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OBJECTIVES: To verify the analytical performance of a new mass spectrometry-based method, termed MASS-FIX, when screening for plasma cell disorders in a routine clinical laboratory. PATIENTS AND METHODS: Results from 19,523 unique patients tested for an M-protein between July 24, 2018, and March 6, 2020, by a combination serum protein electrophoresis (SPEP) and MASS-FIX were examined for consistency with pretest implementation performance. MASS-FIX's ability to verify abnormal results from SPEP and free light chain measurements was then compared with that of immunofixation electrophoresis (IFE) using a separate cohort of 52,586 patients tested by SPEP/IFE during the same period. RESULTS: Overall, 62.4% of our cohort was negative for an M-protein. Importantly, 7.3% of all specimens had an M spike on SPEP (0.1 to 8.5 g/dL) and MASS-FIX detected an M-protein in all these samples. Of all samples, 30.3% had M-proteins that were detected by MASS-FIX but the SPEP finding was too small for quantification. Of the positive samples, 5.7% contained a therapeutic monoclonal antibody. Of the positive samples, 4.1% had an N-glycosylated light chain (biomarker of high-risk plasma cell disorders). MASS-FIX confirmed a higher percentage of SPEP abnormalities than IFE. MASS-FIX was slightly more sensitive than IFE when confirming an M-protein in samples with an abnormal free light chain ratio. MASS-FIX had a very low sample repeat rate (1.5%). MASS-FIX was highly automatable resulting in a higher number of samples/technologist/day than IFE (â¼30% more). CONCLUSION: Overall, MASS-FIX was successful in maintaining validation characteristics. MASS-FIX was more sensitive in confirming SPEP abnormalities when compared with IFE. Ability to detect therapeutic monoclonal antibodies and glycosylated light chains was distinctly advantageous.
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Cadeias Leves de Imunoglobulina/sangue , Cadeias lambda de Imunoglobulina/sangue , Paraproteinemias/diagnóstico , Biomarcadores/sangue , Eletroforese das Proteínas Sanguíneas/métodos , Feminino , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Paraproteinemias/sangue , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Plasma cell disorders (PCDs) are typically characterized by excessive production of a single immunoglobulin, defined as a monoclonal protein (M-protein). Some patients have more than one identifiable M-protein, termed biclonal. Traditional immunofixation electrophoresis (IFE) cannot distinguish if two bands of the same isotype represent biclonal proteins or M-proteins with some other feature. A novel assay using immunoenrichment coupled to matrix-assisted laser desorption ionization time-of-flight mass-spectrometry (Mass-Fix) was applied to determine whether two bands of the same isotype represented (1) monomers and dimers of a single M-protein, (2) an M-protein plus a therapeutic monoclonal antibody (t-mAb), (3) an M-protein with light chain glycosylation, or (4) two distinct biclonal M-proteins. METHODS: Patient samples with two bands of the same isotype identified by IFE were enriched using nanobodies against IgG, IgA, IgM, or κ and λ light chains then analyzed by Mass-Fix. Light chain masses were used to differentiate IgGκ M-proteins from t-mAbs. Mass differences between peaks were calculated to identify N-glycosylation or matrix adducts. High-resolution mass spectrometry was used as a comparator method in a subset of samples. RESULTS: Eighty-one residual samples were collected. For IgA, 93% (n = 25) were identified as monoclonal. For IgG, 67% (n = 24) were monoclonal, and 33% (n = 12) were truly biclonal. Among the monoclonal IgGs, the second band represented a glycosylated form for 21% (n = 5), while 33% (n = 8) had masses consistent with a t-mAb. 44% (n = 8) of IgM samples were biclonal, and 56% (n = 10) were monoclonal, of which one was glycosylated. CONCLUSIONS: We demonstrate the utility of mass spectrometry in the characterization of multiple IFE bands of the same isotype. Improved reporting accuracy of M-proteins is useful for monitoring of patients with PCDs.
