BACKGROUND: Primary plasma cell leukemia (PPCL) is the most aggressive disorder among plasma cell malignancies, with new diagnostic criteria recently established by the International Myeloma Working Group. Studies have shown that PPCL patients receiving a combination of novel agents, but not eligible for transplantation, may have a median survival up to 2 years, extended to 3 years or more in those undergoing transplant procedures. These findings remain unsatisfactory, particularly if compared with progresses obtained in multiple myeloma. DESIGN: A European Myeloma Network (EMN) expert panel reviewed the most recent literature and selected the areas of major concern in the management of PPCL by generating and rank ordering key questions using the criterion of clinical relevance. Multistep procedures were utilized to achieve a consensus on recommendations. The Delphi questionnaire method was used and a consensus of at least 80% was reached for all final statements. RESULTS: An extended overview of current biological, clinical, prognostic, and therapeutic aspects of PPCL, including ongoing and close to start clinical trials, is presented. Furthermore, updated guidelines for the management of PPCL and practical recommendations are provided, in the context of current knowledge about this disease, also looking at possible future perspectives to ameliorate the outcome of these patients. CONCLUSIONS: PPCL still remains an unmet clinical need. Notwithstanding, some not negligible progresses have been recently achieved. The European Myeloma Network panel strongly support ongoing and planned clinical trials, as well as biological studies based on novel technologies, strategies, and treatment options that could represent breakthroughs we have been waiting for too long.
- Klíčová slova
- Delphi consensus, EMN, guidelines, high-risk multiple myeloma, practical recommendations, primary plasma cell leukemia,
- MeSH
- konsensus * MeSH
- lidé MeSH
- mnohočetný myelom terapie diagnóza patologie MeSH
- plazmocelulární leukemie * terapie diagnóza patologie MeSH
- prognóza MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Geografické názvy
- Evropa MeSH
Extramedullary multiple myeloma (EMM) is an aggressive form of multiple myeloma (MM). This study represents the most comprehensive next-generation sequencing analysis of EMM tumors (N = 14) to date, uncovering key molecular features and describing the tumor microenvironment. We observed the co-occurrence of 1q21 gain/amplification and MAPK pathway mutations in 79% of EMM samples, suggesting that these are crucial mutational events in EMM development. We also demonstrated that patients with mutated KRAS and 1q21 gain/amplification at the time of diagnosis have a significantly higher risk of EMM development (HR = 2.4, p = 0.011) using data from a large CoMMpass dataset. We identified downregulation of CXCR4 and enhanced cell proliferation, along with reduced expression of therapeutic targets (CD38, SLAMF7, GPRC5D, FCRH5), potentially explaining diminished efficacy of immunotherapy. Conversely, we identified significantly upregulated EZH2 and CD70 as potential future therapeutic options. For the first time, we report on the tumor microenvironment of EMM, revealing CD8+ T cells and NK cells as predominant immune effector cells using single-cell sequencing. Finally, this is the first longitudinal study in EMM revealing the molecular changes from the time of diagnosis to EMM relapse.
- MeSH
- kostní dřeň patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mnohočetný myelom * genetika patologie MeSH
- mutace MeSH
- nádorové biomarkery genetika MeSH
- nádorové mikroprostředí * genetika MeSH
- prognóza MeSH
- senioři MeSH
- vysoce účinné nukleotidové sekvenování * MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- nádorové biomarkery MeSH
BACKGROUND: Gamma-heavy chain disease is a rare disease, described so far in approximately 150 cases. The aim of this work was laboratory dia-gnostics of immunoglobulin heavy chain disease. MATERIALS AND METHODS: A 60-year-old patient was referred to the University Hospital in Ostrava for suspected marginal zone lymphoma from gastric bio-psy. Staging examinations including bone marrow trepanobio-psy and PET/CT were added; special examinations required serum protein electrophoresis, immunofixation electrophoresis, determination of polyclonal immunoglobulins, free light chains, and immunoglobulin heavy/light chain pairs. Isoelectric focusing in agarose gel followed by affinity immunoblotting and SDS electrophoresis was added due to unclear findings. RESULTS: 0.1 % of plasma cells were found in the bone marrow, of which 87 % were clonal (pathological) plasma cells, followed by the cyt cytotype LAMBDA + CD38 + CD138 + CD45 + CD19 + CD56- CD27 + CD81- CD117-. Monoclonal heavy chains were found in the patients serum. No monoclonal immunoglobulin heavy or light chains were detected in urine. The PET/CT examination showed generalized lymphadenopathy, splenomegaly and inhomogeneous accumulation of fluorodeoxyglucose in axillary and appendicular skeleton, but without the presence of typical osteolytic lesions. CONCLUSION: Monoclonal heavy chains of immunoglobulins are a rare disease. In contrast to the detection of a complete paraprotein molecule, additional methods must be used to confirm them. The finding of monoclonal heavy chain gamma in the serum of the study patient is related to the presence of marginal zone lymphoma, which was proven from a gastric bio-psy. The study was supported by the project of MH CZ - DRO - FNOs /2017 (Biobank in Teaching Hospital Ostrava) The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.
- Klíčová slova
- SDS electrophoresis, electrophoresis, heavy chain disease, immunofixation electrophoresis, isoelectric focusing,
- MeSH
- imunoglobuliny - gama-řetězce krev MeSH
- lidé středního věku MeSH
- lidé MeSH
- nemoc z těžkých řetězců krev diagnóza MeSH
- prognóza MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- Názvy látek
- imunoglobuliny - gama-řetězce MeSH
Nowadays, bortezomib, a proteasome inhibitor, is widely used in treatment of newly diagnosed or relapsed multiple myeloma. The aim of this study was to analyze efficiency of bortezomib retreatment in patients with relapsed or refractory multiple myeloma. From 2004 to 2016, 283 patients were retrospectively evaluated at all hematological centers in the Czech Republic. Bortezomib was administered at the standard dosing and in combined therapy with corticosteroids, chemotherapy or thalidomide. Before bortezomib retreatment, 61% of patients received previous lenalidomide treatment, 40.6% autologous transplantation, and median number of prior lines of therapy was three. In total, 21% of patients were refractory to the first bortezomib treatment. In bortezomib retreatment, overall response rate was 34.5%, median progression-free survival was 7.8 months (95% CI: 6.7-8.9), median duration of response was 10.5 months (95% CI: 8.0-13.0) and median overall survival was 20.3 months (95% CI: 17.9-22.7). Grade 3-4 adverse events included thrombocytopenia, neutropenia, anemia and infection. Neuropathy grade 2 or higher occurred in 19.4% of patients. We conclude that bortezomib retreatment is an effective and safe therapeutic alternative for relapsed or refractory multiple myeloma patients.
- MeSH
- bortezomib terapeutické užití MeSH
- lidé MeSH
- mnohočetný myelom farmakoterapie MeSH
- opakovaná terapie MeSH
- protokoly protinádorové kombinované chemoterapie MeSH
- recidiva MeSH
- retrospektivní studie MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
- Názvy látek
- bortezomib MeSH
Lenalidomide (LEN) is an immunomodulator with clinical activity against myeloma cells. Based on the pivotal phase 3 trials MM-009 and MM010, the combination of lenalidomide and dexamethasone(DEX) was approved for patients with multiple myeloma who received at least one prior therapy. Here, we evaluated LEN/DEX therapy in unselected population and subsequently in selected sub-groups of patients with relapsed/refractory multiple myeloma followed in the Registry of Monoclonal Gammopathies of the Czech Myeloma Group. Altogether 858 patients were treated with LEN/DEX in the Czech Republic and Slovakia until end of 2017. The analyzed sub-groups were defined as patients with high risk cytogenetic aberrations and patients with relapsed and refractory MM. The overall response rate (ORR; partial remission or better response, PR) in the whole group of patients was 46.3% for all lines of therapy, 26.4% for high-risk group and 32.1% for relapsed and refractory group. Medians of overall survival (OS) in the same cohorts were as follows: 25.6, 15.7 and 18.5 months, progression free survival (PFS) was: 11.2, 6.4 and 9.0 months respectively. The most common adverse events were hematologic and infectious. In conclusion we found that our results correlated with those found in other studies in terms of response rates, survival measures, and also of treatment toxicity.
