[Multiple myeloma : an overview of advances in biology and treatment]. / Le myélome multiple : un tour d'horizon des nouveautés dans sa biologie et son traitement.

Multiple myeloma is the second most common hematological malignancy, characterized by an uncontrollable proliferation of clonal plasma cells. Although progresses in understanding its pathobiology and its treatment are made every day, it remains incurable. Since myeloma is more and more common, especially in the elderly, we would like to propose an overview of its pathobiology, diagnostic criteria and treatment «guidelines¼.

Deuxième pathologie hématologique la plus fréquente, le myélome multiple est une maladie plasmocytaire qui reste actuellement incurable. Pourtant, tous les jours, des progrès sont effectués au niveau de la compréhension de sa physiopathologie et de l'élaboration de stratégies de traitement. Vu son caractère de plus en plus répandu, surtout chez la personne âgée, nous proposons un tour d'horizon de sa physiopathologie, de ses critères diagnostiques et des grandes lignes de sa prise en charge.

[An illustrative case of the POEMS syndrome]. / Cas clinique. Un cas illustratif de POEMS syndrome.

POEMS syndrome is a rare and invalidating entity characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and dermatoses. The diagnosis of this condition is often late and challenging due to the heterogeneity of clinical forms. The light chains secreted by the clonal plasmocytes cause overproduction of VEGF (Vascular Endothelial Growth Factor) responsible for the appearance of the clinical manifestations of POEMS. The diagnostic approach is based on different clinical and biological criteria. Patients with a solitary plasmacytoma are candidates for radiotherapy treatment. Patients with diffuse bone involvement or bone marrow infiltration are best treated by systemic drugs. The response to treatment may take several months before clinical and biological improvement. Early diagnosis and dedicated management limit the clinico-functional impact of POEMS.

Le POEMS syndrome est une entité rare et invalidante caractérisée par une polyneuropathie, une organomégalie, une endocrinopathie, une gammapathie monoclonale et des atteintes dermatologiques. Le diagnostic de cette infection est souvent tardif et représente un véritable défi au vu de l'hétérogénéité des formes cliniques. Les chaînes légères sécrétées par les plasmocytes clonaux entraînent une surproduction de VEGF (Vascular Endothelial Growth Factor) responsable de la plupart des manifestations cliniques du POEMS. La démarche diagnostique repose, en pratique, sur des critères cliniques dont les principaux sont la polyneuropathie et la gammapathie monoclonale. Le bilan d'extension reprend le dosage du VEGF, l'électrophorèse et l'mmunofixation des protéines sériques. Un bilan radiologique permet d'objectiver des lésions osseuses ostéosclérotiques ou des adénopathies et l'électromyogramme la polyneuropathie. Les patients qui souffrent d'un plasmocytome en l'absence d'une infiltration médullaire de plasmocytes clonaux sont des candidats au traitement par radiothérapie. Les patients avec une atteinte osseuse diffuse ou une localisation médullaire recevront un traitement systémique. La réponse au traitement peut prendre plusieurs mois avant une amélioration clinique et biologique. Un diagnostic précoce et une prise en charge spécifique limitent l'impact clinico-fonctionnel du POEMS.

Prevention, monitoring and treatment of cardiovascular adverse events in myeloma patients receiving carfilzomib A consensus paper by the European Myeloma Network and the Italian Society of Arterial Hypertension.

BACKGROUND: The novel proteasome inhibitor carfilzomib alone or in combination with other agents is already one of the standard therapies for relapsed and/or refractory multiple myeloma (MM) patients and produces impressive response rates in newly diagnosed MM as well. However, carfilzomib-related cardiovascular adverse events (CVAEs) - including hypertension (all grades: 12.2%; grade ≥3: 4.3%), heart failure (all grades: 4.1%; grade ≥3: 2.5%) and ischemic heart disease (all grades: 1.8%; grade ≥3: 0.8%) - may lead to treatment suspensions. At present, there are neither prospective studies nor expert consensus on the prevention, monitoring and treatment of CVAEs in myeloma patients treated with carfilzomib. METHODS: An expert panel of the European Myeloma Network in collaboration with the Italian Society of Arterial Hypertension and with the endorsement of the European Hematology Association aimed to provide recommendations to support health professionals in selecting the best management strategies for patients, considering the impact on outcome and the risk-benefit ratio of diagnostic and therapeutic tools, thereby achieving myeloma response with novel combination approaches whilst preventing CVAEs. RESULTS: Patients scheduled to receive carfilzomib need a careful cardiovascular evaluation before treatment and an accurate follow-up during treatment. CONCLUSIONS: A detailed clinical assessment before starting carfilzomib treatment is essential to identify patients at risk for CVAEs, and accurate monitoring of blood pressure and of early signs and symptoms suggestive of cardiac dysfunction remains pivotal to safely administer carfilzomib without treatment interruptions or dose reductions.

