RESUMO
Activation of NF-kappaB has been noted in many tumor types, however only rarely has this been linked to an underlying genetic mutation. An integrated analysis of high-density oligonucleotide array CGH and gene expression profiling data from 155 multiple myeloma samples identified a promiscuous array of abnormalities contributing to the dysregulation of NF-kappaB in approximately 20% of patients. We report mutations in ten genes causing the inactivation of TRAF2, TRAF3, CYLD, cIAP1/cIAP2 and activation of NFKB1, NFKB2, CD40, LTBR, TACI, and NIK that result primarily in constitutive activation of the noncanonical NF-kappaB pathway, with the single most common abnormality being inactivation of TRAF3. These results highlight the critical importance of the NF-kappaB pathway in the pathogenesis of multiple myeloma.
Assuntos
Regulação Neoplásica da Expressão Gênica , Mieloma Múltiplo/genética , Mutação/genética , NF-kappa B/genética , Proteínas de Neoplasias/metabolismo , Adenoviridae , Proteína 3 com Repetições IAP de Baculovírus , Antígenos CD40/genética , Antígenos CD40/metabolismo , Células Cultivadas , Enzima Desubiquitinante CYLD , Ativação Enzimática , Imunofluorescência , Deleção de Genes , Perfilação da Expressão Gênica , Humanos , Immunoblotting , Técnicas Imunoenzimáticas , Hibridização in Situ Fluorescente , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Receptor beta de Linfotoxina/genética , Receptor beta de Linfotoxina/metabolismo , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , NF-kappa B/metabolismo , Subunidade p50 de NF-kappa B/genética , Subunidade p50 de NF-kappa B/metabolismo , Subunidade p52 de NF-kappa B/genética , Subunidade p52 de NF-kappa B/metabolismo , Proteínas de Neoplasias/genética , Hibridização de Ácido Nucleico , Plasmídeos , Reação em Cadeia da Polimerase , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Fator 2 Associado a Receptor de TNF/genética , Fator 2 Associado a Receptor de TNF/metabolismo , Fator 3 Associado a Receptor de TNF/genética , Fator 3 Associado a Receptor de TNF/metabolismo , Transfecção , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Proteína Transmembrana Ativadora e Interagente do CAML/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases , Quinase Induzida por NF-kappaBRESUMO
The systemic capillary leak syndrome (SCLS) is a rare disorder characterized by transient episodes of hypotensive shock and anasarca thought to arise from reversible microvascular barrier dysfunction. Although the high prevalence of a monoclonal gammopathy of unknown significance in SCLS suggests a pathogenic contribution of endogenous immunoglobulins, the mechanisms of vascular hyperpermeability remain obscure. Herein, we report clinical and molecular findings on 23 patients, the largest SCLS case series to date. Application of episodic SCLS sera, but neither the purified immunoglobulin fraction nor sera obtained from patients during remission, to human microvascular endothelial cells caused vascular endothelial cadherin internalization, disruption of interendothelial junctions, actin stress fiber formation, and increased permeability in complementary functional assays without inducing endothelial apoptosis. Intravenous immunoglobulin, one promising therapy for SCLS, mitigated the permeability effects of episodic sera. Consistent with the presence of endogenous, nonimmunoglobulin, circulating permeability factor(s) constrained to SCLS episodes, we found that vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2), were elevated in episodic SCLS sera but not in remission sera. Ab-based inhibition of Ang2 counteracted permeability induced by episodic SCLS sera. Comparable experiments with anti-VEGF Ab (bevacizumab) yielded less interpretable results, probably because of endothelial toxicity of VEGF withdrawal. Our results support a model of SCLS pathogenesis in which nonimmunoglobulin humoral factors such as VEGF and Ang2 contribute to transient endothelial contraction, suggesting a molecular mechanism for this highly lethal disorder.
