ALBERT

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: 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. Bortezomib-melphalan-prednisone (VMP) and melphalan-prednisone-Thalidomide (MPT) are the 2 standards of care upfront in Multiple Myeloma (MM) ineligible for transplantation, along with Bendamustine-prednisone in a very limited indication in Europe. These regimens are based on an alkylator plarform, to which cyclophosphamide might replace melphalan in some countries. For patients initially exposed to Thalidomide several options are offered at first relapse with bortezomib or lenalidomide-based therapy and vive versa at subsequent relapses. For patients initially exposed to bortezomib, either they are retreated with a bortezomib-based regimen or receive a lenalidomide-based therapy, but these patients often have never been exposed to thalidomide throughout their myeloma disease history. We hypothesized that patients that will receive the 3 agents, thalidomide first followed by bortezomib and lenalidomide at subsequent relapses, will have a prolonged survival compared to patients that had bortezomib-based first followed by lenalidomide at subsequent relapses but never been exposed to thalidomide upfront. We sought to understand the prognostic impact of receiving versus being spared from Thalidomide in elderly MM newly diagnosed. Method. A total of 76 patients were recruited, 37% had receive thalidomide and 63% never been exposed to thalidomide. Patients were required to be aged ≥65 years, NDMM treated with either thalidomide upfront or never been exposed to thalidomide upfront or later in the myeloma disease course. Response rate was determined according to IMWG. All survival endpoints were evaluated using Kaplan-Meier estimates and compared with the log-rank test. Results. Overall, the median age was 73 years (range, 65 - 85), with 46% aged 〉75. The m:f ratio was 1.2, 49% of the patients were ISS 3, the median b2m was 4.5mg/L, 33% had an ECOG score ≥ 2, 47% renal insufficiency, 11% had elevated LDH, 8% presence of plasmacytoma, and 11% had adverse FISH (del17p, t(4;14) and or t(14;16)). There was no difference between the 2 studied groups, according to exposure or not to thalidomide. In the thalidomide group, all patients had MPT initially for a median of 8 cycles (range 3 – 12), at a median dose of thalidomide of 100mg/day (50-200), 11% dose reduction, an ORR of 79%, a median PFS of 30 months (CI95% 27;32). In the bortezomib group upfront, patients received Vd, VCd or VMP upfront. The median dose administered of bortezomib was 1.3mg/m², for a median of 5 cycles (2-9). The ORR was 67%, a median PFS of 17 months (CI95% 13;20) with 44% at 2-years PFS. With a median follow-up of 5 years, 93% had relapse, 47% have died. We then sought to compare the OS according to whether the patients were exposed to thalidomide. Interestingly, the median OS of the thalidomide group was 4 years (CI95% 3;5) versus 5 years for the group with no exposition to thalidomide (3.5;6), p=ns. The estimated 6-years OS was 32% and 44% for the 2 groups, respectively. Conclusion. The sequence of bortezomib-based regimen upfront followed by lenalidomide with no exposure to thalidomide in transplant ineligible patients appeared to be slightly superior to the sequence including-based regimen upfront followed by bortezomib and lenalidomide at subsequent relapses. This data needs to be confirmed in a larger study, but it seems that thalidomide could be spared for elderly NDMM that receive bortezomib-based and lenalidomide-based regimens with possibly an improvement of OS in this latter group with a prolonged follow up. Disclosures Gay: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees. Zweegman:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Background. Pomalidomide in association