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3.
Blood Rev ; : 100646, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31810754

RESUMO

The question of how myeloma cells cause destruction of skeletal tissue has interested scientists for many years, and knowledge in this field has developed in parallel with the understanding of physiological bone remodeling. The identification of bioactive proteins of the cytokine class during the last decades of the previous century and mapping of their role in the regulation of anabolic and catabolic processes in bone, led to a sequence of hypotheses about how the same peptides also could be involved in myeloma-driven bone destruction. Although bone remodeling is now understood in detail, there is still no clear unified theory of how myeloma cells degrade bone. The reason for this could be that there is no single mechanism that is active in every patient. The common trait is possibly that myeloma cells benefit from bone destruction per se, and the strategy they use to accomplish this vary between patients.

4.
Am J Hematol ; 94(12): 1364-1373, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31571261

RESUMO

Minimal residual disease (MRD) tracking, by next generation sequencing of immunoglobulin sequences, is moving towards clinical implementation in multiple myeloma. However, there is only sparse information available to address whether clonal sequences remain stable for tracking over time, and to what extent light chain sequences are sufficiently unique for tracking. Here, we analyzed immunoglobulin repertoires from 905 plasma cell myeloma and healthy control samples, focusing on the third complementarity determining region (CDR3). Clonal heavy and/or light chain expression was identified in all patients at baseline, with one or more subclones related to the main clone in 3.2%. In 45 patients with 101 sequential samples, the dominant clonal CDR3 sequences remained identical over time, despite differential clonal evolution by whole exome sequencing in 49% of patients. The low frequency of subclonal CDR3 variants, and absence of evolution over time in active multiple myeloma, indicates that tumor cells at this stage are not under selective pressure to undergo antibody affinity maturation. Next, we establish somatic hypermutation and non-templated insertions as the most important determinants of light chain clonal uniqueness, identifying a potentially trackable sequence in the majority of patients. Taken together, we show that dominant clonal sequences identified at baseline are reliable biomarkers for long-term tracking of the malignant clone, including both IGH and the majority of light chain clones.

5.
Haematologica ; 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31515355

RESUMO

Data on the impact of long term treatment with IMiDs on health-related quality of life is limited. The HOVON-87/NMSG18 study was a randomized, phase 3 study in newly diagnosed transplant ineligible patients with multiple myeloma, comparing melphalan-prednisolone in combination with thalidomide or lenalidomide, followed by maintenance therapy until progression (MPT-T or MPR-R). The EORTC QLQ-C30 and MY20 questionnaires were completed at baseline, after 3 and 9 induction cycles and 6 and 12 months of maintenance therapy. Linear mixed models and minimal important differences were used for evaluation. 596 patients participated in health-related quality of life reporting. Patients reported clinically relevant improvement in global quality of life, future perspective and role and emotional functioning, and less fatigue and pain in both arms. The latter being of large effect size. In general, improvement occurred after 6 to 12 months of maintenance only and was independent of WHO performance at baseline. Patients treated with MPR-R reported clinically relevant worsening of diarrhea, and patients treated with MPT-T reported a higher incidence of neuropathy. Patients who remained on lenalidomide maintenance therapy for at least 3 months reported clinically meaningful improvement in global QoL and role functioning at 6 months, remaining stable thereafter. There were no clinically meaningful deteriorations, but patients on thalidomide reported clinically relevant worsening in neuropathy. In general, health-related quality of life improves both during induction and maintenance therapy with IMiDs. Side effect profile of treatment did not negatively affect global quality of life, but it was, however, clinically relevant for the patients. (Clinicaltrials.gov identifier: NTR1630).

6.
Leuk Lymphoma ; 60(1): 118-123, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29965787

RESUMO

This multicenter retrospective study included 101 patients (median age 62 years) with secondary plasma cell leukemia (sPCL). The median time from initial multiple myeloma diagnosis to sPCL was 31 months. Fifty-five out of 72 patients (75%) who received any therapy were treated with immunomodulators (IMiDs) and/or proteasome inhibitors (PIs), and 14/72 (19%) underwent salvage autologous stem cell transplantation (ASCT). The overall response rate in patients who received ASCT or PI (either alone or in combination) was higher than in those who did not (93% vs. 36% and 60% vs. 30%, respectively). The median overall survival (OS) in patients who received therapy was 4.2 months (95% CI: 1.3; 8.0) with a 1-year OS of 19%. Platelet count ≤100 × 109/L at sPCL diagnosis was the only independent predictor of a poorer OS in treated patients (HR = 3.98, p = .0001). These findings suggest that patients with sPCL may benefit from salvage ASCT- and PI-based regimens.


