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To conduct a cost-effectiveness assessment of lenalidomide plus dexamethasone (Rd) vs bortezomib plus melphalan and prednisone (VMP) as initial treatment for transplant-ineligible patients with newly-diagnosed multiple myeloma (MM), from a U.S. payer perspective.A partitioned survival model was developed to estimate expected life-years (LYs), quality-adjusted LYs (QALYs), direct costs and incremental costs per QALY and LY gained associated with use of Rd vs VMP over a patient's lifetime. Information on the efficacy and safety of Rd and VMP was based on data from multinational phase III clinical trials and a network meta-analysis. Pre-progression direct costs included the costs of Rd and VMP, treatment of adverse events (including prophylaxis) and routine care and monitoring associated with MM. Post-progression direct costs included costs of subsequent treatment(s) and routine care and monitoring for progressive disease, all obtained from published literature and estimated from a U.S. payer perspective. Utilities were obtained from the aforementioned trials. Costs and outcomes were discounted at 3% annually.Relative to VMP, use of Rd was expected to result in an additional 2.22 LYs and 1.47 QALYs (discounted). Patients initiated with Rd were expected to incur an additional $78,977 in mean lifetime direct costs (discounted) vs those initiated with VMP. The incremental costs per QALY and per LY gained with Rd vs VMP were $53,826 and $35,552, respectively. In sensitivity analyses, results were found to be most sensitive to differences in survival associated with Rd vs VMP, the cost of lenalidomide and the discount rate applied to effectiveness outcomes.Rd was expected to result in greater LYs and QALYs compared with VMP, with similar overall costs per LY for each regimen. Results of this analysis indicated that Rd may be a cost-effective alternative to VMP as initial treatment for transplant-ineligible patients with MM, with an incremental cost-effectiveness ratio well within the levels for recent advancements in oncology.

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.

Irrigated agriculture is undergoing rapid change and is facing issues related to climate change, population growth, consumption patterns, competition for resources and cost of development. The challenge is whether water availability for irrigation along with rainfed production will be sufficient to meet growing food demand and improve global food security. Traditionally governments have been responsible for developments in the irrigation sector through planning, design and construction of projects. Trends toward decentralization, fiscal crisis and growth of the private sector have led government to divest some of its role to user organizations and the private sector. This has been known as the participatory approach to irrigation management and has been adopted widely by many countries with a range of institutional arrangements. Many irrigation and drainage schemes worldwide perform below their capacity. To modernize and improve this capacity will require innovation and technical advancement, but in addition issues of policy, governance, management and institution must be addressed. Copyright © 2014 John Wiley & Sons, Ltd.

Depuis les annees 1980, les traitements d’entretien dans le myelome multiple (MM) n’avaient pas fait la preuve d’un benefice. Avec l’arrivee ces dix dernieres annees des nouveaux agents et notamment des immunomodulateurs (IMiDs), la question du traitement d’entretien dans le MM a pu etre recemment reconsideree. De nombreux essais de phase 3 ontmontre un benefice de l’utilisation du thalidomide dans cette indication en termes de reponse, de survie sans progression et pour certains de survie globale. Cependant, la survenue d’effets secondaires necessite frequemment son arret premature. Le lenalidomide, un autre IMiD pourvu d’une meilleure tolerance clinique, est alors apparu comme le candidat ideal en traitement d’entretien dans le MM. Les resultats intermediaires des essais de phase 3 sont encourageants. Dans cette revue de la litterature, nous discuterons les resultats des essais de phase 3 portant sur le traitement d’entretien dans le MM par thalidomide et par lenalidomide.

Resume Le myelome multiple (MM) est une hemopathie maligne caracterisee par le developpement d'un clone de plasmocytes tumoraux envahissant la moelle hematopoietique. Le pronostic demeure sombre a l'heure actuelle, malgre les progres realises avec l'introduction du procede d'intensification therapeutique avec autogreffe de cellules souches peripheriques (ASCT). Dans ce contexte, l'arrivee recente de molecules innovantes, telles que le thalidomide et ses analogues (essentiellement le lenalidomide) ou le bortezomib, premier inhibiteur du proteasome developpe en clinique, a revolutionne la comprehension et l'approche therapeutique du MM. Cette revue se propose de faire le point sur l'amelioration des techniques d'ASCT et sur la place de plus en plus importante des molecules innovantes dans le schema therapeutique du MM. Par ailleurs, le MM touchant essentiellement le sujet âge, la prise en charge specifique de cette tranche d'âge sera detaillee.

Item does not contain fulltext Out of 690 allogeneic matched sibling donor transplants for multiple myeloma reported to the European Group for Blood and Marrow Transplantation (EBMT) registry, 334 were performed during the period 1983-93 (all with bone marrow) and 356 during 1994-98 [223 with bone marrow and 133 with peripheral blood stem cells (PBSCs)]. The median overall survival was 10 months for patients transplanted during the earlier time period and 50 months for patients transplanted with hone marrow during the later period. The use of PBSCs was associated with earlier engraftment but no significant survival benefit compared to bone marrow transplants during the same time period. The improvement in survival since 1994 with the result of a significant reduction in transplant-related mortality, which was 38%, 21% and 25% at 6 months and 46%, 30% and 37% at 2 years during the earlier period, and the later period with bone marrow and PBSCs respectively. Reasons for the reduced transplant-related mortality appeared to be fewer deaths owing to bacterial and fungal infections and interstitial pneumonitis, in turn a result of earlier transplantation and less prior chemotherapy. Better supportive treatment and more frequent use of cytokines may also play a role. The improvement in survival was not directly related to the increased use of PBSCs.

Monoclonal gammopathy of undetermined significance (MGUS) is a frequent entity in the general population. The incidence rate of fortuitous discovery of a monoclonal component in asymptomatic patients is increasing nowadays. The majority of MGUS is being addressed to a hematologist for diagnosis or follow-up by their generalist practitioners. The management of MGUS consists of a clinical and biological surveillance as per published and validated international guidelines available for MGUS diagnosis and follow-up. MGUS thus may not necessarily need a specialized consultation and follow-up in a hematology ward, as we believe it could be performed by generalist practitioners.We studied 190 patients addressed to our hematology department of Lille for diagnosis or follow-up of MGUS.Among the patients, 9.5% developed a malignant hemopathy (multiple myeloma or Waldenström macroglobulinemia). Among patients diagnosed with MGUS of IgG isotype and a monoclonal component15 g/L, 96.2% showed no pejorative outcome: these represent simple and routine prognostic factors that can be assessed at diagnosis in order to predict the risk of progression. Those patients could have easily been followed by their generalist practitioner from the diagnosis of MGUS.A specialist's consultation would still be recommended for patients with pejorative factors at diagnosis, or if a clinical or biological event that could suggest progression occurs during follow-up, or in case of MGUS with complication, in which cases patients would need a specialized management in a hematology department.

Resume Le POEMS syndrome est une affection multisystemique correspondant a un acronyme: polyneuropathie, organomegalie, endocrinopathie, gammapathie monoclonale, manifestations cutanees (skin changes). De nombreuses autres manifestations peuvent etre rencontrees: le plus souvent œdemes generalises, cachexie, thrombocytose, polyglobulie, plus rarement hypertension arterielle pulmonaire, microangiopathie glomerulaire. Le syndrome inflammatoire biologique est rarement important. L'organomegalie peut etre soit une hepatomegalie et/ou une splenomegalie et/ou des adenopathies dont l'examen anatomopathologique peut parfois mettre en evidence un aspect de maladie de Castelman. La distinction entre POEMS syndrome et myelome osteocondensant est discutable. L'importance de la gammapathie monoclonale est en regle generale modeste, souvent inferieure a 30 g/L et il s'agit toujours d'une chaine legere λ. Contrairement au myelome multiple, il n'y a pas d'hypercalcemie, de fracture osseuse ou d'insuffisance renale liee a la chaine legere ou d'augmentation majeure de l'immunoglobuline monoclonale au cours de l'evolution. Les plasmocytes medullaires sont inferieurs a 15 % et leurs caracteristiques sont celles rencontrees dans les gammapathies monoclonales de signification indeterminee. La physiopathologie est inconnue mais une hyperproduction de cytokines pro-inflammatoires en particulier du TNFα de l'IL-6 et de l'IL-1β ont ete decrites. Il semble egalement exister un defaut de production des antagonistes de ces cytokines. Certaines manifestations cliniques semblent reliees a l'exces de certaines cytokines en particulier l'IL-6 et le TNFa. L'aggravation de la polyneuropathie et les signes generaux essentiellement marques par une cachexie progressive emaillent le cours evolutif et sont responsables de la plus part des deces. En dehors des corticoides et du traitement chirurgical ou radiotherapique d'une lesion osseuse unique, le traitement est decevant. La survie a 5 ans est de 60 %.

The purpose of this study was to assess the value of the serum amyloid P (SAP) component scintigraphy in patients with primary amyloidosis (AL).Pure human SAP labeled with iodine-123 (123I-SAP) was given intravenously to 24 patients with biopsy-proven systemic amyloidosis (15 without multiple myeloma = group 1, and 9 with multiple myeloma = group 2) and to 6 patients with multiple myeloma without any clinical or biological signs of amyloidosis (group 3). Whole-body images as well as regional views and tissue retention levels were obtained after 24 hours. Our study was approved by the institutional review committee and all individuals gave informed consent and were prospectively studied (median 13 months, range 1 to 47 from the date of the scintigraphy to May 1995).Organ localization of 123I-SAP, indicating the presence of substantial visceral amyloid deposits, was observed in all patients in group 1 and 2. The organ uptake of 123I-SAP included the spleen (1 patient was splenectomized) in 20 of 23 cases (87%), the liver in 15 of 24 (60%), and the kidneys in 6 of 24 (25%). Myocardial 123I-SAP was never seen although 13 out of the 24 patients had clinical or echographic data for amyloidosis. Twenty-four hour tissue retention was significantly elevated in all patients (group 1 and group 2): 55.66% +/- 19.16% in group 1 and 34.37% +/- 24.92% in group 2, as compared with normal levels24%. The sensitivity of the technique was 79% when only organ uptake was considered but reached 100% when tissue retention was also considered. The 24-hour tissue retention might be correlated with the severity of the amyloidosis: mean survival in patients with tissue retention greater than 50% was 11.3 months versus 24.5 months in patients with levels less or equal to 50%. Five of the 6 patients with multiple myeloma without evidence of amyloidosis had abnormal 123I-SAP imaging and 24-hour tissue retention levels. In 2 of them, amyloidosis was secondly detected. In the 9 patients who had two scintigraphies, variations in 24-hour tissue retention values were in accordance with the clinical evaluation.Spleen and liver distribution of amyloidosis is mostly revealed by 123I-SAP scintigraphy in patients with AL amyloidosis. The uptake of 123I-SAP appeared in proportion to the quantity of amyloidosis present in different tissues, and the relative quantity of amyloid deposits in the myocardium, carpal tunnel, digestive tract, and kidneys was often small and seldom visualized by 123I-SAP scintigraphy. In contrast 24-hour tissue retention levels were abnormal in all cases of known AL amyloidosis. This may be a positive argument for the diagnosis of amyloidosis when histopathological tests are normal. Tissue retention levels appear important as they may be correlated with survival.

AIMS--To determine whether a particular phenotype or antigen is preferentially related to monoclonal gammopathies of undetermined significance (MGUS). METHODS--Bone marrow specimens from 56 patients with MGUS were stained immunocytochemically (ABC peroxidase) for CD38, CD56, CD9, CD10, CD19, CD20, CD22, and MB2. Specimens from patients recently diagnosed with multiple myeloma and reactive bone marrow samples were studied in parallel. RESULTS--CD38 was expressed on all plasma cells from all MGUS samples tested, while 36% were positive for CD56, CD9 and MB2 were both expressed strongly; CD20 was moderately expressed, and staining for CD10 and CD22 was uncommon. For these five B cell antigens there was no clear difference between their expression in MGUS and in multiple myeloma. A great difference was found for CD19: in MGUS this antigen was expressed on 2-91% of plasma cells (mean 35%) and 77% patients had > 10% positive plasma cells; in multiple myeloma its expression was low and only 12% patients had > 10% positive plasma cells. When these results were converted to numbers of CD19 positive plasma cells per 100 nucleated bone marrow cells, reactive bone marrow and MGUS specimens had a similar number of positive plasma cells. There was no correlation between expression of any of the antigens tested. CONCLUSIONS--Many of the so-called pre-B, B or activation antigens are present on plasma cells from MGUS specimens, and expression of CD9, CD10, CD20, CD22, MB2, and CD38 in MGUS was very similar to that in multiple myeloma. CD56 was frequently expressed in MGUS. In this series CD19 was highly expressed in MGUS but not in multiple myeloma. Plasma cells bearing this antigen could represent the non-neoplastic process and determination of its expression could be useful for the diagnosis of MGUS.

Background Osteonecrosis of the jaw (ONJ) has been reported in patients receiving bisphosphonates for metastatic bone disease. ONJ incidence, risk factors, and outcomes were evaluated in a combined analysis of three phase III trials in patients with metastatic bone disease receiving antiresorptive therapies. Patients and methods Patients with bone metastases secondary to solid tumors or myeloma were randomly assigned to receive either s.c. denosumab (120 mg) or i.v. zoledronic acid (4 mg) every 4 weeks. On-study oral examinations were conducted by investigators at baseline and every 6 months. Oral adverse events were adjudicated by an independent blinded committee of dental experts. Results Of 5723 patients enrolled, 89 (1.6%) patients were determined to have ONJ: 37 (1.3%) received zoledronic acid and 52 (1.8%) received denosumab (P = 0.13). Tooth extraction was reported for 61.8% of patients with ONJ. ONJ treatment was conservative in >95% of patients. As of October 2010, ONJ resolved in 36.0% of patients (29.7% for zoledronic acid and 40.4% for denosumab). Conclusions In this combined analysis of three prospective trials, ONJ was infrequent, management was mostly conservative, and healing occurred in over one-third of the patients. Educating physicians about oral health before and during bone-targeted therapy may help reduce ONJ incidence and improve outcomes.

For relapsed or refractory multiple myeloma (RRMM), a series of novel agents (thalidomide, bortezomib and lenalidomide) has emerged during the latest decade, but their use in routine clinical practice is not well documented as well as the cost of RRMM.Our aim is to review the therapeutic management of such patients in France and to estimate the associated costs.A retrospective cohort study, based on chart reviews, was conducted in French Haematology Departments over the period 2004-2007 and the associated direct costs estimated.One hundred and two patients with a relapse after first-line therapy were selected from five centres. The average follow-up from diagnosis or the date of first relapse to death or to the latest news was respectively 56.25 and 23.53 months. Novel agents were used in 73% of all cases, and in all cases of first relapse. Thalidomide and bortezomib were respectively the most frequently used second-line (57%) and third-line treatments (44%). The average number of lines of treatment received per patient as from first relapse was 2.75 (min 1; max 8) and the mean direct cost per month was estimated at 3130 € after the first relapse. This cost was represented in greater part by the cost of chemotherapy drugs (66%).The use of novel agents such as thalidomide, bortezomib and lenalidomide for RRMM is highly prevalent in France from the first relapse. The associated medical cost is substantial mainly due to the cost of the new agents.

Resume Entre Janvier 1980 et Janvier 1990, une tumeur testiculaire a ete revelatrice d'un lymphome malin non hodgkinien (LNH) chez 12 malades. Les âges variaient de 16 a 83 ans, 9 patients ayant plus de 50 ans. Dans 7 observations, le bilan pretherapeutique revele une ou plusieurs autres localisations viscerales, et dans 6 observations une masse tumorale de 10 cm ou plus. Le degre d'extension selon la classification d'Ann Arbor est le suivant IE: 3 cas; IIE: 1 cas; IV: 8 cas. Le type histologique selon la classification internationale est lymphoblastique (2 cas), a petites cellules non clivees de type Burkitt (1 cas), immunoblastique (2 cas), diffus a grandes cellules (2 cas), diffus mixte (3 cas), diffus a petits lymphocytes (1 cas) et inclassable (1 cas). Sept patients ont fait l'objet d'une orchidectomie qui n'a ete suivie dans 3 cas d'aucun traitement complementaire. Neuf patients ont subi une polychimiotherapie, intensive dans 6 cas. La mediane de survie est de 30 mois. Quatre malades, tous traites de facon intensive, sont en etat de premiere remission complete persistante. Cette etude confirme la rarete des LNH testiculaires. Il s'agit presque toujours sur le plan histologique de formes de malignite elevee ou intermediaire, survenant avec predilection chez le sujet âge et comportant des facteurs de mauvais pronostic. Cependant l'avenement des polychimiotherapies intensives semble devoir transformer l'evolution de ces formes, comme celle des autres LNH agressifs comportant des localisations plus courantes.

Lenalidomide is an immunomodulatory drug derived from thalidomide. It was developed to maximize the anti-inflammatory and anti-neoplasic properties of thalidomide and to reduce its toxicity. The molecular mechanism of action of lenalidomide is unclear, but its therapeutic activity is mainly due to its well defined anti-inflammatory, immunomodulatory, anti-proliferative and anti-angiogenic properties. In relapsed or refractory multiple myeloma (MM), lenalidomide, combined with standard dose dexamethasone, is superior to dexamethasone alone in terms of time to progression, response rate and overall survival. The most commonly reported adverse events include haematological toxicity with manageable neutropenia and thrombopenia. Lenalidomide does not trigger the limiting toxicities of thalidomide: somnolence, neuropathy and constipation. Lenalidomide, in combination with dexamethasone, is indicated for the treatment of MM patients who have received at least one prior therapy and is administered orally at the dose of 25 mg q.d. for 21 days of 28-day cycles. The drug is being investigated for the treatment of newly diagnosed MM. In this review, we summarize the pharmacokinetic, pharmacodynamic and clinical trial data on lenalidomide.

e28 Immunomodulatory drugs (IMiDs) directly trigger multiple myeloma (MM) cell apoptosis, abrogate adhesion to bone marrow (BM), modulate cytokines, inhibit angiogenesis, and augment T-cell, NK-cell, andNK-T cell function while downregulating Tregs. Binding to cereblon is implicated in both their direct cytotoxic and immunerelated effects. Importantly, they can augment immune therapies in MM, evidenced by increasing antibody-dependent cellular cytotoxicity and clinical activity of the mAbs elotuzumab, daratubumab, and SAR650984, and immunotoxin indatuximab ravtansine. MM cells and accessory cells that augment MM cell growth and suppress host immune function, including myeloid derived suppressor cells (MDSCs) and plasmacytoid dendritic cells (pDCs), express PD-L1; immune effector T and NK cells express PD-1. Moreover, PD-L1 expression increases with progression from normal to MGUS to active MM, and with progression from newly diagnosed to relapsed and refractory disease. Preclinical studies show that anti-PD-1 Ab, -PD-L1 Ab, or both can induce autologous effector cell-mediated cytotoxicity. Anti-PD-L1 Ab can induce MM-cell specific CD4 and CD8 CTLs and NK cell cytotoxicity, even in the presence of MDSCs and pDCs, thereby inhibiting MM cell growth in the BM. PD-L1 is induced on MM and accessory cells in the BM, as is PD-1 on immune effector cells. Importantly, IMiDs downregulate PDL-1 expression on MM and accessory cells and PD-1 on immune effector cells, thereby enhancing CD4, CD8, and NK-cell mediated MM cytotoxicity in the presence of BM accessory cells. Peptide-based vaccine strategies are also being evaluated in smouldering MM to block progression to active disease, as are MM cell/DC fusion vaccines to treat minimal residual disease posttransplant and improve outcome. In both cases, CD4 and CD8 MM-specific immune responses have been triggered by vaccination; this can be increased by lenalidomide (LEN) and/or checkpoint inhibition. A randomized trial is now comparing LEN with LEN plus MM cell/DC fusion vaccine posttransplant; it is likely that LEN and checkpoint inhibition will be combined, to generate sustained autologous memory anti-MM immunity. Immune approach combinations including mAbs, vaccines, IMiDs, and checkpoint inhibitors offer great potential to overcome effects of immune suppressive cytokines and accessory cells in the BM microenvironment, restore host CD4, CD8, and NK cell antitumour immunity, and so improve patient outcome in MM.

Using Cox models, we established a new prognostic system based on simple clinical parameters in a training series of 232 patients whose diagnoses were made before 1989. Adverse prognostic factors for survival (P

Purpose. - Thalidomide, a major teratogen drug, was rehabilitated mainly in malignant hemopathy. Current knowledge and key points. - Thalidomide-mechanisms of action are well known, multiple, they combine immunomodulatory, antiangiogenic properties, and the modulation of cytokines, particularly tumour necrosis factor-alpha. Multiple trials are ongoing, however, the main indication remain multiple myeloma with a response rate of 30% in relapsed patients. Future prospects and projects. - New structural analogues of the thalidomide which priviligiate some of the thalidomide-specific mechanisms of action, the selected cytokine inhibitory drugs (SelCIDS) and the immunomodulatory drugs (IMiDs) family are under evaluation. The IMiDs, which mechanism is based on stimulation of T lymphopoiesis rather than inhibition of tumour necrosis factor-alpha, are under clinical trials in multiple myeloma with interesting results.