High-risk Gene Expression Profile Research Articles

Navigating High-Risk and Ultrahigh-Risk Multiple Myeloma: Challenges and Emerging Strategies.

Despite significant improvement in the outcomes of patients with newly diagnosed multiple myeloma (NDMM) with novel therapies, there is still an underserved high-risk (HR) population that experiences early disease progression and death. With the median survival crossing 10 years, we defined ultrahigh-risk (uHR)MM as MM leading to death within 24-36 months of diagnosis and HRMM as MM leading to death within 36-60 months. Several features have emerged as markers of uHRMM: the co-occurrence of two or more high-risk cytogenetic abnormalities, extramedullary disease, plasma cell leukemia and a high-risk gene expression profiling signature. The heterogeneous risk definition across trials, the few trials available designed for HR patients, and the small HR subgroups in all-comers trials make it difficult to generate recommendations with high levels of evidence. Nevertheless, regardless of treatment administered, several studies consistently showed that achieving and maintaining measurable residual disease negativity is now considered the main factor able to mitigate the adverse prognosis related to baseline features. For fit patients with HR transplant-eligible (TE) NDMM, quadruplet induction/consolidation treatment with anti-CD38 monoclonal antibodies, immunomodulatory agents, proteasome inhibitors and dexamethasone, and autologous stem-cell transplant and maintenance with, if available, at least a doublet combination could be considered the option of choice. For non-TE NDMM, considering the recent data generated and carefully reviewing those upcoming, quadruplet treatment consisting of anti-CD38 monoclonal antibodies, immunomodulatory agents, proteasome inhibitors, and dexamethasone should also be considered. Future trials integrating BCMA-directed novel generation immunotherapies hold great potential for further advancing the treatment landscape in all NDMM patients with HR disease.

Post-ASCT consolidation with EPD or ERD in patients with high-risk multiple myeloma.

7534 Background: Patients (pts) with high-risk (HR) Multiple Myeloma (MM), characterized by at least two cytogenetic abnormalities often experience rapid disease progression and early relapse post-autologous stem cell transplant (ASCT) with median Progression-Free Survival (PFS) of 24 or 12 months with or without lenalidomide maintenance (Panopoulou et al, Blood 2023). This study assesses the efficacy and safety of EPD (Elotuzumab, Pomalidomide, Dexamethasone) or ERD (Elotuzumab, lenalidomide , Dexamethasone) as consolidation therapy post-ASCT in HR MM pts. Methods: In this single-center retrospective study, we reviewed records of MM pts treated with consolidative ERD or EPD from September 2016 to March 2023. We collected baseline MM characteristics, treatment history, adverse events (AEs), and survival outcomes. HR MM pts were defined by 2 or more cytogenetic abnormalities (del 17p, 1q21 gain or amplification, t(14;16), t(14;20), complex karyotype) and/or high-risk gene expression profiling scores (GEP, SKY92). All patients, aged ≥21, underwent ≥1 full cycle of EPD or ERD post-ASCT, administered for a total of four 28-day cycles, following the standard dosing regimen with a rapid dexamethasone taper over the last two cycles. Results: A total of 78 HR MM pts, median age 64 years with 51.2% males and 71.7% caucasians were included. Of them, 62 pts received ERD and 16 received EPD. FISH revealed 62.7% of pts had 2 or more high risk cytogenetic abnormalities. Other pts expressed a combination of cytogenetic abnormalities and/or high-risk GEP or SKY92 scores. The table shows improvement in MRD negativity rates from 21.7% to 26.9% pre and post consolidation, and in VGPR or better from 78.2% to 85.8%. Median PFS for all pts, defined from the time of ASCT to disease progression, was 26.9 months. Most common adverse effects were anemia (71.7%), fatigue (55.1%) and thrombocytopenia (51.2%). Five patients experienced grade 3 adverse events, including 3 with infectious etiology (3.8%) and 2 with immune-mediated toxicity (2.5%). No treatment-related serious adverse events were reported. Conclusions: Four cycles of EPD or ERD consolidation therapy post-ASCT, demonstrated promising efficacy in HR MM pts. The observed median PFS of 26.9 months was comparable to that seen with chronic lenalidomide maintenance and superior to patients who do not receive lenalidomide maintenance. The improvement in PFS was achieved with a fixed duration rather than continuous therapy and without lenalidomide-associated toxicities such as secondary malignancies, chronic diarrhea, and financial toxicity. Further prospective confirmatory studies are needed. [Table: see text]

Socioecologic Factors and Racial Differences in Breast Cancer Multigene Prognostic Scores in US Women