with dexamethasone is approved for RRMM in 3rd line and beyond based on the MM-003 multicenter international phase 3 study that demonstrated greater efficacy for Pomalidomide plus dexamethasone over high dose dexamethasone. However, MM-003 mainly recruited advanced RRMM with a median of 5 prior lines. Few data is available regarding real life Pomalidomide-based treatment in 3rd and 4th line RRMM. The aim of this study was to study efficacy and safety of Pomalidomide-based treatment in 3rd and 4th line RRMM. Methods. We studied 108 consecutive RRMM treated with Pomalidomide-based treatment in 3rd and 4th line in a multicenter-based study. All assessment made according to IMWG. Results. The median age was 62.5 (range, 30-86), with 36% older than 65 years, sex ratio M/F 1.25 and ISS disease stage 2 or 3 in 58%. 100% were exposed to bortezomib and refractory to Lenalidomide. 52 patients (48%) had pomalidomide-based therapy as 3rd, and 56 (52%) as 4th line. 73% of patients received a double-based therapy (Pomalidomide plus Dexamethasone) and 27% received a triple based therapy (Pomalidomide, Cyclophosphamide and Dexamethasone). Overall ORR was 55%, with 20% ≥VGPR including 5% CR, and was not statistically different in 3rd versus 4th line, and with PCd versus Pd, although the former was always better. With a median f-up of 45 months, overall 77% and 49% had relapsed and died, respectively, with significantly less in benefit to combination and 3rd line compared to Pd and 4th line (p=0.020). The median PFS was 6 (CI95% 2.3;9.6) and 9 (5.5;12.5) months in 3rd and 4th line (p=0.04), and 6 (CI95% 2.8;9.2) and 12 (8.5;15.5) months in Pd and PCd (p=0.04), respectively. Interestingly, the estimated 3 years PFS for 3rd line and PCd was 34% and 32% respectively, greatly superior to 4th line and Pd, 13% and 18%, respectively. Similarly, the median OS from start of Pomalidomide was not reached in 3rd and in PCd lines versus 23months (5;49), (p=0.04), and 32 months (5;-) for 4th line and Pd use, respectively. Pomalidomide was never permanently discontinued for safety issues, but 30 (28% of patients had to reduced pomalidomide dose, 25% to N-1 that is 3mg/d and 3% at N-2 that is 2mg/d. Expectedly, more patients (increased by 10%) had to reduce pomalidomide dose in 4th line compared to 3rd line, although it was not statistically significant, but not with PCd versus Pd. Indeed Cyclophosphamide but not pomalidomide is reduced in modified in dose or scheme when facing safety issues. No patient died related to adverse events. AEs leading to pomalidomide-based modification in schema included hematological in 40% and non hematological AEs in 12% of patients. Overall, the most common adverse events grade 3 or 4 were neutropenia (22%), anemia (11%), thrombocytopenia (7%) and infectious disease (5%). Conclusion. Pomalidomide-based therapy demonstrates efficacy in the real life with a manageable safety profile. We demonstrate herein that early use and combination improves MM on pomalidomide in the real life. Further prospective studies are warranted to confirm this data on a larger MM population. Disclosures Hulin: Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Perrot:Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Celgene: Honoraria. Macro:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress. Laribi:Hospira: Other: Grant; Amgen: Other: Personal fees; Novartis: Other: Grant and personal fees; Gilead: Other: Personal fees; Roche: Other: Grant; Takeda: Other: Grant and personal fees; Sandoz: Other: Grant; Teva: Other: Grant. Leleu:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: Background. Bortezomib-melphalan-prednisone (VMP) is a standard of care upfront in Multiple Myeloma (MM) ineligible for transplantation, where bortezomib was given twice weekly intra veinously. Based on the VISTA study, the median TTP was 24.0 months, the median OS 56.4 months, the ORR (IMWG) 71% and the CR rate 30%. This regimen was then improved with a weekly administration of bortezomib starting at cycle 1 (called Palumbo design) or cycle 2 (called Mateos design). In the once-weekly schedule, the median PFS was 33.1 months, the median OS was not reached, the ORR 85% and the CR rate 30%. Recently, subcutaneous bortezomib was approved in association to dexamethasone in relapsed MM that proved non-inferior to standard intravenous administration in terms of efficacy, with an improved safety profile, particularly with regard to the rate of neuropathy. As a consequence, physicians have switched to Bortezomib subcutaneous administration in the VMP regimen in many countries. We aimed to study the impact of subcutaneous bortezomib in the VMP regimen (VscMP) in elderly MM newly diagnosed (NDMM). Method. A total of 40 patients were recruited for the current study. Patients were required to be aged ≥65 years, NDMM treated with subcutaneous Bortezomib, Melphalan and Prednisone. Patients had VscMP either according to VISTA schedule or to Palumbo (weekly) schedule. Response rate was determined according to IMWG. All survival endpoints were evaluated using Kaplan-Meier estimates and compared with the log-rank test. Results. The median age was 79 years (range, 67 - 90), with 28 patients (70%) aged 〉75 and 18 patients (45%) aged 〉80. The m:f ratio was 1.2, 77% of the patients were ISS 2 or 3, 32% had an ECOG score ≥ 2, and 10% had adverse FISH (del17p and/or t(4;14)). 15 patients were treated in the VISTA schedule and 25 in the weekly schedule (Palumbo design). No patients have had Mateos design. For the cohort as a whole, the median TTP was 32 months, the median OS is not reached with 81% 5-years estimate, the ORR 75% and the CR rate 17,5%; that demonstrated that subcutaneous bortezomib is non-inferior to IV data reported in historical studies for the VMP regimen. Similarly, there was not much difference in terms of efficacy between patients that had bortezomib subcutaneous weekly versus twice a week: weekly: the median OS is not reached, the ORR 80% and the CR rate 13%; twice a week: the median OS is not reached, the ORR 84% and the CR rate 20%. With regards to the safety profile of VMP given with bortezomib subcutaneous, it seemed to offer an improved safety profile: 12.5% of grade 3 or 4 hematologic toxicity versus 47% in the literature. It does not seem to be any difference in neurological toxicity, with 5% of grade ≥2 peripheral neuropathy in our study, as to the VISTA study. Interestingly, we have seen no clear difference in terms of safety profile between the two schedule designs, VMP twice a week versus weekly using bortezomib sub cutaneous, which tend to confirm the improved safety profile of VMP with bortezomib used subcutaneously. Conclusion. The use of subcutaneous bortezomib in the standard of care bortezomib-melphalan-prednisone regimen in elderly MM newly diagnosed had comparable efficacy than the intravenous administration. Importantly, the subcutaneous administration is associated to improved safety profile in comparison with previously published data. This dataset might encourage the use of the twice weekly subcutaneous bortezomib in the VMP regimen for patients considered fit. Disclosures No relevant conflicts of interest to declare.

Description: Background. Melphalan plus prednisone and bortezomib combination is the most frequent standard of care used upfront for newly diagnosed elderly myeloma (eNDMM). Despite significant improvements with bortezomib sub-cutaneous administration and weekly schedule, safety profile issues remain with MPV, that only can be resolved with lowering the doses, albeit of the potential loss of efficacy. Carfilzomib (K), a novel generation proteasome inhibitor, has different safety profile with absence of neuropathy. Carmysap, a phase I/II trial of twice weekly Carfilzomib plus MP in eNDMM, demonstrated carfilzomib MTD at 36mg/m2. The safety profile appeared otherwise good for this frail population. We hypothesized that Carfilzomib can be used on a weekly schedule allowing to increase the dose of Carfilzomib given its positive safety profile. Methods. IFM2012-03 (carmysap weekly) is a phase 1/2 multicenter symptomatic eNDMM (65 and older) study to determine MTD during the phase 1 part and VGPR+CR rate (IMWG criteria) during the phase 2 part of KMP (Carfilzomib Weekly Plus Melphalan and Prednisone) regimen. Inclusion criteria required absolute neutrophils ≥1G/L, untransfused platelet count ≥75G/L, hemoglobine ≥8.5g/dL and clairance creatinine ≥30ml/min. Induction comprised nine 5 weeks cycles. K is given 36, 45, 56 and 70 mg/m2 on days 1, 8, 15, 22 IV route in combination to oral Melphalan 0.25mg/kg/j and oral prednisone 60mg/m2, both on days 1 to 4. Maintenance. Carfilzomib. 36 mg/m2 weekly, every two weeks IV route for 1 year. Melphalan and Prednisone is not pursued at maintenance. Analysis is done on ITT. Recruitment was 6 patients per cohort, 3 DLTs defined MTD at the lower N-1 dose. We will report at ASH the results of the phase 1 and 2. Results. 32 NDMM recruited, 30 treated in the study, 6 per cohort at K 36 mg/m², 45, 56, and 70 twice per DSMB request. The median age was 76 with 2/3rd older than 75, sex ratio M/F 1.2, R-ISS 2 and 3 in 80%.There was one DLT at K 36 (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) and 2 at 70 (vomiting grade 3 and liver cholestase enzyme grade 3) across the 2 70 cohorts. As a whole for the study, the ORR is 87.5%, with 45.7% at least in CR. At data cut-off, with a median follow-up at 15 months, one patient had progressed and 2 had died of whom one of cardiac dysfunction considered K related at 56. The safery profile appeared well tolerated, however, 22 SAE were reported for a total of greater than 200 cycles administered of KMP. Of particular interest, 19 SAEs were reported across the K 56 and 70 cohorts, 6 of which were cardiovascular origin. Conclusion. IFM2012-03, KMP weekly, Carfilzomib plus Melphalan and Prednisone in elderly NDMM has reached RP2D at 70mg/m2 of K. The SAE signal at the highest dose of K 70 raise concerns on using K 70 in patients older than 75-80 years old, and the DSMB may recommend for these patients to limit the RP2D at 56mg/m2 of K. Updated data for phase 1 and 2 portions will be presented at ASH for the first time. Disclosures Leleu: TEVA: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Karlin:celgene: Consultancy, Honoraria; Bristol: Consultancy; takeda: Consultancy; janssen-cilag: Consultancy, Honoraria; amgen: Consultancy, Honoraria. Meuleman:Celgene: Consultancy; Bristol-Myers-Squibb: Consultancy; Takeda: Consultancy; Amgen: Consultancy. Roussel:AMGEN: Consultancy, Other: lecture fees, Research Funding; sanofi: Other: lecture fees; celgene: Consultancy, Other: lecture fees, Research Funding; janssen: Consultancy, Other: lecture fees; BMS: Other: lecture fees. Decaux:The Binding Site: Other: supply of free light chain assays , Research Funding; SIEMENS: Honoraria, Other: supply of free light chain assays , Research Funding. Hulin:celgene: Honoraria; Bristol: Honoraria; Janssen: Honoraria; Amgen: Honoraria; takeda: Honoraria. Attal:amgen: Consultancy, Research Funding; sanofi: Consultancy; celgene: Consultancy, Research Funding; janssen: Consultancy, Research Funding. Moreau:Celgene: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Facon:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Bristol: Consultancy; Janssen: Consultancy, Speakers Bureau; Karyopharm: Consultancy; Novartis: Consultancy; Millenium/Takeda: Consultancy.

Description: Background. Progression by serum free light chain (sFLC) test without or preceding progression with intact immunoglobulin (Ig) is called light chain escape. This event alone is not considered a progression for patients with Multiple Myeloma (MM) according to International guidelines, although it is often considered a progression in real life and by clinical trials' investigators. We therefore sought to determine whether light chain escape would be a predictor of relapse and thus question a possible need to modify the current criteria for progression according to the International Myeloma Working Group (IMWG). Material and method. We have reviewed 325 (323 for analysis) patients that presented with a progression in the IFM/DFCI2009 phase 3 study (Attal et al. NEJM 2017). Among these 323 patients, 260 had initial tumor bulk measurement with intact Ig by serum protein electrophoresis test (SPEP; Ig ≥ 10 g/L) and 63 light chain MM (Ig 〈 10 g/L) measured using urine protein electrophoresis (UPEP). All progressions were validated in the central laboratory of CHU de Nantes (Dr T. Dejoie) and followed IMWG recommendations. sFLC increase was determined by absolute increase ≥ 100 mg/L and ≥ 25% from nadir value of the difference between involved and uninvolved FLC (ΔiFLC). Light chain escape was defined as sFLC increase without progression by SPEP (Ig increase ≥ 5 g/L and ≥ 25%) or UPEP (increase ≥ 200 mg/24h and ≥ 25%). Results. Among the 260 patients with intact Ig at diagnosis, 3 (1.15%) patients presented a light chain escape: progression by sFLC test without progression by SPEP. In parallel, 228 patients (87.7%) progressed by SPEP, of whom 18/228 (6.25%) showed a sFLC increase preceding the increase of intact Ig, with a median delay of 63 days. Among the 63 light chain MM, 6 (9.5%) patients presented a light chain escape: progression by sFLC test without progression by UPEP. Interestingly, 6 other patients (9.5%) progressed by SPEP even though Ig was 〈 10 g/L at diagnosis. Of the remaining 46 patients, 38 (60.3%) showed sFLC increase before progression by UPEP. Finally, 8 patients (12.7%) progressed but with intact Ig pauci-secreting MM meeting none of the M spike based progression criteria. Median time from iFLC nadir to ΔiFLC ≥ 100 mg/L was 280 days for light chain MM, 496 days for intact Ig MM, and 651 days for light chain escape. Median time from ΔiFLC ≥ 100 mg/L to follow-up visit to assess progression was 402 days light chain MM, 536 days for intact Ig MM, and 713 days for light chain escape. Overall, 9 (3%) patients had true light chain escape with progression by sFLC test without any other progression criteria. In parallel, in 56 (17%) patients, sFLC increase preceded progression to MM by standard test (SPEP or UPEP). Still the vast majority of patients had a regular relapse using the standard markers for progression. Conclusion. Based on a large study of patients treated into a phase 3 clinical trial with centralized assessment of response and progression, we showed that 20% of patients had progression by sFLC without meeting standard progression markers, of whom 3% had true light chain escape and 17% early light chain increase. Even though true light chain escape seems to be a rare phenomenon, analysis of sFLC test could help to avoid delayed or missed diagnosis of progression in 20% of patients in this clinical trial. This data should be confirmed in another database to assess whether a modification in the progression criteria in MM International guidelines should be proposed. Disclosures Hulin: Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Roussel:Amgen: Consultancy; Celgene: Consultancy; Takeda: Consultancy. Hebraud:Amgen: Consultancy; Janssen: Consultancy, Other: Lecture fees; travel and accommodation for congress, Research Funding; Sanofi: Consultancy; Takeda: Consultancy; Celgene: Consultancy, Other: Lecture fees, Research Funding. Karlin:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support. Belhadj:Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Decaux:Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Garderet:Amgen: Consultancy; Takeda: Consultancy; Celgene: Consultancy. Facon:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; 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; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Avet-Loiseau:Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Moreau:Amgen: 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; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Attal:Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janseen: Consultancy, Research Funding; Sanofi: Consultancy. Leleu:Karyopharm: Honoraria; Gilead: Honoraria; Incyte: Honoraria, Other: steering committee membership ; Roche: Honoraria; Sanofi: Honoraria, Other: steering committee membership steering committee membership ; Novartis: Honoraria, Other: steering committee membership ; Amgen: Honoraria, Other: steering committee membership ; Merk: Honoraria, Other: steering committee membership ; Takeda: Honoraria, Other: steering committee membership ; BMS: Honoraria, Other: steering committee membership ; Celgene: Honoraria, Other: steering committee membership ; Janssen: Honoraria, Other.