Assuntos
Leucemia Plasmocitária/terapia , Mieloma Múltiplo/complicações , Terapia de Salvação/métodos , Transplante de Células-Tronco , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Fatores Imunológicos/uso terapêutico , Leucemia Plasmocitária/etiologia , Leucemia Plasmocitária/mortalidade , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Inibidores de Proteassoma/uso terapêutico , Estudos Retrospectivos , Análise de Sobrevida , Transplante Autólogo , Resultado do Tratamento
7.
Oncotarget ; 9(89): 36048, 2018 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-30542518

RESUMO

[This corrects the article DOI: 10.18632/oncotarget.4245.].

8.
Oncotarget ; 9(62): 32024-32035, 2018 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-30174794

RESUMO

Characterization of CD8+ T cells in the tumor microenvironment (TME) is important to predict responses to checkpoint therapy. The TME in multiple myeloma is the bone marrow, which also is an immune organ where immune responses are generated and memory cells stored. The presence of T cells with other specificities than the tumor in the bone marrow may affect the search for biomarkers to predict responses to immunotherapy in myeloma. Here, we found similar proportions of PD1+ CD8+ T cells and similar levels of PD1 expression on CD8+ T cells in the bone marrow of myeloma patients and healthy controls. PD1 expression on CD8+ T cells did not correlate with tumor load suggesting that at least some of the PD1+ CD8+ T cells were specific for non-myeloma antigens. Indeed, PD1+ EBV-specific CD8+ T cells were detected it the bone marrow of patients. Terminal effectors (Teff), effector memory (Tem) and central memory (Tcm) cells as well as exhausted T cells were all found in the myeloma bone marrow. However, myeloma patients had more terminal effectors and fewer memory cells than healthy controls suggesting that the tumor generate an immune response against myeloma cells in the bone marrow. The presence of CD8 EOMEShigh Tbetlow T cells with intermediate levels of PD1 in myeloma patients suggests that T cell types, that are known to be responsive to checkpoint therapy, are found at the tumor site.

10.
Biomark Res ; 6: 21, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29946468

RESUMO

Chemerin is a recently discovered adipokine shown to be involved in both inflammatory and metabolic processes. Here, we demonstrate that chemerin serum levels are elevated in patients with multiple myeloma and that it increases with disease progression. We found that chemerin is expressed by stromal cells and preadipocytes, whereas its receptor CCRL2 is expressed by primary myeloma cells, suggesting a paracrine signaling loop between bone marrow stromal cells/adipocytes and myeloma cells. This is the first study exploring chemerin and its receptors in multiple myeloma.

11.
Leukemia ; 32(7): 1542-1560, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29720735

RESUMO

During the last few years, several new drugs have been introduced for treatment of patients with multiple myeloma, which have significantly improved the treatment outcome. All of these novel substances differ at least in part in their mode of action from similar drugs of the same drug class, or are representatives of new drug classes, and as such present with very specific side effect profiles. In this review, we summarize these adverse events, provide information on their prevention, and give practical guidance for monitoring of patients and for management of adverse events.


Assuntos
Antineoplásicos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Mieloma Múltiplo/complicações , Antineoplásicos/uso terapêutico , Gerenciamento Clínico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/terapia , Humanos , Incidência , Terapia de Alvo Molecular/efeitos adversos , Mieloma Múltiplo/tratamento farmacológico , Guias de Prática Clínica como Assunto , Medição de Risco
12.
Nat Commun ; 9(1): 1649, 2018 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-29695719

RESUMO

Recently, we identified ELL2 as a susceptibility gene for multiple myeloma (MM). To understand its mechanism of action, we performed expression quantitative trait locus analysis in CD138+ plasma cells from 1630 MM patients from four populations. We show that the MM risk allele lowers ELL2 expression in these cells (Pcombined = 2.5 × 10-27; ßcombined = -0.24 SD), but not in peripheral blood or other tissues. Consistent with this, several variants representing the MM risk allele map to regulatory genomic regions, and three yield reduced transcriptional activity in plasmocytoma cell lines. One of these (rs3777189-C) co-locates with the best-supported lead variants for ELL2 expression and MM risk, and reduces binding of MAFF/G/K family transcription factors. Moreover, further analysis reveals that the MM risk allele associates with upregulation of gene sets related to ribosome biogenesis, and knockout/knockdown and rescue experiments in plasmocytoma cell lines support a cause-effect relationship. Our results provide mechanistic insight into MM predisposition.