Disproportionately aggressive tumor biology among non-Hispanic Black women with early-stage, estrogen receptor (ER)-positive breast cancer contributes to racial disparities in breast cancer mortality. It is unclear whether socioecologic factors underlie racial differences in breast tumor biology. To examine individual-level (insurance status) and contextual (area-level socioeconomic position and rural or urban residence) factors as possible mediators of racial and ethnic differences in the prevalence of ER-positive breast tumors with aggressive biology, as indicated by a high-risk gene expression profile. This retrospective cohort study included women 18 years or older diagnosed with stage I to II, ER-positive breast cancer between January 1, 2007, and December 31, 2015. All data analyses were conducted between December 2022 and April 2023. The primary outcome was the likelihood of a high-risk recurrence score (RS) (≥26) on the Oncotype DX 21-gene breast tumor prognostic genomic biomarker. Among 69 139 women (mean [SD] age, 57.7 [10.5] years; 6310 Hispanic [9.1%], 274 non-Hispanic American Indian and Alaskan Native [0.4%], 6017 non-Hispanic Asian and Pacific Islander [8.7%], 5380 non-Hispanic Black [7.8%], and 51 158 non-Hispanic White [74.0%]) included in our analysis, non-Hispanic Black (odds ratio [OR], 1.33; 95% CI, 1.23-1.43) and non-Hispanic American Indian and Alaska Native women (OR, 1.38; 95% CI, 1.01-1.86) had greater likelihood of a high-risk RS compared with non-Hispanic White women. There were no significant differences among other racial and ethnic groups. Compared with non-Hispanic White patients, there were greater odds of a high-risk RS for non-Hispanic Black women residing in urban areas (OR, 1.35; 95% CI, 1.24-1.46), but not among rural residents (OR, 1.05; 95% CI, 0.77-1.41). Mediation analysis demonstrated that lack of insurance, county-level disadvantage, and urban vs rural residence partially explained the greater odds of a high-risk RS among non-Hispanic Black women (proportion mediated, 17%; P < .001). The findings of this cohort study suggest that the consequences of structural racism extend beyond inequities in health care to drive disparities in breast cancer outcome. Additional research is needed with more comprehensive social and environmental measures to better understand the influence of social determinants on aggressive ER-positive tumor biology among racial and ethnic minoritized women from disadvantaged and historically marginalized communities.

Abstract 6121: Racial differences in the intratumoral immune cell infiltrate in luminal breast cancer

Abstract Background: Black women have a higher rate of breast cancer mortality compared with their non-Hispanic White (NHW) counterparts, with an 80% higher likelihood of breast cancer death from axillary node-negative, ER-positive (a.k.a. luminal) tumors (Hoskins et al, JAMA Oncol 2021). Black women are 30% more likely to have ER-positive tumors with a high-risk gene expression profile, indicating a role for tumor biology in this disparity (Hoskins et al, JAMA Oncol 2023). The underlying biological mechanisms responsible are unknown. The aim of this study was to investigate the immune cell infiltrate in ER-positive breast tumors as a potential driver of disproportionately aggressive luminal tumor biology among Black women. Methods: Gene expression data from ER-positive tumors diagnosed in women identified as Black or NHW in The Cancer Genome Atlas (TCGA) were deconvoluted with the CIBERSORT tool to estimate the relative intratumoral proportion of 22 immune cell types within each tumor. Differential analysis of imputed immune cell fractions comparing race was conducted with the Mann-Whitney test. P-values were adjusted for multiple comparisons with the false discovery rate (FDR) method. Linear regression of previously reported ancestry estimates for breast cancer patients in TCGA (Huo, et al, JAMA Oncol 2017) was used to test for association between African ancestry and proportion of regulatory T cells (Tregs) in tumors from Black women. Results: CIBERSORT analysis of tumors found a significantly increased proportion of Tregs in tumors from Black (n=86) than NHW (n=534) patients, with log2 fold-change= 0.74 (FDR-corrected p-value= 0.01). Plasma cells, T follicular helper cells and M0 macrophages were increased in tumors from Black women with uncorrected p-values &amp;lt; 0.05, but racial differences in these cell types were not significant after FDR correction (p &amp;gt;0.1). Ancestry analysis among Black women indicated that African ancestry was not associated with the intratumoral proportion of Tregs (1 SD change in proportion African ancestry was associated with 0.06 standard deviation increase in Tregs, p &amp;gt; 0.3). Confirmation of findings with a racially diverse breast tumor TMA from an independent cohort is ongoing and results will be presented. Conclusions: Increased pro-tumorigenic Treg infiltrate in ER-positive breast tumors from Black women may contribute to a disproportionately aggressive tumor phenotype and racial survival disparity. The findings could have therapeutic implications and suggest that immune checkpoint inhibitors may have increased activity against luminal breast cancer in Black patients. Although this study did not show a statistically significant effect for genetic admixture within African Americans, larger studies are needed to distinguish the contribution of ancestry vs. social context, environmental, and behavioral factors as the driver of this racial difference in tumor biology. Citation Format: Neha Hippalgaonkar, George Chlipala, Dezheng Huo, Garth Rauscher, Naiche Adler, Jan Kitajewski, Kent Hoskins. Racial differences in the intratumoral immune cell infiltrate in luminal breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6121.

Total Therapy (TT)-4: A Phase 3 Trial Comparing L-TT4 and S-TT4 and Tandem Auto Transplants in Standard Risk Multiple Myeloma

BACKGROUND: In the context of the TT4 study, a phase 3 trial was conducted to investigate whether a modified fixed duration treatment approach, known as L-TT4, could reduce toxicity while maintaining efficacy in tandem transplants for low-risk multiple myeloma (MM) defined by gene expression profiling. Here we report final analysis of TT4 study with long-term follow up of 11.7 years. METHODS: Treatment modification involved reducing the number of induction and consolidation cycles from 2 cycles each in the standard S-TT4 regimen to 1 cycle in L-TT4. The transplant regimen in L-TT4 was further adjusted by administering melphalan in a fractionated schedule of 50mg/m2 per day for 4 days (MEL50x4), instead of a single high-dose (MEL200) to reduce toxicity. To compensate for the potential decrease in effectiveness, bortezomib, thalidomide and dexamethasone (VTD) added for synergy between MEL50x4 and VTD. Maintenance was with 3 years of bortezomib, lenalidomide and dexamethasone The goal of this trial was to evaluate the impact of these modifications on toxicity levels and treatment outcomes in patients undergoing tandem transplants for multiple myeloma. Patients were enrolled in the period of August 2008 until March 2016. Data cut-off was July,2023. Results: Our study consisted of 380 patients after excluding 2 patients who were identified as high-risk gene expression profile (S-TT4:238, L-TT4:142). Median age was 58.7 years (range: 30-76 years) with 11.6% of enrolled patients identified as African Americans. 91.4% of enrolled patients completed at least one auto transplant and 78.3% of patient completed tandem transplants. The median follow-up duration for all patients of 11.66 years (interquartile range: 10.11-13.27 years). Median progression free survival (PFS) was 6.54 years (95% confidence interval (CI): 5.75-7.72 years)) with 10-year PFS of 39% (95% CI: 34.3-44.4%). Median overall survival (OS) was 12.6 years (95% CI: 11.6 years-not reached (NR)) with 10-year OS of 58.4% (95% CI:53.5%-63.7%). No statistically significant difference between S-TT4 vs. L-TT4 (median PFS: 7.33 years (95% CI: 6.01-9.44 years), median OS: 13.1 years (95% CI:12.30 years-NR) vs. (median PFS: 5.74 years (95% CI: 4.63-7.41 years),median OS:11.8 years (95% CI:9.21 years-NR) with OS hazard ratio of L-TT4 vs. S-TT4 of 1.17 (95% CI: 0.86-1.58, p=0322). [Figure] PFS HR of L-TT4 vs. S-TT4 of 1.21 (95% CI: 0.94-1.56, P=0.132). Early mortality (defined as death in the first year of enrollment) occurred in 6.1% of enrolled patients. No difference in treatment related mortality was found between L-TT4 and S-TT4. Grade III-V toxicities and maximum grade for system organ classes with at least 5% of the population experiencing an event showed no difference between L-TT4 vs. S-TT4 in all adverse events except grade III/IV infections which was higher in L-TT4 (60% vs. 44%, p=0.002). Secondary acute myeloid leukemia (AML) and/or myelodysplastic syndrome (MDS) occurred in 21 (5.5%) patients with the median time from diagnosis to diagnosis of AML and/or MDS of 4.5 years. AML and/or MDS was more frequently seen in patients assigned to L-TT4 when compared to S-TT4 though this difference was not statistically significant (7% vs. 4.6, P=0.317 ) Conclusion: Fixed duration therapy including multi-agent chemotherapy and tandem autologous stem cell transplantation and 3 years of extended therapy resulted in excellent patients' outcomes with median OS of 12.6 years and at least one in three patients being progression free for at least 10 years. Conditioning with single high-dose (MEL200) as used in S-TT4 resulted in similar outcomes compared to fractionated MEL50x4 combined with VTD with better safety profile and thus should be the preferred approach.

High-risk gene expression in colorectal liver metastasis: Potential for novel therapies.

147 Background: Over half of patients with colorectal cancer (CRC) develop liver metastases. While immunotherapy is an emerging treatment of solid tumors, its use among CRC patients is limited. Furthermore, gene expression patterns of liver-specific CRC metastases remain unclear. The purpose of this study was to identify a high-risk gene expression profile for patients with colorectal liver metastasis (CRLM) to better inform prognosis and development of novel targeted therapies. Methods: Fifty-three FFPE CRLM samples from patients who underwent complete metastatectomy from 2009-2017 were examined. Expression profiling of extracted RNA was performed using NanoString Immuno-Oncology (IO360) 750-gene panel. Statistical analyses using cutoffs of absolute log 2-fold change≥1.5 and p-value≤0.05 were performed. Patients were analyzed by extremes of outcomes: survival time in the lowest quartile compared to those still alive at last follow-up. Results: Eight differentially expressed genes were associated with poor survival. Overexpressed genes included IL6R, CXCL2, C7, MGMT, PCK2, CSF1 and LILRB4 (Table). PLA2G2A was under-expressed. Conclusions: This study demonstrates differential gene expression associated with poor survival among patients with CRLM. Specific genes of interest include IL6R, MGMT, CSF1 and LILRB4. IL6R is a known effector in tumor proliferation via IL-6 signaling from tumor-associated macrophages, myeloid-derived suppressor cells (MDSCs) and T-cells. MGMT repairs alkylating DNA damage and is implicated in carcinogenesis and response to chemotherapy. CSF1 promotes macrophage differentiation to M2 phenotype, suppressing inflammation and anti-tumor defense mechanisms. LILRB4 activation via MDSCs leads to T-cell inhibition. These overall suggest a myeloid-dominant tumor immune microenvironment and represent important potential therapeutic targets. Next steps include performing immunohistochemistry to validate findings at the protein level and investigate the tumor intrinsic role using human cell lines.[Table: see text]

Gene Expression Profiling Is a Strong Predictor of Clinical Outcomes in Newly Diagnosed Multiple Myeloma