Description: Background. Thalidomide is one of the most prescribed regimens upfront in eNDMM, e.g. elderly myeloma, essentially as melphalan-prednisone-Thalidomide (MPT). Several options are offered at 1st and 2nd relapse to patients initially exposed to Thalidomide with either bortezomib or lenalidomide-based therapy. On the other hand, the second most prescribed drug in elderly myeloma upfront is Bortezomib, primarily as Bortezomib-melphalan-prednisone (VMP), the 2nd standard of care upfront in Multiple Myeloma (MM) ineligible for transplantation. Interestingly, lenalidomide is the drug of choice at first relapse in the vast majority of cases in most countries where lenalidomide is approved at first relapse and beyond. In this situation, it is likely that the patients would not receive thalidomide throughout the disease course of myeloma. We sought to analyse whether patients not exposed to thalidomide upfront, and that were solely exposed to the 2 drugs, bortezomib-based regimen and lenalidomide-based therapy would have a lower survival than patients exposed to all 3 drugs, e.g. thalidomide, lenaldiomide and bortezomib. Method. A total of 145 patients were recruited in this multicentric study, 46,2% were in the thalidomide upfront exposed arm and 53,8% had never been exposed to thalidomide. Patients were required to be aged ≥65 years, NDMM treated with either thalidomide upfront or never been exposed to thalidomide upfront or later in the myeloma disease course. If not exposed to thalidomide, the patients were to have received bortezomib upfront and lenalidomide first relapse or vice versa. In the thalidomide group, all patients had MPT initially for a median of 8 cycles (range 3 - 12), at a median dose of thalidomide of 100mg/day (50-200), with 11% dose reduction. In the non-exposed thalidomide group, all patients had bortezomib upfront, patients received Vd, VCd or VMP upfront; lenalidomide was then given at first relapse to all patients. The median dose administered of bortezomib was 1.3mg/m², for a median of 5 cycles (2-9). Results. Overall, the median age was 73 years (range, 65 - 85), with 35% aged 〉75. The M/F ratio was 1.1, 38% were ISS 3, the median b2m was 5.5mg/L, 26% had an ECOG score ≥ 2, 42% had renal insufficiency, 11% had elevated LDH, 8% presence of plasmacytoma, and 14% had adverse FISH (del17p, t(4;14) and or t(14;16)). There was no difference in patients' characteristics across studied groups, according to exposure or not to thalidomide. With a median follow-up of 5 years, 60% have died overall; 69% in the thalidomide exposed group versus 52% in the thalidomide non-exposed group (p=0.027). The median OS of thalidomide exposed patients was 55.7 months (46;65) versus 44 months (35;53) in the thalidomide non exposed patients (p=0.079). In the thalidomide exposed group, the median PFS of the thalidomide, bortezomib then lenalidomide lines were 27 months (24;30), 11 months (8;13) and 13 months (10;15). In the thalidomide non-exposed group, the median PFS of bortezomib then lenalidomide lines were 17 months (13;21) and 13 months (6;20). We then studied the survival of patients from onset of first relapse in the thalidomide exposed group, e.g. upon treatment with bortezomib, followed by lenalidomide at subsequent relapse, 22.5 months (10;34) compared to patients in the thalidomide non-exposed group that received bortezomib upfront and lenalidomide at first relapse, 44 months (35;53), p=0.005. Conclusion. Overall, thalidomide exposed versus non exposed groups had similar OS, while OS was significantly lower in the thalidomide exposed patients at first relapse onset versus in the thalidomide non exposed patients from diagnosis. This data seems to recommend use of bortezomib- and lenalidomide-based regimens as early as possible in the myeloma disease course, but not to abandon thalidomide. Study of the impact of thalidomide in the post bortezomib, lenalidomide and pomalidomide era might thus be important to study and optimize. Disclosures Karlin: Amgen: Honoraria; BMS: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Legros:BMS: Speakers Bureau; ARIAD: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Garderet:Bristol-Myers Squibb: Consultancy. Hulin:Celgene Corporation: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria. Stoppa:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria. Moreau:Janssen: Other: Adboard; Novartis: Other: Adboard; Takeda: Other: Adboard; Amgen: Other: Adboard; Celgene: Honoraria, Other: Adboard. Facon: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; Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: 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. Zweegman:Janssen: 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, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. 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. Terpos:Janssen: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Amgen: Honoraria, Research Funding. Leleu:LeoPharma: Honoraria; Pierre Fabre: Honoraria; BMS: Honoraria; Novartis: Honoraria; TEVA: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Chugai: Honoraria.

