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Le bortézomib est un médicament essentiel pour la prise en charge du myélome multiple. Cependant, ce médicament anticancéreux neurotoxique est responsable d’une neuropathie périphérique chimio-induite (CIPN).Cette étude transversale monocentrique a été menée pour évaluer la prévalence et la sévérité de la CIPN sensorielle et motrice, les comorbidités et traitements chez les patients atteints de myélome multiple après la fin du traitement par bortézomib. Un questionnaire papier a été envoyé aux patients pour enregistrer les scores de CIPN sensorielle et motrice, la douleur neuropathique, l’anxiété et la dépression, les scores de qualité de vie et les analgésiques en cours.La prévalence de la CIPN sensorielle était de 29,6% (intervalle de confiance à 95% : 16,7 ;39,1) parmi les 67 patients inclus pendant une durée moyenne de 2,9 ± 2,8 ans depuis la dernière administration de bortézomib. Les scores de CIPN motrice étaient significativement plus élevés pour les patients avec une CIPN sensorielle que pour ceux sans (p < 0,001). La douleur neuropathique a été dépistée chez 14,9% des patients atteints de CIPN sensorielle. Parmi eux, 66,7% avaient des analgésiques en cours, mais aucun n’était traité par la duloxétine. Une analyse multivariée a révélé que le traitement par thalidomide (odds-ratio : 6,67 ; IC95% : 1,25 ; 35,52), p = 0,03) et les deux voies d’administration (intraveineuse et sous-cutanée) de bortézomib (odds-ratio : 13,40 ; IC95% : 1,29 ; 139,08), p = 0,03) étaient associés à la CIPN sensorielle.La CIPN sensorielle affecte un quart des patients après la fin du traitement par bortézomib et a été associée à une détresse psychologique.

Acquired hemophilia A (AHA) is a rare and potentially severe bleeding disorder caused by circulating autoantibodies directed against factor (F) VIII. Apart from idiopathic cases, AHA is associated with autoimmune diseases, cancers, use of medications, pregnancy and the post-partum period. We report the case of a 78-year-old a male patient presenting with symptoms of a hematoma after a fall three days previously. He is medically followed for multiple myeloma and bullous pemphigoid. Laboratory investigations revealed isolated and recent increased of activated partial thromboplastin time (80,6/32,1s) and a markedly low FVIII activity (< 1%). The high-titer of FVIII inhibitor (19 Bethesda units/mL) confirmed the diagnosis of AHA diagnosis. The symptoms were noticeably alleviated following bortezomib, cyclophosphamide and dexamethasone therapy. This report describes a rare case of AHA associated with bullous pemphigoid and multiple myeloma. These pathologies induce an immunity modification that can predispose or be associated with the development of anti-FVIII inhibitors. This case illustrates two possible physiopathological hypotheses for the development of AHA, which will be discussed in this case report.

Multiple myeloma treatment. Multiple myeloma is still an incurable disease but the recent therapeutics progress have revolutionized its management and improved prognosis. The first-line treatment of younger patients undoubtedly rests on the therapeutic intensification with autologous peripheral stem cell transplantation. The induction and especially the consolidation phases are complementary in this intensive program with the aim to obtain a deep and lasting response. Triple associations with proteasome inhibitor, immunomodulator and dexamethasone are the standard treatment. Maintenance by Lenalidomide will certainly become a standard of care in the near future for a period yet to be defined. For older patients the associations VMP and Rd are validated and are to be discussed on a case-by-case basis. In relapse, the combinations of chemotherapy are also the rule.Traitement du myélome multiple. Le myélome multiple est encore actuellement une maladie incurable, mais les progrès thérapeutiques des dernières années ont révolutionné sa prise en charge et permis d’améliorer le pronostic. Le traitement de première ligne des patients les plus jeunes repose indiscutablement sur l’intensification thérapeutique avec autogreffe de cellules souches périphériques. Les phases d’induction et surtout de consolidation sont complémentaires dans ce programme intensif visant à obtenir une réponse profonde et durable. Les associations triples inhibiteur du protéasome-immunomodulateur-dexaméthasone sont le traitement de référence. L’entretien par le lénalidomide va certainement devenir incontournable dans un futur proche : sa durée reste cependant encore à définir. Pour les patients âgés, les associations VMP (bortézomib-melphalan-dexaméthasone) et Rd (lénalidomide- dexaméthasone faible dose) sont validées, et le choix à discuter au cas par cas. En rechute, les combinaisons de plusieurs médicaments sont également la règle.

Daratumumab is a monoclonal antibody that targets CD38. It has an anti-tumor action on the myeloma cell and an immunomodulatory action. For relapsing and/or refractory myeloma patients, daratumumab is effective both alone and in combination and significantly improves progression-free survival. Daratumumab has been approved in 2016 in France for treatment of relapses or refractory multiple myeloma.

