Multiple myeloma (MM) is an incurable malignancy of plasma cells. Epidemiological studies indicate a substantial heritable component, but the underlying mechanisms remain unclear. Here, in a genome-wide association study totaling 10,906 cases and 366,221 controls, we identify 35 MM risk loci, 12 of which are novel. Through functional fine-mapping and Mendelian randomization, we uncover two causal mechanisms for inherited MM risk: longer telomeres; and elevated levels of B-cell maturation antigen (BCMA) and interleukin-5 receptor alpha (IL5RA) in plasma. The largest increase in BCMA and IL5RA levels is mediated by the risk variant rs34562254-A at TNFRSF13B. While individuals with loss-of-function variants in TNFRSF13B develop B-cell immunodeficiency, rs34562254-A exerts a gain-of-function effect, increasing MM risk through amplified B-cell responses. Our results represent an analysis of genetic MM predisposition, highlighting causal mechanisms contributing to MM development.

• MeSH
• B-lymfocyty imunologie   metabolismus   MeSH
• celogenomová asociační studie * MeSH
• genetická predispozice k nemoci * MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé MeSH
• maturační antigen B-buněk * genetika   MeSH
• mendelovská randomizace MeSH
• mnohočetný myelom * genetika   MeSH
• receptor TACI genetika   MeSH
• studie případů a kontrol MeSH
• telomery genetika   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• maturační antigen B-buněk * MeSH
• receptor TACI MeSH
• TNFRSF13B protein, human MeSH Prohlížeč

Thousands of non-coding variants have been associated with increased risk of human diseases, yet the causal variants and their mechanisms-of-action remain obscure. In an integrative study combining massively parallel reporter assays (MPRA), expression analyses (eQTL, meQTL, PCHiC) and chromatin accessibility analyses in primary cells (caQTL), we investigate 1,039 variants associated with multiple myeloma (MM). We demonstrate that MM susceptibility is mediated by gene-regulatory changes in plasma cells and B-cells, and identify putative causal variants at six risk loci (SMARCD3, WAC, ELL2, CDCA7L, CEP120, and PREX1). Notably, three of these variants co-localize with significant plasma cell caQTLs, signaling the presence of causal activity at these precise genomic positions in an endogenous chromosomal context in vivo. Our results provide a systematic functional dissection of risk loci for a hematologic malignancy.

• MeSH
• adaptorové proteiny signální transdukční genetika   imunologie   MeSH
• B-lymfocyty imunologie   patologie   MeSH
• chromatin chemie   imunologie   MeSH
• chromozomální proteiny, nehistonové genetika   imunologie   MeSH
• genetická predispozice k nemoci * MeSH
• hodnocení rizik MeSH
• intergenová DNA genetika   imunologie   MeSH
• lidé MeSH
• lokus kvantitativního znaku MeSH
• mnohočetný myelom farmakoterapie   genetika   imunologie   patologie   MeSH
• nádorové proteiny genetika   imunologie   MeSH
• plazmatické buňky imunologie   patologie   MeSH
• polymorfismus genetický MeSH
• primární buněčná kultura MeSH
• proteiny buněčného cyklu genetika   imunologie   MeSH
• protokoly protinádorové kombinované chemoterapie MeSH
• regulace genové exprese u nádorů MeSH
• represorové proteiny genetika   imunologie   MeSH
• sekvence nukleotidů MeSH
• transkripční elongační faktory genetika   imunologie   MeSH
• typy dědičnosti MeSH
• výměnné faktory guaninnukleotidů genetika   imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• CDCA7L protein, human MeSH Prohlížeč
• CEP120 protein, human MeSH Prohlížeč
• chromatin MeSH
• chromozomální proteiny, nehistonové MeSH
• ELL2 protein, human MeSH Prohlížeč
• intergenová DNA MeSH
• nádorové proteiny MeSH
• PREX1 protein, human MeSH Prohlížeč
• proteiny buněčného cyklu MeSH
• represorové proteiny MeSH
• SMARCD3 protein, human MeSH Prohlížeč
• transkripční elongační faktory MeSH
• výměnné faktory guaninnukleotidů MeSH
• WAC protein, human MeSH Prohlížeč