Diagnosis, treatment, and response assessment in solitary plasmacytoma: updated recommendations from a European Expert Panel.

Solitary plasmacytoma is an infrequent form of plasma cell dyscrasia that presents as a single mass of monoclonal plasma cells, located either extramedullary or intraosseous. In some patients, a bone marrow aspiration can detect a low monoclonal plasma cell infiltration which indicates a high risk of early progression to an overt myeloma disease. Before treatment initiation, whole body positron emission tomography-computed tomography or magnetic resonance imaging should be performed to exclude the presence of additional malignant lesions. For decades, treatment has been based on high-dose radiation, but studies exploring the potential benefit of systemic therapies for high-risk patients are urgently needed. In this review, a panel of expert European hematologists updates the recommendations on the diagnosis and management of patients with solitary plasmacytoma.

Prevention and management of adverse events of Novel agents in multiple myeloma: A consensus of the european myeloma network.

During the last few years, several new drugs have been introduced for treatment of patients with multiple myeloma, which have significantly improved 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 drugs 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.Leukemia accepted article preview online, 18 December 2017. doi:10.1038/leu.2017.353.

Whole-body computed tomography versus conventional skeletal survey in patients with multiple myeloma: a study of the International Myeloma Working Group.

For decades, conventional skeletal survey (CSS) has been the standard imaging technique for multiple myeloma (MM). However, recently whole-body computed tomography (WBCT) has been implemented into the diagnostic criteria of MM. This analysis compares sensitivity and prognostic significance of WBCT and CSS in patients with smoldering MM (SMM) and MM. Fifty-four of 212 patients (25.5%) had a negative CSS and a positive WBCT for osteolytic lesions (P<0.0001). Of 66 patients with SMM based on CSS, 12 (22.2%) had osteolytic lesions on WBCT. In comparison, WBCT failed to detect some bone destructions in the appendicular skeleton possibly due to limitations of the field of view. Presence of lytic bone lesions in WBCT was of borderline prognostic significance (P=0.051) for SMM patients, with a median time to progression of 38 versus 82 months for those without bone destructions. In conclusion, WBCT identifies significantly more sites of bone destruction than CSS. More than 20% of patients with SMM according to CSS have in fact active MM detectable with WBCT. On the basis of this and other studies, WBCT (either computed tomography (CT) alone or as part of a positron emission tomography-CT protocol) should be considered the current standard for the detection of osteolytic lesions in MM.

Management of relapsed multiple myeloma: recommendations of the International Myeloma Working Group.

The prognosis for patients multiple myeloma (MM) has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens that possess a high level of anti-tumor activity. In spite of this important progress, however, nearly all MM patients ultimately relapse, even those who experience a complete response to initial therapy. Management of relapsed MM thus represents a vital aspect of the overall care for patients with MM and a critical area of ongoing scientific and clinical research. This comprehensive manuscript from the International Myeloma Working Group provides detailed recommendations on management of relapsed disease, with sections dedicated to diagnostic evaluation, determinants of therapy, and general approach to patients with specific disease characteristics. In addition, the manuscript provides a summary of evidence from clinical trials that have significantly impacted the field, including those evaluating conventional dose therapies, as well as both autologous and allogeneic stem cell transplantation. Specific recommendations are offered for management of first and second relapse, relapsed and refractory disease, and both autologous and allogeneic transplant. Finally, perspective is provided regarding new agents and promising directions in management of relapsed MM.

Cellular immunotherapy in multiple myeloma: lessons from preclinical models.

The majority of multiple myeloma patients relapse with the current treatment strategies, raising the need for alternative therapeutic approaches. Cellular immunotherapy is a rapidly evolving field and currently being translated into clinical trials with encouraging results in several cancer types, including multiple myeloma. Murine multiple myeloma models are of critical importance for the development and refinement of cellular immunotherapy. In this review, we summarize the immune cell changes that occur in multiple myeloma patients and we discuss the cell-based immunotherapies that have been tested in multiple myeloma, with a focus on murine models.

[Monoclonal gammopathies of undetermined significance - update for referring physicians]. / Gammapathie monoclonale de signification indéterminée : information destinée aux médecins referents.

Monoclonal gammopathies of undetermined significance (MGUS) are frequently diagnosed in the global population. Because of its possible transformation into a hematological malignancy, the identification of a MGUS requires a regular and generally long follow-up. However, this risk of transformation differs between the individuals and different laboratory criteria have been identified as predictive factors for progression and were combined in scoring systems that allow correct classification of individuals. The management of these patients needs to be adapted according to the calculated risk profile.

Plasma cell leukemia: consensus statement on diagnostic requirements, response criteria and treatment recommendations by the International Myeloma Working Group.

Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma characterized by the presence of circulating plasma cells. It is classified as either primary PCL occurring at diagnosis or as secondary PCL in patients with relapsed/refractory myeloma. Primary PCL is a distinct clinic-pathological entity with different cytogenetic and molecular findings. The clinical course is aggressive with short remissions and survival duration. The diagnosis is based upon the percentage (≥ 20%) and absolute number (≥ 2 × 10(9)/l) of plasma cells in the peripheral blood. It is proposed that the thresholds for diagnosis be re-examined and consensus recommendations are made for diagnosis, as well as, response and progression criteria. Induction therapy needs to begin promptly and have high clinical activity leading to rapid disease control in an effort to minimize the risk of early death. Intensive chemotherapy regimens and bortezomib-based regimens are recommended followed by high-dose therapy with autologous stem cell transplantation if feasible. Allogeneic transplantation can be considered in younger patients. Prospective multicenter studies are required to provide revised definitions and better understanding of the pathogenesis of PCL.

Unexplained cardiac failure leading to the identification of a Belgian family affected by hereditary amyloidosis.

We report the diagnosis of hereditary amyloidosis that affected a Belgian family that was initially diagnosed in a 73 year old woman. This patient was admitted with complaints of congestive heart failure. Cardiac work-up showed myocardial hypertrophy with zones of hyperintensity, suggestive for amyloidosis that was confirmed on a rectal biopsy. A hereditary form of amyloidosis was found by showing the Val30Met mutation within the transthyretin gene, that was also found in her asymptomatic son. This case shows that genetic testing is crucial in cases of unexplained amyloidosis and can help in the diagnosis and follow-up of patients and family members.

[Mantle cell lymphoma: management in 2011]. / Lymphome du manteau: prise en charge 2011.

Mantle cell lymphoma is a rare form of non Hodgkin lymphomas. Diagnosis is made by demonstrating a typical immunophenotype as well as the presence of a translocation between chromosomes 11 and 14 with overexpression of cyclin D1. First line therapy for young patients consists in 3 cycles of "R-CHOP21" alternated with 3 "R-DHAP21" and followed by an autograft conditioned by total body irradiation, cyclophosphamide and aracytine. For patients over 65 years of age, the treatment of choice consists in 8 cycles of "R-CHOP21". Maintenance treatment is under evaluation. Allografting is the only chance of cure in relapsed patients with good performance status. Targeted therapies will improve the prognosis of this disease.

[Current management of myelodysplastic syndromes]. / Prise en charge actuelle des syndromes myélodysplasiques.

Treatment of myelodysplastic syndromes (MDS) has improved in recent years with better results of allogeneic stem cell therapy (SCT), the advent of new therapeutic options such as hypomethylating agents and lenalidomide, the introduction of iron chelation therapy and the implication of erythropoietic stimulating agents in the treatment of anemia. In this review, we summarize the different diagnostic and prognostic criteria and outline the different treatment options we have in 2011.

The Belgian 2010 consensus recommendations for the treatment of multiple myeloma.

Since the introduction of novel therapeutic agents including thalidomide, lenalidomide and bortezomib, the prognosis of multiple myeloma (MM) has significantly improved. These agents have been incorporated into numerous treatment schedules for newly diagnosed as well as more advanced MM patients. Hence, the therapeutic options for MM have become more complex and subject to rapid changes. The multiple myeloma study group (MMSG) of the Belgian Hematological Society has established recommendations for the treatment of MM as based on an extensive review of the literature which is also summarized in this paper. The recommendations are the result of a consensus opinion between haematologists with experience in the field and representing most haematology centres in Belgium. Where applicable, reimbursement criteria are also taken into account. The consensus recommendations should be a reference for use by clinical haematologists in daily practice.

[Retroperitoneal fibrosis and multiple myeloma: fortuitous association?]. / Fibrose rétropéritonéale et myélome multiple : association fortuite ?

We report a 59-year-old man presenting with retroperitoneal fibrosis (RF) associated with IgG lambda multiple myeloma. Recent clinical and immunohistochemical findings suggest that RF might be a particular expression of plasma cell/lymphoid dyscrasia, and that this association is not merely fortuitous. We review the pathophysiological evidence supporting this hypothesis.

Antitumour and antiangiogenic effects of Aplidin in the 5TMM syngeneic models of multiple myeloma.

Aplidin is an antitumour drug, currently undergoing phase II evaluation in different haematological and solid tumours. In this study, we analysed the antimyeloma effects of Aplidin in the syngeneic 5T33MM model, which is representable for the human disease. In vitro, Aplidin inhibited 5T33MMvv DNA synthesis with an IC(50) of 3.87 nM. On cell-cycle progression, the drug induced an arrest in transition from G0/G1 to S phase, while Western blot showed a decreased cyclin D1 and CDK4 expression. Furthermore, Aplidin induced apoptosis by lowering the mitochondrial membrane potential, by inducing cytochrome c release and by activating caspase-9 and caspase-3. For the in vivo experiment, 5T33MM-injected C57Bl/KaLwRij mice were intraperitoneally treated with vehicle or Aplidin (90 microg kg(-1) daily). Chronic treatment with Aplidin was well tolerated and reduced serum paraprotein concentration by 42% (P<0.001), while BM invasion with myeloma cells was decreased by 35% (P<0.001). Aplidin also reduced the myeloma-associated angiogenesis to basal values. This antiangiogenic effect was confirmed in vitro and explained by inhibition of endothelial cell proliferation and vessel formation. These data indicate that Aplidin is well tolerated in vivo and its antitumour and antiangiogenic effects support the use of the drug in multiple myeloma.

Endothelial cell-driven regulation of CD9 or motility-related protein-1 expression in multiple myeloma cells within the murine 5T33MM model and myeloma patients.

The cell surface expression of CD9, a glycoprotein of the tetraspanin family influencing several processes including cell motility and metastasis, inversely correlates with progression in several solid tumors. In the present work, we studied the expression and role of CD9 in multiple myeloma (MM) biology using the 5T33MM mouse model. The 5T33MMvitro cells were found to be CD9 negative. Injection of these cells in mice caused upregulation of CD9 expression, while reculturing them resulted in downregulation of CD9. Coculturing of CD9-negative 5T33MMvitro cells with BM endothelial cells (BMECs) resulted in a partial retrieval of CD9. Laser microdissection followed by real-time polymerase chain reaction and immunohistochemistry performed on bone sections of 5T33MMvivo diseased mice demonstrated strong local expression of CD9 on MM cells in contact with BMEC compared to MM cells further away. These findings were also confirmed by immunohistochemistry in MM patients. Neutralizing anti-CD9 antibodies inhibited transendothelial invasion of CD9-expressing human MM5.1 and murine 5T33MMvivo cells. In conclusion, we provide evidence that CD9 expression by the MM cells is upregulated in vivo by close interaction of the cells with BMEC and that CD9 is involved in transendothelial invasion, thus possibly mediating homing and/or spreading of the MM cells.

Factor V inhibitor after injection of human thrombin (tissucol) into a bleeding peptic ulcer.

Endoscopic injection of fibrin glue into a bleeding peptic ulcer is an effective and safe treatment modality. The present report describes a patient who developed rectal bleeding from an arteriovenous malformation after endoscopic injection of fibrin glue containing human thrombin into a gastric ulcer. Additional laboratory investigations revealed the presence of an inhibitor against coagulation factor V, which resulted in severe coagulopathy, triggering the bleeding. Acquired factor V inhibitors have frequently been reported with the use of bovine thrombin, but to our knowledge, they have never been documented in patients exposed to human thrombin. Endoscopists should be aware of this rare, but potentially serious, complication.