The safety of the community treatment with oral anticancer therapies is a strong theme of the cancer plan 2014-2019. The objective of this study was to develop a Pharmaceutical Counseling Guide to improve medication adherence in patients treated for multiple myeloma with oral anticancer therapies. A multidisciplinary professional working group selected a list of relevant medication adherence-related items that served as the framework for the design of the pharmaceutical counseling support materials in patient-accessible language. The readability, understanding and memorization of the information were validated in ten patients treated for myeloma. Twelve items were selected for treatment information (5 items), treatment planning (5 items), and adverse drug effects (2 items). A pharmacist guide, a patient guide, a medication schedule, and three self-questionnaires to evaluate medication knowledge and understanding of patients were developed. The patient test resulted in changes in these documents. This study carried out the initial validation of documents to standardize the pharmaceutical counseling for patients treated for myeloma so that it can be reproduced from one patient to another regardless of the pharmacist, by standardizing the information issued. This study needs to be completed by a final validation in myeloma patients, free from oral anticancer therapies.

Chemotherapy-induced peripheral neuropathy (CIPN) is common with specific semiological characteristics. When CIPN appears, there are many difficulties in guaranteeing sustained treatment, especially with optimal protocol. Moreover, CIPN have bad repercussions on quality of life after cancer disease. In this article, we have achieved a current state of CIPN and try to report details about semiological characteristics and topography. We have also produced some epidemiological data. Nonetheless, we have not voluntarily introduced treatment because it will be the topic of further work.

Digital ulcers generally arise in a context of microangiopathy-related focal ischemia. In women, connective tissue diseases are the main etiology, while in men the cause is often diffuse arterial disease, e.g. Leo-Buerger disease, or emboligenic heart disease. A paraneoplastic origin of digital necrosis due to ischemia is rarely reported. A 75-year-old man presented with cyanosis of the fingertips and toes that had begun one month earlier. The physical examination found pulp ulcers on the fingers and toes of both hands and feet. Two weeks later, necrotic damage developed distally, with no other associated symptoms. Blood tests were suggestive of Kahler disease; immunodeficiency disorders tests were negative; the cyroglobulin test was positive. Multiple-drug chemotherapy was followed by clinical improvement. Distal necrotic damage is a frequent inaugural symptom in vascular disease. If the common causal mechanisms (iatrogenic, occupational, toxic, atheromatous, emboligenic heart disease, or systemic disease) have been ruled out, it is important to search for a blood disorder or cancer as the cause of distal necrotic damage.

Disease relapse remains the first cause of mortality of hematological malignancies after allogeneic hematopoietic stem cell transplantation (allo-HCT). The risk of recurrence is elevated in patients with high-risk cytogenetic or molecular abnormalities, as well as when allo-HCT is performed in patients with refractory disease or with persistent molecular or radiological (PET-CT scan) residual disease. Within the frame of the 7th annual workshops of the francophone society for bone marrow transplantation and cellular therapy, the working group reviewed the literature in order to elaborate unified guidelines for the prevention and treatment of relapse after allo-HCT. For high risk AML and MDS, a post transplant maintenance strategy is possible, using hypomethylating agents or TKI anti-FLT3 when the target is present. For Philadelphia positive ALL, there was a consensus for the use of post-transplant TKI maintenance. For lymphomas, there are no strong data on the use of post-transplant maintenance, and hence a preemptive strategy is recommended based on modulation of immunosuppression, close follow-up of donor chimerism, and donor lymphocytes infusion. For multiple myeloma, even though the indication of allo-HCT is controversial, our recommendation is post transplant maintenance using bortezomib, due to its a good toxicity profile without increasing the risk of GVHD.

La leucémie à plasmocytes, variante la plus agressive des gammapathies monoclonales, résulte d'une prolifération monoclonale de cellules plasmocytaires habituellement secrétantes. Sa présentation clinique est plus agressive que le mylome multiple, avec une masse tumorale plus importante. Une chimiothérapie intensive utilisant des agents alkylants ou des anthracyclines ou des schémas à base d'ihnibiteurs de protéasome, en l'occurence le bortezomib, a amélioré l'issus de la maladie et ce médicament devitn la base du traitement de la leucémie à plasmocytes. Dans cet article, nous rapportons une série de trois observations de leucémies à plasmocytes primaires diagnostiquées et traitées dans le service d'hématologie clinique de l'hopital militaire d'instruction Mohammed V à Rabat, Journal Marocain des Sciences Médicales, Vol. 20, No 2 (2016)

L'amylose AL systémique primitive est un désordre hématologique rare. La plupart des recommandations thérapeutiques sont basées sur des études de phase II ou des comparaisons rétrospectives et des séries de cas. Le but de cette étude était de décrire les cas d'amylose primitive AL et de faire une comparaison entre le protocole standard Melphlan-Dexamethasone et les nouveaux agents dans le traitement de première ligne de ces patients. Il s'agissait d'une étude rétrospective, descriptive et multicentrique, portant sur l'ensemble des cas d'amyloses AL colligées durant une période s'étalant de juillet 2009 à juin 2016 au sein de 2 centres hospitaliers militaires. Vingt cinq patients ont été colligés dans notre série (12 traités par le Melphalan-Dexamethasone et 13 par des protocoles contenant au moins du Bortézomib ou du Lénalidomide). Il n'y avait pas de différence significative entre les 2 groupes en termes de caractéristiques épidémiologiques, cliniques ou pronostiques. Après un suivi médian de 40 mois, la survie globale médiane était de 54 mois dans le groupe melphalan-Dexamethasone et de 60 mois dans le groupe nouvelles thérapeutiques (P = 0,98). Concernant la survie sans progression, elle était de 18 mois pour le groupe traitement standard contre 11 mois pour le 2ème groupe (P = 0,08). Dans notre petite série nous n'avons pas trouvé une supériorité des nouvelles thérapeutiques par rapport au protocole classique. Ce résultat doit être confirmé par la réalisation d'une vraie étude prospective surtout en raison du coûtde ces nouvelles molécules qui ne sont pas toujours accessibles surtout dans les pays en voie de développement.

Monoclonal immunoglobulin (Ig) deposition disease (MIDD) is a rare complication of plasma cell disorders, defined by linear Congo red-negative deposits of monoclonal light chain (LCDD), heavy chain (HCDD) or both (LHCDD) along basement membranes. MIDD should be suspected in patients presenting with glomerular proteinuria and monoclonal gammopathy, but none of these criteria is necessary for the diagnosis although renal involvement is prominent. Since an abnormal serum κ/λ ratio is found in virtually all MIDD patients, including those with HCDD, serum free light chain assay should be included in the initial workup in patients older than 50 presenting with kidney disease. Bortezomib-based regimens are efficient and well tolerated, resulting in improvement in both renal and global survival, comparatively to historical series. High dose melphalan with autologous stem cell transplantation may be proposed as second line therapy in selected patients. The achievement of hematological response, based on the difference between involved and uninvolved serum free light chains (dFLC), is mandatory. In a recent series, post-treatment dFLC

Cryoglobulins are circulating immunoglobulins that precipitate with cold temperature and dissolve with rewarming. Type 1 cryoglobulinemia is composed of a single monoclonal immunoglobulin and is associated with renal involvement in up to 40% of cases. Type 1 cryoglobulinemia is related to an underlying B-cell haematological malignancy in 60% of patients. In the remaining cases, in the absence of criteria for malignancy, the diagnosis of monoclonal gammopathy of renal significance should be established. The clinical and biological setting and histological features of type 1 cryoglobulinemia are globally similar to those of mixed cryoglobulinemia. In case of haematological malignancy, the treatment is guided by the nature of the underlying disease, and aims at inducing haematological remission, which is necessary for the renal response. The management of monoclonal gammopathy of renal significance has been clarified by an international consensus group and is based on the nature of the underlying clone. In case of monoclonal cryoglobulinemia associated with a plasma-cell clone (IgG or IgA), the treatment is based on the combination of bortezomib, cyclophosphamide and dexamethasone. In case of IgM monoclonal cryoglobulinemia, the treatment is similar to that of Waldenström macroglobulinemia, and is based on rituximab. The clinical course of renal monoclonal cryoglobulinemia is intimately associated with the haematological response, and is usually favourable.

Monoclonal immunoglobulin (Ig) deposition disease (MIDD) is a rare complication of plasma cell disorders, defined by linear Congo red-negative deposits of monoclonal light chain (LCDD), heavy chain (HCDD) or both (LHCDD) along basement membranes. Renal involvement is prominent. Treatment strategies, including the impact of novel anti-myeloma agents remain poorly defined. We retrospectively studied 49 MIDD patients who received a median of 4.5 cycles of intravenous Bortezomib (1.3mg/m2) +dexamethasone (BD) (n=25), BD+cyclophosphamide (n=18), or BD+thalidomide or lenalidomide (n=6). The hematological diagnosis was monoclonal gammopathy of renal significance (n=38), symptomatic multiple myeloma (n=10), and Waldenström macroglobulinemia (n=1). The overall hematologic response rate, based on the difference between involved and uninvolved serum free light chains (dFLC), was 91%. After median follow-up of 54 months, 5 patients had died and 2 had reached end-stage renal disease. Renal response was achieved in 26 patients (53%), with 35% increase in median eGFR and 86% decrease in median 24-hour proteinuria. Predictive factors of renal response were pre-treatment eGFR>30mL/min/1.73m2 and post-treatment dFLC30mL/min/1.73m2 avant traitement, et dFLC

National audience; Résumé Auparavant caractérisé par un très mauvais pronostic, le myélome multiple (MM) est aujourd’hui compatible avec une survie prolongée, grâce aux progrès majeurs liés à l’utilisation des « nouveaux agents » : les inhibiteurs du protéasome (dont le bortézomib) et les IMiD (immunomodulateurs, tels que la thalidomide ou le lénalidomide). Cependant, la grande majorité des patients – si ce n’est tous les patients – vont rechuter et devenir éventuellement réfractaires à tous les traitements disponibles, y compris ces nouveaux agents. Il reste donc des progrès à faire dans cette situation, notamment via le développement de la prochaine génération d’inhibiteurs du protéasome et d’IMiD, et le développement de nouvelles classes thérapeutiques. Cette revue se concentre sur le pomalidomide, un IMiD de nouvelle génération dont l’utilisation a été récemment approuvée par la Food and Drug Administration (FDA) aux États-Unis et l’European Medicines Agency (EMA) en Europe, pour les patients présentant un myélome multiple en rechute ou réfractaire, ayant déjà reçu au moins 2 lignes thérapeutiques dont le lénalidomide et le bortézomib, et dont la maladie a progressé au cours de leur dernière ligne de traitement. Abstract Once characterized by a very poor outcome, multiple myeloma (MM) now has a significantly prolonged survival, with major improvements allowed by the use of “novel agents”: proteasome inhibitors (first-in-class bortezomib) and immunomodulatory compounds (IMiDs; first-in-class thalidomide and lenalidomide). However, the vast majority – if not all – of patients with MM ultimately end up being refractory to all existing drugs, including these efficient novel agents. There is a clear unmet medical need in this situation, which warrants the development of the next generation of proteasome inhibitors and IMiDs, as well as new drug classes. This review focuses on pomalidomide, the next generation IMiD, recently approved by the US FDA and the EMA for patients with relapsed or refractory MM who have received at least two prior therapies, including lenalidomide and bortezomib, and have demonstrated disease progression on their last therapy

Plasma cell leukemia (PCL) is a rare disorder which develops spontaneously (primary PCL) or evolves in patients with multiple myeloma (secondary PCL). It is defined by the presence of 2 × 10(9)/L peripheral blood plasma cells or plasmacytosis accounting for more than 20 % of the differential white cell count. PCL presents more often extramedullary involvement, anemia, thrombocytopenia, hypercalcemia, as well as impaired renal function. Cytogenetic abnormalities and mutations observed in PCL lead to escape from immune surveillance and independence from the bone marrow microenvironment with changes in expression of adhesion molecules or chemokines receptors. The outcome of PCL has improved with combination approaches with novel agents (including bortezomib and immunomodulatory drugs, such as lenalidomide) and with autologous stem cell transplantation. Allogeneic hematopoietic stem cell transplantation is currently available for young patients. This article is an overview of this rare and severe disease and the different therapeutics options that are recommended.

Plasma cell leukemia (LP) is a rare hematologic malignancy. Its prognosis is very derogatory. It is defined by the presence in circulating blood of more than 2 G/L plasmocytes or greater than 20% of the total leukocytes. It comes in two forms: secondary plasma cell leukemia complicating multiple myeloma (MM) and primary setting. Its incidence is estimated at 0.9% of patients with acute leukemia and 2-4% of patients with MM. We report, through three observations, the clinical presentation of the plasma cell leukemia, its cytological features, immunophenotypic, physiopathological and therapeutic care.

Cryofibrinogenaemia is an under-recognized cutaneous thrombotic vasculopathy that may be revealed by purpura or chronic necrotic ulcerations. We report two original cases characterized by their severity, their association with a monoclonal gammopathy and their excellent response to treatment.A 38-year-old woman was admitted for large necrotic leg ulcers appearing 1 year earlier and already investigated. Non-specific signs were seen on a previous skin biopsy and the diagnosis of a factitious disorder was considered at that time. Further investigations revealed circulating cryofibrinogen associated with IgG kappa monoclonal gammopathy without cryoglobulinaemia. Plasmapheresis followed by bortezomid-dexamethasone to treat the monoclonal gammopathy resulted in rapid and complete healing of the ulcers, militating in favour of its involvement in cryofibrinogen formation. The second patient, a 91-year-old woman, was referred to our department for acute necrotic purpura of the legs. Skin biopsy revealed leukocytoclastic vasculitis. Glomerular nephropathy with acute renal failure and multiple arterial thromboses were associated with the skin condition. The cryofibrinogen assay was positive without cryoglobulinaemia and other causes of vasculitis were ruled out. The main component was monoclonal IgG lambda. Prednisone-cyclophosphamide treatment led to complete healing of the skin lesions and to recovery from the systemic consequences of cryofibrinogen without sequelae.Routine screening for cryofibrinogen in plasma should be performed to explore cutaneous symptoms of unexplained thrombotic vasculopathy, even in the presence of a non-specific skin biopsy. Specific treatment of cryofibrinogenaemia associated monoclonal gammopathy appears to be highly effective against manifestations of cryofibrinogenaemia.

The use of targeted therapies is increasing in the treatment of cancer. Monoclonal antibodies and tyrosine kinase inhibitors are the most commonly used but other classes such as mTOR inhibitors are increasingly prescribed. These treatments are often given in the long term in metastatic and maintenance treatments. It is therefore important to monitor the occurrence of immediate toxicities but also later and cumulative toxicities. Renal toxicities of targeted therapies are most often due to structural damages of the nephron. The anti-epidermal growth factor receptor (EGFR) and anti-vascular endothelial growth factor receptor (VEGFR) have renal side effects since growth factor receptors are expressed in the kidney. The toxicity of molecules such as bortezomib, erlotinib and lapatinib are less known. The approvals by the Food and Drugs Administration (FDA) and European Medicines Agency (EMA) of sorafenib, sunitinib and temsirolimus were based on studies of less than 3,000 patients. In this context, there is little data on their acute and chronic tolerance, including on the kidneys. This short review synthesizes the physiopathological hypotheses, early diagnosis and treatment of renal toxicity of major targeted therapies available in 2011.

