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In Western countries, Cryptosporidium parvum infection is considered a rare opportunistic parasitic disease, most commonly seen in immunocompromised patients. Although most cases have been described in Acquired ImmunoDeficiency Syndrome (AIDS) patients, an increase of cases in other immunocompromised patients has been noted. We hereby describe the case of two patients from our institution in Northern France with heavily pre-treated multiple myeloma, both of whom underwent allogeneic stem cell transplants, who presented late Cryptosporidium infections while treated on novel agents. These cases illustrate novel examples of infection in multiple myeloma as survival improves and novel treatment approaches are being applied.

Background Streptococcus pneumoniae infection causes morbidity and mortality in multiple myeloma patients. Pneumococcal vaccination is commonly given to immunocompromised myeloma patients; however response data are sparse. Here, we present longitudinal response data to pneumococcal vaccination in multiple myeloma patients. Method Twenty‐eight multiple myeloma patients were included, 25 of whom were newly diagnosed. All the patients received two vaccines Prevnar13® and Pneumo23®. Serotype‐specific IgG was measured by ELISA for all 23 vaccine serotypes at baseline, and then sequentially at different time points postvaccination until treatment ended. Response to vaccination is available for 20 patients. The primary endpoint was the incidence rate of patients who obtained an isotype response serum concentration after vaccination. Secondary endpoints included detailed isotype increase, time to first increase, further assessment of a decreased anti‐pneumococcal serum concentrations following treatment including autologous stem cell transplantation (ASCT), rate of infection with a special attention to pneumococcal infection. Results The median age was 66 years and the male to female ratio was 0.6. Anti‐pneumococcal capsular polysaccharide (anti‐PCP23) IgG, IgG2, IgA, and IgM responses were detected within 1 week postvaccination. Response to at least one subtype of antibody was obtained in 85% (n = 17) of patients, for at least two subtypes in 65% (n = 13), for at least three subtypes in 55% (n = 11), and 2 patients responded to all four subtypes. The median increase in the concentration of anti‐PCP23 isotypes was threefold following vaccination, with the highest increase observed when Pneumo23® was given more than 30 days after Prevnar13®. The anti‐pneumococcal geometric mean concentration decreased significantly for all subtypes over time independently of treatment approaches. Conclusion Myeloma has the ability to demonstrate a response to pneumococcal vaccine, independently of preexisting hypogammaglobulinemia and possibly of treatment‐induced immunodepression. We also observed a drop in the serum response overtime and following autologous transplantation. Further studies in larger sample are needed to understand the benefit of vaccination strategies in these patients.

PURPOSE The wide heterogeneity in multiple myeloma (MM) outcome is driven mainly by cytogenetic abnormalities. The current definition of high-risk profile is restrictive and oversimplified. To adapt MM treatment to risk, we need to better define a cytogenetic risk classification. To address this issue, we simultaneously examined the prognostic impact of del(17p); t(4;14); del(1p32); 1q21 gain; and trisomies 3, 5, and 21 in a cohort of newly diagnosed patients with MM. METHODS Data were obtained from 1,635 patients enrolled in four trials implemented by the Intergroupe Francophone du Myélome. The oldest collection of data were used for model development and internal validation. For external validation, one of the two independent data sets was used to assess the performance of the model in patients treated with more current regimens. Six cytogenetic abnormalities were identified as clinically relevant, and a prognostic index (PI) that was based on the parameter estimates of the multivariable Cox model was computed for all patients. RESULTS In all data sets, a higher PI was consistently associated with a poor survival outcome. Dependent on the validation cohorts used, hazard ratios for patients in the high-risk category for death were between six and 15 times higher than those of patients in the low-risk category. Among patients with t(4;14) or del(17p), we observed a worse survival in those classified in the high-risk category than in those in the intermediate-risk category. The PI showed good performance for discriminating between patients who died and those who survived (Harrell’s concordance index greater than 70%). CONCLUSION The cytogenetic PI improves the classification of newly diagnosed patients with MM in the high-risk group compared with current classifications. These findings may facilitate the development of risk-adapted treatment strategies.

International audience; No abstract available

Single agent daratumumab has shown clinical activity in relapsed, refractory multiple myeloma (RRMM). The Intergroupe Francophone du Myélome 2014-04 trial was designed to further investigate daratumumab in combination with dexamethasone in triple RRMM patients. Patients received daratumumab infusions in combination with weekly dexamethasone until disease progression or unacceptable toxicity. Fifty-seven patients were included in the trial and evaluable for response. The overall response rate and the clinical benefit rate were 33% (n = 19) and 48% (n = 27), respectively. Five (8·8%) patients achieved a very good partial response or better. The median time to response was 4 weeks. For responding patients, the median progression-free survival was 6·6 months, compared to 3·7 months (3·0-5·5) for those with a minimal or stable disease. The median overall survival (OS) for all patients was 16·7 months (11·2-24·0). For responding patients, the median OS was 23·23 months, whereas that of patients with progressive disease was 2·97 months. The incidence of infusion-related reactions was 37%; all cases were manageable and did not lead to dose reduction or permanent treatment discontinuation. These data demonstrate that treatment with daratumumab and dexamethasone results in a meaningful long-term benefit with an acceptable safety profile for patients with triple RRMM.