Introduction: Gene expression profiling (GEP) of purified CD138+ bone marrow plasma cells (PC) in patients with newly diagnosed multiple myeloma (MM) has proven to be a reliable prognostic tool. In this study, we aimed to describe the clinical outcomes of all consecutive NDMM patients with available GEP pre-treatment and compare GEP with standard FISH in determining relapse free survival (RFS) and overall survival (OS).Methods: From April 2014 until January 2017, we identified 104 patients with NDMM who had baseline GEP70 analysis at our institution. GEP70 was performed using CD138+ cells from bone marrow samples at diagnosis through MyPRS® (Signal Genetics, Little Rock, AR). Fisher's exact test was used to evaluate the associations between two categorical variables. The Wilcoxon rank sum test was used to evaluate the difference in continuous variables between patient groups. Kaplan-Meier method was used to estimate the time to event endpoints including RFS and overall survival (OS). The log-rank test was used to evaluate the differences in the time to event endpoints between different risk group categories. Univariate Cox proportional hazards model was used to evaluate the association between a continuous variable and RFS/OS. Statistical software SAS 9.3 (SAS, Cary, NC) and S-Plus 8.2 (TIBCO Software INc., Palo Alto, CA) were used for all analysis.Results: Median age was 63 (37-89) (Table 1a). Patients presented with lytic lesions (78%), anemia (78%), kidney dysfunction (13%) and hypercalcemia (31%). One patient did not meet CRAB criteria or biomarkers of malignancy, but had severe recurrent infections attributed to underlying myeloma requiring initiation of systemic therapy which prompted resolution of infections. One patient was initiated on therapy based on an i:u sFLC ratio of 165. All patients with available data for initial treatment (n=101), were treated either with bortezomib (63%), carfilzomib (37%) in combination with lenalidomide (86%) or cyclophosphamide (14%) and dexamethasone (100%). All patients received at least a three-drug combination as initial treatment, with 73% of patients receiving an upfront autologous transplant. Upfront autoSCT improved RFS (n=9/66; 14%) compared to non- or delayed autoSCT (n=8/25; 32%; p=0.03) but did not affect OS (p=0.86). Two patients (2 %) proceeded to an upfront allogeneic transplant as part of a clinical trial. With up to 36 months of follow up (range 0.9-35.9 months), 74% of patients are relapse free and 86% of patients are alive (Table 1b). GEP risk category predicted RFS (p=0.0005) in this series of patients (Figure 1). Table 1c shows GEP risk subtypes with clinical outcomes and association to FISH abnormalities. Uniformly, patients with high risk FISH abnormalities and low risk GEP had better clinical outcomes than patients with high risk GEP. High risk GEP patients represented 20% of all NDMM in this cohort. At one year, about 50% of these patients had relapsed or died compared to only 5% of patients in all of the other categories of GEP. By FISH, only t(14;16) predicted RFS (p=0.0001). Neither FISH nor GEP significantly predicted OS (P>0.05) although there were trends for worse survival for high risk GEP and FISH t(14;16).Conclusion: In this cohort of NDMM patients treated with modern therapies with most patients having received an autoSCT, GEP risk profiling was one of the best predictors of RFS. Longer follow up will be needed to determine prediction of OS in this cohort of patients. [Display omitted] DisclosuresLee:Eutropics Pharmaceuticals: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; Pimera Inc: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Daiichi Sankyo: Research Funding. Patel:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Consultancy; Celgene: Consultancy. Thomas:Celgene: Research Funding; Bristol Myers Squibb: Research Funding. Neelapu:Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karus: Research Funding; Cellectis Inc.: Research Funding; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Poseida Therapeutics, Inc: Research Funding. Orlowski:BioTheryX: Consultancy, Membership on an entity's Board of Directors or advisory committees. Manasanch:adaptive biotechnologies: Consultancy; quest diagnostics: Research Funding; sanofi: Research Funding; merck: Research Funding; celgene: Consultancy; takeda: Consultancy.

Gene Expression Profiling (GEP) As a Prognostic Indicator of Multiple Myeloma, Irrespective of Disease Stage, Prior Treatment and Prior Transplant - a Single Center Experience

BackgroundMultiple myeloma (MM) risk is classified using fluorescence in situ hybridization (FISH) routine cytogenetics, and gene expression profiling (GEP). GEP is a clinically validated tool for prognostication of MM in newly diagnosed and relapsed patients (pts), its role in very heavily treated stages is less clear. A study (Nishihori et al, ASH, 2016) concluded that GEP is useful regardless of disease stage. We aim to determine the prognostic significance of GEP heavily pre-treated MM cohort.Methods299 pts with MyPRSTM GEP results at Hackensack University Medical Center (NJ) between 2012 and 2016 were included. High risk GEP was defined with the validated cutoff score of >45.2, high risk FISH was determined according to the mSMART classification as del17p, t(14,16), t(14,20). Chi-square tests were performed on categorical data and Wilcoxon rank sum tests on continuous data. Overall survival (OS) and progression free survival (PFS) were performed using Kaplan-Meier.ResultsMedian age was 63 years (range, 25-91), 170 pts (56%) were men, 81 pts (28%) had International Staging System (ISS) 3 and 191 pts (62%) had Durie-Salmon Staging (DSS) III. 245 pts (81%) had at least one bone marrow transplant (BMT). Median time from myeloma diagnosis to GEP was 30.1 (range 0.1-178.4) months. Most pts had GEP on diagnosis but 24% were heavily pretreated (range, 1-6 lines of treatment), and 13% had a BMT prior to GEP testing. 77 pts (25%) had high-risk disease based on GEP with a median score of 36.5 (range, 9.03-84.05). Molecular subtypes were hyperdiploidy (HY) 31%, cyclin family (CD)-2 20%, low bone disease (LB) 13%, proliferation (PR) 11%, MAF associated (MF) 10%, CD-1 8%, and MMSET associated (MS) 6%. Median OS and PFS were significantly inferior in patients with high-risk by GEP, 25 vs 33 months (p<0.021), 13 vs 21 months (p<0.004) respectively. Molecular subtypes were not individual predictors of OS (p<0.2). When MF, MS and PR subtypes were combined, they had inferior OS compared to other subtypes but this was not statistically significant (p<0.3).ConclusionsGEP can accurately predict risk status in heavily pre-treated and post-transplant MM pts. In conclusion, our data confirm that GEP is a good prognostic indicator in MM pts irrespective of disease stage and prior treatments. Further prospective studies with larger samples and correlating with baseline and intra-treatment GEP are needed. DisclosuresRichter:Janssen: Speakers Bureau; BMS: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vesole:Takeda: Speakers Bureau; Celgene: Speakers Bureau. Siegel:Celgene, Takeda, Amgen Inc, Novartis and BMS: Consultancy, Speakers Bureau; Merck: Consultancy. Biran:Takeda: Speakers Bureau; Celgene, Amgen: Consultancy, Speakers Bureau.

Gene Expression Profiling (GEP) Is More Prognostic of OS and Post-ASCT PFS Compared to FISH in High-Risk Multiple Myeloma — a Single Center Experience

BackgroundAlthough there have been significant improvements in survival for patients with multiple myeloma (MM), those with high-risk disease defined by CD-138 selected FISH, gene-expression profiling, and cytogenetics have a median overall survival (OS) of 2 years or less. The mSMART classification defines high risk myeloma as del17p, t(14,16), t(14,20), and a high risk signature (cutoff of score 45.2) GEP. We aim to determine the prognostic significance of GEP together with FISH in a MM single center cohort.Methods232 newly diagnosed pts with MyPRSTM GEP, and CD-138 selected FISH results were analyzed. Risk classification was defined as above. Chi-square and Cox regression were used for statistical analysis. Overall survival (OS) and progression free survival (PFS) transplant were analyzed by Kaplan-Meier.ResultsMedian age was 62 years (range, 25-90), 139 pts (60%) were men, and 57 pts (24%) had ISS 3. 60 pts (25%) had high-risk disease based on GEP with a median score of 36.5 (range, 9.03-84.05), and 81 pts (34%) had high-risk disease based on FISH. Median OS and PFS were significantly inferior in patients with high-risk by GEP vs low-risk GEP, 78% vs 89% (p<0.004), 61% vs. 67% (p<0.002) respectively. There was no statistically significant difference on OS based on FISH results. The double high-risk classification of high-risk GEP/high-risk FISH had statistically significant lower OS and PFS when compared to low-risk GEP/low-risk FISH (HR 2.64, 95%CI: 1.55-4.48, p<0.003), and (HR 2.74, 95%CI: 1.62-4.62, p<0.0002). It also had a trend towards worse OS and PFS that was not statistically significant compared to low-risk GEP/high-risk FISH (HR 1.29, 95%CI: 0.788-2.111, p<0.3115), and (HR 2.64, 95%CI: 1.55-4.48, p<0.003) respectively; and high-risk GEP/low-risk FISH (HR 1.66, 95%CI: 0.73-3.80, p<0.22), and (HR 1.43, 95%CI: 0.634-3.25, p<0.38) respectively. Finally the association of high-risk GEP and TP53 was not an independent predictor of worse OS or PFS (HR 0.831, 95%CI: 0.530-1.303, p<0.42) and (HR 0.962, 95%CI: 0.612-1.51, p<0.866), respectively.ConclusionsGEP was an independent predictor of OS and PFS in our cohort. The combination of GEP and FISH to identify a double high risk population was not superior to GEP alone. This may be due to the fact that some high risk GEP subtypes are associated with high risk translocations reported by FISH, decreasing the role of high risk status by both GEP and FISH. Further prospective studies with larger samples and longer follow up periods are warranted to better characterize high risk MM pts. [Display omitted] DisclosuresSiegel:Celgene, Takeda, Amgen Inc, Novartis and BMS: Consultancy, Speakers Bureau; Merck: Consultancy. Richter:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau. Vesole:Takeda: Speakers Bureau; Celgene: Speakers Bureau. Biran:Celgene, Amgen: Consultancy, Speakers Bureau; Takeda: Speakers Bureau.

MAGE-a Inhibits Apoptosis in Multiple Myeloma through Regulation of Bim and PUMA

MAGE-a Inhibits Apoptosis in Multiple Myeloma through Regulation of Bim and PUMA

Daratumamab in High Risk Relapse/Refractory Myeloma Patients Effect of 1q21 Gain and GEP70 Status