Assuntos
Alelos , Cromossomos Humanos Par 5/genética , Regulação Neoplásica da Expressão Gênica , Mieloma Múltiplo/genética , Proteínas Ribossômicas/genética , Fatores de Elongação da Transcrição/genética , Medula Óssea/patologia , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Regulação para Baixo , Perfilação da Expressão Gênica , Técnicas de Inativação de Genes , Predisposição Genética para Doença , Humanos , Mieloma Múltiplo/patologia , Plasmócitos/metabolismo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Proteínas Ribossômicas/metabolismo , Ribossomos/genética , Ribossomos/metabolismo , Fatores de Elongação da Transcrição/metabolismo , Regulação para Cima
13.
Cancer Med ; 7(6): 2256-2268, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29673108

RESUMO

Lenalidomide (Len) plus dexamethasone (Dex) is approved for the treatment of relapsed or refractory multiple myeloma (RRMM). It is possible that single-agent Len may be effective as prolonged treatment regimen in RRMM once patients demonstrate an initial response to Len+Dex induction. Patients with RRMM who responded to first-line Len+Dex in an observational study (NCT01430546) received up to 24 cycles of either Len (25 mg/day) or Len+Dex (25 mg/day and 40 mg/week) as prolonged treatment in a subsequent phase 2 clinical trial (NCT01450215). In the observational study (N = 133), median time to response was 1.7 (range 0.6-9.6) months. A complete response to all treatments received in both studies was observed in 11% of patients; very good partial response and partial response rates were 31% and 38%, respectively. Corresponding response rates in the subgroup of patients who did not enter the phase 2 trial (n = 71) were 3%, 18%, and 39%, respectively. Rates of disease progression at 2 years in the phase 2 trial were 47% versus 31% for Len versus Len+Dex (P = 0.14). After 36 months median follow-up in surviving patients, median time to progression was not reached with Len+Dex and was 24.9 months (95% confidence interval 12.5-not calculable, P < 0.001) with Len. Three-year OS among the total observational study population was 61% (95% CI, 52-69%). The corresponding rate among patients who entered the phase 2 clinical trial was 73% (95% CI, 60-83%) and was significantly lower among those patients who achieved ≥PR but did not proceed into the phase 2 trial (55%; P = 0.01). In the phase 2 trial, OS was 73% in both treatment arms (P = 0.70). Neutropenia and thrombocytopenia were more common with prolonged (phase 2 trial) versus short-term (observational study) Len administration but remained manageable. Prolonged treatment with Len with or without Dex provides sustained, clinically relevant responses and demonstrates an acceptable safety profile.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Dexametasona/uso terapêutico , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/farmacologia , Anti-Inflamatórios/farmacologia , Dexametasona/farmacologia , Feminino , Humanos , Lenalidomida/farmacologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia
14.
N Engl J Med ; 378(10): 924-930, 2018 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-29514032

RESUMO

Familial erythrocytosis with elevated erythropoietin levels is frequently caused by mutations in genes that regulate oxygen-dependent transcription of the gene encoding erythropoietin ( EPO). We identified a mutation in EPO that cosegregated with disease with a logarithm of the odds (LOD) score of 3.3 in a family with autosomal dominant erythrocytosis. This mutation, a single-nucleotide deletion (c.32delG), introduces a frameshift in exon 2 that interrupts translation of the main EPO messenger RNA (mRNA) transcript but initiates excess production of erythropoietin from what is normally a noncoding EPO mRNA transcribed from an alternative promoter located in intron 1. (Funded by the Gebert Rüf Foundation and others.).


Assuntos
Eritropoetina/genética , Mutação da Fase de Leitura , Mutação com Ganho de Função , Policitemia/congênito , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Eritropoetina/biossíntese , Feminino , Deleção de Genes , Genes Dominantes , Ligação Genética , Humanos , Masculino , Repetições de Microssatélites , Linhagem , Policitemia/genética , Biossíntese de Proteínas , RNA Mensageiro/metabolismo
15.
Br J Haematol ; 180(6): 831-839, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29315478