Assuntos
Síndrome de Vazamento Capilar/etiologia , Endotélio Vascular/fisiopatologia , Doença Aguda , Junções Aderentes/efeitos dos fármacos , Junções Aderentes/ultraestrutura , Adulto , Idoso , Angiopoietina-2/antagonistas & inibidores , Angiopoietina-2/sangue , Anticorpos Monoclonais Humanizados/farmacologia , Apoptose/efeitos dos fármacos , Bevacizumab , Síndrome de Vazamento Capilar/sangue , Síndrome de Vazamento Capilar/fisiopatologia , Permeabilidade Capilar , Células Cultivadas/efeitos dos fármacos , Doença Crônica , Convalescença , Citoesqueleto/ultraestrutura , Células Endoteliais/efeitos dos fármacos , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Paraproteinemias/sangue , Paraproteinemias/complicações , Proteínas Recombinantes/farmacologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/farmacologiaRESUMO
IgD monoclonal gammopathies are uncommon. They are seen rarely as a monoclonal gammopathy of undetermined significance and are present in 1%-2% of patients with multiple myeloma. In light-chain amyloidosis, IgD monoclonal proteins are found in ap-proximately 1% of patients. When an IgD monoclonal protein is found, amyloidosis is often omitted from the differential diagnosis. In the present study, we reviewed the natural history of IgD-associated amyloidosis among 53 patients seen over 41 years. The distribution of clinical syndromes suggests that these patients have a lower frequency of renal and cardiac involvement. The overall survival of these patients does not appear to be different from that of patients who have light-chain amyloidosis associated with another monoclonal protein.
Assuntos
Amiloidose/metabolismo , Amiloidose/patologia , Imunoglobulina D/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Amiloidose/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Taxa de SobrevidaRESUMO
Light-chain (AL) amyloidosis remains incurable despite recent therapeutic advances. Given the activity of the lenalidomide-alkylating agent combination in myeloma, we designed this phase 2 trial of lenalidomide, cyclophosphamide, and dexamethasone in AL amyloidosis. Thirty-five patients, including 24 previously untreated, were enrolled. Nearly one-half of the patients had cardiac stage III disease and 28% had ≥ 3 organs involved. The overall hematologic response (≥ partial response [PR]) rate was 60%, including 40% with very-good partial response or better. Using serum-free light chain for assessing response, 77% of patients had a hematologic response. Organ responses were seen in 29% of patients and were limited to those with a hematologic response. The median hematologic progression-free survival was 28.3 months, and the median overall survival was 37.8 months. Hematologic toxicity was the predominant adverse event, followed by fatigue, edema, and gastrointestinal symptoms. A grade 3 or higher toxicity occurred in 26 patients (74%) including ≥ grade 3 hematologic toxicity in 16 patients (46%) and ≥ grade 3 nonhematologic toxicity in 25 patients (71%). Seven patients (20%) died on study, primarily because of advanced disease. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) is an effective combination for treatment of AL amyloidosis and leads to durable hematologic responses as well as organ responses with manageable toxicity. The trial was registered at www.clinicaltrials.gov (NCT00564889).
Assuntos
Amiloidose/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Nefropatias/tratamento farmacológico , Talidomida/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Amiloidose/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/efeitos adversos , Dexametasona/efeitos adversos , Feminino , Seguimentos , Cardiopatias/tratamento farmacológico , Cardiopatias/metabolismo , Humanos , Cadeias Leves de Imunoglobulina/metabolismo , Nefropatias/metabolismo , Lenalidomida , Masculino , Pessoa de Meia-Idade , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
Standard myeloma treatment response criteria are determined principally by changes in the monoclonal protein. Reduction in the size of the proliferative component of malignant plasma cells may be an additional metric of assessing response to therapy. We retrospectively analyzed 176 patients with newly diagnosed myeloma with a measurable plasma cell labeling index (PCLI) at diagnosis and repeat measurement 4 months after initiation of therapy. PCLI response was defined as a ≥ 60% reduction. Baseline PCLI is an independent prognostic factor; therefore, we categorized patients into 3 groups: PCLI ≥ 3% (high), ≥ 1% (intermediate), and < 1% (low). Patients achieving a greater PCLI response had improved median overall survival of 54 months compared with 29 months in nonresponders (P = .02). Improved median overall survival with PCLI response occurred in the high initial PCLI group (28 vs 7 months; P = .003) and intermediate group (64 vs 24 months; P = .002). The application of PCLI response and serum M-spike response together provided further prognostic information. On multivariate analysis, the prognostic value of PCLI response was independent of ß(2)-microglobulin, elevated creatinine, serum M-spike response, and baseline PCLI. We conclude that a significant reduction in plasma cell proliferation in patients with newly diagnosed myeloma is an important predictor of survival.
