ALBERT

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. 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: 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.