Lenalidomide is manageable and effective in multiple myeloma, particularly in elderly patients. Surprisingly, the combination of lenalidomide with rituximab produced clinically significant anemia at 25 mg/day for 21/28 days, the highest possible dose, in Waldenstrom's Macroglobulinemia (WM). We aimed to determine the maximum tolerated dose (MTD) of single agent lenalidomide and determine its impact on WM. RV-WM-0426 is a multicenter dose escalation open label phase 1/2 study of lenalidomide in relapsed/refractory WM (RRWM). Lenalidomide was given orally 21/28 days per cycle for 1 year, at escalated dose of 15 to 20 mg during phase 1 to determine the MTD; the phase 2 part was conducted at the MTD. Seventeen RRWM patients were included. The MTD was established at 15 mg/day 21/28. By ITT analysis, the overall response rate was 29%. With a median follow-up of 36 months, median TTP was 16 months (95% CI 5.5-26), the 5-year OS was 91%. The most frequent adverse events ≥ grade 3 at 15 mg were 14% anemia and 43% neutropenia. The MTD of lenalidomide is 15 mg/day 21/28 days in RRWM. Lenalidomide is active in the treatment of RRWM and the safety profile appears manageable. Future studies may look into combinations of lenalidomide and continuous dosing.

Resume Introduction Les gammapathies monoclonales de signification indeterminee (MGUS pour monoclonal gammopathy of undetermined significance) sont frequentes dans la population generale. L’augmentation des decouvertes fortuites de pics d’immunoglobuline monoclonale conduit a l’envoi d’un nombre croissant de patients presentant une MGUS, en consultation de diagnostic ou de suivi chez l’hematologue par les medecins generalistes. La prise en charge d’une MGUS se resume a une surveillance clinico-biologique, surveillance qui pourrait etre realisee en ambulatoire sans necessairement passer par une consultation specialisee avec un hematologue. Methodes Nous avons etudie une population de 190 patients adresses pour diagnostic ou suivi d’une MGUS au CHRU de Lille. Resultats Parmi les patients, 9,5 % ont evolue vers une hemopathie maligne (myelome multiple ou maladie de Waldenstrom). Des parametres pronostiques simples au diagnostic permettent de preciser le risque d’evolution : ainsi, dans notre etude, 96,2 % des patients presentant une MGUS d’isotype IgG avec un pic monoclonal inferieur a 15 g/L n’ont pas eu d’evolution pejorative. Ces derniers auraient potentiellement pu beneficier d’une simple surveillance par le medecin generaliste des le diagnostic de MGUS, d’autant qu’il existe des recommandations internationales claires et consensuelles de diagnostic et de suivi des MGUS. Conclusion L’adressage au specialiste pourrait ainsi n’etre que secondaire a un signe pejoratif au diagnostic ou a une evolution defavorable de la MGUS constatee au cours de la surveillance clinique et biologique, et pour laquelle une prise en charge specialisee serait necessaire.

BACKGROUND Accurate quantification of immunoglobulin A (IgA) monoclonal immunoglobulins by serum protein electrophoresis (SPEP) can be difficult and can impact the assessment of response among patients with multiple myeloma (MM). Therefore, there is a need to identify new assays that better reflect disease burden and response to treatment, and correlate with patient outcome. IgA Hevylite (HLC) measures IgA kappa and IgA lambda separately and provides precise quantitative measurements of the monoclonal IgA expression and polyclonal-isotype matched suppression. In the current study, the authors assessed the usefulness of these assays in the diagnosis of IgA MM and sought to comment on the prognostic value of the assays. METHODS A study of 157 patients with IgA MM for whom diagnostic samples were available was performed. HLC measurements were performed on a nephelometer and the results were compared with those of electrophoresis. RESULTS All presentation sera (100 IgA kappa specimens and 57 IgA lambda specimens) were found to have abnormal IgA HLC ratios (IgA kappa median ratio: 336.2 [range, 8.2-7353] and IgA lambda ratio: 0.011 [range, 0.0003-0.45]). In comparison, SPEP bands were quantifiable in only 105 of 157 samples (67%) (median, 28.5 g/L [range, 2.2 g/L-98 g/L]). Of the total of 157 patients, 12 patients (8%) presented with oligosecretory myeloma (

BACKGROUND: Lenalidomide in combination with dexamethasone (Len=Dex) is indicated for patients with recurrent=refractory multiple myeloma (RRMM) who were treated with 1 prior therapy until evidence of disease progression. The objective of the current study was to determine the efficacy and safety profile of long-term exposure to Len=Dex. METHODS: A total of 50 patients with RRMM who were treated with long-term Len for 2 years from 2 Intergroupe Francophone du My� (IFM) centers (Lille and Nancy) were included in the current study. RESULTS: The median age of the patients was 58 years, with 30% of the patients aged >65 years, 49% having an International Staging System stage of 2 and 3, 12% having severe renal insufficiency, and 8% demonstrating an adverse result on fluorescence in situ hybridization. Approximately 56% of the patients received treatment with Len=Dex for 3 years. The median duration of treatment with Len=Dex was 3 years (range, 2 years-7 years). The response rates for partial response or better and very good partial response or better for the overall cohort were 96% and 74%, respectively, which is similar to patients exposed to Len for 3 years. With a median follow-up of 4 years, 19 (38%) patients had stopped treatment with Len=Dex. The time to disease progression rate at 37 months was 78% and 91%, respectively, in patients exposed to Len for 2 years to

Brentuximab vedotin is a new antibody-drug conjugate composed of the anti-CD30 chimeric monoclonal antibody and the potent antimicrotubule drug monomethylauristatin E. In two phase II clinical trials, treatment with single-agent brentuximab vedotin resulted in response rates of 75% in relapsed/refractory Hodgkin lymphoma and 86% in relapsed/refractory systemic anaplastic large-cell lymphoma. Peripheral sensory neuropathy (40%) and neutropenia (20%) were the most frequent side effects, generally mild and manageable. After a large use in a compassionate program, brentuximab vedotin was approved in France in October 2012 for the treatment of Hodgkin lymphoma after failure of autologous stem cell transplantation or after failure of at least two prior multiagent chemotherapy regimens in patients non eligible for autologous transplantation, and for the treatment of systemic anaplastic large-cell lymphoma after failure of at least one prior multiagent chemotherapy regimen.

L’introduction des IMiD (pour immunomodulatory drugs) dans l’arsenal therapeutique du myelome a conduit a l’amelioration de son pronostic. Neanmoins, elle fut aussi marquee par l’augmentation de l’incidence des thromboses, veineuses et arterielles, qui pouvait atteindre 30-50 % selon les series. Cette observation a incite a mettre en place des mesures prophylactiques systematiques de la thrombose chez les patients traites par IMiD. Des tentatives de standardisation de ces mesures ont ete faites, avec la redaction de recommandations internationales. Ces dernieres ne permettent cependant pas de repondre a l’integralite du probleme, en commencant par la definition des facteurs de risques et le choix de la prophylaxie thromboembolique adequate. A travers une revue de la litterature, nous identifions les facteurs de risques et les differentes mesures prophylactiques en vue de proposer une strategie therapeutique optimale.

Allogeneic hematopoietic cell transplantation (allo-HCT) is indicated for patients with relapsed or refractory Hodgkin lymphoma (HL). Although long-term disease control can be achieved, relapse is still frequent. The programmed cell death protein 1 (PD-1) pathway-blocking antibody nivolumab has shown substantial therapeutic activity and an acceptable safety profile in patients with relapsed or refractory HL who did not receive allo-HCT. However, PD-1 blocking strategy can increase the risk of graft-versus-host disease (GVHD) in murine models. We retrospectively assessed the efficacy and toxicity of nivolumab as a single agent in 20 HL patients relapsing after allo-HCT. GVHD occurred in 6 patients (30%) after nivolumab initiation. All 6 patients had prior history of acute GVHD. The patients with nivolumab-induced GVHD were managed by standard treatment for acute GVHD. Two patients died as a result of GVHD, 1 of progressive disease and 1 of complications related to a second allo-HCT. Overall response rate was 95%. At a median follow-up of 370 days, the 1-year progression-free survival rate was 58.2% (95% CI, 33.1%-76.7%) and the overall survival rate was 78.7% (95% CI, 52.4%-91.5%). Among 13 patients still in response, 6 received a single dose of nivolumab and 7 remain on nivolumab. Compared with standard options for this indication, our results show that nivolumab is effective with an acceptable safety profile.

Introduction: Systemic Light-chain amyloidosis (AL) is a clonal plasma-cell disorder, and has therefore benefited from the numerous therapeutic advances in multiple myeloma (MM). Nonetheless, outcome of refractory AL patients remains dire, especially in patients with severe end-organ damage. Daratumumab, a monoclonal antibody directed against CD38, has yielded significant results in MM, but data in AL, although promising, are scarce. Methods: Between November 2016 and July 2018, 15 relapsed or refractory patients with histologically proven AL from five different French centres from the Hauts-de-France region received ongoing daratumumab at the dose of 16 mg/kg, weekly for the first two cycles, twice a month from cycle 3-6, and monthly after cycle seven. All patients had, at least, previously received a proteasome inhibitor (PI) or immunomodulatory drug (IMiD). Efficacy and safety data were assessed retrospectively after required authorization (CNIL registration n°2197989). Results: Fifteen patients with a median number of previous lines of two [1-5] were included. Overall, the population was frail, with a median ECOG of one [range: 0 - 3], CIRS comorbidity score of 14 [8 - 27] and Charlson score of four [1 - 8]. Three of the patients had symptomatic MM according to International Myeloma Working Group criteria. All had elevated free light chains (mean 536 mg/L [38 - 1411]). The mean number of organ involved per patient was three [1-6]; 67% had evidence of cardiac involvement, including Mayo-Clinic stage III in all patients but one; 60% had kidney involvement, including two patients on chronic haemodialysis. Patients received a median of six cycles [1 - 17]. The overall haematological response was 73%, with at least a very good partial response (VGPR) in 33% of cases. Best haematological response was achieved after one cycle [1 - 10]. Eleven patients were evaluable for organ response, which was achieved in 36% of patients, after a median 3.5 cycles [3 - 5]. Infusion-related reactions occurred in 33% of patients, all were grade I-II. Infection occurred in 47% of patients, 60% being grade III or greater. At last follow-up, 67% of patients were still on daratumumab; two patients died, one from progressive disease and another from infection. Discussion: As previous results suggest, daratumumab yields promising results in relapsed AL patients in terms of both haematological and organ-response. Short-time to response is particularly striking in this study as it is a well-known determinant of outcome in AL. These results are particularly remarkable given the frailty and the severity of our population. Frailty indexes have long been used in haematology especially in MM where it is now established that an ECOG score ≥2 or a Charlson score ≥2 impairs overall survival. CIRS score has also been used in cancer patients, where the cut-off to predict mortality varies between 3-4 and 6-7 in chronic lymphocytic leukaemia and acute myeloid leukaemia, respectively. In our cohort, the median Charlson index was over two in 83% of patients and the CIRS was greater than six in all patients, emphasizing the frailty of this real-life AL-population. This may be explained by the extent of organ involvement and the multiple prior treatment received. All but one cardiac patients had Mayo stage III disease, 93% had two or more organs involved, and had dFLC>60mg/L at diagnosis. This indicates high-risk patients, who are less inclined to respond to treatment. Despite these high-risk characteristics, even with a short follow-up, we observed organ responses. As expected, the deeper the haematological response was, the more likely organ response was observed. Even though the general toxicity profile was favourable, the incidence of high-grade infection ought to be noted. Although it may be explained by a combination of factors (i.e. previous treatment, frailty, co-morbidities), infection could outweigh any benefit in terms of overall survival. Shorter treatment course, response or frailty-driven treatment strategies alongside prophylactic measures should therefore be evaluated prospectively in this high-risk population. Conclusion: Single agent daratumumab shows promising results, yielding rapid and deep haematological responses, with an acceptable safety profile, in a frail real-life AL population. Nonetheless, close attention should be paid in the future to infection and its relation to frailty in this specific group of patients. Disclosures Herbaux: Abbvie: Consultancy, Honoraria; Gilead Sciences, Inc.: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Facon:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Boyle:Janssen: Honoraria, Other: travel grants; Gilead: Honoraria, Other: travel grants; Amgen: Honoraria, Other: travel grants; La Fondation de Frace: Research Funding; Abbvie: Honoraria; Celgene: Honoraria, Other: travel grants; Takeda: Consultancy, Honoraria.

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

In Europe and North America, the majority of patients diagnosed with cancer are over 65 years of age. This particularly applies to myeloma, a clonal late B-cell disorder, with a median age at diagnosis of 69 years of age. Besides differences in terms of tumor biology, cancer decisionmaking in the elderly is often complicated by the presence of comorbidities and psychosocial factors. We provide a comprehensive review of the epidemiology, biological and clinical features of this disease in elderly patients as well as the diagnostic and treatment strategies that may be implemented in this population.