International audience; Various renal disorders are associated with monoclonal gammopathies, secondary to tissue deposition or precipitation of a monoclonal immunoglobulin (Ig) or a fragment thereof (isolated Ig light chain or heavy chain). They are classified according to the localization of renal lesions, either glomerular or tubular and to the pattern of ultrastructural organization of Ig deposits. Renal disease in monoclonal gammopathies may be isolated, or associated with various systemic symptoms particularly in AL amyloidosis, Randall-type monoclonal Ig deposition disease and monoclonal cryoglobulinemias. Except for myeloma cast nephropathy, which occurs in the setting of high-mass myeloma and is recognized after electrophoretic analysis of proteinuria and AL amyloidosis, which diagnosis is usually made after pathological examination of non-invasive tissue specimens (i.e. abdominal fat or minor salivary glands), a kidney biopsy is required to identify the other types of renal disorders associated with monoclonal gammopathies and to estimate renal prognosis. Renal pathological diagnosis is difficult and relies on careful examination of kidney biopsy samples, by light microscopy, immunofluorescence studies using conjugates specific for Ig light and heavy chains, IgG sub-classes and heavy chain constant domains and by electron microscopy. In some cases, additional studies are required to identify the nature of deposits, such as immuno-electron microscopy or mass spectrometric-based proteomic analysis after laser dissection. In patients with renal disorders related to Ig light chain precipitation or deposition (myeloma cast nephropathy, AL amyloidosis, Randall-type light chain deposition disease), measurement of serum free light chains at baseline and throughout follow-up is mandatory to evaluate clonal response to chemotherapy. A more than or equal to 50% decrease in serum free light chain levels is associated with increased renal and patient survival. In AL amyloidosis, serum levels of markers of cardiac disease (NT-proBNP and troponin) are also closely associated with prognosis. Efficient chemotherapy, tailored to the underlying plasma cell or lymphoproliferative disorder and adapted to renal function, should be promptly introduced, even in the absence of overt malignant haematological disease. Renal prognosis and patient survival (particularly in AL amyloidosis and cast nephropathy) are closely associated with the rapid achievement of an haematological response. The combination of melphalan plus dexamethasone (MDex) is currently used as first-line chemotherapy in systemic AL amyloidosis. Bortezomib-based regimens are commonly employed as first-line treatment in myeloma cast nephropathy and Randall-type monoclonal Ig deposition disease and as second line therapy in AL amyloidosis patients with advanced cardiomyopathy or refractory to previous chemotherapy. Solid organ transplantation (heart and kidney) should be considered in patients with AL amyloidosis or Randall-type monoclonal Ig deposition disease and advanced cardiac or renal failure. Prolonged graft and patient survival may be obtained, providing that recipients do not have other severe organ involvement or symptomatic myeloma and that haematological remission has been achieved with chemotherapy before or after organ transplantation.

International audience; Systemic AL amyloidosis is a rare complication of monoclonal gammopathies. Renal manifestations are frequent, mostly characterized by heavy proteinuria, with nephrotic syndrome and renal failure in more than half of the patients at diagnosis. Without treatment, median survival does not exceed 12 months. Amyloid heart disease and diffusion of amyloid deposits are associated with reduced survival. Treatment of systemic AL amyloidosis has been profoundly modified with the introduction of international criteria for the definition of organ involvement and hematologic response, and with the use of sensitive tests for the measurement of serum-free light chain levels. Melphalan plus dexamethasone is now established as the gold standard for first line treatment of systemic AL, with similar efficacy and reduced treatment-related mortality compared to high-dose therapy. Modern chemotherapy regimens, based on the use of novel agents such as bortezomib and lenalidomide, might further improve patient survival.

Le bortézomib, premier inhibiteur du protéasome, est en France actuellement le traitement de référence du myélome multiple. C'est un produit coûteux dont la stabilité de la solution reconstituée et conditionnée en seringue n'est que de 8h à 25°C sel on le laboratoire, et de 5 jours à 5°C selon la publication d'André et al, Ann Pharmacotherapy 2005;39:1462-66. Il est difficile de préparer les seringues à l'avance ou de conserver, selon une procédure sécurisée, une seringue dont l'administration serait reportée au-delà de cette limite. L'étude de la stabilité d'une solution de bortézomib à 1 mg/mL conditionnée en seringue de polypropylène, avec comme critères de validation une perte de principe actif inférieure à 5% et une apparition de produit de dégradation inférieure à 1%, nous a montré que la solution de bortézomib à 1mg/mL est stable 35 jours après conservation entre 2 et 8°C, et 14 jours à température ambiante. Trois produits de dégradation sont apparus au réfrigérateur et six à température ambiante.Ces résultats permettent l'organisation :- en dose banding : dose standardisée non nominative ou- en préparation standardisée nominativeLa préparation de seringues à l'avance et la mise à disposition immédiate permet le limiter le temps de passage du patient en hôpital de jour. La réattribution des seringues non utilisées, selon une procédure de ré-étiquetage sécurisée, permet de n'avoir aucune perte financière en cas de préparation à l'avance et d'une annulation de cure.La stabilité sur 35 jours à conservation entre 2 et 8°C a permis la réorganisation du circuit du Velcade® dans l'unité de préparation des cytotoxiques de l'hôpital de Brabois. Nous travaillons désormais en préparation standardisée nominative anticipée.