The European Myeloma Network provides recommendations for the management of the most common complications of multiple myeloma. Whole body low-dose computed tomography is more sensitive than conventional radiography in depicting osteolytic disease and thus we recommend it as the novel standard for the detection of lytic lesions in myeloma (grade 1A). Myeloma patients with adequate renal function and bone disease at diagnosis should be treated with zoledronic acid or pamidronate (grade 1A). Symptomatic patients without lytic lesions on conventional radiography can be treated with zoledronic acid (grade 1B), but its advantage is not clear for patients with no bone involvement on computed tomography or magnetic resonance imaging. In asymptomatic myeloma, bisphosphonates are not recommended (grade 1A). Zoledronic acid should be given continuously, but it is not clear if patients who achieve at least a very good partial response benefit from its continuous use (grade 1B). Treatment with erythropoietic-stimulating agents may be initiated in patients with persistent symptomatic anemia (hemoglobin <10g/dL) in whom other causes of anemia have been excluded (grade 1B). Erythropoietic agents should be stopped after 6-8 weeks if no adequate hemoglobin response is achieved. For renal impairment, bortezomib-based regimens are the current standard of care (grade 1A). For the management of treatment-induced peripheral neuropathy, drug modification is needed (grade 1C). Vaccination against influenza is recommended; vaccination against streptococcus pneumonia and hemophilus influenza is appropriate, but efficacy is not guaranteed due to suboptimal immune response (grade 1C). Prophylactic aciclovir (or valacyclovir) is recommended for patients receiving proteasome inhibitors, autologous or allogeneic transplantation (grade 1A).

• MeSH
• anemie diagnóza   etiologie   terapie   MeSH
• infekce diagnóza   etiologie   terapie   MeSH
• lidé MeSH
• management bolesti MeSH
• management nemoci * MeSH
• mnohočetný myelom komplikace   MeSH
• nemoci kostí diagnóza   etiologie   terapie   MeSH
• nemoci ledvin diagnóza   etiologie   terapie   MeSH
• nemoci periferního nervového systému diagnóza   etiologie   terapie   MeSH
• žilní tromboembolie diagnóza   etiologie   terapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• směrnice pro lékařskou praxi MeSH

Recent developments have led to remarkable improvements in the assessment and treatment of patients with multiple myeloma (MM). New technologies have become available to precisely evaluate the biology and extent of the disease, including information about cytogenetics and genetic abnormalities, extramedullary manifestations and minimal residual disease. New, more effective drugs have been introduced into clinical practice, which enable clinicians to significantly improve the outcome of patients but also pose new challenges for the prevention and management of their specific side effects. Given these various new options and challenges, it is important to identify the minimal requirements for diagnosis and treatment of patients, as access to the most sophisticated advances may vary depending on local circumstances. Here, we propose the minimal requirements and possible options for diagnosis, monitoring and treatment of patients with multiple myeloma.

• MeSH
• lidé MeSH
• mnohočetný myelom patofyziologie   terapie   MeSH
• monitorování fyziologických funkcí MeSH
• recidiva MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

PURPOSE: To provide an update on recent advances in the management of patients with multiple myeloma who are not eligible for autologous stem-cell transplantation. METHODS: A comprehensive review of the literature on diagnostic criteria is provided, and treatment options and management of adverse events are summarized. RESULTS: Patients with symptomatic disease and organ damage (ie, hypercalcemia, renal failure, anemia, or bone lesions) require immediate treatment. The International Staging System and chromosomal abnormalities identify high- and standard-risk patients. Proteasome inhibitors, immunomodulatory drugs, corticosteroids, and alkylating agents are the most active agents. The presence of concomitant diseases, frailty, or disability should be assessed and, if present, treated with reduced-dose approaches. Bone disease, renal damage, hematologic toxicities, infections, thromboembolism, and peripheral neuropathy are the most frequent disabling events requiring prompt and active supportive care. CONCLUSION: These recommendations will help clinicians ensure the most appropriate care for patients with myeloma in everyday clinical practice.

• MeSH
• lidé MeSH
• mnohočetný myelom diagnóza   terapie   MeSH
• paliativní péče MeSH
• prognóza MeSH
• transplantace hematopoetických kmenových buněk MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH