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: Melphalan-Prednisone + bortezomib (MPV) is one of the standard of care for the frontline treatment of patients with symptomatic multiple myeloma non eligible for high-dose therapy. In the pivotal VISTA trial for approval of MPV, the main toxicity was grade 3-4 peripheral neuropathy (PN) described in 14% of the cases. Carfilzomib (CFZ), the second-in-class proteasome inhibitor has shown promising activity and a favorable toxicity profile with low PN rates. Therefore, the option of combining CFZ with MP (CMP) is an attractive one. Therefore we designed a phase I/II study to determine the maximum tolerated dose (MTD) of CMP and to assess safety and efficacy. In the phase I portion of the trial, CFZ was started at 20mg/m2, then escalated to 27, 36, and 45mg/m2, administered IV over 30 minutes in 42-day cycles on D1/2/8/9/22/23/29/30 for 9 cycles. Melphalan 9mg/m2 and prednisone 60mg/m2 were given PO D1–4 of every 42-day cycle. MTD was based on dose-limiting toxicity (DLT) in cycle 1 defined as any grade 4 (G4) hematologic adverse event (AE), any hematologic AE preventing aministration of ≥ 2 CFZ doses except G4 thrombocytopenia without bleeding or G4 neutropenia ≤ 7days, ≥ G3 febrile neutropenia, or any ≥G3 nonhematologic AE. As of July 6, 2013, 24 pts have been enrolled in phase I: 6 for each dose level. There were 2 DLTs at 45mg/m2 (fever plus hypotension) resulting in a MTD of 36mg/m2. In Phase II, 44 additional patients received CMP at 36mg/m2 CFZ for N=68 total PhI/II patients (50 patients overall treated at the dose pf 36mg/m2). The median age of the series was 72 years, with 36% of the patients presenting with ISS3. Overall response rate was 89.5% including 56% ≥ very good partial response. With a median follow-up of 12 months, the projected 2y OS was 87%, and the median event-free survival was 22 months. CMP was well tolerated and only 1 patient developed grade 3 PN. These promising results compare favorably to those of MPV, MP+Thalidomide, MP+lenalidomide (R), and R+dex in similar pts. CFZ 36mg/m2 + MP is tolerable and effective in elderly patients with symptomatic newly diagnosed MM. Treatment is ongoing, 20% of the patients are receiving their last cycles of CMP. Final safety and efficacy data will be presented during the meeting. Disclosures: Moreau: CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau. Off Label Use: FRONTLINE TREATMENT WITH CARFIZOMIB. Hulin:CELGENE: Honoraria; JANSSEN: Honoraria. Leleu:CELGENE: Honoraria; JANSSEN: Honoraria. Roussel:CELGENE: Honoraria; JANSSEN: Honoraria. Attal:CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau. Facon:CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau.

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: 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 Induction therapy followed by autologous stem cell transplantation (ASCT) is the standard of care for patients with symptomatic multiple myeloma less than 66 years old. The quality of response to the induction treatment is an important prognostic factor and is predictive of progression free survival (PFS) following ASCT. The triplet combinations bortezomib-thalidomide-dexamethasone (VTD) and bortezomib-cyclophosphamide-dexamethasone (VCD) have demonstrated high response rates in prospective phase 2 and phase 3 clinical trials, they are 2 of the most commonly used induction regimens prior to ASCT, and are both recommended in the International guidelines. To date, no comparative data from prospective randomized trials of the safety and efficacy of VTD vs VCD are available. This provided the rationale for the phase 3 investigation of VTD vs VCD prior to ASCT in patients with de novo MM in this randomized multicenter study (NCT01564537). Methods Patients with de novo symptomatic MM less than 66 years old were prospectively randomized to receive either 4 cycles of VTD (arm A) or 4 cycles of VCD (arm B) followed by ASCT. The VTD regimen consisted of four 21-day cycles of bortezomib 1.3 mg/m²/d, subcutaneously (SC) D1, 4, 8 and 11, Dexamethasone 40 mg/d, PO D1 to 4, D9 to 12 and Thalidomide 100 mg/d, PO D1 to D21. The VCD regimen consisted of four 21-day cycles of bortezomib 1.3 mg/m²/d, SC D1, 4, 8 and 11, Dexamethasone 40 mg/d, PO D1 to 4, D9 to 12 and Cyclophosphamide 500 mg/m²/d, PO D1, 8, 15. Patients were stratified according to ISS (1-2 versus 3) and cytogenetics (high-risk defined by 17p deletion and t(4;14) versus other).The primary endpoint was very good partial response (VGPR) rate following 4 cycles. Response was assessed in a central lab according to the IMWG criteria. Assuming a VGPR rate of 60% in the VTD arm versus 45% in the VCD arm (15% difference), the possibility to detect a statistically significant difference required the enrolment of 340 patients overall (170 per arm). Adverse events were graded using the NCI CTCAE catalogue, version 4.0. Results From 11/2013 to 02/2015, 358 patients were enrolled into the study. 18 were screening failures, and 170 were randomized each to arm A (VTD) and arm B (VCD). The median age was 60 years (range, 26-65), 62% of the patients were male, and overall, the patient characteristics were well-balanced across the 2 arms of the study. The median number of induction cycles administered in both arms was 4 (1-4). On an intent-to-treat basis, the overall response rate (〉 partial response [PR]) was 92.3% in arm A, including a 10.7% complete response (CR) rate and a VGPR rate of 66.7%, while in arm B the overall response rate was 84%, with a 9.5% CR and a 56.2% VGPR rate. VGPR and PR rates were significantly higher in the VTD arm with p-values of 0.04 and 0.02, respectively. Seven patients died during induction therapy (2%), 3 in arm A from infections (2) and pulmonary embolism (1), and 4 in arm B from progression to extramedullary myeloma (2) and infections (2). Grades 3 / 4 peripheral neuropathy occurred in 4% and 2.2% in Arm A and B, respectively. Grade 3/4 neutropenia was seen in 11.9% vs 22.5% in Arm A and B, respectively. Conclusion This trial is the first prospective randomized comparison of 4 cycles of VTD versus 4 cycles of VCD administered as induction therapy prior to ASCT. VTD was shown to be significantly superior to VCD in terms of VGPR and PR rates. Neuropathy rates low in both arms, while neutropenia was more frequent with VCD. Disclosures Moreau: Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: 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; Novartis: 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. Hulin:Celgene Corporation: Honoraria; Janssen: Honoraria; Bristol Myers Squibb: Honoraria; Amgen: Honoraria. MACRO:celgene: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees. Garderet:Bristol-Myers Squibb: Consultancy. Stoppa:Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Facon: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; 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; 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. Laribi:Hospira SAS: Research Funding. Avet-Loiseau:jansen: Membership on an entity's Board of Directors or advisory committees; onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees; onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Attal:jansen: Honoraria; celgene: Membership on an entity's Board of Directors or advisory committees.

Description: Background. Protein electrophoresis and immunofixation in the serum (SPEP - SIF) and urine (UPEP – UIF) have been routinely used for decades for characterizing and quantifying the M protein in Multiple Myeloma (MM). However, these techniques are notoriously tarnished with inaccuracy, despite improvements in recent years. The most important breakthrough in the field in recent years was the discovery of the Serum Free Light Chain Assay (sFLC), a routine quantitative and automated assay that measures kappa and lambda sFLC, however this was added to / rather than replaced traditional tests in the diagnostic armamentarium of MM. Recently, a new test quantifying paired clonal and non-clonal immunoglobulins (heavy/light chains HLC i.e. IgGκ/IgGλ) in serum was developed. Here we aim to assess the new HLC assays as tools to replace SPEP / IFE during MM patient monitoring Materials and methods. 110 Myeloma treated with pomalidomide and dexamethasone in two IFM studies (IFM 2009-02 in end stage RRMM and IFM 2010-02 in del17p and t(4;14) RRMM ) were included. The criteria for selection were that patients had measurable intact immunoglobulin myeloma according to IMWG criteria (M spike ≥10g/L), using serum and/or urine protein electrophoresis, with exclusion of patients solely measurable on UPEP and sFLC. All sera were collected centrally before initiation of treatment and sequentially every cycle until progression. Hevylite® (HLC) was measured in the biology laboratory of CHRU of Lille, France and results compared to traditional measurements. Along with SPEP, SIF, UPEP, UIF, and sFLC, we have also measured IgA HLC (IgA k and IgA l) and IgG (IgG k and IgG l) and the corresponding difference (clonal - non clonal) and ratio (clonal/non clonal). Results. Overall, 80% were measurable on SPEP with a median serum level of 31g/L (CI95% 19;42), and the remaining also had UPEP measurable myeloma with a median serum level of 0.66g/24h (CI95% 0.4;1.3). The median involved HLC level was 29.7g/L (CI95% 17.6;43.3), the median involved HLC difference clonal - non clonal was 28.8g/L (CI95% 15.6;42.7), the median involved HLC ratio clonal / non clonal was 51.9 (CI95% 18.3;203.9). Since all patients had a measurable intact immunoglobulin-based disease according to IMWG criteria, we have first confirmed that patients had also a measurable disease by HLC. All patients had an abnormal HLC ratio but one patient, who was measurable with an abnormal IgG L involved HLC test. Approximately 32% of patients had an M-spike below 20g/L and/or an electrophoretic migration in beta region meaning in the range of lack of sensitivity of the techniques used, all of whom had a measurable disease using involved HLC level and/or a measurable HLC ratio. We then sought to study the response rate according to HLC, and for that purpose we applied the exact same criteria as to the sFLC-based response criteria recommended by IMWG (e.g. normal ratio is CR and if abnormal ratio, then

Description: Key PointsSerum FLC analysis is a more sensitive indicator of disease than urinalysis. Improved sensitivity of serum over urine measurements during monitoring translates into valuable prognostic information.

Description: Abstract 354 Introduction The Intergroupe Francophone du Myelome (IFM) has shown that induction tteatment prior to ASCT with VD is superior to VAD in terms of complete response (CR) or CR plus very good partial response(VGPR) both before and after ASCT (Harousseau 2008 Joint ASH/ASCO session). The Italian group has presented impressive results with the three-drug combination VTD.(Cavo Blood 2008;112:)However in both studies, peripheral neuropathy (PN)was the most frequent adverse event (9% Grade 3) Patients and Methods. The IFM has conducted a randomized trial comparing four 21-day cycles of induction with VD(V1.3 mg/m2/d on days 1,4,8,11 plus D 40mg:d on days 1-4 and 8-11 for the first 2 cycles, on days 1-4 for the last 2 cycles) or vTD (v 1mg/m2 /d on days 1,4,8,11 plus thalidomide 100mg:d d1-21 plus dexamethasone same dosing as for VD). Results were assessed after cycle 2 and 4 and after ASCT. Responses were evaluated according to IMW uniform criteria . Samples for serum and urine electrophoreses were centralized (HAL,CHU Nantes). In the vTD arm, if after cycle 2, the response was. Results From 03/2008 to 01/2009, 205 patients with newly diagnosed symptomatic MM and up to 65 years of age were recruited and randomized at diagnosis (stratification according to β-2 microglobulin and presence of del(13) by FISH). The two groups were well balanced as regards initial prognostic parameters : age, ISS,β-2microglobulin,hemoglobin,calcium and creatinine levels, incidence of del(13),t(4.14) and del(17p.).As of August 15th, 191 patients are evaluable for response after cycle 4 ( 95 VD,96 vTD). According to investigators'assessment,the efficacy results are the following (VD vs vTD): CR rate 12%vs 14% (p = 0.68), ,≥VGPR 36%vs 50 % (p=0.047), ≥PR 81%vs 91%(p = 0.06),stable disease 12%vs 5%, progression/failure 7%vs 4%.In the vTD arm the doses of v and T were increased due to ≥3 6 %vs 2 % (p=0.17) Conclusion The combination of reduced-dose bortezomid and thalidomide induces significantly more CR+VGPR than the VD with usual doses of V.Despite the addition of thalidomide, the incidence of PN was markedly reduced In the vTD arm with only 2% Grade ≥3 PN. vTD should be considered a new standard for induction treatment prior to ASCT Disclosures: Harousseau: Janssen Cilag: 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. Avet-Loiseau:janssen cilag: Honoraria; celgene: Honoraria. Facon:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Attal:Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Description: Introduction: Response to conventional therapies for patients with T-cell prolymphocytic leukemia (T-PLL) is usually poor and is associated with short survival. The BCL-2 antagonist venetoclax was recently found to have some clinical activity in this disease (B Boidol et al., Blood, 2017); however, these early data suggest that this drug will not provide prolonged response when given as monotherapy. Several other drug classes have demonstrated preclinical activity in T-PLL, including HDAC inhibitors (HDACi), JAK/STAT inhibitors (JAK/STATi), and TCR pathway inhibitors (TCRi), particularly ITK inhibitors. To determine which drug(s) may be the optimal combination partner(s) for venetoclax in T-PLL, we utilized a functional approach known as BH3 profiling. This assay measures how close a cell is to the threshold of apoptosis ("priming") and identifies which anti-apoptotic proteins a cell depends on for survival. We also utilized a variant known as dynamic BH3 profiling (DBP) to measure early changes in pro-apoptotic signaling after various drug treatments. Methods: Clinically annotated primary T-PLL patient samples were obtained from the French Innovative Leukemia Organization network after informed consent. Peripheral blood mononuclear cells were isolated by Ficoll and viably frozen and later thawed for the experiments. Baseline BH3 profiling to measure cytochrome C (cyto-C) release was performed as per Ryan et al., Methods, 2013, and DBP as per Montero et al., Cell, 2015. Viability was assessed by AnnexinV/Hoechst staining. Ex vivo drug treatments included: BH3 mimetics (BCL-2i: venetoclax (VEN), MCL-1i: AZD5991, S63845), HDACi (belinostat = BEL), JAK/STATi (ruxolitinib = RUX) and TCRi (PRN694 = PRN). Protein expression was assessed by standard Western Blot. Primary CLL cells were used in some experiments as a comparator. To mimic the lymph node microenvironment, DBP and viability assays were performed in co-culture with the stromal cell line NK.tert. Tumoral DNA was also extracted, and we performed NGS on a panel of 29 genes, including ATM and TP53, as well as Sanger sequencing to assess for IL2R, JAK1, JAK3, STAT5B mutations. Statistical analyses were by unpaired and paired t-test with a two-tailed nominal p ≤ 0.05 considered as significant. Results: Samples were evaluated from 31 T-PLL patients. Baseline BH3 profiling revealed that, compared to CLL cells, T-PLL cells are less primed for apoptosis but have comparable dependency on MCL-1. BCL-2 dependency was found to be significantly lower in T-PLL than CLL (cyto-C release 48.8%; 62.7% p=0.0005), and to decrease further in the presence of stroma (Figure A, cyto-C release from 72.6% to 36.2%, p = 0.01). Consistent with our BH3 profiling results, the degree of BCL-2 dependency in T-PLL cells was strongly associated with the amount of apoptotic cell death induced by VEN (R2 -0.58, p=0.004), whereas MCL1 dependency was strongly associated with the cell death induced by the MCL1 inhibitors S63845 and AZD5991 (R2 -0.59, p=0.002 and R2 -0.68, p=0.0005 respectively, Figure B). We next performed DBP to assess the changes in apoptotic priming in T-PLL cells induced by HDACi, JAK/STATi and TCRi. To utilize doses similar to what can be achieved in patients, we assessed BEL 1mM, RUX 1mM and PRN 1mM. BEL and RUX increased overall T-PLL cell priming and BCL2 dependency (delta cyto-C release of 26.8%, p=0.004 and 14.8%, p=0.01 respectively Figure C), with no effect on MCL1 dependency. PRN had no significant effect on priming. Consistent with the DBP data, our viability assays showed that BEL and RUX induced significantly more cell death when combined with VEN compared to PRN (Figure D). Mutations in ATM, TP53, and JAK/STAT pathway genes were observed in cells from 35%, 6%, and 53% of patients, respectively, and did not impact the ex vivo activity of these drugs. Conclusion: We report the first data for BH3 profiling in T-PLL. We found that this disease is heterogeneously dependent on both BCL-2 and MCL-1, and that the lymph node microenvironment may decrease BCL-2 dependency. HDACi and JAK/STATi both enhance BCL-2 dependence, thereby sensitizing T-PLL cells to VEN. Ongoing studies will help further define the mechanism underlying these promising new combinations for T-PLL. Disclosures Herbaux: BMS: Honoraria; Gilead: Honoraria; Takeda: Honoraria; Abbvie: Honoraria; Janssen: Honoraria. Valentin:Roche: Other: Travel reimbursement; Abbvie Inc: Other: Travel reimbursement. Morschhauser:F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Bayer: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Staber:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda-Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; MSD: Honoraria, Speakers Bureau. Davids:AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding; AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees; Research to Practice: Honoraria.