EGFR may be considered as an old target, which can be inhibited both by monoclonal antibodies and tyrosine kinase inhibitors. Those molecular targeted strategies are now approved in a wild range of tumors: colorectal cancer, lung cancer, pancreatic cancer and head and neck cancer. This paper proposes to describe the development of anti-EGFR drugs, highlighting several strategies points. Predicting biomarkers have been extensively studied for these agents, sustaining the hallmarks of the development of molecular targeting drugs.

After diffuse large B-cell lymphoma, follicular lymphoma is the most frequent non-Hodgkin's lymphoma. It remains incurable, except for localized diseases. Advanced disease has to be treated only in the presence of clinical and/or biology aggressiveness. These patients should be treated by rituximab (Mab-Thera) associated to polychemotherapy comprising cyclophosphamide, vincristine and prednisone. After this therapy, the benefit of rituximab in maintenance has to be confirmed. Autologous stem cell transplantation is now reserved for young patients in first relapse. Allogenic stem cell transplantation is also an interesting option. The other therapeutic options comprise radio-immunotherapy with 90Y ibritumomab tiuxetan (Zevalin) and bortezomib (Velcade).

Waldenström's macroglobulinemia (WM) is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells, along with the presence of an IgM monoclonal gammopathy in the blood. WM remains incurable with a median of 8-year of overall survival for patients with symptomatic WM. Treatment is postponed for asymptomatic patients and progressive anemia is the most common indication for initiation of treatment. The main therapeutic options include alkylating agents, nucleoside analogues, and rituximab, either alone or in combination. Studies involving new combination chemotherapy are ongoing and preliminary results are encouraging. However, there are several limitations to these approaches. The complete response rate is low and the treatment free survival is short in many patients, no specific agent or regimen has been shown to be superior to another, and no treatment has been specifically approved for WM. As such, new therapeutic agents are needed for the treatment of WM. In ongoing efforts, we and others have sought to exploit advances made in the understanding of the biology of WM so as to better target therapeutics for this malignancy. These efforts have led to the development of proteasome inhibitors as bortezomib, several Akt/mTor inhibitors, such as perifosine and Rad001. Many other agents and monoclonal antibodies are currently being tested in clinical trials and seem promising. This article provides an update of the current preclinical studies and clinical efforts for the development of novel agents in the treatment of WM.

Bortezomib (Velcade) is a proteasome used in the treatment of myeloma. It is associated with a number of adverse cutaneous effects, often described as papulonodular rash on the upper half of the body. We report a new case characterised by the presence of CD30+ lymphocytic infiltrate in the lesions.A 62-year-old woman receiving six courses of bortezomib for stage IIIA IgA myeloma presented a skin eruption during the second course of treatment that involved rounded papular or papulonodular elements on the upper body. Histopathological examination of a skin biopsy sample showed clinical picture reminiscent of Sweet's syndrome but including a significant number of CD30+ lymphocytes. The skin rash recurred to a greater or lesser degree during subsequent courses of therapy, but it was not necessary to discontinue the treatment. Symptoms subsided after the final course of bortezomib.Skin eruptions with bortezomib are a common occurrence but generally do not prevent continuation of treatment. While they have given rise to a variety of histopathological pictures, clinical settings such as those seen with our patient appear common. In terms of histopathology, the rash is reminiscent of Sweet's syndrome but our case differed in terms of the presence of CD30+ infiltrate. The latter may be compared with reactional infiltrates of the same type seen during use of other treatments for malignant blood diseases. The underlying mechanism is poorly understood.

Bortezomib (Velcade) is a proteasome inhibitor used in the treatment of myeloma and other blood dyscrasias. We report the cases of two patients who developed a peculiar toxic rash suggestive of Sweet's syndrome while receiving bortezomib; one patient also presented giant mucous membrane ulcerations.Case 1: bortezomib treatment was started in a 62-year-old man for mantle cell lymphoma. Ten days after the first treatment cycle, giant, painful oral ulcerations were noted but they resolved spontaneously. One week after the second cycle, further oral ulceration appeared, this time with a papulonodular skin rash. Histology showed neutrophilic dermal infiltrates in the skin with predominantly lymphocytic inflammation of the oral mucosa. Bortezomib was stopped and all lesions resolved with colchicine treatment. Case 2: a 46-year-old woman was receiving bortezomib treatment for plasma cell leukemia. A febrile skin rash appeared two days after the first treatment cycle but resolved spontaneously. After the first bortezomib injection during the next cycle, painful papules and nodules appeared on the trunk. The skin biopsy results were consistent with Sweet's syndrome. The lesions disappeared spontaneously. Dexamethasone was administered concomitantly with bortezomib in the ensuing cycles and there was no relapse of the skin lesions.Bortezomib-induced skin lesions are common and usually do not justify treatment withdrawal. Published observations of bortezomib-induced eruption occasionally show clinical and histological features of Sweet's syndrome, but there has been no mention of oral mucosal ulcerations. In our cases, these could be related to bortezomib-induced neutrophilic dermatosis.

Bortezomid is a potent proteasome inhibitor used in patients with relapsing or refractory multiple myeloma and provides a 35% response with a median duration of response of 12 months. Numerous adverse effects are known, mainly comprising haematological and neurological complications. A wide variety of cutaneous complications have also been described in 10 to 20% of patients.We report a case of bortezomib-induced Sweet syndrome. The diagnostic criteria required for drug-induced Sweet syndrome were present.The importance of this description is that this induced Sweet syndrome may not necessarily require cessation of bortezomid since administration of corticosteroids prevents its recurrence.

