ALBERT

Description: Key Points Pom-Dex is active and well tolerated in adverse cytogenetic patients with early RRMM, particularly in those with del(17p). Pom-Dex prolonged OS in adverse cytogenetic patients with early RRMM.

Description: Xanthomas are a common manifestation of lipid metabolism disorders. They include hyperlipemic xanthoma, normolipemic xanthoma, and a related condition, necrobiotic xanthogranuloma (NXG). All 3 forms can be associated with monoclonal immunoglobulin (MIg). In an attempt to improve diagnosis, understanding, and treatment of this association, we retrospectively analyzed a personal series of 24 patients (2 hyperlipemic xanthoma, 11 normolipemic xanthoma, and 11 NXG) and 230 well-documented reports from the literature. With the exception of the nodules and plaques featured in NXG, the clinical presentation of xanthomatous lesions usually resembled that seen in common hyperlipidemic forms and could not be used to suspect MIg-associated xanthomas. Extracutaneous sites were not rare. The MIg was an IgG in 80% of cases. Myeloma was diagnosed in 35%. Hypocomplementemia with low C4 fraction was present in 80% of studied patients. Low C1 inhibitor serum levels were found in 53%. Cryoglobulinemia was detected in 27%. These abnormalities suggest immune complex formation because of interactions between the MIg and lipoproteins and argue in favor of a causal link between MIg and xanthomas. Monoclonal gammopathy therapy could thus be an option. Indeed, among the patients who received chemotherapy, hematologic remission was accompanied by improvement in xanthoma lesions in several cases.

Description: Background. POEMS syndrome is a rare form of B cell dyscrasia combining a proliferation usually of plasma cells, a polyneuropathy, osteocondensing bone lesions and multiple other clinical signs. The pathogenesis is not well understood but VEGF plays a major role. In patients with one or two sclerotic plasmacytoma and no bone marrow involvement, first line therapy should include radiation. For patients with diffuse sclerotic lesions, bone marrow involvement or absence of any bone lesion and for those who have not demonstrated stabilization of their disease 3 to 6 months after completing radiation systemic therapy is indicated, the most effective being high dose chemotherapy with autologous stem cell transplant (ASCT). Radiation of a single lesion is effective in about every other case and is accompanied by a fairly slow improvement of the neurological symptoms, often after initial worsening. ASCT seems to be accompanied by a number of important complications, in particular engraftment syndrome. Outside these 2 treatments there is no consensus therapy. Lenalidomide (LEN), a drug without serious neurological toxicity, has the advantage of being both anti-angiogenic and cytotoxic to malignant plasma cells (Richardson PG, Blood 2002;100(9):3063-7). We have recently reported a series of 20 French patients with POEMS syndrome treated by LEN with a good efficacy. We now report the first 27 patients of a prospective phase II trial using LEN + dexamethasone (LEN-DEX), 2 cycles preceding radiation or high dose treatment trying to obtain a rapid clinical response and to avoid engraftment syndrome or 9 cycles followed by 1 year LENalone in patients who cannot receive radiation or ASCT. Methods. Newly diagnosed or relapsing patients with POEMS syndrome who needed to be treated were eligible. Patients who can be treated by local radiation or intensive treatment with stem cell support receive two 28 day cycles of LEN 25 mg PO Days 1-21 and DEX 40 mg PO Days 1,8,15,22 before radiation or intensive treatment (Group 1), the other patients receive 9 cycles of the same LEN-DEX (Group 2) and then 12 cycles of continuous low dose LEN (10 mg). LEN dose was tapered to 10 mg for patients with a creatinine clearance between 30 and 50 ml/min and DEX to 20 mg for patients above 75 years of age and for those who were frail patients. Main eligibility criteria included a diagnosis of POEMS syndrome according to criteria by Dispenzieri et al (Am J Hematol 2012;87(8):804-14), an age of 18 or more, a creatinine clearance above 30 ml/min, no prior treatment with or contraindication to LEN and no uncontrolled thrombosis. Serum and plasma VEGF, serum electrophoresis, immunofixation and free light chain measurements were centrally monitored. Neurologic evaluations were performed using the Overall Neuropathy Limitations Scale (ONLS), the Neurological Impairment Scale (NIS) and the 10 meter walk test (10MWT). The primary endpoint was evaluation of the effectiveness of LEN-DEX combination using biological responses (decrease of monoclonal protein and serum VEGF level) and secondary endpoints were clinical and particularly neurological responses. Results. Twenty-seven patients have been included in 12 centres, median age was 61 (range 32-75), the median follow-up was 6.6 months (range 2-24). Eighteen patients were in group 1, with radiotherapy in 10 patients and ASCT in 8 patients; 9 patients were in group 2. Nineteen patients were in first line and 