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Anticorpos Monoclonais/sangue , Imunoeletroforese/métodos , Proteínas do Mieloma/análise , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/química , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/química , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Proteínas do Mieloma/química , Multimerização Proteica , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Multiple myeloma (MM) is a heterogeneous disease that may be evaluated by a broad array of imaging and laboratory techniques to measure disease activity and predict prognosis. Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scanning has been shown to be predictive of patient outcomes throughout the disease course. We sought to corroborate these findings by examining the prognostic impact of PET/CT scanning in the posttransplant setting. We retrospectively analyzed PET/CT scans in 229 MM patients receiving an autologous stem cell transplant (ASCT) near day 100, and correlated these findings with time to progression(TTP) and overall survival (OS) to assess the impact of day 100 PET/CT scan findings as an independent prognostic factor. The median OS for the entire cohort was 61.5 months (95% confidence interval [CI], 49-75) and the median TTP was 18.5 months (95% CI, 15.4-21.8). Among patients with abnormal day 100 PET findings (PET+), median TTP was 12.4 months vs 24 months among those with normal PET findings (PET-) (P < .0001). The median OS in the PET+ group was 46 months compared with 99 months in the PET- group (P < .0001). We conclude that an abnormal PET/CT scan near day 100 post-ASCT is predictive of shorter TTP and OS, with prognostic significance retained after adjusting for disease response and other prognostic variables in MM.
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Fluordesoxiglucose F18 , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/diagnóstico por imagem , Mieloma Múltiplo/terapia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons , Prognóstico , Estudos RetrospectivosRESUMO
Immunoglobulin light chain (AL) amyloidosis is a clonal plasma cell disorder leading to progressive and life-threatening organ failure. The heart and the kidneys are the most commonly involved organs, but almost any organ can be involved. Because of the nonspecific presentation, diagnosis delay is common, and many patients are diagnosed with advanced organ failure. In the era of effective therapies and improved outcomes for patients with AL amyloidosis, the importance of early recognition is further enhanced as the ability to reverse organ dysfunction is limited in those with a profound organ failure. As AL amyloidosis is an uncommon disorder and given patients' frailty and high early death rate, management of this complex condition is challenging. The treatment of AL amyloidosis is based on various anti-plasma cell therapies. These therapies are borrowed and customized from the treatment of multiple myeloma, a more common disorder. However, a growing number of phase 2/3 studies dedicated to the AL amyloidosis population are being performed, making treatment decisions more evidence-based. Supportive care is an integral part of management of AL amyloidosis because of the inherent organ dysfunction, limiting the delivery of effective therapy. This extensive review brings an updated summary on the management of AL amyloidosis, sectioned into the 3 pillars for survival improvement: early disease recognition, anti-plasma cell therapy, and supportive care.
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Amiloidose de Cadeia Leve de Imunoglobulina/terapia , Mieloma Múltiplo/terapia , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/diagnóstico , Medição de RiscoRESUMO
BACKGROUND: Multiple myeloma (MM) is a heterogeneous clonal plasma cell disorder leading to differences in clinical outcomes such as overall survival (OS) among patients. We hypothesized that with expensive, novel therapeutic agents and paradigm shifts to maintain continuous therapy and improvement in OS, patients with MM are subject to the pressures of financial toxicity and the need for social support, which may be of prognostic importance. MATERIALS AND METHODS: In this study, we examined the records of 122,458 patients from the National Cancer Database (NCDB) to determine the significance of socioeconomic factors such as estimated annual household income and education level, which were based on the patient's ZIP Code and the United States Census Bureau's 5-year report from 2008 to 2012. These socioeconomic factors, in addition to marital status, were then assessed individually and as a cumulative socioeconomic score for prognostic significance in a cohort of 2543 patients treated at a tertiary care center utilizing known biologic risk factors, such as cytogenetic risk, International Staging System classification, and serum lactate dehydrogenase levels. RESULTS: Only marital status and estimated annual household income at diagnosis negatively impacted OS in a univariate analysis, but not in the context of a multivariable analysis incorporating known biologic risk factors. CONCLUSION: Future analyses in other academic and non-academic centers located in urban and rural regions are required to understand the socioeconomic drivers of OS disparity among patients with MM observed nationally.
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Estresse Financeiro/epidemiologia , Disparidades em Assistência à Saúde/estatística & dados numéricos , Renda/estatística & dados numéricos , Estado Civil/estatística & dados numéricos , Mieloma Múltiplo/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Características da Família , Feminino , Custos de Cuidados de Saúde/estatística & dados numéricos , Disparidades em Assistência à Saúde/economia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/economia , Mieloma Múltiplo/terapia , Prognóstico , Sistema de Registros/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Risco , Centros de Atenção Terciária/economia , Centros de Atenção Terciária/estatística & dados numéricos , Adulto JovemRESUMO
Immunoenrichment-based matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), termed MASS-FIX, offers several advantages over immunofixation for the detection and isotyping of serum monoclonal protein, including superior sensitivity and specificity, the ability to differentiate therapeutic monoclonal antibodies, and the rapid identification of light chain (LC) N-glycosylation. We identified 6315 patients with MASS-FIX performed at our institution since 2018. Of these, 4118 patients (65%) with a wide array of plasma cell disorders (PCD), including rare monoclonal gammopathies of clinical significance, had a positive MASS-FIX. Two-hundred twenty-one (5%) of the MASS-FIX positive patients had evidence of LC N-glycosylation, which was more commonly identified in IgM heavy chain isotype, kappa LC isotype, and in diagnoses of immunoglobulin light chain (AL) amyloidosis and cold agglutinin disease (CAD) compared to other PCD. This cross-sectional study describes the largest cohort of patients to undergo MASS-FIX in routine clinical practice. Our findings demonstrate the widespread utility of this assay, and confirm that LC N-glycosylation should prompt suspicion for AL amyloidosis and CAD in the appropriate clinical context.
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Paraproteinemias/sangue , Idoso , Estudos Transversais , Feminino , Glicosilação , Humanos , Cadeias Pesadas de Imunoglobulinas/sangue , Cadeias Leves de Imunoglobulina/análise , Cadeias Leves de Imunoglobulina/sangue , Imunoglobulina M/análise , Imunoglobulina M/sangue , Cadeias kappa de Imunoglobulina/análise , Cadeias kappa de Imunoglobulina/sangue , Masculino , Pessoa de Meia-Idade , Paraproteinemias/diagnóstico , Paraproteínas/análise , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodosRESUMO
OBJECTIVE: To evaluate the clinical outcomes of patients with primary plasma cell leukemia (pPCL) defined by 5% or greater clonal circulating plasma cells on peripheral blood smear and treated with novel agent induction therapies. PATIENTS AND METHODS: A cohort of 68 patients with pPCL diagnosed at the Mayo Clinic in Rochester, Minnesota, from January 1, 2000, to December 31, 2019, and treated with novel agent induction therapies was evaluated. RESULTS: The median follow-up was 46 (95% CI, 41 to 90) months. The median bone marrow plasma cell content was 85% (range, 10% to 100%) and median clonal circulaitng plasma cell percentage on the peripheral blood smear was 26% (range, 5% to 93%). There was a preponderance of t(11;14) primary cytogenetic abnormality in this cohort. The median time to next therapy (TTNT) and overall survival (OS) for all patients with pPCL patients in this cohort was 13 (95% CI, 9 to 17) and 23 (95% CI, 19 to 38) months, respectively. However, when stratified by cytogenetic risk, the median TTNT and OS were 16 and 51 months for standard risk vs 9 and 19 months for high risk (P=.01 for OS). CONCLUSION: Primary plasma cell leukemia remains an aggressive disease with poor prognosis despite novel agent-based therapies. Some patients have better than expected survival and this phenomenon may be influenced by the absence of high-risk cytogenetics. Newer treatment regimens are needed to improve the prognosis of this devastating disease.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Leucemia Plasmocitária/mortalidade , Leucemia Plasmocitária/terapia , Adulto , Estudos de Coortes , Feminino , Humanos , Leucemia Plasmocitária/diagnóstico , Leucemia Plasmocitária/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Minnesota , Prognóstico , Análise de Sobrevida , Transplante Autólogo , Resultado do TratamentoRESUMO
The utility of systemic light chain (AL) amyloidosis staging systems has been validated for newly diagnosed patients, but their role in restaging after treatment has not been explored. We designed this study to evaluate whether the currently used systems are of prognostic value at 3 and 6 months of starting first-line treatment, and whether stage migration from diagnosis impacts survival. This is a retrospective study including Mayo Clinic patients with AL amyloidosis diagnosed between 1 January 2006 and 30 June 2019; 536 and 204 patients had restaging data for at least 1 system at 3 and 6 months, respectively. Using modified Mayo 2004 staging at 3 months, median overall survival (OSs) were 11.8, 10.8, 4.6, and 1.1 years for stage I, II, IIIa, and IIIb, respectively. Using Mayo 2012, median OSs were 11.8, 9.0, 5.2, and 0.8 years for stage I, II, III, and IV, respectively. Using modified Mayo 2004 staging at 6 months, median OSs were not reached (NR), NR, 5.4, and 0.9 years for stage I, II, IIIa, and IIIb, respectively. Using Mayo 2012, OSs were NR, NR, 4.6, and 0.9 years for stage I, II, III, and IV, respectively. Worsening stage at 3 or 6 months was associated with worse survival than retaining baseline stage. In conclusion, the current staging systems can be used for restaging at 3 and 6 months from treatment initiation. Migration to higher stage predicts poor prognosis.