Assuntos
Proliferação de Células , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Plasmócitos/citologia , Adulto , Idoso , Medula Óssea/metabolismo , Medula Óssea/patologia , Proteína C-Reativa/metabolismo , Feminino , Imunofluorescência , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Índice Mitótico , Mieloma Múltiplo/patologia , Prognóstico , Taxa de Sobrevida , Microglobulina beta-2/metabolismoRESUMO
The efficacy of retreatment with immunomodulatory drugs (IMiDs) among patients with multiple myeloma who received this class of drugs for initial therapy is unknown. We studied 140 patients who received either thalidomide-dexamethasone (81; 58%) or lenalidomide-dexamethasone (59; 42%) as first-line therapy of multiple myeloma followed by repeat IMiD (thalidomide [34; 24%] or lenalidomide [106; 76%]) as one of the salvage regimens. A median of 2 treatments (range, 1-6), including a stem cell transplant in 105 patients (75%), were administered before IMiD-based salvage therapy. The median time from diagnosis to repeat exposure to IMiD was 28 months. Among the 113 evaluable patients, 50 (44%) achieved at least a partial response, and 63 (56%) achieved less than a partial response to repeat IMiD. Response rates with lenalidomide retreatment were higher than with repeat administration of thalidomide.
Assuntos
Antineoplásicos/uso terapêutico , Dexametasona/uso terapêutico , Fatores Imunológicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Adulto , Idoso , Feminino , Humanos , Lenalidomida , Masculino , Pessoa de Meia-Idade , RetratamentoRESUMO
Detection of specific chromosomal abnormalities by FISH and metaphase cytogenetics allows risk stratification in multiple myeloma; however, gene expression profiling (GEP) based signatures may enable more specific risk categorization. We examined the utility of 2 GEP-based risk stratification systems among patients undergoing initial therapy with lenalidomide in the context of a phase 3 trial. Among 45 patients studied at baseline, 7 (16%) and 10 (22%), respectively, were high-risk using the GEP70 and GEP15 signatures. The median overall survival for the GEP70 high-risk group was 19 months versus not reached for the rest (hazard ratio = 14.1). Although the medians were not reached, the GEP15 also predicted a poor outcome among the high-risk patients. The C-statistic for the GEP70, GEP15, and FISH based risk stratification systems was 0.74, 0.7, and 0.7, respectively. Here we demonstrate the prognostic value for GEP risk stratification in a group of patients primarily treated with novel agents. This trial was registered at www.clinicaltrials.gov as #NCT00098475.
Assuntos
Antineoplásicos/uso terapêutico , Dexametasona/uso terapêutico , Perfilação da Expressão Gênica , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Talidomida/análogos & derivados , Idoso , Aberrações Cromossômicas , Feminino , Humanos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Talidomida/uso terapêutico , Resultado do TratamentoRESUMO
The POEMS syndrome is associated with elevated vascular endothelial growth factor (VEGF) levels. Several studies have compared serum VEGF levels between POEMS patients and other disease entities showing higher serum VEGF in POEMS syndrome; however, it is unknown whether serum levels are reliable and reproducible given variable platelet release of VEGF. We therefore compared plasma levels of VEGF in 29 patients with POEMS syndrome with those of other disorders (n = 76). We demonstrated that plasma VEGF levels are useful in differentiating POEMS from other plasma cell dyscrasias, neuropathic processes, and multisystem illnesses. Plasma VEGF is also useful in monitoring disease activity after treatment and correlates with clinical improvements better than hematologic response.
Assuntos
Síndrome POEMS/diagnóstico , Fator A de Crescimento do Endotélio Vascular/sangue , Hiperplasia do Linfonodo Gigante/sangue , Hiperplasia do Linfonodo Gigante/diagnóstico , Estudos de Coortes , Seguimentos , Humanos , Gamopatia Monoclonal de Significância Indeterminada/sangue , Gamopatia Monoclonal de Significância Indeterminada/diagnóstico , Síndrome POEMS/sangue , Polineuropatias/sangue , Polineuropatias/diagnóstico , Valor Preditivo dos Testes , Indução de Remissão , Estudos Retrospectivos , Fator A de Crescimento do Endotélio Vascular/análiseRESUMO
Pomalidomide at doses of 2 or 4 mg/d has demonstrated excellent activity in patients with multiple myeloma (MM). We opened 2 sequential phase 2 trials using the pomalidomide with weekly dexamethasone (Pom/dex) regimen at differing doses to study the efficacy of this regimen in patients who have failed both lenalidomide and bortezomib. Pomalidomide was given orally 2 or 4 mg daily with dexamethasone 40 mg weekly. Thirty-five patients were enrolled in each cohort. Confirmed responses in the 2-mg cohort consisted of very good partial response (VGPR) in 5 (14%), partial response (PR) in 4 (11%), minor response (MR) in 8 (23%) for an overall response rate of 49%. In the 4-mg cohort, confirmed responses consisted of complete response (CR) in 1 (3%), VGPR in 3 (9%), PR in 6 (17%), MR in 5 (14%) for an overall response rate of 43%. Overall survival at 6 months is 78% and 67% in the 2- and 4-mg cohort, respectively. Myelosuppression was the most common toxicity. This nonrandomized data suggests no advantage for 4 mg over the 2 mg daily. Pomalidomide overcomes resistance in myeloma refractory to both lenalidomide and bortezomib. This trial is registered at http://ClinicalTrials.gov, number NCT00558896.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ácidos Borônicos/uso terapêutico , Dexametasona/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Pirazinas/uso terapêutico , Talidomida/análogos & derivados , Administração Oral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib , Dexametasona/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Análise de Sobrevida , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Talidomida/uso terapêutico , Falha de Tratamento , Resultado do TratamentoRESUMO
Multiple myeloma (MM) is a plasma cell neoplasm that proceeds through a premalignant state of monoclonal gammopathy of unknown significance; however, the molecular events responsible for myelomagenesis remain uncharacterized. To identify cellular pathways deregulated in MM, we addressed that sumoylation is homologous to ubiquitination and results in the attachment of the ubiquitin-like protein Sumo onto target proteins. Sumoylation was markedly enhanced in MM patient lysates compared with normal plasma cells and expression profiling indicated a relative induction of sumoylation pathway genes. The Sumo-conjugating enzyme Ube2I, the Sumo-ligase PIAS1, and the Sumo-inducer ARF were elevated in MM patient samples and cell lines. Survival correlated with expression because 80% of patients with low UBE2I and PIAS1 were living 6 years after transplantation, whereas only 45% of patients with high expression survived 6 years. UBE2I encodes the sole Sumo-conjugating enzyme in mammalian cells and cells transfected with a dominant-negative sumoylation-deficient UBE2I mutant exhibited decreased survival after radiation exposure, impaired adhesion to bone marrow stroma cell and decreased bone marrow stroma cell-induced proliferation. UBE2I confers cells with multiple advantages to promote tumorigenesis and predicts decreased survival when combined with PIAS1. The sumoylation pathway is a novel therapeutic target with implications for existing proteasomal-based treatment strategies.