8 already treated. Only 2 patients experienced grade 3-4 adverse events due to LEN (cytopenia) and 2 patients had allergic rashes, no thrombotic event occurred. No engraftment syndrome was noted in the 5 patients already treated with ASCT. To date, no patient have died. Evolution of VEGF median values in serum and plasma, M-spike and dFLC levels and evolution of neurological measurements are reported in table 1. Neurological improvement was very rapid in some patients, using ONLS and 10MWT 11/18 evaluable patients had a neurological improvement after 2 cycles with an improvement of 1 or more of the ONLS score and/or change of 0.1 m/s or more in the 10MWT. Only one patient who progressed after nine cycles received another therapy. Conclusion. This is the first prospective trial of LEN-DEX in POEMS syndrome. This combination seems well tolerated in this disease with a good efficacy on VEGF measurements and rapid neurological improvement in the majority of patients. Updated data will be presented at the meeting. Figure 1 Figure 1. Disclosures Jaccard: Celgene: Drug supply to Trial Other. Tournilhac:mundipharma: Honoraria, Other, Research Funding; GSK: Honoraria, Other, Research Funding; Roche: Honoraria, Other, Research Funding. Moreau:celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: The t(4;14)(p16.3;q32) leads to the ectopic expression of two oncogenes, the Multiple Myeloma Set Gene (MMSET) and the Fibroblast Growth Factor 3 (FGFR3). It is found in 15% of patients with multiple myeloma (MM) and indicates a poor prognosis. To identify the clinico-biological features associated with this adverse prognosis, we prospectively studied a series of 79 patients with t(4;14) MM.Between March 2002 and July 2007, a t(4;14) was detected by real time quantitative PCR of the IGH/MMSET and FGFR3 transcripts in 79 patients. The clinico-biological data were analysed at diagnosis and at relapse. Response rate and time to progression (TTP) after successive lines of chemotherapy, and overall survival (OS), according to beta2m and haemoglobin level, and expression of FGFR3, were evaluated. Among the 79 patients (median age:55 years), 18 (22.8%) had a MGUS or smouldering myeloma and 61 (77.2%) had a symptomatic MM. At diagnosis, no clinical or radiological feature was significantly associated. As expected, 15 patients (18%) had a t(4;14) without expression of FGFR3. IgA isotype was found in 41% and del(13) in 90% of patients. Contrasting with previous studies, only 52% of symptomatic MM had elevated beta2m (〉3mg/L). Fourty-two patients (53.1%) received autologous stem cell transplantation (ASCT). In those, the overall response (OR) was 90%. Among those responders, 16% had a complete response (CR) and 53% had a very good partial response (VGPR). Median TTP after ASCT was only 12 months. At relapse, aggressive features (plasmocytoma, cytopenias, acute renal failure, circulating plasma cells) were observed in 23% of cases. After 2nd line chemotherapy, response rate was only 49% and TTP was 6.4 months. Noteworthy, there was a trend toward a better TTP in patients treated with bortezomib as compared to thalidomide in 2nd line therapy (p=0.06). Median OS after ASCT was 31 months, independently of FGFR3 expression and isotype. OS was not significantly different in patients with and without high beta2m (〉3mg/L) or low hemoglobin (

Description: It is important to have an effective therapy for patients with multiple myeloma (MM) at first relapse, particularly if an autologous stem cell transplant (ASCT) is considered at this stage. This multicenter, phase 2 trial evaluated the efficacy and safety of weekly oral pomalidomide-cyclophosphamide-dexamethasone (PCD) in patients with MM in first relapse after treatment with lenalidomide-bortezomib-dexamethasone (RVD). All patients had received RVD as induction and consolidation therapy, plus lenalidomide maintenance for 1 year (arm A). Half had also received an ASCT after induction (arm B). At MM relapse, all patients received 4 oral cycles of pomalidomide 4 mg (days 1-21), cyclophosphamide 300 mg (days 1, 8, 15, and 22), and dexamethasone 40 mg (days 1-4 and days 15-18 of a 28-day cycle; PCD). Responding patients in arm A underwent ASCT and received 2 additional cycles of PCD, whereas those in arm B received 5 cycles of PCD. All patients received pomalidomide-dexamethasone maintenance until disease progression. Primary end point was partial remission or better after the initial 4 cycles of PCD. Responses were obtained in 82/97 (85%) patients evaluated: complete remission (n = 1; 1%), very good partial remission (n = 32; 33%), and partial remission (n = 49; 51%). Three patients (3%) had stable disease, and 6 (6%) had disease progression (6 response failures). Forty-five (94%) of the 48 patients in arm A underwent planned ASCT. PCD was effective therapy after first relapse with RVD. After 4 cycles, the rate of partial remission or better was 85%, and 94% of planned ASCTs were performed. Toxicity was mostly hematologic and manageable. This trial was registered at www.clinicaltrials.gov as #NCT02244125.

Description: Evaluation of MRD in multiple myeloma (MM) is becoming an important trial endpoint, especially in young patients. With current intensive approaches, the complete remission (CR) rates are up to 70%, making conventional evaluations of response quite useless. More sensitive tools are mandatory. Two techniques may help investigators to reach this goal, flow cytometry (FCM) and NGS. We applied both techniques to the IFM part of the IFM/DFCI 2009 trial. Briefly, this trial enrolled 700 patients under 66 years of age who were randomized to receive either 8 cycles of VRD (Velcade®-Revlimid®-Dexamethasone) (arm A), or 3 VRD cycles, high-dose melphalan, followed by two consolidation VRD cycles (arm B). All patients received a lenalidomide maintenance for 12 months. A bone marrow MRD evaluation was planned before and after maintenance for all patients achieving at least very good partial response (VGPR). A one-mL bone marrow aspirate was sent overnight to one of the central labs. The primary purpose was to assess MRD by FCM. When extra cells were available, they were frozen as a dry pellet for NGS analyses, using the LymphoSight® platform (Sequenta/Adaptive Inc.). A total of 246 patients have been evaluated by NGS before maintenance and 178 after maintenance. Patients were classified in 3 categories: negative (〈 10-6), low-positive (between 10-4 and 10-6), and positive (〉 10-4). At pre-maintenance, 87 patients were negative, 80 were low-positive, and 79 were positive. At post-maintenance, these numbers were respectively 86, 52, and 40. Using a cutoff at 10-6, patients below 10-6 at pre-maintenance presented a 3-year PFS at 83%, vs 53% for patients 〉 10-6. At post-maintenance, these % were 90% and 59% respectively. When restricted to patients in CR, the 3-year PFS was 87% and 63% at pre-maintenance, and 92% and 64% at post-maintenance (Figure). Finally, we compared the two MRD techniques. Using a 7-color FCM strategy, the sensitivity level was 10-4. Amongst the 163 patients negative with the FCM approach, 84 (51 %) patients were positive using NGS and among 72 patients positive with FCM, 67 (93%) were also positive using NGS. In the subgroup of patients with negative MRD using FCM, the 3 year PFS was 86% for NGS negative patients vs 66 % for NGS positive at pre-maintenance and 91% vs 65% at post maintenance. Looking at high-risk patients, 26 patients with t(4;14), and 16 with del(17p) were evaluated. Half of the t(4;14) patients achieved MRD negativity, versus only 1/16 patients with del(17p). Interestingly, 9/13 patients with t(4;14) who achieved MRD negativity, and 0/1 patients with del(17p) did not relapse, showing the importance of achieving deep response in these high-risk patients. In conclusion, this study clearly demonstrates that a sensitive technique like NGS is able to predict PFS in patients treated with modern approaches. Figure 1. Figure 1. Disclosures Avet-Loiseau: Takeda: Research Funding; Celgene: Research Funding; Janssen: Research Funding. Hulin:celgene: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees. Arnulf:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Garderet:Bristol-Myers Squibb: Consultancy. Karlin:Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; BMS: Honoraria; Janssen: Honoraria; Celgene: Honoraria. 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. Richardson:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Faham:Adaptive Biotechnologies: Employment, Equity Ownership. Facon:Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: 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; Janssen: 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; 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. Moreau:Novartis: Honoraria, Other: Adboard; Takeda: Other: Adboard; Celgene: Honoraria, Other: Adboard; Janssen: Honoraria, Other: Adboard; Takeda: Honoraria, Other: Adboard; Amgen: Other: Adboard; Amgen: Other: Adboard; Novartis: Other: Adboard. Attal:celgene: Membership on an entity's Board of Directors or advisory committees; jansen: Honoraria.