IntroductionDespite significant improvement in overall survival, most multiple myeloma (MM) patients inevitably, yet unpredictably, develop refractory disease. The purpose of this study was to evaluate the effect of daratumumab as single agent or in combination in high risk relapse refractory (RR) myeloma population.MethodsThe UAMS Myeloma data base was interrogated to identify patients with relapsed refractory Multiple Myeloma who received daratumumab either a monotherapy or in combination with other agents. Patient were risk stratified to high and low risk MM using gene expression profile (GEP) studies on bone marrow specimens collected within one year from the time of relapse. Patients were further risk stratified based on interphase FISH used for CKS1B (1q21), AHCYL1 (1p13), TP53 (17p13), and ERBB2 (17q11). A 20% cutoff point was used for detection of significant abnormalities. Gene expression profiling was performed on the U133 plus 2.0 microarrays. High risk was defined by ≥ 0.66 GEP-70 score. The patients were followed with serum Immunoglobin levels, Serum and urine M component, serum free light chains, PET CT and bone marrow examinations as indicated. Response rates were determined as per the IMWG criteria. Patients were treated using a dose of daratumumab at 16 mg/kg administered weekly for weeks 1 to 8; every two weeks for weeks 9 to 24; and then every four weeks until progression. Daratumumab and immunomodulatory drug combination (mostly pomalidomide) was used in 80% of treated patients, in the remaining 20% daratumumab was used in combination with proteasome inhibitors. Fourteen percent of patients received daratumumab in combination with both IMID and PI drugs.ResultsEighty MM patients were identified with a median age of 58 years, 56% were male. The median time from diagnosis to daratumumab treatment was 5 years. All patients were previously exposed and failed proteasome inhibitors and IMiD drugs. Ninety-five percent progressed after autologous transplant. In 35 patients, interphase FISH at baseline identified 1q21 gain and 32 subjects carried high risk disease according to the GEP 70 score. Seven patients had deletion of 17p13. Seven patients received daratumumab as single agent 73 in combination therapy. The median event free survival for the entire study group was eight months, median for OS was not reached, however, patients with high risk GEP 70 and 1q21 gain experienced a significantly inferior outcome presenting with median EFS and OS of 4 and 12 months respectively (P < 0.001). Event free and overall survival are shown by subgroup in Figure 1.ConclusionsPatients with high risk relapse/refractory myeloma defined by interphase FISH 1q21 gain and or GEP 70 high risk disease do not have a satisfactory response to daratumumab even in combination with IMID or PI drugs. This data suggests that anti MM activity of daratumumab may be impacted by genomic risk factors. Prospective studies are warranted to assess efficacy of daratumumab containing regimens at earlier stage of disease in this higher risk population. [Display omitted] DisclosuresDavies:Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Morgan:Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

A Phase II Trial of the Anti -PD-1 Monoclonal Antibody Pembrolizumab (MK-3475) + Lenalidomide + Dexamethasone As Post Autologous Stem Cell Transplant Consolidation in Patients with High-Risk Multiple Myeloma

Introduction: High-risk multiple myeloma (HRMM) patients (pts) will relapse post-autologous stem cell transplant (ASCT) within 1-2 years. Blockade of the PD-1/PD-L1 interaction on activated T-cells may allow the re-establishment of an effective anti-MM immune response. Our hypothesis is that in the post-ASCT setting, where the host immune system is in significant flux, the PD-1/PDL-1 blockade using pembrolizumab (pem), a monoclonal antibody to PD-1, in combination with the immunomodulatory drug (IMiD) lenalidomide (len) and dexamethasone (dex), will prolong post-ASCT remission by eradicating any existing clones and recapturing the smoldering immunophenotype.Methods: The open-label, Phase II, single center trial of pem + len + dex enrolled pts with HRMM 3-6 months post-ASCT. Pts received pem 200 mg IV day 1; len 25 mg po daily days 1-14; and dex 40 mg daily days 1,8,15 of a 21-day cycle for a total of 2 cycles and then an additional 2 cycles of pem + len without corticosteroids at the same dose and frequency. Pts were eligible if they had HRMM defined by ISS stage 3 and/or del 13q by cytogenetics, and/or 1q amplification, 1p deletion (del), p53 del, t(4;14), t(14;16), t(14;20), hypodiploidy by FISH, and/or high-risk gene expression profile score. Exploratory biomarker analysis of the immune phenotype and composition of the intestinal microbiome at pre-treatment, day 1 of each cycle of treatment and end of treatment are currently being done.Results: Fifteen pts were screened, 12 received at least one dose of therapy and thus were deemed evaluable. Baseline characteristics are shown in Table 1. Thirty-three percent were ISS 3, 41.6% received induction bortezomib-len-dex; 33% received induction carfilzomib-len-dex, and the remaining 24.9% received bortezomib-based induction. Overall response rate (ORR) to upfront therapy was 100% with 1 (8.3%) achieving a complete remission (CR), 5 (41.6%) achieving a very good partial remission and 6 (50%) achieving a partial remission to induction. Table 2 shows best response to treatment by cycle. Four pts (33%) have achieved a stringent CR. Of the 4 pts who have completed therapy, 2 were negative for minimal residual disease by multiparametric flow cytometry. Median follow-up is 8.5 months. None of the pts progressed. All patients had AEs of any grade, defined by AEs attributed to pembro/len/dex rather than from ASCT. A total of 90 adverse events (AEs) were reported, with 94% grade 1 or 2 and 5.6% grade 3 (Table 3). The most common hematologic AE was neutropenia (41.7%), with 3 pts (25%) grade 1 and 2, and 2 pts (16.6%) grade 3. The most common non-hematologic AEs were intermittent constipation (16.6%), diarrhea (16.6%), fatigue (8.3%), and increased ALT (8.3%) and were all grade 1 and 2. Non-hematologic grade 3 AEs occurred in 2 pts and included hypoxia and maculopapular rash. There was 1 serious AE, H. influenza pneumonia requiring inpatient admission, and was not thought to be related to pem. After Merck studies using the combination of pem and IMiDS were placed on hold by the FDA, this study was suspended as of 7/5/17.Conclusions: The combination of pem and len with steroids appears to be well tolerated in the post-ASCT setting in pts with high-risk MM. More mature efficacy follow-up and correlative data will be available at the time of presentation. [Display omitted] DisclosuresBiran:Takeda: Speakers Bureau; Celgene, Amgen: Consultancy, Speakers Bureau. Vesole:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Richter:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau; BMS: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Siegel:Celgene, Takeda, Amgen Inc, Novartis and BMS: Consultancy, Speakers Bureau; Merck: Consultancy.

Differences in disease characteristics and outcomes in older versus younger adults with multiple myeloma.

e20041 Background: Older adults are underrepresented in clinical trials in multiple myeloma (MM), as are the risk prognostication schema derived from them, which limits their generalizability to this age group. Despite appropriate fitness, older adults may not be offered the same therapies as their younger counterparts. In this study, we compared disease characteristics and their associations with outcomes in older and younger adults with MM. Methods: We obtained data for newly diagnosed MM patients from the MM Research Foundation CoMMpass registry (version IA16), a prospective observational study with highly annotated clinical data, cytogenetics, and longitudinal outcomes. Chi-square or Fisher’s exact test were used for comparisons of categorical variables. Progression free survival (PFS) and overall survival (OS) curves were constructed using the Kaplan–Meier method and compared with the log-rank test. Cox proportional hazard models were computed to estimate hazard ratio (HR) and 95% confidence interval (CI) for association between pre-treatment variables and outcomes. Results: 1,143 patients were analyzed, including 853 patients (pts) under age 70 years (&lt; SEV) and 290 pts age 70+ years (SEV+). SEV+ had a higher frequency of ISS score 3 (p &lt; 0.001), lower estimated glomerular filtration rate (median 57.6 vs 74.7 mL/min/1.73m2, p &lt; 0.001), and worse ECOG performance status (PS) (p = 0.01). Of the cytogenetic abnormalities analyzed [del17p, gain1q, t(4;14), t(8;14), t(14;16), t(14;20), and hyperdiploidy], SEV+ had higher frequency of gain1q (42% vs 33%, p = 0.02) and t(14;20) (3% vs 1%, p = 0.03) compared with younger adults. SEV+ received less proteasome inhibitor + immunomodulatory imide triplet induction therapy (27% vs 55%, p &lt; 0.001) and less frontline autologous stem cell transplant (ASCT) (22% vs 59%, p &lt; 0.001). SEV+ were less likely to achieve &gt;complete response to induction therapy compared to &lt; SEV (32% vs 18%, p &lt; 0.001). SEV+ had worse PFS (HR 1.8, 1.6-2.2, p &lt; 0.001) and OS (2.3, 1.8-2.9, p &lt; 0.001) compared to &lt; SEV. On multivariate analysis, increasing ISS, gain1q, high risk gene expression profiling (UAMS70), and lack of triplet induction with frontline ASCT were associated with both poorer PFS and OS in &lt; SEV. For SEV+, multivariate analysis revealed that increasing ISS, t(14;16), and lack of triplet+ASCT were associated with inferior PFS, while age, male sex and increasing ISS were associated with inferior OS. Conclusions: Older adults have a greater prevalence of ISS 3, gain1q, and t(14;20) compared with younger adults but only ISS translates into inferior PFS or OS within this group. Increased access to triplet induction therapy and expanding access to frontline ASCT among older adults may help to improve outcomes in this growing subset of patients.

Exogenous Thyroid Hormone Is Associated with Shortened Survival and Upregulation of High-Risk Gene Expression Profiles in Steroid Receptor-Positive Breast Cancers.

Thyroid disease is a frequent comorbidity in women with breast cancer, and many require thyroid hormone replacement therapy (THRT). We postulated that THRT has a deleterious clinical effect mechanistically through hormonal interactions, nuclear receptor cross-talk, and upregulation of high-risk breast cancer genes. Observational studies of patients with lymph node-negative (LN-) breast cancer (n = 820 and n = 160) were performed to test interactions between THRT and clinical, histologic, outcome, and treatment variables. Differences between the two cohorts include but are not limited to patient numbers, decades of treatment, duration of follow-up/treatment, tumor sizes, incidence, and type and dose/regimen of antihormonal and/or chemotherapeutic agents. In vivo and vitro models, in silico databases, and molecular methods were used to study interactions and define mechanisms underlying THRT effects. THRT significantly and independently reduced disease-free and breast cancer-specific overall survival of only the steroid receptor (SR)-positive (as compared with SR-negative) node-negative patients in both long-term observational studies. Patients with SR+ LN- breast cancer who received THRT and tamoxifen experienced the shortest survival of all treatment groups. A less potent interaction between THRT and aromatase inhibitors was noted in the second patient cohort. Using in vivo and in vitro models, TH administration enhanced estrogen and TH-associated gene expression and proliferation, nuclear colocalization of estrogen receptor and thyroid hormone receptor, and activation of genes used clinically to predict tumor aggression in SR+ breast cancer, including the IGF-IR, WNT, and TGFβ pathways. We show clinically significant adverse interactions between THRT, estrogenic, and oncogenic signaling in patients with SR+ LN- breast cancer.