Malignant gliomas are the most common neoplasm of the central nervous system and patients prognosis remains dismal, despite aggressive surgery, radio- and chemotherapy. Radiotherapy is a major treatment modality in this tumoral type but its usefulness is limited by normal brain tissue toxicity. The concomitant administration of a radiosensitizing agent is an innovative strategy to improve ionizing radiations efficacy. Bortezomib (Velcade®) belongs to a new class of anticancer agents, i.e. the proteasome inhibitors, and this molecule has been approved for the treatment of multiple myeloma. Our objectives are to study the radiosensitizing properties of bortezomib on two human malignant glioma models xenografted onto nude mice. Our work was designed to evaluate the impact of treatment fractionation on the antitumor activity of the concomitant association of bortezomib and radiotherapy. Our results show that bortezomib is a potent radiosensitizer on our two malignant glioma models but these properties are lost when treatments are fractionated according to a typical clinical schedule. In conditions of fractionated treatment, we demonstrate that bortezomib reduces the radio-induced apoptosis. This may be linked to the loss of the inhibitory properties of bortezomib secondary to consecutive infusions. We also evaluate the importance of the transcription factor NF-kB in the radioresponse of the malignant glioma xenografts used. Finally, our work emphasizes on the importance of performing preclinical studies using doses and therapeutic schedule mimicking the clinical settings to provide more predictive results of treatment response in Humans., Les gliomes malins, tumeurs du système nerveux central les plus fréquentes ont un pronostic particulièrement sombre. Parmi les traitements standards de ce type de tumeurs, la radiothérapie occupe une place prépondérante mais son utilisation est limitée en raison de la mauvaise tolérance du tissu cérébral normal. Une des stratégies visant à améliorer l'efficacité de la radiothérapie consiste en l'administration concomitante d'un agent radiosensibilisant. Les inhibiteurs de protéasome sont une nouvelle classe d'agents anticancéreux et le bortézomib (Velcade®), chef de file de cette nouvelle classe, possède une AMM dans le traitement du myélome multiple. Les objectifs de nos travaux sont d'évaluer le potentiel radiosensibilisant du bortézomib sur deux modèles de gliome malin humain xénogreffés chez la souris nude. Nous avons apporté une attention particulière à l'impact du fractionnement du bortézomib et de la radiothérapie sur l'efficacité antitumorale de l'association. Nos résultats montrent que le bortézomib est un radiosensibilisant puissant sur les deux modèles de gliome malin utilisés mais que ce pouvoir est perdu lorsque les deux modalités thérapeutiques sont délivrées selon des doses et des schémas d'administration pertinents au regard de la clinique. En condition de traitement fractionné, nos études montrent également que le bortézomib induit une diminution de l'apoptose radio-induit, probablement en lien avec une perte de son activité inhibitrice du protéasome au fil des injections. Enfin, la place du facteur de transcription NF-kB dans la réponse à la radiothérapie fractionnée ou non pour le type tumoral que nous avons étudié est discutée. En conclusion, nos travaux insistent sur la nécessité de réaliser des études précliniques dans des conditions les plus proches possibles de la situation clinique, afin d?apporter des éléments plus prédictifs de la réponse chez l'Homme.

Mast cell disorders are defined by an abnormal accumulation of tissue mast cells in one or more organ systems. Clinical symptoms in mastocytosis result from mast cells derived mediators and, less frequently, from destructive infiltration of mast cells. Systemic mastocytosis is regressive among children, whereas the disease is persistent among adults. A clonal haematological non-mast cell lineage disease can be associated. The clinical course in these patients is variable ranging from asymptomatic for years to highly aggressive and rapidly devastating. Until recently, the only treatment of this incurable disease was symptomatic.Recent advances were done in understanding the physiopathology of this myeloproliferative syndrome which results from an activating mutation of the stem cell factor receptor: C-Kit. A somatic C-Kit mutation is usually detectable in mast cells and their progenitors. Different mutations were found and the mutation D816V is the most frequent. Their specific transduction paths were also studied. Diagnosis of systemic mastocytosis does not only rest upon pathological examination but also on molecular as well as immunological and immunochemical tools.Physiopathological advancements led to suggest new treatments in order to directly inhibit proliferative paths of masts cells such as tyrosine kinase inhibitors and rapamycin.

Although the number of men presenting with metastatic prostate cancer has decreased significantly over the last several years, the death rate for those men is essentially unchanged. Effective treatments have not existed for prostate cancer progressing after androgen deprivation therapy until recently. Docetaxel based chemotherapy has demonstrated to extend patient survival in two large randomized studies. These studies have provided the impetus to combine docetaxel with novel biologic drugs to further consolidate the gains in long-term outcome. With the arrival of new therapies such as epothilone analogues, small molecule receptor tyrosine kinase inhibitors, monoclonal antibodies, bone-targeted drugs, antisense oligonucleotides, antiangiogenics drugs and endothelin receptor antagonists, the future of prostate cancer therapy appears promising.

The treatment of elderly patients with multiple myeloma was based for the last forty years on the combination of alkeran plus prednisone. The survival was short. Three new molecules, thalidomide, bortezomib and revlimid are completely changing the way we treat myeloma as well as the prognosis. These new molecules are tested either alone or in combination. The addition of thalidomide to alkeran plus prednisone has increased overall survival of two years. For the first time, major therapeutic improvements are emerging giving rise to better prognosis.

After decades of minimal progress, two new classes of drugs with novels mechanisms of action: immunomodulatory drugs (thalidomide and lenalidomide) and proteasome inhibitors (bortezomib) have shown great activity for the treatment of multiple myeloma.Thalidomide acts by a variety of mechanisms; its efficacy is well known in disease relapse especially associated with dexamethasone. Recent results prove that combination of thalidomide with melphalan and prednisone should be considered as the first line standard of care in elderly patient. The main side effects are peripheral neuropathy and deep-vein thrombosis. Bortezomib is the first proteasome inhibitor. It is approved for the treatment in first disease relapse. The combination with glucocorticoids is synergistic. This combination in induction treatment before autologous stem cell transplantation is promising, as well as the combination with melphalan and prednisone in elderly patient. The main toxicities are fatigue and peripheral neuropathy. Lenalidomide is a structural analogue of thalidomide. Its efficacy in combination with dexamethasone has been proved in relapsing patients. The main toxicity is hematologic. Utilisation as first line treatment is also promising.These three drugs have toxicities predictable and manageable and can be used successively or in combination for greater effectiveness. They have an impact on the multiple myeloma treatment strategies and on the disease course itself.

Thalidomide, administered orally, bortezomib (Velcade) intravenously and lenalidomide (Revlimid), also orally, are three agents that act on myeloma relapse. Thalidomide acts by a variety of mechanisms and is toxic to the peripheral nervous system as well as teratogenic. It acts in synergy with dexamethasone. Recent results prove that its use as first-line treatment combined with oral conventional "MP" chemotherapy improves survival in patients older than 65 years. Its use as first-line treatment with this chemotherapy appears likely. Bortezomib is the first drug in the proteasome inhibitor class. It too is toxic to the peripheral nervous system and synergistic with dexamethasone. Several studies show its efficacy as first-line 'induction treatment' with dexamethasone, in patients to receive a subsequent autologous stem cell transplantation. The combination of bortezomib and "MP" is also promising. Lenalidomide, a structural analog of thalidomide, is effective in relapsing patients. Its toxicity is essentially hematologic. It is also synergistic with dexamethasone and promising as first-line treatment. These different drugs can be used successively at relapse, making myeloma a chronic disease. They can also be used together for greater effectiveness. These combinations will replace conventional chemotherapies in the future.

Multiple myeloma is a blood disease that is often easy to diagnose, relying on a combination of an excessive medullary plasmacytosis, a serum and/or urinary monoclonal immunoglobulin and one or several signs of organ involvement (anemia, renal failure, bone lesions, hypercalcaemia, infections). The beta2m, serum albumin, and certain chromosomal anomalies of the malignant clone are the essential prognostic factors. Intensive treatment with auto-transplantation of stem cells of peripheral blood is a significant development from which patients less than or equal to 65 years of age have benefited. The diphosphonates are combined with chemotherapy in order to limit the effect on bones, and recombinant erythropoietin is used in certain patients. Above all, therapeutic progress has been made thanks to thalidomide, bortezomib and lenalidomide, even if the optimal utilisation of these molecules is still to be determined.

Proteasome-mediated proteolysis is a mechanism for mediating important regulatory proteins within the cell. Proteins that have been targeted for degradation by the proteasome are convalently tagged with a poly-ubiquitin protein chain prior to be recognized by the 19S subunit of proteasome. This degradation system controls the expression of a wide variety of cellular targets including tumor suppressors such as p53, inhibitor of nuclear factor NFkappaB, cyclin-dependent kinase inhibitors such as p21 and p27. Because of these functions, the proteasome has become a new target for cancer treatment. The potent and selective proteasome inhibitor, PS-341 or Velcade was approved in the United States and launched in may 2003 for the treatment of multiple myeloma patients who have received at least two prior therapies. On April 2004, the European commission granted marketing authorization for Velcade with the same indication. The same year 2004, the Nobel Prize in chemistry was awarded to three researchers "for the discovery of ubitiquin-mediated protein degradation", a regulated process by which proteins are cleaved into peptides inside cells.

Since last years, the proteasome has emerged as a real and exciting target for anticancer therapy. Velcade (bortezomib, formerly known as PS341) remains the first selective proteasome inhibitor that has demonstrated significant preclinical activity in several tumor models and a significant efficacy in patients with refractory or relapsed multiple myeloma, resulting in an accelerated approval in US and Europe in such a setting. The major biological effect of bortezomib is the inhibition of the nuclear transcription factor NFkappaB, with subsequent inhibition of the growth tumor cells, induction of apoptosis, inhibition of angiogenesis and of cellular adhesion. The better understanding of the role of proteasome in the regulation of tumor cell growth has led to the development of new therapeutic approaches, notably in patients with multiple myeloma but also seems to hold interesting promises in other hematologic malignancies and solid tumors. This review provides a summary of the rationale for using proteasome inhibitors and an update on available and ongoing clinical studies involving human malignancies.