Purpose: Solitary plasmacytoma (SP) is a localized proliferation of monoclonal plasma cells in either bone or soft tissue, without evidence of multiple myeloma (MM), and whose prognosis is marked by a high risk of transformation to MM. Experimental Design: We studied the impact of FDG-PET/CT (2[18F]fluoro-2-deoxy-D-glucose positron emission tomography–computed tomography) on the risk of transformation of SP to overt MM among other markers in a series of 43 patients diagnosed with SP. Results: Median age was 57.5 years; 48% of patients had an abnormal involved serum-free light chain (sFLC) value, and 64% had an abnormal sFLC ratio at diagnosis. Thirty-three percent had two or more hypermetabolic lesions on initial PET/CT, and 20% had two or more focal lesions on initial MRI. With a median follow-up of 50 months, 14 patients transformed to MM with a median time (TTMM) of 71 months. The risk factors that significantly shortened TTMM at diagnosis were two or more hypermetabolic lesions on PET/CT, abnormal sFLC ratio and involved sFLC, and to a lesser extent at completion of treatment, absence of normalized involved sFLC and PET/CT or MRI. In a multivariate analysis, abnormal initial involved sFLC [OR = 10; 95% confidence interval (CI), 1–87; P = 0.008] and PET/CT (OR = 5; 95% CI, 0–9; P = 0.032) independently shortened TTMM. Conclusions: An abnormal involved sFLC value and the presence of at least two hypermetabolic lesions on PET/CT at diagnosis of SP were the two predictors of early evolution to myeloma in our series. This data analysis will need confirmation in a larger study, and the study of these two risk factors may lead to a different management of patients with SP in the future. Clin Cancer Res; 20(12); 3254–60. ©2014 AACR.

Background: An increased incidence of second primary malignancies (SPM) is described in chronic lymphocytic leukemia (CLL). Current hypothesis to explain this phenomenon mainly relies on immunosuppression conferred by both CLL itself and CLL treatment. The imputability of fludarabine has been long recognized but the risk associated with monoclonal antibodies, especially rituximab recently shown to improve overall survival in CLL when combined with fludarabine and cyclophosphamide (FC), remains unknown. Materials and methods: We conducted a retrospective study of the incidence of secondary cancers in 1255 CLL patients diagnosed since 1980 in the University Hospital of Lille to better characterize the possible risk of SPM associated with rituximab Results: Of 1255 patients, 651 (52%) received therapy including rituximab (38%), FC (26.7%), F alone (22.4%), chlorambucil (27.5%), alemtuzumab (15.5%) and bendamustine (9.3%). Rituximab was given either in combination with FC (27.5%), other chemotherapy (2.6%) or as a single-agent (3.5%). There was no significant difference in terms of age (58 versus 62 years), gender, Binet stage, cytogenetic abnormalities and number of regimen received between patients treated with or without rituximab. Median follow-up was 6 years for all patients (range 2-23), 4.8 years (range, 2-8) since initiation of therapy for patients treated without rituximab and 3.6 years (range, 0.2-11) for patients who received rituximab. Median overall survival (OS) was 18 years for patients treated with R-chemotherapy versus 11 years for patients treated with chemotherapy alone (p Table 1. Incidence of SPM p Treatment, %- Purine analogs- FC- RFC- Chlorambucil- Bendamustine- Alemtuzumab- CorticothŽrapie - 1,9 10,5* 24,4* 4,9 0 3,5 0 Conclusion: In this large single center retrospective study, we found an earlier and significantly increased incidence of SPM, mainly skin cancers, in CLL patients treated with R-chemotherapy compared to those given chemotherapy alone. It remains to be determined whether this increased SPM incidence is a due to a direct toxicity of rituximab or merely a collateral consequence of improved OS observed after rituximab. Disclosures Facon: Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Membership on an entity's Board of Directors or advisory committees. Cazin:ROCHE: Consultancy; MUNDIPHARMA: Honoraria, Research Funding; NOVARTIS: Honoraria; GILEAD,: Honoraria. Morschhauser:Genentech Inc./Roche: Other: Advisory boards.

