Katz, Michael

Abstract While there are certain common clinical features in myeloma, the disease shows significant heterogeneity with regard to disease progression, and responses to therapy, affecting both survival and toxicities. Heritable variations in a wide variety of genes and pathways affecting cellular functions and drug responses likely impact patient outcomes. In the Bank On A Cure (BOAC) program we have developed a custom chip that assesses 3,404 SNPs representing variations in cellular functions and pathways that may be involved in myeloma progression and response. The chip has gone through rigorous quality controls checks for high call rates, accuracy, and reproducibility that will be presented. Using the BOAC chip, we have conducted studies to look for SNPs that may identify biologic variations that are associated with good or poor response across a variety of treatments. In this study we looked for SNPs that may distinguish short term and long term survivors in two phase III clinical trials: ECOG E9486 and intergroup trial S9321. E9487 patients were treated with VBMCP followed by randomization to no further treatment, IFN-alpha, or cylcophosphamide; and, although there was variation in survival, no significant differences in survival were noted among the 3 arms of the trial. Patients included in this SNP study from S9321 received VAD induction followed by randomization to VBMCP or high dose melphalan + TBI. SNP profiles were obtained for patients with less than 1 year EFS (n=20 in E9487; n=50 in S9321) and patients showing greater than 3 years EFS (n=32 in E9486; n=41 in S9321). Statistical approaches were performed to identify single and groups of SNPs that best discriminated the survival groups. Previous studies have suggested genetic variations in drug metabolism genes, p-glycoprotein transport, and DNA repair genes may influence survival outcomes. Our results show significant survival associations of genetic variations in genes within these functional categories (eg. GST, XRCC, ABCB, and CYP genes). Although genetic variations were found that were uniquely associated with each clinical trial, several of these genetic variations show survival associations that increase in significance when the two trials were examined as a conglomerate data set. Grouping genetic variations through common pathway approaches using gene set enrichment analysis, as well as clustering or partitioning algorithms, further improve the value of the SNPs as potential prognostic markers of survival outcomes. These results and statistical approaches will be presented, and represent steps toward identifying patient variations in biologic mechanisms important in predicting therapeutic outcomes.

8592 Background: Accrual to NCI clinical trials(CT)is often slower than planned at times mandating premature closure resulting in loss of valuable resources and delay of scientific progress. Methods: The NCI-MYSC AWG identified 10 potential BtA. SWOG, ECOG and Alliance investigators were queried and agreed that these barriers impede accrual (results stratified for academic and community sites). The MYSC AWG developed in collaboration with NCI and FDA strategies to overcome these barriers. Results: Strategies listed for the 3 most often cited BtA: 1. Reimbursement for CT related expenses:increase awareness of improved reimbursement for phase II CT; tailor reimbursement according to CT complexity; request funds from industry and other sources ( http://biqsfp.cancer.gov ) for qualifying ancillary CT components. 2. Spectrum of available treatment options influences CT participation: educate patients and providers about the significance of a new CT using social media, presentations at national meetings and by adding educational material to CT protocol; encourage opinion leaders and advocacy groups not to promote a new therapy as “standard” in the absence of phase III data. 3. Requirement of CT specific therapy at NCI designated sites only: “MYSC AWG Drug Administration Table” describes NCI/FDA approved rules for CT specific drug administration; CT protocol will outline which standard treatment components of a CT can be administered at any site as long as protocol specific guidelines are followed and conduct is supervised by enrolling investigator. Examples of additional strategies to overcome identified BtA: determine feasibility, indication and insurance coverage of CT specific tests during protocol development; discourage narrow eligibility criteria; avoid competing CT; allow up to 1 cycle of commercially available therapy prior to enrollment; CIRB support for phase II CT. Conclusions: The MYSC Accrual Working Group developed in collaboration with NCI and FDA strategies to overcome barriers to myeloma clinical trial accrual. These strategies may be applicable to NCI-sponsored clinical trials evaluating interventions in other diseases.