Assuntos
Mieloma Múltiplo/metabolismo , Plasmócitos/metabolismo , Processamento de Proteína Pós-Traducional , Proteína SUMO-1/metabolismo , Células da Medula Óssea/metabolismo , Adesão Celular/genética , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Mutação , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Inibidoras de STAT Ativados/biossíntese , Proteína SUMO-1/genética , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/biossíntese , Transplante de Células-Tronco , Células Estromais/metabolismo , Transplante Homólogo , Enzimas de Conjugação de Ubiquitina/biossínteseRESUMO
The objective of this case-control study was to compare the efficacy and toxicity of lenalidomide plus dexamethasone (len/dex) versus thalidomide plus dexamethasone (thal/dex) as initial therapy for newly diagnosed myeloma. We retrospectively studied 411 newly diagnosed patients treated with len/dex (228) or thal/dex (183) at the Mayo Clinic. The differences were similar in a matched-pair analysis that adjusted for age, sex, transplantation status, and dexamethasone dose. The proportions of patients achieving at least a partial response to len/dex and thal/dex were 80.3% versus 61.2%, respectively (P < .001); very good partial response rates were 34.2% and 12.0%, respectively (P < .001). Patients receiving len/dex had longer time to progression (median, 27.4 vs 17.2 months; P = .019), progression-free survival (median, 26.7 vs 17.1 months; P = .036), and overall survival (median not reached vs 57.2 months; P = .018). A similar proportion of patients in the 2 groups experienced at least one grade 3 or 4 adverse event (57.5% vs 54.6%, P = .568). Main grade 3 or 4 toxicities of len/dex were hematologic, mainly neutropenia (14.6% vs 0.6%, P < .001); the most common toxicities in thal/dex were venous thromboembolism (15.3% vs 9.2%, P = .058) and peripheral neuropathy (10.4% vs 0.9%, P < .001). Len/dex appears well-tolerated and more effective than thal/dex. Randomized trials are needed to confirm these results.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Dexametasona/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Talidomida/análogos & derivados , Talidomida/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Estudos de Casos e Controles , Terapia Combinada , Dexametasona/efeitos adversos , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Terapia de Salvação/métodos , Taxa de Sobrevida , Talidomida/efeitos adversos , Adulto JovemRESUMO
Over the years, the definition of solitary plasmacytoma of bone (SPB) has shifted in part due to more modern testing capabilities. We hypothesized that outcomes data based on antiquated testing would not reflect outcomes using modern staging. To address both how widely applied adequate diagnostic staging is and what the progression rates of SPB as defined with state-of-the-art staging are, we performed a retrospective chart review of those patients with a diagnosis of SPB seen at our institution over the past decade. Two groups were studied: all patients with SPB (n = 127); and those patients referred to our institution for an indication other than progression (n = 91). The median PFS for those two groups were 26 months and 42 months, respectively. At baseline, only a minority of patients had state-of-the-art staging. The 5 patients with both modern imaging and a negative bone marrow had a 21 month PFS of 100%. Patients with plasmacytoma plus, one plasmacytoma but bone marrow consistent with monoclonal gammopathy of undetermined significance, fare worse than true SPB. The use of modern testing is imperative to characterize a patient's risk for progression. PET/CT plays an important role in the diagnostic work-up.
Assuntos
Neoplasias Ósseas/diagnóstico , Oncologia/métodos , Plasmocitoma/diagnóstico , Padrões de Prática Médica , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/patologia , Neoplasias Ósseas/patologia , Neoplasias Ósseas/fisiopatologia , Neoplasias Ósseas/terapia , Estudos de Coortes , Progressão da Doença , Registros Eletrônicos de Saúde , Feminino , Humanos , Masculino , Oncologia/tendências , Pessoa de Meia-Idade , Gamopatia Monoclonal de Significância Indeterminada/etiologia , Estadiamento de Neoplasias , Plasmocitoma/patologia , Plasmocitoma/fisiopatologia , Plasmocitoma/terapia , Estudos Retrospectivos , Análise de Sobrevida , Estados UnidosRESUMO