RESUMO

We report a multicentre retrospective study that analysed clinical characteristics and outcomes in 117 patients with primary plasma cell leukaemia (pPCL) treated at the participating institutions between January 2006 and December 2016. The median age at the time of pPCL diagnosis was 61 years. Ninety-eight patients were treated with novel agents, with an overall response rate of 78%. Fifty-five patients (64%) patients underwent upfront autologous stem cell transplantation (ASCT). The median follow-up time was 50 months (95% confidence interval [CI] 33; 76), with a median overall survival (OS) for the entire group of 23 months (95% CI 15; 34). The median OS time in patients who underwent upfront ASCT was 35 months (95% CI 24·3; 46) as compared to 13 months (95% CI 6·3; 35·8) in patients who did not receive ASCT (P = 0·001). Multivariate analyses identified age ≥60 years, platelet count ≤100 × 109 /l and peripheral blood plasma cell count ≥20 × 109 /l as independent predictors of worse survival. The median OS in patients with 0, 1 or 2-3 of these risk factors was 46, 27 and 12 months, respectively (P < 0·001). Our findings support the use of novel agents and ASCT as frontline treatment in patients with pPCL. The constructed prognostic score should be independently validated.


Assuntos
Leucemia Plasmocitária/mortalidade , Leucemia Plasmocitária/terapia , Transplante de Células-Tronco , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoenxertos , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Plasmocitária/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida
16.
Haematologica ; 102(7): 1266-1272, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28385781

RESUMO

Circulating tumor DNA is a promising biomarker to monitor tumor load and genome alterations. We explored the presence of circulating tumor DNA in multiple myeloma patients and its relation to disease activity during long-term follow-up. We used digital droplet polymerase chain reaction analysis to monitor recurrent mutations, mainly in mitogen activated protein kinase pathway genes NRAS, KRAS and BRAF Mutations were identified by next-generation sequencing or polymerase chain reaction analysis of bone marrow plasma cells, and their presence analyzed in 251 archived serum samples obtained from 20 patients during a period of up to 7 years. In 17 of 18 patients, mutations identified in bone marrow during active disease were also found in a time-matched serum sample. The concentration of mutated alleles in serum correlated with the fraction in bone marrow plasma cells (r=0.507, n=34, P<0.002). There was a striking covariation between circulating mutation levels and M protein in ten out of 11 patients with sequential samples. When relapse evaluation by circulating tumor DNA and M protein could be directly compared, the circulating tumor DNA showed relapse earlier in two patients (3 and 9 months), later in one patient (4 months) and in three patients there was no difference. In three patients with transformation to aggressive disease, the concentrations of mutations in serum increased up to 400 times, an increase that was not seen for the M protein. In conclusion, circulating tumor DNA in myeloma is a multi-faceted biomarker reflecting mutated cells, total tumor mass and transformation to a more aggressive disease. Its properties are both similar and complementary to M protein.


Assuntos
Biomarcadores Tumorais , Ácidos Nucleicos Livres , DNA de Neoplasias , Mieloma Múltiplo/genética , Mutação , Idoso , Biomarcadores , Análise Mutacional de DNA , Progressão da Doença , Feminino , Humanos , Biópsia Líquida , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Proteínas do Mieloma , Estadiamento de Neoplasias , Estudos Retrospectivos , Sequenciamento Completo do Exoma
17.
Oncotarget ; 8(12): 19427-19442, 2017 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-28038447

RESUMO

Plasma cell leukemia is a rare and aggressive plasma cell neoplasm that may either originate de novo (primary PCL) or by leukemic transformation of multiple myeloma (MM) to secondary PCL (sPCL). The prognosis of sPCL is very poor, and currently no standard treatment is available due to lack of prospective clinical studies. In an attempt to elucidate factors contributing to transformation, we have performed super-SILAC quantitative proteome profiling of malignant plasma cells collected from the same patient at both the MM and sPCL stages of the disease. 795 proteins were found to be differentially expressed in the MM and sPCL samples. Gene ontology analysis indicated a metabolic shift towards aerobic glycolysis in sPCL as well as marked down-regulation of enzymes involved in glycan synthesis, potentially mediating altered glycosylation of surface receptors. There was no significant change in overall genomic 5-methylcytosine or 5-hydroxymethylcytosine at the two stages, indicating that epigenetic dysregulation was not a major driver of transformation to sPCL. The present study constitutes the first attempt to provide a comprehensive map of the altered protein expression profile accompanying transformation of MM to sPCL in a single patient, identifying several candidate proteins that can be targeted by currently available small molecule drugs. Our dataset furthermore constitutes a reference dataset for further proteomic analysis of sPCL transformation.


Assuntos
Biomarcadores Tumorais/metabolismo , Transformação Celular Neoplásica/patologia , Regulação Leucêmica da Expressão Gênica , Leucemia Plasmocitária/patologia , Mieloma Múltiplo/patologia , Proteoma/análise , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Metilação de DNA , Perfilação da Expressão Gênica , Humanos , Leucemia Plasmocitária/genética , Leucemia Plasmocitária/metabolismo , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Proteômica/métodos , Células Tumorais Cultivadas
18.
Blood Adv ; 1(10): 619-623, 2017 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-29296704

RESUMO

Although common risk alleles for multiple myeloma (MM) were recently identified, their contribution to familial MM is unknown. Analyzing 38 familial cases identified primarily by linking Swedish nationwide registries, we demonstrate an enrichment of common MM risk alleles in familial compared with 1530 sporadic cases (P = 4.8 × 10-2 and 6.0 × 10-2, respectively, for 2 different polygenic risk scores) and 10 171 population-based controls (P = 1.5 × 10-4 and 1.3 × 10-4, respectively). Using mixture modeling, we estimate that about one-third of familial cases result from such enrichments. Our results provide the first direct evidence for a polygenic etiology in a familial hematologic malignancy.

19.
Blood Adv ; 1(27): 2656-2666, 2017 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-29296919

RESUMO

Multiple myeloma (MM) is a hematologic cancer characterized by expansion of malignant plasma cells in the bone marrow. Most patients develop an osteolytic bone disease, largely caused by increased osteoclastogenesis. The myeloma bone marrow is hypoxic, and hypoxia may contribute to MM disease progression, including bone loss. Here we identified interleukin-32 (IL-32) as a novel inflammatory cytokine expressed by a subset of primary MM cells and MM cell lines. We found that high IL-32 gene expression in plasma cells correlated with inferior survival in MM and that IL-32 gene expression was higher in patients with bone disease compared with those without. IL-32 was secreted from MM cells in extracellular vesicles (EVs), and those EVs, as well as recombinant human IL-32, promoted osteoclast differentiation both in vitro and in vivo. The osteoclast-promoting activity of the EVs was IL-32 dependent. Hypoxia increased plasma-cell IL-32 messenger RNA and protein levels in a hypoxia-inducible factor 1α-dependent manner, and high expression of IL-32 was associated with a hypoxic signature in patient samples, suggesting that hypoxia may promote expression of IL-32 in MM cells. Taken together, our results indicate that targeting IL-32 might be beneficial in the treatment of MM bone disease in a subset of patients.

20.
Tidsskr Nor Laegeforen ; 136(17): 1452-7, 2016 09.
Artigo em Inglês, Norueguês | MEDLINE | ID: mdl-27686205

RESUMO

BACKGROUND: Congenital thrombotic thrombocytopenic purpura (TTP) is a rare, hereditary disorder. Clinically it presents as episodic microangiopathic haemolytic anaemia and thrombocytopenia with varying degrees of damage to internal organs. The condition may present in neonates, but can also present for the first time in adulthood. The prevalence of congenital TTP is particularly high in Norway, and it is therefore important for Norwegian doctors to be aware of the condition. In this article we review the main characteristics of the disease, including its diagnosis and management, and introduce potential new treatments for the future. METHOD: The article is based on a literature search in PubMed as well as the authors' own research and clinical experience. RESULTS: There was great variation in the severity of congenital TTP: from neonatal mortality to disease-free intervals of several years. Episodes are generally precipitated by a trigger. Acute episodes are treated with plasma infusions, and approximately half of all patients experience frequent episodes and require prophylactic infusions to avoid organ damage. The risk of episodes is greatest in neonates, during pregnancy and in association with infections. INTERPRETATION: There is little research-based evidence regarding long-term prognosis in congenital TTP. There is also a need for guidelines to help identify candidates for prophylactic treatment. An international patient registry would provide useful information and form the basis for better guidelines on the monitoring and treatment of these patients.


Assuntos
Púrpura Trombocitopênica Trombótica , Proteína ADAMTS13/genética , Algoritmos , Transfusão de Sangue , Humanos , Noruega/epidemiologia , Púrpura Trombocitopênica Trombótica/congênito , Púrpura Trombocitopênica Trombótica/diagnóstico , Púrpura Trombocitopênica Trombótica/epidemiologia , Púrpura Trombocitopênica Trombótica/terapia
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