- MeSH
- analýza přežití MeSH
- dexamethason * škodlivé účinky terapeutické užití MeSH
- lenalidomid * škodlivé účinky terapeutické užití MeSH
- lidé MeSH
- mnohočetný myelom * farmakoterapie mortalita MeSH
- protinádorové látky škodlivé účinky terapeutické užití MeSH
- protokoly protinádorové kombinované chemoterapie MeSH
- registrace * statistika a číselné údaje MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
- Slovenská republika MeSH
- Názvy látek
- dexamethason * MeSH
- lenalidomid * MeSH
- protinádorové látky MeSH
The main goal was to find a simple prognostic to evaluate overall survival of patients older than 65 years of age with myeloma. Retrospective registry-based analysis from the Registry of Monoclonal Gammopathies was conducted. Patients over 65 years with symptomatic myeloma were included. The four major parameters with impact on survival were identified: male gender, age > 75, creatinine > 152 μmol/L, and ECOG performance status 2-4. The patients were scored as good (0 points), intermediate good (1 point), intermediate poor (2 points), poor (3-4 points). Patients (1410 MM) were included. Median OS (months) was 65.7 (95% CI 49.8-81.7) for good, 51.0 (44.1-57.8) for intermediate good, 32.2 (26.2-38.2) for intermediate poor, and 18.9 (15.1-22.7) for poor. The differences in OS were statistically significant (p < 0.0001). Good score was used as reference for hazard ratios, which for each other score were 1.43 (1.09-1.84) for intermediate good, 2.58 (2.00-3.33) for intermediate poor, and 3.88 (2.94-5.10) for poor. Time to progression showed medians (months) 20.5 (17.4-62.4) for good, 19.3 (17.0-21.7) for intermediate good, 19.6 (16.2-23.0) for intermediate poor, and 13.0 (10.8-15.2) for poor. The suggested scoring system provides readily available information about the prognosis of MM patients above 65 years.
- Klíčová slova
- Multiple myeloma, Older adults, Prognostic factors,
- MeSH
- lidé MeSH
- míra přežití MeSH
- mnohočetný myelom mortalita terapie MeSH
- přežití bez známek nemoci MeSH
- registrace * MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- věkové faktory MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
- multicentrická studie MeSH
Multiple myeloma is a plasma cell dyscrasia. It is the second most common hematological malignancy which is characterized by proliferation of clonal plasma cells producing harmful monoclonal immunoglobulin. Despite treatment modalities greatly evolved during the last decade, small amount of aberrant residual cells reside in patients after therapy and can cause relapse of the disease. Characterization of the residual, resistant clones can help to reveal important therapeutic targets for application of effective and precious treatment. We use CD38, CD45, CD56 and CD19 sorted aberrant plasma cells to perform next generation sequencing of their exome. Among the 213 genes in which at least one variant was present, the most interesting was found gene NRAS, one of the most often mutated gene in multiple myeloma, and homologs of 88 gene panel previously used for multiple myeloma sequencing among which was a gene previously identified as gene meaningful in bortezomib resistance. Nevertheless, the results of next generation exome sequencing need to be interpreted with caution, since they rely on bioinformatical analysis, which is still being optimized. The results of next generation sequencing will also have to be confirmed by Sanger sequencing. Final results supported by larger cohort of patients will be published soon.Key words: multiple myeloma - minimal residual disease - exome - next generation sequencing.
- MeSH
- bortezomib farmakologie MeSH
- CD antigeny metabolismus MeSH
- chemorezistence účinky léků genetika MeSH
- GTP-fosfohydrolasy genetika MeSH
- lidé MeSH
- membránové proteiny genetika MeSH
- mnohočetný myelom farmakoterapie genetika patologie MeSH
- plazmatické buňky metabolismus patologie MeSH
- reziduální nádor MeSH
- sekvenování exomu * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- multicentrická studie MeSH
- Názvy látek
- bortezomib MeSH
- CD antigeny MeSH
- GTP-fosfohydrolasy MeSH
- membránové proteiny MeSH
- NRAS protein, human MeSH Prohlížeč
Monoclonal antibodies represent a standard part in the treatment of oncologic patients, but their efficacy in multiple myeloma used to be unsatisfactory. Daratumumab monotherapy was approved by the American FDA in 2015, after unprecedented results were obtained in a heavily pre-treated group of patients. In 2016 daratumumab was approved in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of myeloma patients who have received at least one prior therapy.The toxicity of the drug is low, and is dominated by infusion-related reactions in more or less half of patients. The development as well as the management of these sometimes urgent reactions is described in depth in this review. As multiple myeloma is characterized by the presence of paraprotein (monoclonal antibody) and CD38 is a ubiquitous antigen, several unexpected complications have been reported during the administration of the drug. In this review, we aim to describe and offer some solutions for the complications that may be encountered during daratumumab treatment, such as interference with serum protein electrophoresis and immunofixation assays that may confuse the assessment of the hematological response, interference with blood compatibility testing that may cause a delay in the delivery of compatible transfusions, and difficulties that may occur in flow cytometric analysis of minimal residual disease. Because of the high activity of daratumumab and its expected widespread use, clinicians should be aware of its side effects and their management. It is also very important to inform colleagues in clinical laboratories about the initiation of daratumumab treatment in particular patient.Key words: multiple myeloma - daratumumab - infusion related reaction - flow cytometry - transfusionThis work was supported by the Czech Ministry of Education, Youth and Sports (project no. IRP- 201550) and by the Czech Ministry of Health (15-29667A).The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Accepted: 22. 8. 2016Submitted: 12. 5. 2016.
- MeSH
- bortezomib aplikace a dávkování MeSH
- dexamethason aplikace a dávkování MeSH
- elektroforéza sérových bílkovin MeSH
- lenalidomid MeSH
- lidé MeSH
- mnohočetný myelom farmakoterapie MeSH
- monoklonální protilátky aplikace a dávkování škodlivé účinky MeSH
- protokoly protinádorové kombinované chemoterapie škodlivé účinky terapeutické užití MeSH
- průtoková cytometrie MeSH
- thalidomid aplikace a dávkování analogy a deriváty MeSH
- určování krevní skupiny a křížové zkoušky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- bortezomib MeSH
- daratumumab MeSH Prohlížeč
- dexamethason MeSH
- lenalidomid MeSH
- monoklonální protilátky MeSH
- thalidomid MeSH
Proteasome inhibitors are the backbone in the treatment of multiple myeloma with 3 of its representatives (bortezomib, carfilzomib, and ixazomib) having already been approved. There is a different situation altogether in the treatment of amyloid light chain (AL) amyloidosis where owing to the rarity of this entity neither of these drugs has currently gained approval. Amyloid light chain plasma cells are possibly more vulnerable to bortezomib than myeloma plasmocytes because of a slightly distinct mechanism of action, which is described in depth in this manuscript. Bortezomib is highly active and rapidly effective as a single agent and even more potent in combination with dexamethasone and alkylators. Bortezomib-based regimens have become a standard part of the initial treatment of AL amyloidosis in the majority of centers. We have reviewed all available data on bortezomib in various combinations and settings. Carfilzomib seems to be effective but also toxic in these fragile patients with a high rate of cardiac events. Oral ixazomib has shown a surprisingly high efficacy with manageable toxicity and has received the Food and Drug Administration Breakthrough Therapy designation in 2014 for relapsed AL amyloidosis patients. In this review we have comprehensively described the current available knowledge of these 3 proteasome inhibitors and their use in AL amyloidosis.
- Klíčová slova
- Amyloidosis, NEOD001, bortezomib, carfilzomib, ixazomib, multiple myeloma,
- MeSH
- inhibitory proteasomu aplikace a dávkování farmakologie terapeutické užití MeSH
- lidé MeSH
- mnohočetný myelom farmakoterapie patologie MeSH
- primární amyloidóza farmakoterapie patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- inhibitory proteasomu MeSH
Multiparameter flow cytometry (MFC) has become standard in the management of patients with plasma cell (PC) dyscrasias, and could be considered mandatory in specific areas of routine clinical practice. It plays a significant role during the differential diagnostic work-up because of its fast and conclusive readout of PC clonality, and simultaneously provides prognostic information in most monoclonal gammopathies. Recent advances in the treatment and outcomes of multiple myeloma led to the implementation of new response criteria, including minimal residual disease (MRD) status as one of the most relevant clinical endpoints with the potential to act as surrogate for survival. Recent technical progress led to the development of next-generation flow (NGF) cytometry that represents a validated, highly sensitive, cost-effective and widely available technique for standardized MRD evaluation, which also could be used for the detection of circulating tumor cells. Here we review current applications of MFC and NGF in most PC disorders including the less frequent solitary plasmocytoma, light-chain amyloidosis or Waldenström macroglobulinemia.
- MeSH
- lidé MeSH
- paraproteinemie diagnostické zobrazování patologie MeSH
- průtoková cytometrie metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
