeterminada/diagnóstico , Algoritmos , Biópsia , Testes Hematológicos , Humanos , Cadeias Leves de Imunoglobulina/sangue , Imunoglobulinas/urina , Nefropatias/etiologia , Nefropatias/metabolismo
20.
Br J Haematol ; 168(5): 671-8, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25363150

RESUMO

This retrospective analysis was conducted in 64 patients diagnosed with type I cryoglobulinaemia (CG) followed at two French centres. Median follow-up was 6·75 years. CG was IgG in 60% and IgM in 40% of all cases and was asymptomatic in 16 patients (25%). Cold-triggered ischaemic skin manifestations were observed in 33 patients (51%). Neurological manifestations were observed in 15 patients and renal manifestations in 13. Most of the patients with necrotic purpura (14/16, P = 0·009) and renal manifestations (11/13, P = 0·057) had IgG CG. IgG CG was associated with monoclonal gammopathy of undetermined significance (MGUS), myeloma, chronic lymphocytic leukaemia and lymphoplasmocytic lymphoma in 18, 13, 5 and 2 patients, respectively. IgM CG was associated with MGUS and Waldenström macroglobulinaemia in 8 and 18 cases, respectively. One third of patients did not receive any specific treatment. Various treatments, including rituximab, were administered to 25/31 patients with IgG CG and 6/25 patients with IgM CG due to CG-related symptoms. Rituximab was ineffective in all cases associated with a predominantly plasmacytic proliferation. To conclude, type I CG has specific clinico-biological characteristics compared to type II CG. Furthermore, there are differences in terms of related manifestations between type I IgG and type I IgM CG.


Assuntos
Anticorpos Monoclonais Murinos/administração & dosagem , Antineoplásicos/administração & dosagem , Crioglobulinemia , Imunoglobulina G/sangue , Paraproteinemias , Macroglobulinemia de Waldenstrom , Idoso , Anticorpos Monoclonais Murinos/efeitos adversos , Antineoplásicos/efeitos adversos , Crioglobulinemia/sangue , Crioglobulinemia/tratamento farmacológico , Crioglobulinemia/patologia , Feminino , Seguimentos , Humanos , Isquemia/sangue , Isquemia/tratamento farmacológico , Isquemia/patologia , Rim/patologia , Nefropatias/sangue , Nefropatias/tratamento farmacológico , Nefropatias/patologia , Masculino , Paraproteinemias/sangue , Paraproteinemias/tratamento farmacológico , Paraproteinemias/patologia , Estudos Retrospectivos , Rituximab , Pele/irrigação sanguínea , Pele/patologia , Dermatopatias/sangue , Dermatopatias/tratamento farmacológico , Dermatopatias/patologia , Macroglobulinemia de Waldenstrom/sangue , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/patologia
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