Lenalidomide with dexamethasone is a standard induction treatment regimen for newly diagnosed myeloma (although a Federal Drug Administration indication is still absent). In the context of the Phase 3 clinical trial E4A03 (lenalidomide plus dexamethasone in low or high doses), we queried whether a fluorescence in situ hybridization (FISH)-based genetic classification into high risk (HR) and standard risk (SR) multiple myeloma (MM) would remain clinically significant. Of 445 E4A03 patients, 126 had FISH analysis; 21 were classified HR with t(4;14), t(14;16), or 17p13 deletions. Median survival follow-up approached 3 years. Patients with FISH data tended to be younger and healthier compared to the rest of the study population and, consequently, had superior overall survival (OS) results. Within the FISH cohort, shorter OS in the HR versus SR group (P = 0·004) corresponded to a hazard ratio of 3·48 [95% confidence interval: (1·42-8·53)], an effect also observed in multivariate analysis. Two-year OS rates were 91% for SR MM and 76% for HR MM. There was also evidence of interaction between risk status and treatment (P = 0·026). HR patients were less likely to attain good partial response (SR 46% and HR 30%, Odds Ratio = 2·0 [0·7-5·6]), but overall response rates were not different. FISH-based risk classification retained prognostic significance in patients receiving lenalidomide-based induction.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/classificação , Mieloma Múltiplo/tratamento farmacológico , Idoso , Dexametasona/administração & dosagem , Feminino , Humanos , Hibridização in Situ Fluorescente/métodos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/genética , Prognóstico , Análise de Sobrevida , Talidomida/administração & dosagem , Talidomida/análogos & derivadosRESUMO
The outcome of patients with multiple myeloma is dictated primarily by cytogenetic abnormalities and proliferative capacity of plasma cells. We studied the outcome after initial therapy with lenalidomide-dexamethasone among 100 newly diagnosed patients, risk-stratified by genetic abnormalities and plasma cell labeling index. A total of 16% had high-risk multiple myeloma, defined by the presence of hypodiploidy, del(13q) by metaphase cytogenetics, del(17p), IgH translocations [t(4;14), or t(14;16)] or plasma cell labeling index more than or equal to 3%. Response rates were 81% vs 89% in the high-risk and standard-risk groups, respectively. The median progression-free survival was shorter in the high-risk group (18.5 vs 36.5 months, P < .001), but overall survival was comparable. Because of unavailability of all tests for every patient, we separately analyzed 55 stringently classified patients, and the results were similar. In conclusion, high-risk patients achieve less durable responses with lenalidomide-dexamethasone compared with standard-risk patients; no significant differences in overall survival are apparent so far. These results need confirmation in larger, prospectively designed studies.
Assuntos
Dexametasona/administração & dosagem , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Talidomida/análogos & derivados , Adulto , Idoso , Aberrações Cromossômicas , Intervalo Livre de Doença , Feminino , Humanos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Plasmócitos , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Medição de Risco , Taxa de Sobrevida , Talidomida/administração & dosagem , Resultado do TratamentoRESUMO
The rate of asymptomatic amyloidosis (AL) among patients with newly diagnosed multiple myeloma (MM) or smoldering multiple myeloma (SMM) is unknown. We evaluated number and clinical significance of asymptomatic AL in consecutive MM and SMM patients, not having recognition of symptomatic AL at the time of their diagnostic bone marrow biopsy. Bone marrow biopsies were stained with Congo red and considered diagnostic for AL in case of positive Congo red staining with apple-green birefringence. Biopsies from 144 patients were evaluated: 77 had a diagnosis of MM and 67 of SMM. The median age was 59 (range 26-84) years; the median follow-up was 76 months (range 0-216). Immunoglobulin isotypes were 96/144 (67%), IgG; 23/144 (16%), IgA; 12/144 (8%), light chain only; 1/77 (1%), IgD; and biclonal or indeterminate, 12/144 (8%). Fifty-eight percent (84/144) were κ restricted. The presence of amyloid was found in two cases (1%, 95% CI -0.6 to 3.2), one in MM, and one in SMM group, and none had or developed signs or symptoms suggestive of organ involvement by amyloid. Among the 142 other patients without amyloid deposition in their index bone marrow, one (0.7%, 95% CI -0.6 to 2.0) developed symptomatic AL after 119 months.
Assuntos
Amiloidose/complicações , Amiloidose/diagnóstico , Doenças Assintomáticas , Medula Óssea/patologia , Cadeias Leves de Imunoglobulina , Mieloma Múltiplo/diagnóstico , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Amiloidose/epidemiologia , Amiloidose/patologia , Doenças Assintomáticas/epidemiologia , Biópsia , Feminino , Humanos , Cadeias Leves de Imunoglobulina/análise , Cadeias Leves de Imunoglobulina/metabolismo , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/epidemiologia , Mieloma Múltiplo/patologia , Estudos RetrospectivosRESUMO
The combination of lenalidomide and low-dose dexamethasone is an effective treatment for multiple myeloma (MM). Addition of alkylating agents to lenalidomide or thalidomide results in increased response rates and deeper responses. We designed this trial to study the combination of cyclophosphamide, lenalidomide, and dexamethasone (CRd) as initial therapy for MM. Fifty-three patients with previously untreated symptomatic MM was enrolled. Patients received 4-week treatment cycles consisting of lenalidomide (25 mg daily for 3 weeks), dexamethasone (40 mg weekly), and cyclophosphamide (300 mg/m(2) weekly for 3 weeks). A partial response or better was seen in 85% of patients including 47% with a very good partial response or better. The toxicities were manageable with over 80% of planned doses delivered; six patients went off study for toxicity. The median progression free survival (PFS) for the entire group was 28 months (95% CI: 22.7-32.6) and the overall survival (OS) at 2 years was 87% (95% CI: 78-96). Importantly, 14 patients with high-risk MM had similar PFS and OS as the standard-risk patients (n = 39). CRd is an effective and well-tolerated regimen for upfront therapy of MM with high response rates and excellent 2-year OS, and is suitable for long-term therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Dexametasona/uso terapêutico , Progressão da Doença , Feminino , Humanos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Proteínas do Mieloma/análise , Neutropenia/induzido quimicamente , Pacientes Desistentes do Tratamento , Análise de Sobrevida , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Talidomida/análogos & derivados , Talidomida/uso terapêuticoRESUMO
The systemic capillary leak syndrome (SCLS) is a rare disease of reversible plasma extravasation and vascular collapse accompanied by hemoconcentration and hypoalbuminemia. Its cause is unknown, although it is believed to be a manifestation of transient endothelial dysfunction due to endothelial contraction, apoptosis, injury, or a combination of these. Fewer than 150 cases of SCLS have been reported, but the condition is probably underrecognized because of its nonspecific symptoms and signs and high mortality rate. Patients experience shock and massive edema, often after a nonspecific prodrome of weakness, fatigue, and myalgias, and are at risk for ischemia-induced organ failure, rhabdomyolysis and muscle compartment syndromes, and venous thromboembolism. Shock and edema reverse almost as quickly as they begin, at which time patients are at risk for death from flash pulmonary edema during rapid fluid remobilization. Diagnosis is made clinically and by exclusion of other diseases that cause similar symptoms and signs, most notably sepsis, anaphylaxis, and angioedema. Acute episodes are treated with vasopressor therapy and judicious fluid replacement, possibly with colloid solutions for their osmotic effects, to prevent the sequelae of underperfusion. Between episodes, patients may be treated with theophylline and terbutaline, which clinical experience suggests may reduce the severity and frequency of acute episodes. Prognosis is uncertain, but patients who survive an initial severe SCLS episode are estimated to have a 10-year survival rate greater than 70%. Much remains to be learned about SCLS, and clinicians should consider the diagnosis in patients with unexplained edema, increased hematocrit, and hypotension.
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Síndrome de Vazamento Capilar , Síndrome de Vazamento Capilar/diagnóstico , Síndrome de Vazamento Capilar/etiologia , Síndrome de Vazamento Capilar/fisiopatologia , Síndrome de Vazamento Capilar/terapia , Diagnóstico Diferencial , Humanos , PrognósticoRESUMO