Background. Lenalidomide plus Dexamethasone is approved at first relapse and beyond in Europe, and has transformed the prognosis of Myeloma in the relapse setting. Lenalidomide plus Dexamethasone is approved until progression, that could last for years, the median PFS in phase 3 studies being at 17 months at first relapse, but many patients eventually reach 5 to 7 years these days. Dexamethasone was showed to enhance lenalidomide-antitumor efficacy and to prolong the progression-free survival. However, long term exposure to dexamethasone is also known to be associated to an array of adverse events. Finally, IMiDs are known to act through immunomodulation a class-based mechanism. It is possible that lenalidomide might show efficacy on the long run without need to dexamethasone use, at least for some patients with myeloma. We sought to study the impact of dexamethasone discontinuation beyond six months and one year, and compare this analysis to patients treated on lenalidomide plus dexamethasone. Method. We have recruited 200 relapse refractory myeloma patients for this study from various IFM centers. The patients were to be older than 18 years old and treated with lenalidomide plus dexamethasone. We sought to study the impact of the various ways to use dexamethasone in the real life, and therefore dexamethasone was given according to physician decision. We identified groups according to dexamethasone given high dose (4 days 160mg total in a raw), given once a week at 40mg (considered standard dose), given at lower dose (considered low dose) and a group that had dexamethasone discontinued. Patients were not allowed to have other type of combination but lenalidomide plus dexamethasone. Result. A total of 200 patients were analyzed, median age of 57 years old (range 25-76). 17,5% patients had renal dysfunction at diagnosis. ISS was 2 for 20% and 3 for 20%. Approximately 10% had either del17p or t(4;14). 7% of patients had previous history of venous thrombosis before the treatment. Response rate, survival, including TTP, PFS, EFS and overall survival will be presented at ASH with updated follow-up. Conclusion. This study aims to investigate the importance of long run and exposure to Dexamethasone in the Lenalidomide-Dexamethasone regimen. We also wished to assess the optimal dose of dexamethasone that could be given to patients with prolonged exposure to lenalidomide plus dexamethasone. Disclosures Arnulf: Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. MACRO:millenium: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Membership on an entity's Board of Directors or advisory committees. Leleu:LeoPharma: Honoraria; Pierre Fabre: Honoraria; BMS: Honoraria; Novartis: Honoraria; TEVA: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Chugai: Honoraria.

Background Immunoglobulin D (IgD) multiple myeloma represent uncommon immunoglobulin isotypes, accounting for 2% of cases with limited information is available regarding the prognosis of these isotypes. They have been considered to have a more aggressive course than the more common Immunoglobulin of IgG and IgA isotypes in the era of conventional chemotherapy. Several studies have reported the outcome of IgD MM after autologous hematopoietic stem cell transplantation (ASCT) in recent years, but none in the context of novel agents currently the backbone of almost all if not all lines of therapy upfront. We sought to study the prognostic impact of novel agents used upfront on IgD MM treated in several IFM (Intergroupe Francophone du Myélome) centres. Method This study has included a group of 21 patients with IgD MM that were treated from 1994 to 2012 across 5 IFM centres. IgD MM was diagnosed as outline in international consensus criteria. Response and survival criteria were used as depicted in the IMWG consensus criteria published. Results Median age was 59 years (min max 38-80), sex ratio was 1.7, 75% had lambda light chain, 65% had severe bone disease and 20% one to 3 bone lesions, 55% had severe renal insufficiency, 30% had hypercalcemia, 55% profound anemia. Finally, 39% had adverse FISH either del17p or t(4;14) on bone marrow plasma cells and 50% were ISS 3 with beta2M greater than 5mg/L. 80% had receive novel agents containing regimens upfront, including 70% in the context of ASCT and 75% a bortezomib-based regimen. Overall, 65% reached at least VGPR with a median time to first response at 4 months (IQ 1-5). IgD MM had a greater chance to reach VGPR on bortezomib-based regimen, 80% versus 50% for patients on thalidomide-based regimen; furthermore, ASCT also improved the depth of response rate with 85% versus 20% that reached VGPR, respectively (p=0.022). The presence of renal insufficiency at initiation did not affect the incidence and depth of response rate as expected. With a median follow-up of 65 months, 40% have relapsed and 35% have died. The median TTP and OS was 3 years (CI95% 3;7) and 6 years (CI95% 5;9), respectively. Although not significant due to the limited number of patients the median OS was much shorter in the group treated with conventional agents as to novel agents, 5 years (2;8) versus not reached with a 6-year event free of 53%. Similarly, the patients that have received a thalidomide-based regimen upfront had a shorter OS as to bortezomib-based regimen, 1.9 years (1;nr) versus 5.8 years (2;9) although not statistically significant. Interestingly, ASCT improved TTP but not OS, with 1.6 years (1;2.5) versus not reached (6-year event free is 63%) as median TTP in patients non ASCT and ASCT, respectively (p=0.045). Conclusion Despite the retrospective analysis and the small number of patients, our study showed that the use of ASCT and bortezomib-based regimen improve the prognosis of IgD MM. This data analysis confirms that IgD MM should be treated according to current guidelines upfront that recommend use of a bortezomib-based regimen in the context of ASCT in fit patients. Treatment options including the role of consolidation and maintenance may further improve the outcomes of these patients. Disclosures: No relevant conflicts of interest to declare.