Description: Abstract 3408 Poster Board III-296 The t(4;14)(p16.3;q32), leading to the ectopic expression of two potential oncogenes, the Multiple Myeloma Set Gene (MMSET) and the Fibroblast Growth Factor 3 (FGFR3), is found in 15% of patients with multiple myeloma (MM) and is associated with a very poor prognosis. We previously shown in patients under 65 years of age that High Dose Therapy followed by Peripheral Blood Stem Cell Transplantation (HDT-PBSCT) provides a high response rate (RR) but a very short median relapse-free survival of only 11 months. In addition, relapses are often aggressive and chemoresistant. Thus, more effective regimen is urgently needed. We prospectively studied 23 t(4;14) MM patients treated with 3 or 4 cycles of a combination of Bortezomib and Dexamethasone (VD) (n=4) or of Bortezomib, Adriamycine and Dexamethasone (PAD) (n=19) as induction treatment before HDT-PBSCT (Melphalan 200 mg/m2). T(4;14) was detected using real time quantitative PCR searching for IGH/MMSET and FGFR3 transcripts. RR, event-free survival (EFS) and overall survival (OS) were evaluated. Median age at diagnosis was 51 years (range, 33-64). Isotype was IgA in 12 (52%) patients. All patients had stage II or III MM. An elevated serum β2m level (〉3.5 mg/L) was found in 14 (61%) patients, and a low haemoglobin (Hb) level (

Description: Background. New standards with increasing efficacy that are also characterized with improving the quality of life are needed for elderly myeloma patients. Although MPT and MPV regimens are remarkable in terms of efficacy, quality of life while on treatment with these 2 regimens remain an issue. The Carmysap twice weekly carfilzomib-based phase 2 study has demonstrated that Carfilzomib at the MTD of 36mg/m² might challenge bortezomib in the VMP standard. However, it has become routine practice to use bortezomib on a weekly schedule, with maintained efficacy and an improved safety profile. We sought to demonstrate that Carfilzomib Weekly plus Melphalan and Prednisone will prove strongly efficacious with acceptable safety profile and quality of life to newly diagnosed elderly multiple myeloma (eNDMM). Methods . IFM2012-03 (also called carmysap weekly) is a phase 1/2 multicenter open label single arm study to determine MTD during the phase 1 part and VGPR+CR rate during the phase 2 part of the study. The inclusion/exclusion criteria of interest were eNDMM (65 and older), with symptomatic and measurable disease, with absolute neutrophils ≥1 G/L, untransfused platelet count ≥75 G/L, hemoglobine ≥8.5 g/dL and clairance creatinine ≥ 30ml/min. We report herein the phase 1 part of the study which last cohort was completed at ASH abstract deadline. For the phase 1 part of the study, each cohort was 6 patients based, and started at 36mg/m² of carfilzomib on days 1, 8, 15, 22 using IV, 30 minutes infusion, route followed by a 13-day rest period per 35-days cycles, melphalan given at 0.25mg/kg/j and oral prednisone 60mg/m², both on days 1 to 4. The subsequent cohorts' doses for carfilzomib were 45, then 56 and finally 70mg/m². 9 cycles were planned as induction followed by a maintenance phase of weekly carfilzomib monotherapy given at 36mg/m² weekly for one year. The MTD was determined when ˃2 DLTs were observed. DLTs were considered during cycle 1 if any hematologic toxicity of grade 4 intensity or preventing administration of 2 or more of the 4 carfilzomib doses of the first treatment cycle, grade ≥3 febrile neutropenia, grade ≥3 gastrointestinal toxicities, any other grade ≥3 nonhematologic toxicity considered related to CMP by the principal investigator, grade ≥ 3 peripheral neuropathy persisting for more than 3 weeks after discontinuation of study drugs. Results. 26 NDMM patients recruited, 24 treated in the study, 6 per cohort at 36 mg/m² carfilzomib +MP, then 45 then 56, and finally at 70mg/m² which cohort cycle 1 is up and running. The median age was 74 with 10 patients older than 75 and sex ratio M/F 65. There was a DLT at 36 mg/m² carfilzomib (grade 4 lymphopenia), one at 45 (lysis syndrome complicated with grade 4 renal insufficiency, two at 56 (cardiac insufficiency grade 3 and febrile neutropenia grade 3). At ASH deadline, all patients from cohort 36 of carfilzomib have completed induction and maintenance up to cycle 6, 5/6 of cohort 45 have completed induction and started the maintenance phase, 5/6 of cohort 56 have completed cycle 6 of induction and pursue within the induction phase, and finally all patients from cohort 70 of carfilzomib are undergoing cycle 1. There are 22 SAE reported for a total of 171 cycles administered of carfilzomib +MP. So far, 3 patients (out of 24) have stopped treatment, including the 2 patients with DLTs, lysis syndrome and cardiac failure, and one patient that presented with pulmonary hypertension later in the disease course on cycle 5 of the 56mg/m² carfilzomib +MP cohort. And, an extra 3 patients have had Carfilzomib dose reduction, 2 patients at 36 from 45 and one at 45 from 56, for neutropenia grade 4, thrombocytopenia grade 4, and Dyspnea grade 3, respectively. Conclusion. The MTD of weekly carfilzomib in the combination to Melphalan and Prednisone could be determined at 70mg/m² in elderly NDMM, demonstrating the good safety profile of carfilzomib in this regimen and fragile population. The complete dataset of the entire study will be updated at ASH with response rate, survival and safety profile. Disclosures Leleu: Chugai: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; BMS: Honoraria; Novartis: Honoraria; TEVA: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Karlin:Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria. Fitoussi:Sandoz: Membership on an entity's Board of Directors or advisory committees. Moreau:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: 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.