e19517 Background: Investigators cite complicated test (T) schedules as barriers to the conduct of clinical trials, especially T that do not contribute to outcome or pt safety. In MM protocols, some T are prone to being done inaccurately (e.g. UPEP, 24 hour urine collections), or are not useful (e.g. uric acid, AST/ALT) in determination of response (R) or safety. These T lead to increased cost, protocol violations, and do not enhance outcome. Methods: We analyzed data submitted for pts on E4A03 to examine frequency of missing data for R T: serum and urine (U) PEP, immunofixation (IFE) bone surveys (BS), and safety labs for C1-4. Results: Table outlines % pts with completed T. Most had T for serum M protein, as well as heme T but serum and U PEP, and IFE dropped off by C4. Other T e.g. uric acid were completed in 77%. Only 79% of pts had a BS repeated at C4. Incorrect or missing U data led to categorization of 16/445 (3.6%) pts as ineligible and was most frequent reason for ineligibility (69%). Missing U data led to 13/26 pts not evaluable. Analysis of SAE during the C1-4 revealed no SAE for hyperuricemia and < 5 SAE for AST/ALT. Only 5% of pts had lab-based SAE filed in 4 C. Conclusions: Required U T and BS to assess R in E4A03 were missing or completed inadequately and caused pts to be ineligible and or not evaluable. Such T need to be eliminated or replaced. Strategies to monitor data submission in real time may reduce subject loss due to T error. The requirement for routine T should be reassessed to create simpler trial design. Clinical trial information: NCT00098475. [Table: see text]

Abstract Abstract 3165 Background: Accrual to large oncology group studies in the United States is often slower than planned, especially in less common malignancies such as Multiple Myeloma (MM). To improve the treatment of patients with MM, it is essential that we address the barriers to accrual (BtA) to national clinical trials. The NCI Myeloma Steering Committee (MYSC) formed the Accrual Working Group (AWG), charged to analyze this problem. Methods: The members of the MYSC have developed a list of 10 potential BtA to NCI MM-CT under the leadership of the AWG at meetings conducted in person and by monthly telephone conference. This list was distributed via Survey Monkey among investigators and research staff of the SWOG, ECOG/ACRIN and Alliance research bases for the purpose of ranking the perceived importance of the 10 selected BtA. Responses based on a 0–5 Likert Scale were analyzed as continuous and categorical. For the latter, responses were grouped: Impedes Accrual – No (0,1), Yes (2–5); Significantly Impedes Accrual – No (0–3), Yes (4,5). Results: 246 survey responses were received. 50 participants who indicated that they had never attempted to or actually never enrolled a patient into a MM-CT were excluded. Of 196 responders, 61% had enrolled at least 5 patients, 43% practiced in academic centers (A) and 57% in community centers (C). 26% identified themselves as research staff, 74% as primarily physician investigators including Principal Investigators (12%). 78% have current access to NCI MM-CT. 46% identified their research base affiliation with SWOG, 20% with ECOG/ACRIN, 17% with Alliance, 17% as CTSU, NRG and other. The majority of survey responders confirmed agreement in the perception that all 10 identified BtA impede accrual, ranging from 60–84% depending on the specific barrier identified, while significant impediment to accrual ascribed to these BtA ranged from 22–47%. The perceived barriers most often cited as impeding accrual were (1) spectrum of available treatment options, (2) level of reimbursement for clinical trial related expenses and (3) patient‘s need for prompt treatment intervention (84%, 80%, 76% respectively). The first two barriers along with the requirement that patients receive their treatment exclusively at the NCI designated treatment site were rated most often as significantly impeding accrual (37%, 47%, 34% respectively). The first two were also identified most often as perceived BtA independent of practice setting (A, C), type of research engagement (physician investigator, research staff) and level of experience with MM-CT. Interestingly, the perception that patients must receive their treatment at the NCI designated treatment site and competing industry sponsored clinical trials were substantially more often cited as impeding accrual in academic centers compared to community centers and by physician investigators compared to research staff. The complexity of required diagnostic work up and the complexity of the treatment protocol and follow up testing were substantially more often cited as BtA in the community setting and by research staff compared to their peers in the academic setting and by physician investigators. The NCI MYSC AWG has proposed specific solutions to potentially lower perceived BtA. These include guidelines to allow protocol specific administration of commercially available agents by the patient‘s local oncologist, a simplified diagnostic work up and treatment plan and eligibility inclusion of patients who have received up to one cycle of specified urgent therapy prior to enrollment in MM-CT. Conclusions: We have queried experienced clinical investigators and research staff on 10 potential MM-CT specific BtA and found substantial consensus among responding participants in this survey. There are apparent differences in perceived BtA between the respondents from academic and community centers as well as between research staff and physician investigators. These data suggest that a structured approach to identification of BtA to clinical trials is feasible and creates opportunities to overcome them. This may have application to clinical trials across other diseases and may also lead to improvements in accrual. Disclosures: Barlogie: Celgene, IMF, MMRF, Millennium, Genzyme: Consultancy; Celgene, IMF, Millennium: Honoraria; Celgene, Novartis, NCI, Millennium, Onyx, Icon: Research Funding; GEP: Patents & Royalties.

Abstract Abstract 4184 Introduction: FACT-MM was developed with the aim to create a disease-specific, patient-reported outcomes (PRO) measure as part of the FACT measurement system to assess multiple myeloma (MM)-related symptoms. Literature review identified 52 MM specific symptoms and concerns. 13 MM expert clinicians rated these 52 items on relevance to health-related quality of life (HRQL) for MM patients and added 11 items for comprehensive PRO assessment in MM. These 63 candidate items were rated by 13 MM patients recruited through the International Myeloma Foundation website. Disease-related symptoms and concerns were described and provided by patients through free-text comments. Information from both the MM expert clinician and MM patient surveys including free-text items was analyzed and 14 highest ranked items were selected for the FACT-MM. The FACT-MM subscale (score 0–56), the FACT-G physical and functional well-being subscales (score 0–28), and the FACT-Neurotoxicity (FACT-Ntx) subscale (score 0–44) was administered to 48 E1A05 participants to assess disease and treatment-related symptoms of patients with newly diagnosed MM receiving 8 cycles of VRd versus Vd. Methods: In this study, the first three of seven sequential assessments were evaluated: baseline, cycle 5 and end of treatment (after cycle 8 or early diconstinuation). Instruments were scored as per the FACT scoring guidelines. Descriptive statistics were provided for each timepoint and changes in scores from baseline. The Wilcoxon rank sum test was used to assess differences in scores by ISS stage and ECOG PS. Pearson correlation coefficients were obtained between the scores. Cronbach's alpha was used to evaluate internal consistency of the FACT-MM. Results: At baseline and end of treatment, 46 and 41 patients, respectively, completed assessments. The FACT-MM demonstrated good to very good internal consistency (Cronbach alpha 0.79 – 0.89). The FACT-MM subscale was significantly correlated with the FACT physical and functional well-being subscales at baseline (r = 0.72), cycle 5 (r = 0.64; r = 0.49) and end of treatment (r = 0.72; r = 0.66). All scores declined modestly by cycle 5 and end of treatment from baseline. While sample size was limited, there appeared association with ECOG PS with higher scores for patients with PS 0 status. Conclusions: The 14-item FACT-MM scale is feasible for use to measure myeloma-related symptoms and has demonstrated acceptable psychometric properties based on findings from E1A05, an ECOG myeloma trial. Disclosures: Cella: Novartis: Research Funding. Fonseca:Consulting:Genzyme, Medtronic, BMS, Amgen, Otsuka, Celgene, Intellikine, Lilly Research Support: Cylene, Onyz, Celgene: Consultancy, Research Funding.

Abstract Abstract 38 INTRODUCTION: Lenalidomide and bortezomib have moved into the management of newly diagnosed multiple myeloma leading to dramatically improved outcomes. As a consequence, the role of upfront autologous peripheral blood stem cell transplant (ASCT) has become more controversial. The ECOG E4A03 clinical trial randomized newly diagnosed MM patients to lenalidomide with high-dose dexamethasone (LD) vs lenalidomide with low-dose dexamethasone (Ld) (Rajkumar et al Lancet Oncol 2010; 11: 29–37). Upon completing four cycles of therapy, pts had the option of ASCT or continuing on the assigned therapy. The purpose of this abstract is to determine the outcome of patients on this trial pursuing early ASCT according to various age-groups. MATERIALS and METHODS: This is a post hoc, retrospective analysis of overall survival within age subgroups stratified by early ASCT status. This is a landmark analysis including only pts surviving the first 4 cycles of therapy. RESULTS: In all three age-groups studied, 1, 2, and 3-year survival probability estimates with ASCT were excellent (Tables 1, 2, and 3). For patients under the age of 65 who survived the first 4 cycles of therapy, overall survival at 3-years was 94% with early ASCT, 78% in pts continuing protocol therapy. Although direct comparison with patients not going to early transplant is not possible because the assignment to early ASCT versus no early ASCT was not randomized, survival with ASCT at 3-years appeared higher. While we attempt to correct for age, the differences may be influenced by other factors such as performance status, comorbidities, response to therapy, etc. The presumption that treatment related mortality (TRM) should be more problematic for older pts undergoing ASCT is addressed by looking at the >65 and >70yo cohorts. In the >65 age group, one-year mortality is similar between the early ASCT population and the no early ASCT population. In the >70 age group, no adverse impact of early ASCT was seen in the first year on overall survival but the sample size is extremely small. In all age groups early ASCT seemed to mitigate some of the survival disadvantage associated with randomization to the LD arm. CONCLUSIONS: This analysis shows that the strategy of lenalidomide plus dexamethasone induction followed by early ASCT has a remarkably good outcome in terms of overall survival in all age groups studied and supports the continued role of early consolidative ASCT in newly diagnosed patients. The risk of early mortality was notably low in the first year in all age groups. The risk of early mortality seems to increase at 2 years for the LD pts not choosing early ASCT and at 3 years for the Ld pts not choosing early ASCT. Selection bias makes it difficult to compare results for pts that chose early ASCT directly to the patients who did not receive early ASCT in this trial. As such, these results emphasize the need for randomized trials investigating the timing of ASCT in myeloma in the era of novel therapy. Disclosures: Siegel: Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide for front line therapy. Abonour:Celgene: Speakers Bureau; Millennium Pharmaceuticals: Speakers Bureau. Callander:Millennium Pharmaceuticals: Research Funding. Fonseca:Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Research Funding; Genzyme: Consultancy; Onyx: Research Funding; Otsuka: Consultancy; Medtronic: Consultancy. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract Abstract 3017 Introduction: Multiple myeloma (MM) is a malignancy of clonal plasma cells with resulting in an increase production of ineffective immunoglobulins with suppression of non-involved immunoglobulins. Patients with MM are at increased risk of infectious complications, particularly to those organisms in which opsonization is one of the key defense mechanisms, e.g. strep and staph infections. Treatment of MM is virtually always associated with further immunosuppression, at least in the immediate term, until the malignant clone is eradicated and normal immunoglobulins are produced. Rationale: Due to further compromise of an already incompetent immune system by initial chemotherapy and the previous suggestion (Oken et al Am J Med 1996; 100:624-628) that prophylactic antibiotics may reduce infectious complications, this study was designed to evaluate the impact of prophylactic antibiotics on the incidence of serious bacterial infections during the first two months of treatment. Methods: Pts with untreated MM receiving chemotherapy were randomized on a 1:1:1 basis to receive either a daily ciprofloxacin (C; 500 mg), trimetheprim-sulfamethoxazole (T; DS bid) or observation (O) for the first 2 months of treatment. Pts were evaluated for serious bacterial infection (grade 3 or 4) during the first two months of myelotoxic/suppressive therapy. Secondary endpoints (EP) included: incidence of non-bacterial infections, resistant organisms due to prophylaxis, the incidence of infection the third month OFF of antibiotic prophylaxis and whether protection against infection is associated with an improved response rate. Results: From July 1998 to January 2008, 212 untreated, symptomatic MM pts being treated with myelotoxic/suppressive chemotherapy were randomized to C (n=69), T (n=76) or O (n=67) for the first 2 months of treatment. The incidence of serious infection (&gt; grade 3 ECOG toxicity criteria and/or hospitalization) was comparable among groups: C=10 (14.7%), T=5 (6.9%), O=9 (14.5%); p= 0.268 which was the primary EP. The incidence of any infection during the first 2 months was also comparable (20% vs 23% vs 22%, respectively, p=0.910). There were 25 grade 2 infections and 4 grade 3 infections involving respiratory (n =13), sepsis/bacteremia (n = 4), and urinary (n =3), joint/bone (n =2), unknown (n =2) or various GI tract (n = 5) and skin (n =1). Eight pts expired within the first 2 months: 2 from MM, 3 cardiac, 2 respiratory, 1 renal (unrelated to MM or Rx) occurring in the C (4), T (1), O (2). Secondary EPs failed to show a difference in the incidence of serious bacterial infection during the third month in the absence of prophylaxis (C=3%, T=4%, O=2%; p=0.874), development of resistant infections, initial response to therapy or overall survival. Conclusions: The use of prophylactic antibiotics did not decrease the incidence of serious infection (&gt; grade 3 and/or hospitalization) nor of any infection within the first 2 months of treatment. Infection prophylaxis did not affect the incidence of infection upon completion of 2 months of therapy (nor, ultimately, at any time during the subsequent 2 years), the response to therapy or to overall survival. Incidentally, there were no documented cases of PCP despite the assumption that MM pts, with compromised immune systems, are more susceptible. The incidence of serious infections in this study, in which few patients received novel agents, is comparable to that observed in more modern regimens even in the presence of mandated/recommended prophylactic antibiotics. Utilizing either lenalidomide plus dexamethasone or clarithromycin, lenalidomide and dexamethasone resulted in &gt; grade 3 infectious complications in 16.7% and 9.7%, respectively, as reported by the Mayo Clinic and Cornell groups, respectively (Gay et al Am J Hematol, in press). Furthermore, in the ECOG E4A03 randomized trial of lenalidomide plus either high dose dexamethasone (LD) or low dose dexamethasone (Ld) in which prophylactic antibiotics were recommended, the incidence of &gt; grade 3 infectious complications were 9.4% and 6.4%, respectively (Rajkumar et al Lancet Oncol 2010; 11: 29–37). We conclude that routine use of prophylactic antibiotics should not be mandated for patients receiving induction chemotherapy. Prophylactic antibiotics should be considered on a case-by-case basis after analyzing the potential infection risk in individuals. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 308 Introduction: The Eastern Cooperative Oncology Group (ECOG) has previously reported the superior 1 and 2 year survival of Ld versus LD as initial therapy in newly diagnosed symptomatic multiple myeloma (MM) (Rajkumar et al Lancet Oncol 2010; 11: 29–37). The 1 year and 2 year OS for Ld vs LD were 96% and 85% vs 88% and 78%, (p < 0.01), respectively. This despite higher ORR in LD vs Ld (79% vs 68%; p = 0.008). The difference in OS was predominantly due to early death in the LD group (5% vs 0.5%; p = 0.003). As a result of this analysis, Ld is now considered the standard of care. However, it should be noted that the majority of these deaths occurred in pts > 65. In this analysis, we evaluated the impact of age on dexamethasone dose intensity and OS. Methods: 445 pts were randomly assigned: 223 to LD and 222 to Ld. Pts were analyzed on an intent-to-treat basis for OS. The pts were analyzed by age in 2 groups: < 65 and > 65 (the age corresponding to transplant eligibility outside the US). The pts > 65 were then further subdivided into >70 and > 75 yrs. Results are expressed as OS probability at 1 and 2 years post randomization. In addition, to eliminate the early death ‘penalty’ in the LD group in the original analysis, a landmark analysis was performed at 4 months. Results: Overall Survival Probability: Intent-to Treat Analysis Overall Survival Probability: 4 month Landmark Analysis Conclusions: As previously reported, OS in the trial at 1 and 2 years was superior with Ld. OS was not superior with LD compared with Ld in any age group despite a higher response rate. This was true even when using a landmark analysis to eliminate the 5% early deaths seen in the first 4 months of treatment. We conclude the following: 1) LD is not definitively superior to Ld in any age group; 2) Given the higher toxicity in the absence of a clear survival benefit with LD, Ld remains the best choice for all ages. This analysis confirms the original opinion that low-dose dexamethasone is the standard of care for all newly diagnosed MM pts, regardless of age. Disclosures: Vesole: Millennium Pharmaceuticals: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Centorcor-Ortho-Biotech: Speakers Bureau. Off Label Use: Lenalidomide for front-line therapy in multiple myeloma. Abonour:Celgene: Speakers Bureau; Millennium Pharmaceuticals: Speakers Bureau. Callander:Millennium Pharmaceuticals: Research Funding. Fonseca:Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Research Funding; Genzyme: Consultancy; Onyx: Research Funding; Otsuka: Consultancy; Medtronic: Consultancy; Intellikine: Consultancy. Siegel:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Membership on an entity's Board of Directors or advisory committees.

Abstract We have taken a genetic strategy to define the mechanisms underlying the increased risk of VTE in myeloma patient treated with thalidomide using clinical trial data derived from the MRC, ECOG, Little Rock and HOVON trial groups. Baseline VTE rates in the MRC IX study, (CTD vs CVAD; n=748 no prophylactic anticoagulation), were 14%. Rates in both arms were equal but in the thalidomide arm, thrombotic events were all DVT’s or PE’s, whereas in the CVAD arm they split equally between line related and VTE’s. In the other comparison (CTD vs MP; n=542), the VTE rate was 17%, all in the thalidomide arm. Rates were similar or higher (30%) in the other trials depending on the intensity of treatment used. We carried out a nested case control on DNA from MRC IX on 90 VTE (45 thalidomide, 45 non-thalidomide related), matched to 180 controls. SNPlex analysis for 60 SNPs in the coagulation cascade, DNA repair, thalidomide, metabolism and myeloma specific pathways, identified 7 genes which affected risk (NBS1, MTHFR, Ku80, Cyp3A5, LGAL52 and IL12B). This suggests three major pathways contribute to the risk of thalidomide related VTE, metabolism of thalidomide, tumour responsiveness and some pro-thrombotic factors. These factors differ from non-thalidomide related risk where a strong pro-inflammatory response is most relevant. We tested this hypothesis further using an expanded panel of 3,404 SNPs (BOAC panel), using the Megalle system. Statistical analysis of this data defined the top 20 thalidomide and non-thalidomide associated SNPs, which were consistent with the initial hypothesis, the results of which exclude variation in the coagulation cascade as being a significant risk factor. We explored this hypothesis further using pathway-based analysis focussing on the MTHFR, DNA repair and WNT pathways on data from the ECOG, HOVON and Little Rock data sets. The biological relevance of the SNPs and genes identified was validated by correlating the level of expression using the Affymetrix U133 CHIP with genetic variation at the DNA level. To verify the relevance of DNA repair variability to tumour response further, we correlated gene expression profiling with response and again Ku80 was identified as one of a cluster of genes defining increased risk. The data suggests that the risk of thalidomide related VTE relates to rapid tumour lysis combined with a prothrombotic tendency, whereas in line related thrombosis, risk is dependent upon a strong proinflammatory response. We are building this genetic data into a clinical risk model in order to allow us to develop a rationale for intervention strategies.

Abstract Background: Bone disease in myeloma occurs as a result of complex interactions between myeloma cells and the bone marrow microenvironment. To date, no studies have evaluated the potential impact of genetic polymorphisms upon and/or within this microenvironment. Patients and Methods: Peripheral blood DNA from 282 patients enrolled in the Total Therapy 2 (TT2) protocol was studied using the previously reported Affymetrix 3k BOAC custom chip to evaluate relevant genetic polymorphisms. DKK1 gene expression and high risk GEP gene signatures were assessed as previously reported (Blood109:4470–4477 and 109:2276–2284 2007). Patients were classified using both full skeletal x-rays and MRI findings. The lower cut-off used was absence of focal abnormalities on x-ray and/or <7 focal lesions on MRI (see JCO25:1121–1128 2007). Results: The top 200 SNPs were first evaluated based upon univariate P values linked to limited or extensive bone disease. The top 50 SNPs with the smallest P values were then selected (eliminating closely linked genes) for recursive partitioning analysis. The recursive partitioning was conducted both with and without the insertion of known biologically relevant SNPs. The pruned tree developed with recursive partitioning proved to be quite stable and incorporated 4 dominant SNPs: rs 3766934 Epoxide hydrolase (EPHX1); sr3783408 MAP kinase; sr 1062637 RNA helicase DDX18; and sr3181366 TNFSF8-TNF-α. No alternate SNP substituted for EPHX1 in the recursive model. The 4 SNP signature of EPHX1 GG, MAP4K5 AG/AA, DDX18 GG/CC plus TNFSF8 CT/TT was highly correlated with the number of MRI lesions: mean 8.66 lesions versus 3.33 for alternate SNPs (P<.001). In the univariate association of standard prognostic factors, 4 SNP signature and 70 and 17 gene models for high risk, the best correlation with bone disease was with the 4 SNPs (P<.0001) followed by the 17 gene GEP model (P=0.05). Using stepwise multivariate regression analysis the best correlation with bone disease was Log2DKK-1 expression (P=.0001) but closely followed by SNPs EPHX1 (P=.0009); MAP4K5 (P=.0071) plus TNFSF8 and serum LDH (P=.02). The various analyses training (2/3) and validation sets were used with assessment of sensitivity and specificity. The microenvironmental 4 SNP signature combined with GEP DKK1 provided the best prediction of myeloma bone disease and overall outcome. Conclusions: This first assessment of genetic polymorphisms linked to myeloma bone disease in myeloma has led to the identification of polymorphisms with both potential biologic relevance and utility in prognostic models of myeloma bone disease including risk stratification for bisphosphonate use. Validation of these findings may allow a search for potential therapeutic targets.