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Amiloidose de Cadeia Leve de Imunoglobulina , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/diagnóstico , Amiloidose de Cadeia Leve de Imunoglobulina/tratamento farmacológico , Prognóstico , Estudos RetrospectivosRESUMO
Unlike IgG monoclonal proteins (MCPs), IgA MCP quantification is unreliable due to beta-migration of IgA MCPs on serum protein electrophoresis (SPEP). The utility of nephelometric quantitative IgA (qIgA) to monitor IgA multiple myeloma (MM) is unclear. We retrospectively studied disease response kinetics using qIgA versus MCPs by SPEP, and developed and validated novel qIgA disease assessment criteria in 491 IgA MM patients. The SPEP MCP nadir occurred a median of 41 (IQR 0-102) days before the qIgA. The median time to achieve a partial response (PR) was shorter using standard IMWG versus qIgA response criteria (32 vs 58 days, p < 0.001). Stratification by qIgA criteria, unlike IMWG criteria, led to clear separation of the progression-free survival curves of patients achieving a PR or very good PR. There was a consistent trend toward earlier detection of disease progression using qIgA versus IMWG progression criteria. In conclusion, monitoring IgA MM using MCP-based IMWG criteria may be falsely reassuring, given that MCP levels on SPEP decrease faster than qIgA levels. The qIgA response criteria more accurately stratify patients based on the progression risk and may detect disease progression earlier, which may lead to more consistent measurement of trial endpoints and improved patient outcomes.
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Imunoglobulina A/sangue , Mieloma Múltiplo/sangue , Idoso , Progressão da Doença , Feminino , Humanos , Imunoglobulina A/metabolismo , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica/métodos , Mieloma Múltiplo/metabolismo , Proteínas do Mieloma/metabolismo , Intervalo Livre de Progressão , Estudos RetrospectivosRESUMO
Three sets of criteria (International Society of Amyloidosis [ISA], Palladini and Kastritis) were independently developed for staging, progression and response criteria to predict renal survival in patients with AL amyloidosis. We evaluated these criteria using a cohort of 495 newly diagnosed AL amyloidosis patients with renal involvement using time to event competing risk analysis at baseline, 3, 6 and 12 months after treatment. Only Palladini and Kastritis had a staging system and both predicted a higher risk of end stage renal disease (ESRD) in the stage III vs stage I patients but only the Palladini model was predictive for stage II patients. At 3 months, risk of ESRD was significantly higher for Palladini and ISA renal progression (hazard ratio [HR] 2.8 [95% CI: 1.5-5.3, p = .001] and 2.5 [CI: 1.4-4.6, p = .004, respectively]), but renal response was not significantly protective; conversely, the risk of ESRD was not significantly higher for the Kastritis renal progression, but was significantly protective for the Kastritis renal responders (HR 0.38 [95% CI: 0.17-0.84], p = .017). Both progression and response with ISA, Palladini and Kastritis criteria were predictive of ESRD at 6 months and 12 months. While the Palladini staging criteria at baseline, and the ISA and Palladini criteria for progression at 3 months performed better than the Kastritis criteria at baseline and 3 months post-treatment, the Kastritis criteria performed better for response 3 months after treatment. All three sets of criteria performed well at and after 6 months post-treatment. These differences are important when choosing endpoints for clinical trials.