BACKGROUND: It has been recently shown that nivolumab, a programmed death 1 (PD-1) blocking antibody, had substantial therapeutic activity and an acceptable safety profile in patients with relapsed or refractory Hodgkin's lymphoma (HL). To our knowledge, this drug has never been tested after allogeneic stem cell transplantation (allo-SCT) mainly because PD-1-blocking strategy may substantially increase the risk of Graft Versus Host Disease (GVHD). Nevertheless, some studies suggested that Reed-Sternberg cells exploit the PD-1 pathway to evade immune detection, possibly explaining why some patients resist to graft-versus-lymphoma effect. PATIENTS AND METHODS: We retrospectively assessed the efficacy and toxicity of nivolumab as a single agent in 12 HL patients relapsing after allo-SCT. All patients had progressive disease at the nivolumab initiation. The dose was 3 mg/kg of body weight every 2 weeks. The median of previous systemic therapies was 9 (range 7-11), including allo-SCT. Patients were required to be off immune suppression for more than 4 weeks prior to nivolumab initiation, with no history of grades III-IV acute or extensive chronic GVHD. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria for AEs (version 4.0). Efficacy was assessed by physical examination before each infusion and per IWG guidelines (Cheson 2007) after four injections of nivolumab. RESULTS: Eight out of 12 patients were evaluable at the time of submission. Median age at time of transplant was 31 (range 28-42) and median time from allo-SCT to study treatment was 11 months (range 3 - 122). Eight patients had related donors and 4 patients had unrelated donors including one haploidentical transplantation. Best response before allo-SCT was RP in 8 patients and RC in 4 patients. Allo-SCT improved response in only 2 patients. Six patients had received therapy for HL progression/relapse post allo-SCT, including donor lymphocyte infusions (n=4). Median number of injection of nivolumab was 4 (range 1-10). Acute GVHD occurred in 2 patients after 1 injection (grade III skin acute GVHD) and 2 injections (grade IV skin acute GVHD) of nivolumab. In one patient, GVHD responded quickly to corticosteroids therapy. The patient who received haplo-identical allo-SCT presented with corticosteroid-refractory grade IV skin GVHD reversed after several extracorporeal photopheresis sessions. Both patients had prior history of grade II acute GVHD in the three months before nivolumab administration and treatment was stopped. Nivolumab did not modify chimerism. The only serious hematological adverse events were grade 4 neutropenia (1 patient) and grade 3 thrombocytopenia (1 patient). No other non-hematological adverse event was observed except a grade 2 cerebellar ataxia. With a median follow-up of 60 days post nivolumab initiation, 1 patient discontinued due to progressive disease, 2 patients due to acute GVHD and 9 patients remain on nivolumab. In our preliminary analysis of efficacy, 7 out of the 8 (87.5%) patients evaluable for response had clinical benefit, with 4 achieving partial response and 3 in complete response according to Cheson 2007 criteria. Of note, one of the patient developing acute GVHD post nivolumab achieved partial response. No data for the other patient presenting with acute GVHD after treatment was available at the time of analysis. CONCLUSIONS: Our preliminary results suggest that nivolumab is effective with manageable toxicity in patients with relapsed or refractory Hodgkin's lymphoma after allo-SCT. These encouraging results emphasize the need to delineate indications and perform prospective protocols. Disclosures Morschhauser: Genentech Inc./Roche: Other: Advisory boards.

Background Light chain amyloidosis (AL) is characterized by a median overall survival (OS) from diagnosis of approximately 3 years, but with clinically overt cardiac involvement this is reduced to 1 year. Bortezomib (B) has shown great promise in the treatment of AL, especially of cardiac involvement. However, efficacy might be hampered by severe safety issues with use of B, primarily of neuropathy type. We sought to study the prognostic impact of the safety profile of B in AL with attention to cardiac involvement. Method This study has included 27 patients with AL, of these 18 had cardiac and 9 kidney but no cardiac involvement. AL was diagnosed as outline in international consensus criteria, as to the hematologic and organ responses. B was given IV twice weekly at the starting dose of 1.3 mg/m², in combination to weekly cyclophosphamide in 13 patients (52%). Results The median age was 63, sex ratio was 18/9, all cardiac AL had Mayo Cardiac Stage III but 3, and none in patients with no cardiac AL. 70% were at diagnostic. Seven patients died during the first month, all of them but one had cardiac AL. We then looked at the safety profile of B in the studied population, and found that 25% and 75% experienced some degree of hematotoxicity in cardiac and in no cardiac AL (p=NS). The non hematology toxicity rate was 62% and 38%, respectively (p=NS). 26% of patients needed dose reduction of B and 33% dose interruption of B in the study before cycle 4, all related to non hematological toxicity of neuropathy, fatigue and GI AEs; and was similar in cardiac as compared to no cardiac AL. The overall hematologic response rate (ORR) was 56% and at least VGPR (with >90% decrease in difference between involved/uninvolved light chain) 41%. The responses were 56% and 39% in cardiac AL, similar to patients with no cardiac involvement (56% and 44%), respectively. The median duration of response was 13 months overall, 10 and 20 months in cardiac and in no cardiac AL, respectively (p=NS). Non hematological toxicity did not impact the response rate or the duration of response. With a median follow-up of 41 months from start of B, 70% relapsed and 59% died in the study as a whole, and 67% and 67% in the cardiac group, respectively. The median time to progression was 20 (95CI 4;35.5) months as a whole, and 13 (9;17) months and 20 (0;43) months in cardiac and in no cardiac AL (p=NS). The median OS was not reached in the cohort as a whole and in patients with no cardiac involvement, but was 5 months in cardiac AL (p=NS); the estimated 4-year OS was 55%, 62% and 50%, respectively. Interestingly, all cardiac AL that survived beyond 6 months remain alive at F-up date. Several variables negatively impacted survival in univariate analysis in the group with cardiac AL, including decreased LVEF (p=0.025), NYHA greater than 2 (p=0.007),Mayo Cardiac Stage III (p=0.028), no hematological (p=0.002) and no organ responses (p=0.05), occurrence of non hematological toxicity (p=0.002) with the consequence of dose reduction of B (p=0.09) and dose interruption of B (p=0.04). In multivariate analysis, independent variables that impacted survival were hematological response (OR = 5.1, 95%CI = 1.5-18; p = 0.011) and non hematological toxicity (OR = 3.6, 95%CI = 0.8-14; p = 0.05). Conclusion Bortezomib is a very rapid and effective therapy for AL particularly of cardiac involvement. However, patients may develop severe side effects with Bortezomib that preclude efficacy of Bortezomib given IV, and consequently impact negatively survival. This data favours use of sub cutaneous Bortezomib in AL although not validated in this indication yet. Disclosures: Leleu: Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Leopharma: Consultancy, Honoraria; Millennium : Honoraria; Amgen: Honoraria; Novartis: Honoraria.

Background. Bortezomib has improved overall survival (OS) in light chain (AL) amyloidosis; however, data on its activity in severe cardiac AL are sparse. Furthermore, the impact of the safety profile of Bortezomib on overall survival in severe cardiac AL amyloidosis remains unknown given the fragile population. We sought to outline the activity and safety profile of Bortezomib in severe cardiac AL amyloidosis. Methods. Twenty-seven patients diagnosed with AL amyloidosis and treated with Bortezomib were included, mean age was 63 years (36-85), with a sex ratio of 18/9. Eighteen patients had cardiac involvement, among which all had Mayo-Clinic stage III staging but 3, and 9 had kidney involvement only. Seventy percent of patients received Bortezomib as a 1st-line therapy, once (19%) or twice weekly (81%), given IV at the starting dose of 1.3g/m2 in combination to Dexamethasone. Thirteen (48%) patients also received an alkylating agent. Results. Overall hematological response rate was 75% in patients who received at least 1 cycle of Bortezomib, and 83% and 62.5% in patients with and without cardiac involvement, respectively. Complete response was obtained in 45%, and 42% and 50% in the 2 groups, respectively. 44% patients with cardiac involvement had an organ response. An hematological toxicity occurred in 26% of patients, similarly in the 2 groups, consisting mainly of thrombocytopenia with no need for treatment modification. Non-hematological toxicity (grade ≥2) rate was 62% in patients with cardiac involvement and 38% in patients with kidney involvement (p=ns), consisting mostly of fatigue, peripheral neuropathy, infection and gastro-intestinal adverse effects, and leading to 25% of dose reduction, and 33% of Bortezomib interruption before cycle 4, similarly in both groups. The median follow-up was 41 months from start of Bortezomib. Seven patients died during the first cycle of treatment, all of them but one had severe stage III cardiac involvement with LVEF In multivariate analysis, independent variables that were associated with poor OS were the number of Bortezomib cycles (inability to receive at least 3 cycles) (OR=34.7; p=0.001), occurrence of a non-hematological toxicity (OR=5.1; p=0.011), and absence of hematological response (OR=3.6; p=0.05). Conclusion. Bortezomib is an effective treatment of AL amyloidosis, and significantly improves the most adverse patients characterized with severe cardiac presentation. However, the safety profile is of particular concern in severe cardiac AL, particularly the non hematological ≥grade 2 incidence rate; patients often characterized with dose reduction or interruption, inability to receive sufficient dose concentration or number of cycles. This study confirms that alteration of the safety profile of Bortezomib may hamper the benefits seen particularly in severe cardiac AL, questioning on the use of weekly and sub-cutaneous Bortezomib for very fragile AL, as optimized in fragile patients with Myeloma. Disclosures No relevant conflicts of interest to declare.