Description: Background Everolimus is an orally bioavailable mTORC inhibitor that has cytostatic activity in lymphoma in vitroand has shown single agent activity in aggressive B-cell lymphomas and Hodgkin’s lymphomas. The combination of everolimus and rituximab has also been recently explored in aggressive CD20+ DLBCL lymphomas with an ORR of bout 40%. The current study investigates the combination of everolimus and rituximab as a treatment for relapsed or refractory indolent lymphoma or transformed indolent CD20+lymphomas. Methods Lymphoma patients were assigned to sequential cohorts of oral dose of RAD001 (5 mg per day, 5 mg every other day), and R, 375 mg/m2 every week (4W) followed by one infusion of R every 2 months. The primary objective was the determination of the maximum tolerated dose (MTD) and the recommended dose (RD) for RAD001/R. Secondary objectives included characterization of safety profile, pharmacokinetics (PK) and anti-tumor activity of RAD001/R. Results 21 patients were included and 20 patients treated (men: 11; women: 10 and median age of 72 (r: 51- 86). Histologies: FL: 8, MCL: 5, MZL: 4, transformed indolent lymphoma: 3, SLL: 1. The MTD was 5 mg/day of RAD001 and R 375mg/m2, as 2/6 patients experienced dose limiting toxicities (DLTs) [grade (G) 4 febrile neutropenia, one G 3 atrial fibrillation]. The RD was RAD001 5 mg every other day with R 375 mg/m2, with no patients experiencing DLTs. 6 pts were treated at the 5 mg every other day without DLT and 7 pts were treated at the same dose in an expansion cohort. Out of the 21 pts included, 2 pts planned at 5 mg every other day were not evaluable due to rapid progression before therapy in one case and at C1 day16 for one case. One pt is not evaluable (ongoing treatment before cycle 3 day1) and 2 pts had a DLT. 16 pts received 2 cycles and were evaluable for response. 6 achieved a response (5 PR and 1Cru), 6 had stable disease and 4 were progressive. As per 06-13, 5 patients are still ongoing in study with 2 pts showing a partial response and a CRu and 3 patients showing stable disease. 9 pts discontinued the treatment due to progression of disease, and 2 patients due to treatment-emergent adverse events: anorexia and pulmonary toxicity at C3 day 8 and C2day 28 respectively. One pt stopped therapy due to a pulmonary infection not related to treatment during cycle 6. Preliminary PK analysis showed a large variability of RAD001 exposure between pts. Preliminary PD analysis confirmed target engagement (S6K) in 5/7 evaluable pts and showed s6K inhibition of phosphorylation at 4 hours post dosing in peripheral blood mononuclear cells stimulated with GM-CSF. Conclusion Preliminary results indicate that the combination of RAD001/R may be effective for the treatment of relapsed or refractory indolent lymphomas or transformed indolent lymphomas and has an acceptable safety profile. Disclosures: Ribrag: Servier: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity’s Board of Directors or advisory committees; Bayer: Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Johnson & Johnson: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Off Label Use: The abstract shows scientific information on SAR3419 which is an investigational product developed by Sanofi. This investigational product is not approved by any health authority for any indication. Karlin:Celgene: Expert board Other, Honoraria; Janssen: Honoraria. Morschhauser:novartis: Honoraria, Research Funding. Tilly:Roche: Honoraria; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Honoraria; Janssen: Honoraria; Amgen: Research Funding. Coiffier:Pfizer: Membership on an entity’s Board of Directors or advisory committees; Roche: Membership on an entity’s Board of Directors or advisory committees.