Goldschmidt, H.

Abstract Abstract 2878 Poster Board II-854 Background: Significant advances have been made in the treatment of myeloma with the introduction of thalidomide, its analogue, lenalidomide, and the proteasome inhibitor bortezomib. While these new drugs have improved the outcome of patients with myeloma, the disease still remains incurable. Effectiveness of upcoming new therapies will need to be assessed in the context of anticipated outcome with the currently available therapies. However, given the rapid pace of development over the past decade, outcome of patients who have relapsed on the new therapies remain unclear. Methods: In order to further study this group of patients, we undertook a study of patients who have relapsed on or are refractory to one of the IMiDs (thalidomide or lenalidomide) as well as bortezomib. A total of 300 cases from 8 sites in the US, 5 sites in Europe and one site in Asia were identified for this study. Enrolled patients had relapsed and refractory multiple myeloma, per the EBMT or IMWG response criteria, after at least 2 prior treatments. Patients were refractory to bortezomib, defined as having no response on a prior bortezomib-containing regimen or experiencing disease progression within 60 days of a bortezomib-containing regimen. Patients also should have relapsed, refractory, intolerant, and/or ineligible in the opinion of the investigator, to other therapies, including an IMiD (thalidomide or lenalidomide). Clinical and laboratory data pertaining to the time of diagnosis and from the time of individual relapses were obtained from the clinical records. The date patients satisfied the above entry criteria was defined as time zero. Results: The current analysis includes the first 119 patients with complete data available. The median age at initial diagnosis was 59 years (range, 31-86 yr); 71% were males. The ISS stage distribution at diagnosis was 33%, 39% and 28% for stages 1, 2, and 3 respectively. 19 patients (37%) had high risk disease by FISH [t(4;14), t(14;16), del17p] or by cytogenetics [del 13, hypodiploidy]. The median time from diagnosis to time zero was 3.8 yrs (range 0.2-18.7 yr) and the median reported lines of therapy before time zero was 2. 74% patients had at least 1 autologous stem cell transplant prior to becoming eligible for the study. Following time zero, 77 (65%) pts had a treatment recorded, including an autologous SCT in 21 (18%), with the treatment regimen starting at a median of 1 month after time zero. A variety of treatment regimens were utilized beyond time zero (median=1; range 0-7). Thirty-two (27%) patients had a response any time following time zero, and only 8 had a subsequent response. Response to the first treatment, or supportive care for patients not treated, recorded following time zero included minor response or stable disease (n=14; 12%), PR (n=17, 14%), and VGPR or better (n=6, 5%). Patients treated with SCT had a higher rate of PR or better compared to patients receiving other treatments (85%; 17/20 vs. 26%; 15/57). In a multivariate analysis, the only significant predictor of a PR or better after time zero was younger age (<60 yrs). The median overall survival (OS) and event free survival (EFS) were 6 mos (95% CI, 4-7 mos) and 1 month (95% CI,1-2 mos) respectively. In a multivariate analysis normal creatinine predicted for a better overall survival and having an IgG M protein type predicted for better EFS. A complete analysis from all 300 patients will be presented at the meeting. Conclusions: This study confirms the poor outcome of patients once they become relapsed and refractory to agents that have become the mainstay of myeloma therapy. The findings highlight the incurable nature of the disease and urgent need to develop newer effective therapeutic agents for this group of patients, who currently do not have effective treatment options. Disclosures: Kumar: CELGENE: Research Funding; MILLENNIUM: Research Funding; BAYER: Research Funding; GENZYME: Research Funding; NOVARTIS: Research Funding. Jagannath:Merck: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Laubach:Novartis: . Palumbo:Ortho Biotech, Janssen-Cilag: Honoraria; Celgene: Honoraria, Speakers Bureau. Richardson:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: 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, Speakers Bureau; Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. San Miguel:Millennium: Membership on an entity's Board of Directors or advisory committees; 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. Siegel:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Sonneveld:Janssen-Cilag: Honoraria. Durie:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees.

Abstract Abstract 743 Background There has been considerable recent focus upon the molecular classification of myeloma. However, the prognostic impact of molecular changes has mostly been assessed from small and/or incomplete studies from single institutions or groups. There has been no large scale analysis of molecular features linked to ISS stage. Methods In order to clarify the overall impact of molecular changes we undertook a collective analysis of 9,897 patients through the International Myeloma Working Group (IMWG). Within this population 2,295 patients had presence of cytogenetic abnormalities (Any CA); 1,713 hypodiploidy; 1,673 hyperdiploidy; 2,309 cytogenetic deletion 13; 3,226 deletion 13 by FISH; 1,573 FISH t(4;14); 1,486 FISH del p17; 1, 683 FISH t(11:14); and 366 FISH t(4;16). Enrolled patients had complete clinical and treatment details available including baseline standard prognostic factors, ISS stage, as well as both progression free survival (PFS) and overall survival (OS) information. Data came from 14 sites: 3 from the US and the remainder from Europe, Asia, and Latin America as for the ISS staging system analyses. Univariate and multivariate analyses were performed. Results Each of the known adverse molecular features had a negative impact upon both PFS and OS (p=002 - <0.0001). Among the deleterious FISH abnormalities the t(4;14) abnormality was the most highly correlated with poorer outcomes by PFS: 4 year estimate: 32% vs. 60% (p<0.0001). The t(4;14) abnormality combined with ISS Stage also significantly enhanced predictive capability: ISS Stage I without t(4;14) OS 81% @ 4 years; ISS Stage III with t(4;14) OS 22% @ 4 years (P<0.0001) [Figure 1]. The best outcomes were for ISS Stage I in the presence of t(11;14): OS 89% @ 4 years. Absence of any one adverse feature correlated with 80-81% OS @ 4 years for Stage I. Presence of any one adverse feature had a more variable impact and correlated with 22%-40% OS at 4 years for Stage III. In univariate correlations the most predictive correlations with OS were presence of Any CA, t(4;14), 17p-, hypodiploidy, cytogenetic 13q- with R2 values of 6.9%, 4.5%, 4.1% and 3.8% respectively. In multivariate analyses, ISS stage provided the best predictions: R2 values = 13.3%. The added contributions from molecular features were: t(4;14) 3.8%; cytogenetic 13q- 2.9%; Any CA 2.3%; and 17p- 1.0%. The maximum total R2 for OS was 22%. Conclusions This large multicenter analysis confirms the correlations between abnormal molecular findings and outcomes. Combinations with ISS Stage provide the best predictive capability. Presence of Any CA, t(4;14), 17p-, hypodiploidy and cytogenetic 13q- contribute to poorer outcomes by ISS stage. The presence of hyperdiploidy and/or t(11;14) contribute to better outcomes. There is thus validation of prior molecular studies related to prognosis utilizing this large IMWG database. Disclosures: No relevant conflicts of interest to declare.

AbstractA venous thromboembolism (VTE) with the subsequent risk of pulmonary embolism is a major concern in the treatment of patients with multiple myeloma with thalidomide. The susceptibility to developing a VTE in response to thalidomide therapy is likely to be influenced by both genetic and environmental factors. To test genetic variation associated with treatment related VTE in patient peripheral blood DNA, we used a custom-built molecular inversion probe (MIP)–based single nucleotide polymorphism (SNP) chip containing 3404 SNPs. SNPs on the chip were selected in “functional regions” within 964 genes spanning 67 molecular pathways thought to be involved in the pathogenesis, treatment response, and side effects associated with myeloma therapy. Patients and controls were taken from 3 large clinical trials: Medical Research Council (MRC) Myeloma IX, Hovon-50, and Eastern Cooperative Oncology Group (ECOG) EA100, which compared conventional treatments with thalidomide in patients with myeloma. Our analysis showed that the set of SNPs associated with thalidomide-related VTE were enriched in genes and pathways important in drug transport/metabolism, DNA repair, and cytokine balance. The effects of the SNPs associated with thalidomide-related VTE may be functional at the level of the tumor cell, the tumor-related microenvironment, and the endothelium. The clinical trials described in this paper have been registered as follows: MRC Myeloma IX: ISRCTN68454111; Hovon-50: NCT00028886; and ECOG EA100: NCT00033332.