Description: Abstract 196 Until recent data, MM concept implies that all clones are linearly related to each other and homogenous in their mutational landscape. However, studies are now contradicting this model and reveal a more complex clonal architecture of Darwinian-like somatic evolution, where tumor progression proceeds in a branching rather than in a linear manner, leading to substantial clonal diversity and coexistence of wide genetic heterogeneity. By use of serial genomic analysis at different points during the disease course of MM patients, Keats et al. found the existence of 3 temporal tumor types, which can either be genetically stable, linearly evolving, or heterogeneous clonal mixtures with shifting predominant clones. In order to confirm these data we study on a large cohort of MM patients the emergence or disappearence by FISH analysis of t(4;14) and t(11;14) between diagnosis and relapse. We selected 444 patients from the IFM cell collection for whom we had a FISH analysis at diagnosis and relapse. Among them, 342 were evaluable for proceeding to FISH analysis. Upon receipt, bone marrow plasma cells were sorted using nanobeads and an anti-CD138 antibody (RoboSep, Stem Cell Technologies). After immuno-magnetic sorting, the plasma cell suspension purity was verified, and only samples with at least 90% of plasma cells were kept. Cells were then fixed in Carnoy's fixative. To test plasma cells for the t(4;14) and t(11;14), we did use specific IGH-FGFR3 and IGH-CCND1 fusion probes (Abbott Molecular). Hybridizations were performed according to the manufacturer's instructions. For analysis, at least 100 plasma cells with correct signals were scored using a Zeiss epifluorescence microscope. Our population baseline data presents usual characteristics: median age at diagnosis was 57 years (36y to 82y), diagnosis was made between 18/05/2000 and 19/08/2008. Relapse occurred between 11/08/2000 and 04/02/2009, with a median PFS of 26.6 months. The t(4;14) was present at diagnosis in 16.7% of the patients (38/232), and 11% (36/322) at relapse; Chi2 test did not find statistical difference between incidence at diagnosis and relapse (p=0.12). The t(11;14) was present in 24.6% of patients at diagnosis (48/195) but only 10.7% (20/187) at relapse (p=0.002). The purpose of our study was to explore clonal evolution during myeloma course. The t(4;14) translocation appeared (negative at diagnosis and positive at relapse) in 13 patients (n=218; 5.96%). On the contrary, t(4;14) disappeared in 11 cases (5.04%, n=218). In the same way, t(11;14) appeared for only 2 patients (1.42%, n=141) and disappeared in six cases (4.25%, n=141). Interestingly, we did not see switch between emergence and disappearance of the two translocations; no patient changed his cytogenetic status for one translocation to the other one. This phenomenon represents an important percentage of patients: for t(4;14), 11% of patients changed their status and 5.67% for t(11;14). Our data are in link with a study by Keats et al. who identified an evolution of aCGH data on a cohort of 28 patients showing changes over time for all their patients. Even if our data did not identify one of the three temporal tumor types described by Keats, the diversity of our findings (gain or loss of t(11;14) or t(4;14) between diagnosis and relapse) is an illustration on a large cohort of the clonal diversity and evolution of MM. Conclusion: this study describes for the first time on a large cohort of patients an aspect of subclonal evolution of MM. We identified a change of cytogenetic status for 11% of t(4–14) and 5,67% of t(11–14). These data illustrate the subclonal evolution of MM and underline the importance to perform novel cytogenetic analysis during disease course because treatment may be influenced by clonal expansion. Disclosures: Hulin: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees. Kolb:janssen: Honoraria; celgene: Honoraria. Facon:onyx: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees. Attal:celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees.