MRI in multiple myeloma : a pictorial review of diagnostic and post-treatment findings

Magnetic resonance imaging (MRI) is increasingly being used in the diagnostic work-up of patients with multiple myeloma. Since 2014, MRI findings are included in the new diagnostic criteria proposed by the International Myeloma Working Group. Patients with smouldering myeloma presenting with more than one unequivocal focal lesion in the bone marrow on MRI are considered having symptomatic myeloma requiring treatment, regardless of the presence of lytic bone lesions. However, bone marrow evaluation with MRI offers more than only morphological information regarding the detection of focal lesions in patients with MM. The overall performance of MRI is enhanced by applying dynamic contrast-enhanced MRI and diffusion weighted imaging sequences, providing additional functional information on bone marrow vascularization and cellularity. This pictorial review provides an overview of the most important imaging findings in patients with monoclonal gammopathy of undetermined significance, smouldering myeloma and multiple myeloma, by performing a 'total' MRI investigation with implications for the diagnosis, staging and response assessment. Main message aEuro cent Conventional MRI diagnoses multiple myeloma by assessing the infiltration pattern. aEuro cent Dynamic contrast-enhanced MRI diagnoses multiple myeloma by assessing vascularization and perfusion. aEuro cent Diffusion weighted imaging evaluates bone marrow composition and cellularity in multiple myeloma. aEuro cent Combined morphological and functional MRI provides optimal bone marrow assessment for staging. aEuro cent Combined morphological and functional MRI is of considerable value in treatment follow-up

Prebiotic effects: metabolic and health benefits

The different compartments of the gastrointestinal tract are inhabited by populations of micro-organisms. By far the most important predominant populations are in the colon where a true symbiosis with the host exists that is a key for well-being and health. For such a microbiota, 'normobiosis' characterises a composition of the gut 'ecosystem' in which micro-organisms with potential health benefits predominate in number over potentially harmful ones, in contrast to 'dysbiosis', in which one or a few potentially harmful micro-organisms are dominant, thus creating a disease-prone situation. The present document has been written by a group of both academic and industry experts (in the ILSI Europe Prebiotic Expert Group and Prebiotic Task Force, respectively). It does not aim to propose a new definition of a prebiotic nor to identify which food products are classified as prebiotic but rather to validate and expand the original idea of the prebiotic concept (that can be translated in 'prebiotic effects'), defined as: 'The selective stimulation of growth and/or activity(ies) of one or a limited number of microbial genus(era)/species in the gut microbiota that confer(s) health benefits to the host.' Thanks to the methodological and fundamental research of microbiologists, immense progress has very recently been made in our understanding of the gut microbiota. A large number of human intervention studies have been performed that have demonstrated that dietary consumption of certain food products can result in statistically significant changes in the composition of the gut microbiota in line with the prebiotic concept. Thus the prebiotic effect is now a well-established scientific fact. The more data are accumulating, the more it will be recognised that such changes in the microbiota's composition, especially increase in bifidobacteria, can be regarded as a marker of intestinal health. The review is divided in chapters that cover the major areas of nutrition research where a prebiotic effect has tentatively been investigated for potential health benefits. The prebiotic effect has been shown to associate with modulation of biomarkers and activity(ies) of the immune system. Confirming the studies in adults, it has been demonstrated that, in infant nutrition, the prebiotic effect includes a significant change of gut microbiota composition, especially an increase of faecal concentrations of bifidobacteria. This concomitantly improves stool quality (pH, SCFA, frequency and consistency), reduces the risk of gastroenteritis and infections, improves general well-being and reduces the incidence of allergic symptoms such as atopic eczema. Changes in the gut microbiota composition are classically considered as one of the many factors involved in the pathogenesis of either inflammatory bowel disease or irritable bowel syndrome. The use of particular food products with a prebiotic effect has thus been tested in clinical trials with the objective to improve the clinical activity and well-being of patients with such disorders. Promising beneficial effects have been demonstrated in some preliminary studies, including changes in gut microbiota composition (especially increase in bifidobacteria concentration). Often associated with toxic load and/or miscellaneous risk factors, colon cancer is another pathology for which a possible role of gut microbiota composition has been hypothesised. Numerous experimental studies have reported reduction in incidence of tumours and cancers after feeding specific food products with a prebiotic effect. Some of these studies (including one human trial) have also reported that, in such conditions, gut microbiota composition was modified (especially due to increased concentration of bifidobacteria). Dietary intake of particular food products with a prebiotic effect has been shown, especially in adolescents, but also tentatively in postmenopausal women, to increase Ca absorption as well as bone Ca accretion and bone mineral density. Recent data, both from experimental models and from human studies, support the beneficial effects of particular food products with prebiotic properties on energy homaeostasis, satiety regulation and body weight gain. Together, with data in obese animals and patients, these studies support the hypothesis that gut microbiota composition (especially the number of bifidobacteria) may contribute to modulate metabolic processes associated with syndrome X, especially obesity and diabetes type 2. It is plausible, even though not exclusive, that these effects are linked to the microbiota-induced changes and it is feasible to conclude that their mechanisms fit into the prebiotic effect. However, the role of such changes in these health benefits remains to be definitively proven. As a result of the research activity that followed the publication of the prebiotic concept 15 years ago, it has become clear that products that cause a selective modification in the gut microbiota's composition and/or activity(ies) and thus strengthens normobiosis could either induce beneficial physiological effects in the colon and also in extra-intestinal compartments or contribute towards reducing the risk of dysbiosis and associated intestinal and systemic pathologies

Heart failure is associated with accelerated age related metabolic bone disease

Background:The heart failure (HF)-syndrome is associated with neuro-hormonal activation, chronic kidney disease (CKD), inflammation and alterations in the phosphorus-metabolism, all of which are involved in regulation of mineral bone density. However, the role of HF as an independent factor associated with metabolic bone disease (MBD) remains unclear. Methods:HF-patients undergoing dual X-ray absorptiometry (DEXA) were matched in a 1:2 fashion against age and gender matched controls without HF, to determine the proportion of osteoporosis (T-score <-2.5). HF-status was tested against known predictors of MBD. Correlation analysis and Z-score analysis were used to assess the impact of HF on age-related bone demineralisation. Results:A total of 190 HF-patients (age = 80 +/- 10 years, female = 61%) were age and gender matched to 380 controls. HF-patients had a higher proportion of osteoporosis (26 vs 17%;p = .007). HF patients had a lower averaged mineral bone density expressed in g/cm(2) (p = .030), T-scores (p = .001) and Z-scores (p <.001). After adjusting for the individual osteoporosis risk-factors of the FRAX-score, difference in baseline features, kidney function and phosphorus-metabolism alterations, heart failure remained independently associated with a lower averaged T-score (Adjusted beta= -0.189;p = .017). Heart failure was associated with an accelerated age-related decline in mineral bone density (p = .0418). Therapies with ACE-I or ARBs and beta-blockers associated with ameliorated bone demineralisation (p = .023, respectivelyp = .029), while loop diuretic associated with worsened bone demineralization (p <.001). Conclusion:Heart failure independently associates with MBD and higher prevalence of osteoporosis. Heart failure aggravates the aged related loss in mineral bone density while treatment with neuro-hormonal blockers seemed to ameliorate this finding

Extramedullary disease in multiple myeloma: a systematic literature review

Extramedullary involvement (or extramedullary disease, EMD) represents an aggressive form of multiple myeloma (MM), characterized by the ability of a clone and/or subclone to thrive and grow independent of the bone marrow microenvironment. Several different definitions of EMD have been used in the published literature. We advocate that true EMD is restricted to soft-tissue plasmacytomas that arise due to hematogenous spread and have no contact with bony structures. Typical sites of EMD vary according to the phase of MM. At diagnosis, EMD is typically found in skin and soft tissues; at relapse, typical sites involved include liver, kidneys, lymph nodes, central nervous system (CNS), breast, pleura, and pericardium. The reported incidence of EMD varies considerably, and differences in diagnostic approach between studies are likely to contribute to this variability. In patients with newly diagnosed MM, the reported incidence ranges from 0.5% to 4.8%, while in relapsed/refractory MM the reported incidence is 3.4 to 14%. Available data demonstrate that the prognosis is poor, and considerably worse than for MM without soft-tissue plasmacytomas. Among patients with plasmacytomas, those with EMD have poorer outcomes than those with paraskeletal involvement. CNS involvement is rare, but prognosis is even more dismal than for EMD in other locations, particularly if there is leptomeningeal involvement. Available data on treatment outcomes for EMD are derived almost entirely from retrospective studies. Some agents and combinations have shown a degree of efficacy but, as would be expected, this is less than in MM patients with no extramedullary involvement. The paucity of prospective studies makes it difficult to justify strong recommendations for any treatment approach. Prospective data from patients with clearly defined EMD are important for the optimal evaluation of treatment outcomes

Extramedullary disease in multiple myeloma: a systematic literature review

Extramedullary involvement (or extramedullary disease, EMD) represents an aggressive form of multiple myeloma (MM), characterized by the ability of a clone and/or subclone to thrive and grow independent of the bone marrow microenvironment. Several different definitions of EMD have been used in the published literature. We advocate that true EMD is restricted to soft-tissue plasmacytomas that arise due to hematogenous spread and have no contact with bony structures. Typical sites of EMD vary according to the phase of MM. At diagnosis, EMD is typically found in skin and soft tissues; at relapse, typical sites involved include liver, kidneys, lymph nodes, central nervous system (CNS), breast, pleura, and pericardium. The reported incidence of EMD varies considerably, and differences in diagnostic approach between studies are likely to contribute to this variability. In patients with newly diagnosed MM, the reported incidence ranges from 0.5% to 4.8%, while in relapsed/refractory MM the reported incidence is 3.4 to 14%. Available data demonstrate that the prognosis is poor, and considerably worse than for MM without soft-tissue plasmacytomas. Among patients with plasmacytomas, those with EMD have poorer outcomes than those with paraskeletal involvement. CNS involvement is rare, but prognosis is even more dismal than for EMD in other locations, particularly if there is leptomeningeal involvement. Available data on treatment outcomes for EMD are derived almost entirely from retrospective studies. Some agents and combinations have shown a degree of efficacy but, as would be expected, this is less than in MM patients with no extramedullary involvement. The paucity of prospective studies makes it difficult to justify strong recommendations for any treatment approach. Prospective data from patients with clearly defined EMD are important for the optimal evaluation of treatment outcomes

Cardiovascular adverse events in modern myeloma therapy - incidence and risks. A review from European Myeloma Network (EMN) and Italian Society of Arterial Hypertension (SIIA)

Cardiovascular disease in myeloma patients may derive from factors unrelated to the disease (age, diabetes, dyslipidemia, obesity, prior cardiovascular diseases), related to the disease (cardiac AL-amyloidosis, hyperviscosity, high-output failure, arteriovenous shunting, anemia, renal dysfunction) and linked to antimyeloma treatment (anthracyclines, corticosteroids, alkylating agents, immunomodulatory drugs, proteasome inhibitors). An accurate knowledge of cardiovascular events, effective dose reductions, prevention and management of early and late cardiovascular side effects of chemotherapeutic agents are essential in current clinical practice. Myeloma experts are obliged to carefully balance drugs' efficacy and toxicity for each individual patient. This review summarizes current data and novel insights on cardiovascular adverse events of today's antimyeloma treatment, focusing on carfilzomib, which is the starting point to develop consensus recommendations on preventing and managing cardiovascular side effects in myeloma patients

Patient-centered practice in elderly myeloma patients: an overview and consensus from the European Myeloma Network (EMN)

Multiple myeloma is a disease typical of the elderly, and, because of the increase in life expectancy of the general population, its incidence is expected to grow in the future. Elderly patients represent a particular challenge due to their marked hete rogeneity. Many new and highly effective drugs have been introduced in the last few years, and resu lts from clinical trials are promising. Besides the availability of novel agents, a careful evaluation of elderly patients showed to be a key factor for the success of therapy. A geriatric assessment is a valid strategy to better stratify patients. In particular, different scores are available today to appropriately assess elderly patients and define their fitness/frailty status. The choice of treatm ent – transplantation, triplets, doublets, or reduced- dose therapies including novel agents – should depend on the patient’s fitness status (fit, intermediate-fit or frail). Second-generation no vel agents have also been evaluated as salvage therapy in the elderly, and these new agents certai nly represent a further step forward in the treatment armamentarium for elderly patients with multiple myeloma

European Myeloma Network recommendations on tools for the diagnosis and monitoring of multiple myeloma: what to use and when.

The diagnosis of multiple myeloma can be challenging, even for experienced physicians, and requires close collaboration between numerous disciplines (orthopedics, radiology, nuclear medicine, radiation therapy, hematology and oncology) before the final diagnosis of myeloma is made. The definition of multiple myeloma is based on the presence of clinical, biochemical, histopathological, and radiological markers of disease. Specific tests are needed both at presentation and during follow-up in order to reach the correct diagnosis and characterize the disease precisely. These tests can also serve prognostic purposes and are useful for follow-up of myeloma patients. Molecular analyses remain pivotal for defining high-risk myeloma and are used in updated patient stratifications, while minimal residual disease assessment via flow cytometry, molecular techniques and radiological approaches provides additional prognostic information on patients' long-term outcome. This pivotal information will guide our future treatment decisions in forthcoming clinical trials. The European Myeloma Network group updated their guidelines on different diagnostic recommendations, which should be of value to enable appropriate use of the recommendations both at diagnosis and during follow-up

European Myeloma Network Group review and consensus statement on primary plasma cell leukemia

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.</p

European Myeloma Network Group review and consensus statement on primary plasma cell leukemia

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