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Amiloidose de Cadeia Leve de Imunoglobulina/complicações , Falência Renal Crônica/etiologia , Índice de Gravidade de Doença , Idoso , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/sangue , Amiloidose de Cadeia Leve de Imunoglobulina/terapia , Rim/fisiopatologia , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/fisiopatologia , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos , PrognósticoRESUMO
INTRODUCTION: Little is known on continued response following completion of therapy in light chain (AL) amyloidosis. METHODS: We studied 373 AL amyloidosis patients who achieved complete response (CR) or very good partial response (VGPR) to first-line therapy. RESULTS: By end of therapy (EOT), 46% of patients achieved a CR and 54% a VGPR. With no further therapy, 17.5% of patients were upstaged from VGPR to CR (delayed CR), with a median of 9 months. Compared with CR and VGPR at EOT, patients with a delayed CR were characterized by higher proportion of t(11;14) and lower rate of trisomies. Autologous stem cell transplant was more frequent in the delayed CR group. Patients with a delayed CR were characterized by minimal residual disease negativity and organ response rates similar to patients with CR at EOT and higher than patients achieving VGPR at EOT. Patients with a delayed CR had a longer PFS/OS compared to patients with CR or VGPR by EOT (median PFS 149 vs 92 vs 52 months, P < .001; 10-year OS 87% vs 71% vs 56%, P < .001). CONCLUSIONS: This study characterizes delayed CR in AL amyloidosis, highlights its prognostic impact which is at least similar to those who achieved CR at EOT, and underlines another aspect of response monitoring.
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Amiloidose de Cadeia Leve de Imunoglobulina/epidemiologia , Terapia Combinada , Gerenciamento Clínico , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/mortalidade , Amiloidose de Cadeia Leve de Imunoglobulina/terapia , Avaliação de Resultados em Cuidados de Saúde , Prognóstico , Fatores de Tempo , Resultado do TratamentoRESUMO
A 24-h urine protein collection (24hUP), the gold standard for measuring albuminuria in systemic AL amyloidosis, is cumbersome and inaccurate. We retrospectively reviewed 575 patients with systemic AL amyloidosis to assess the correlation between a urine albumin to creatinine ratio (uACR) and the 24hUP. The uACR correlated strongly with 24hUP at diagnosis (Pearson's r = 0.87, 95% CI 0.83-0.90) and during the disease course (Pearson's r = 0.88, 95% CI 0.86-0.90). A uACR ≥300 mg/g estimated a 24hUP ≥ 500 mg with a sensitivity of 92% and specificity of 97% (area under the receiver operating curve = 0.938, 95% CI 0.919-0.957). A uACR cutoff of 3600 mg/g best predicted a 24hUP > 5000 g (sensitivity 93%, specificity 94%), and renal stage at diagnosis was strongly concordant using either 24hUP or uACR as the proteinuria measure (k = 0.823, 95% CI 0.728-0.919). In patients with serial urine collections, a > 30% decrease in uACR predicted a > 30% decrease in 24hUP with a sensitivity of 94%. In conclusion, the uACR is a reliable and convenient method for ruling out proteinuria >500 mg per day, prognosticating renal outcomes, and assessing renal response to therapy. Further studies are needed to validate the uACR cutoffs proposed in this study.
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Albuminúria/urina , Amiloidose de Cadeia Leve de Imunoglobulina/urina , Idoso , Albuminúria/terapia , Feminino , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/terapia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Gastrointestinal complications of multiple myeloma (MM) treatment are common and include nausea, constipation, and diarrhea. However, acute gastrointestinal events like perforations are rare. We aimed to describe the characteristics and outcomes of patients with MM that had colonic perforations during their treatment. This is a retrospective study that included patients from all three Mayo Clinic sites who had MM and developed a colonic perforation. All patients were diagnosed with colonic perforations based on CT scans and were surgically treated. Patients diagnosed with AL amyloidosis, a perforated colon complicating neutropenic colitis during ASCT and those with perforation due to colonic cancer were excluded. A high dose of dexamethasone was defined as ≥40 mg dexamethasone once a week. Thirty patients met inclusion criteria. All patients received steroids at doses ≥10 mg once weekly prior to the perforation, while four (11%) were on high-dose dexamethasone without chemotherapy. Fourteen patients were given high doses of dexamethasone. Twenty-five patients required ostomies with all surviving surgery. Twenty-four perforations (80%) were associated with diverticulitis. Treatment with steroids was resumed in 23 patients with no further gastrointestinal complications. The median OS was 20 months following perforation (IQR 8-59). Within the same timeframe 5854 patients were treated at Mayo Clinic for MM, making the risk of bowel perforation 0.5%. Intestinal perforations in MM are rare and, in our series, always occurred with dexamethasone ≥10 mg per week. Urgent surgery is lifesaving and resumption of anti-myeloma treatment appears to be safe.
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Doenças do Colo/induzido quimicamente , Dexametasona/efeitos adversos , Perfuração Intestinal/induzido quimicamente , Mieloma Múltiplo/tratamento farmacológico , Esteroides/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças do Colo/diagnóstico por imagem , Doenças do Colo/cirurgia , Colostomia , Dexametasona/administração & dosagem , Doença Diverticular do Colo/complicações , Feminino , Humanos , Perfuração Intestinal/diagnóstico por imagem , Perfuração Intestinal/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Esteroides/administração & dosagem , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Estados UnidosRESUMO
PURPOSE: Rearrangements involving the MYC protooncogene are common in newly diagnosed multiple myeloma, but their prognostic significance is still unclear. The purpose of this study was to assess the impact of MYC rearrangement on clinical characteristics, treatment response, and survival in patients with newly diagnosed multiple myeloma. EXPERIMENTAL DESIGN: This is a retrospective study including 1,342 patients seen in Mayo Clinic in Rochester, MN, from January 2006 to January 2018, who had cytogenetic testing by FISH at diagnosis, including MYC testing using the break apart FISH probe (8q24.1). RESULTS: A rearrangement involving MYC was found in 8% of patients and was associated with elevated ß2-microglobulin, ≥50% bone marrow plasma cells, IgA multiple myeloma, and the cooccurrence of trisomies. There were no differences in overall response rates between patients with and without MYC rearrangement when induction chemotherapy was proteasome inhibitor (PI)-based, immunomodulatory drug (IMiD)-based or PI + IMiD-based. Overall survival was shorter in patients with MYC rearrangement compared with patients without MYC rearrangement (5.3 vs. 8.0 years, P < 0.001). MYC rearrangement was associated with increased risk of death on multivariate analysis when high-risk cytogenetic abnormalities, ISS stage III, and ≥70 years of age were included (risk ratio: 1.5; P = 0.007). CONCLUSIONS: MYC rearrangement is associated with high disease burden and is an independent adverse prognostic factor in patients with newly diagnosed multiple myeloma.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Aberrações Cromossômicas , Rearranjo Gênico , Mieloma Múltiplo/mortalidade , Proteínas Proto-Oncogênicas c-myc/genética , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
A gain in chromosome 1q (+1q) is among the most common cytogenetic abnormalities in multiple myeloma (MM). It is unclear whether +1q is independently associated with decreased overall survival (OS). The objective of this study was to evaluate the impact of +1q on clinical characteristics, treatment response, and survival outcomes. We included 1376 Mayo Clinic patients diagnosed with MM from 2005 to 2018 who underwent fluorescence in situ hybridization testing at diagnosis with a panel including the +1q probe. A gain in 1q was found in 391 patients (28%) and was associated with anemia, hypercalcemia, high tumor burden, International Staging System (ISS) stage 3, high-risk (HR) translocations, and chromosome 13 abnormalities. There was no difference in overall response or deeper responses to proteasome inhibitor (PI)-, immunomodulatory drug (iMiD)-, or PI plus IMiD-based induction. Time to next treatment was shorter in patients with +1q compared with those without +1q (19.9 vs 27.7 months; P < .001). On univariate analysis, +1q was associated with increased risk of death (risk ratio [RR], 1.9; P < .001), and decreased OS was seen in all treatment groups. +1q was independently associated with decreased OS on multivariate analysis when other HR cytogenetic abnormalities, ISS stage 3, and age ≥70 years were included (RR, 1.5; P < .001). Gain of >1 copy of 1q was not associated with worse OS compared with gain of 1 copy (4.9 vs 4.3 years; P = .21). +1q was associated with high tumor burden, advanced disease stage, and HR translocations. It is independently associated with decreased OS, even in the setting of novel therapy and transplant.
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Mieloma Múltiplo , Idoso , Aberrações Cromossômicas , Cromossomos , Humanos , Hibridização in Situ Fluorescente , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Prognóstico , Resultado do TratamentoRESUMO
Autologous stem cell transplantation (ASCT) is an important treatment modality in multiple myeloma (MM). However, relapse following ASCT is considered almost inevitable. This study aimed to characterize exceptional responders to ASCT, defined as progression-free survival (PFS) >8 years in the absence of maintenance therapy. We retrospectively analyzed patients treated at Mayo Clinic between August 1, 1998 and January 3, 2006, and included those with symptomatic MM, treated with an ASCT within 12 months of diagnosis. We found that 46 (9%) of the 509 patients who underwent ASCT during the study period were exceptional responders. The median duration of follow-up from diagnosis was 16.2 (interquartile range 14.3-17.7) years. The best response to therapy was a complete response (CR) or better in 34 (74%) of patients, and less than a CR in 12 (26%) of patients. The median PFS was 13.8 (95% confidence interval 10.5-18.5) years, and at the time of the last hematology assessment, 24 of 46 (52%) patients remained in remission. In conclusion, we showed that a small subset of patients with MM attains durable disease control without maintenance therapy post ASCT. Pre-emptive identification of these patients may help prevent undue toxicities and costs of subsequent therapy.
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Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/terapia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/epidemiologia , Intervalo Livre de Progressão , Estudos Retrospectivos , Transplante Autólogo , Resultado do TratamentoRESUMO
Cytogenetic abnormalities are found in most multiple myeloma (MM) patients. Although their prognostic value has been well studied, there are limited data on the association of primary cytogenetic abnormalities with disease characteristics and treatment response. This study was designed to evaluate these associations. This is a retrospective study including 2027 Mayo Clinic patients diagnosed with MM between February 2004 and February 2018 who had cytogenetic testing by FISH at diagnosis. Translocations t(4;14), t(14;16), t(6;14), and t(14;20) were associated with anemia, beta2microglobulin >5.5 µg/ml and ≥50% bone marrow plasma cells; t(4;14) was associated with higher serum monoclonal protein and plasma cell proliferation. Overall response rate to proteasome inhibitor (PI)-based treatment was higher for IgH translocations compared to trisomies (83% vs. 71%, P = 0.002), but was higher for trisomies with immunomodulatory drug (IMiD)-based treatment (87% vs. 75%, P < 0.001). Time to next treatment was longer with trisomies than IgH translocation with IMiD-based (32.1 vs. 18.4 months, P < 0.001) and PI + IMiD-based (44.0 vs. 27.4 months, P = 0.003) treatments. Outcomes were superior with PI + IMiD combinations in all groups. Our results show that t(4;14), t(14;16), t(6;14), and t(14;20) are associated with high-risk disease characteristics, and IgH translocations and trisomies may be associated with better responses to PIs and IMiDs, respectively.
Assuntos
Fatores Imunológicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Inibidores de Proteassoma/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aberrações Cromossômicas/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Prognóstico , Estudos Retrospectivos , Translocação Genética/efeitos dos fármacos , Resultado do Tratamento , Trissomia/genéticaRESUMO
Response assessment in light chain (AL) amyloidosis is based on serum and urine monoclonal protein studies. Newly diagnosed patients (n = 373) who achieved very good partial response or complete response (CR) to first line therapy were assessed for the survival impact of each of the monoclonal protein studies. At end of therapy (EOT), negative serum/urine immunofixation (IFE) was achieved in 61% of patients, 72% achieved normal serum free light chain ratio (sFLCR), and the median involved free light chain (iFLC) and difference between involved to uninvolved light chain (dFLC) were 17 mg/L and 5 mg/L, respectively. Overall, 46% of patients achieved a CR at EOT. At EOT, iFLC ≤20 mg/L and dFLC ≤10 mg/L were additive in survival discrimination to negative serum/urine IFE and were independent predictors of overall survival. In contrast, normalization of sFLCR did not add survival discrimination to serum/urine IFE and was not independent predictor of survival. We propose a new definition for hematological CR to include serum/urine IFE negativity plus iFLC ≤20 mg/L or dFLC ≤10 mg/L, instead of the current definition of serum/urine IFE negativity and normal sFLCR. Complete response using dFLC ≤10 mg/L had the best performance in those with significant renal dysfunction and by light chain isotype, making it the preferred partner to IFE. Validation of these results in a multicenter cohort is warranted.