BACKGROUND: High-dose dexamethasone is a mainstay of therapy for multiple myeloma. We studied whether low-dose dexamethasone in combination with lenalidomide is non-inferior to and has lower toxicity than high-dose dexamethasone plus lenalidomide. METHODS: Patients with untreated symptomatic myeloma were randomly assigned in this open-label non-inferiority trial to lenalidomide 25 mg on days 1-21 plus dexamethasone 40 mg on days 1-4, 9-12, and 17-20 of a 28-day cycle (high dose), or lenalidomide given on the same schedule with dexamethasone 40 mg on days 1, 8, 15, and 22 of a 28-day cycle (low dose). After four cycles, patients could discontinue therapy to pursue stem-cell transplantation or continue treatment until disease progression. The primary endpoint was response rate after four cycles assessed with European Group for Blood and Bone Marrow Transplant criteria. The non-inferiority margin was an absolute difference of 15% in response rate. Analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00098475. FINDINGS: 445 patients were randomly assigned: 223 to high-dose and 222 to low-dose regimens. 169 (79%) of 214 patients receiving high-dose therapy and 142 (68%) of 205 patients on low-dose therapy had complete or partial response within four cycles (odds ratio 1.75, 80% CI 1.30-2.32; p=0.008). However, at the second interim analysis at 1 year, overall survival was 96% (95% CI 94-99) in the low-dose dexamethasone group compared with 87% (82-92) in the high-dose group (p=0.0002). As a result, the trial was stopped and patients on high-dose therapy were crossed over to low-dose therapy. 117 patients (52%) on the high-dose regimen had grade three or worse toxic effects in the first 4 months, compared with 76 (35%) of the 220 on the low-dose regimen for whom toxicity data were available (p=0.0001), 12 of 222 on high dose and one of 220 on low-dose dexamethasone died in the first 4 months (p=0.003). The three most common grade three or higher toxicities were deep-vein thrombosis, 57 (26%) of 223 versus 27 (12%) of 220 (p=0.0003); infections including pneumonia, 35 (16%) of 223 versus 20 (9%) of 220 (p=0.04), and fatigue 33 (15%) of 223 versus 20 (9%) of 220 (p=0.08), respectively. INTERPRETATION: Lenalidomide plus low-dose dexamethasone is associated with better short-term overall survival and with lower toxicity than lenalidomide plus high-dose dexamethasone in patients with newly diagnosed myeloma. FUNDING: National Cancer Institute, Rockville, MD, USA.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Término Precoce de Ensaios Clínicos , Feminino , Humanos , Estimativa de Kaplan-Meier , Lenalidomida , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Modelos de Riscos Proporcionais , Medição de Risco , Talidomida/administração & dosagem , Talidomida/análogos & derivados , Fatores de Tempo , Resultado do TratamentoRESUMO
The immunoglobulin free light chain (FLC) assay is an invaluable tool for following patients with oligosecretory plasma cell dyscrasia. Baseline values have also been shown to be prognostic in all plasma cell disorders tested. A looming question, however, is the role it should play in following myeloma patients with disease that is measurable using serum and urine electrophoresis. We used the data and stored samples from a mature Eastern Cooperative Oncology Group clinical trial (E9486) to assess serum levels of FLC at baseline and after 2 months of alkylator-based therapy. For serial determinations, the absolute level of involved serum FLC or the difference of the involved and uninvolved FLC is preferred over the ratio of involved to uninvolved FLC. FLC response after 2 months of therapy was superior to early M-protein measurement to predict overall response. The ideal cut-point for FLC change appears to be between 40% and 50% reduction. The correlation between serial measurements of serum FLC and urine M-protein is inadequate to abolish the serial 24-hour urine protein. Although baseline values of FLC are prognostic in newly diagnosed myeloma patients, serial measurements do not appear to have added value in patients who have M-proteins measurable by electrophoresis.
Assuntos
Cadeias Leves de Imunoglobulina/sangue , Mieloma Múltiplo/diagnóstico , Biomarcadores/sangue , Humanos , Prognóstico , Resultado do TratamentoRESUMO
We report the long-term follow-up results of a phase II trial of thalidomide for early-stage multiple myeloma (MM). Patients were eligible if they had smoldering multiple myeloma (SMM) or indolent MM without the need for immediate therapy. Thalidomide was initiated at a dose of 200 mg/day and adjusted as tolerated. Disease progression was defined using modified American Society of Hematology/Food and Drug Administration consensus panel criteria for SMM. Thirty-one patients were enrolled; 29 (19 SMM and 10 indolent MM) were eligible. The median age was 61 years. Median follow-up of living patients was 10.2 years (range, 7.5-11.0 years). Ten patients (34%) had a partial response (PR) and nine had minimal response (MR) for an MR plus PR rate of 66%. The median time to progression (TTP) to symptomatic myeloma was 35 months. Median TTP was 61 months in those achieving PR, 39 months with MR, and 9 months among those failing to achieve either MR or PR, P = 0.005. Median overall survival from diagnosis was 86 months; median survival from onset of symptomatic myeloma was 49 months. Grade 3-4 nonhematologic adverse events were noted in 55% of patients. Randomized trials are needed to determine the role of early therapy in SMM.