High-risk gene expression profiles for colorectal liver metastases

Presenter: Michael Turgeon MD | Emory University Background: Over half of patients with colorectal cancer develop liver metastases with a minority of patients considered resectable at presentation. While there has been significant progress in the development of new biologics for the treatment of colorectal liver metastases (CRLM), only a small proportion of patients harbor actionable mutations. Furthermore, gene expression patterns of liver-specific metastases remain unclear. Our aim was to identify high-risk gene expression profiles for patients with CRLM to better inform prognosis and the development of novel targeted therapies. Methods: We examined 53 formalin-fixed paraffin-embedded (FFPE) colorectal liver metastasis samples from patients who underwent complete metastasectomy from 2009-2017 at a single institution. Immune cell infiltration was confirmed with CD45 antibody staining via immunohistochemistry (IHC). Targeted mRNA expression profiling was performed with extracted RNA using the NanoString Immune Oncology (IO360) 750-gene panel. Expression counts were normalized by the geometric mean of the positive-control and the most stable housekeeping genes were selected using the geNorm algorithm followed by log2 transformation. The differential expression analysis with fold changes and p-values were calculated using the NanoString methodology. Groups of interest were dichotomized based on synchronous versus metachronous disease and risk profiles. Risk profiles were based on median and quartile overall survival (OS) cut-points. “High-risk” was considered OS below the median or 25th percentile, while “low-risk” was OS above the median, above the 75th percentile, or no death due to disease. Results: Of 53 patients, median overall survival was 58 months. Median follow-up was 36 months. Using the NanoString IO360 panel, we detected no differentially expressed genes between synchronous (n=28) and metachronous (n=25) CRLM. Considering risk profiles, four differentially expressed genes were identified comparing tumors from high-risk (n=4) versus low-risk (n=18) patients based on a median OS cut-point of 45 months. Pathway analysis indicated these gene expression signatures were associated with antigen presentation, DNA repair, and collagen synthesis. When comparing the 25th percentile (high-risk n=2) to the 75th percentile (low-risk n=16), a total of 68 down-regulated genes were detected that were primarily involved in the antigen presentation pathways. Conclusion: Patients with colorectal liver metastases with poor overall survival may have a distinct, “high-risk” gene expression profile that manifests in alterations in antigen presentation, DNA repair, and collagen synthesis pathways. The identified genes serve as promising molecular markers for prognostication and for the development of novel targeted therapies. Next steps include NanoString analysis with an expanded cohort, immunohistochemistry to validate protein expression, and modulation of gene expression in cell lines.

Racial differences in treatment and outcomes in multiple myeloma: a multiple myeloma research foundation analysis

Findings on racial differences in survival in multiple myeloma (MM) have been inconclusive. We assessed differences in outcomes between White and Black individuals among 639 newly diagnosed MM patients in the MM Research Foundation CoMMpass registry with baseline cytogenetic data. Survival curves were constructed using the Kaplan–Meier method. Hazard ratios and 95% confidence intervals were derived from Cox proportional hazard regression models. Age, gender, and stage were similar between Whites (n = 526) and Blacks (n = 113). Blacks had inferior overall survival (OS) compared with Whites and were less likely to receive triplet therapies or frontline autologous stem cell transplant (ASCT). The following factors were significantly associated with inferior OS in multivariate analysis: higher international staging system (ISS) score, ≥1 or ≥2 high-risk cytogenetic abnormalities (HRCA), high-risk gene expression profile (GEP), and lack of ASCT. Multivariate analysis in the Black subset found that only lack of ASCT was significantly associated with inferior OS. The receipt of both triplet induction and ASCT only partly abrogated the effect of race on survival. HRCA did not track with survival in Blacks, emphasizing the need for race-specific risk prognostication schema to guide optimal MM therapy.

A Systematic Review and Meta-Analysis of Gene Expression Profiling for Primary Cutaneous Melanoma Prognosis

To decrease morbidity and mortality from melanoma, it is imperative to identify patients who are at high risk for developing widespread disease. Gene expression profiling (GEP) technology may impact melanoma management as physicians are better equipped to measure prognosis. Many different GEP signatures have been investigated. We searched Pubmed, Cochrane CENTRAL, and Embase for studies on GEP in primary melanoma prognosis and assessed GEP signatures for prognostic and analytic validity and clinical impact. The relationship between GEP and survival was measured using hazard ratios (HR) and odds ratios (OR). We found twenty-nine articles comprising 9 gene signatures meeting inclusion criteria and conducted a meta-analysis on 6 studies on a 31-gene signature. High-risk GEP status was associated with poorer recurrence-free survival (HR=7.22; 95% CI, 4.75-10.98), distant metastasis-free survival (HR=6.62; 95% CI, 4.91-8.91), and overall survival (HR=7.06; 95% CI, 4.44-11.22); as well as sentinel lymph node biopsy positivity (OR=2.99; 95% CI, 2.15-4.15). With recent improvements in treating advanced melanoma, accurately assessing prognosis is important. This study has clinical implications for melanoma patients who may benefit from prognostic testing. These results may be useful to clinicians when ordering GEP testing and help them make better management decisions.

Evomela® Significantly Increases the Risk of Engraftment Syndrome in Patients with Multiple Myeloma Treated with Autologous Stem Cell Transplantation

Evomela® Significantly Increases the Risk of Engraftment Syndrome in Patients with Multiple Myeloma Treated with Autologous Stem Cell Transplantation

Genomic Landscape of Sex Disparities in Multiple Myeloma

Background While survival of patients with multiple myeloma (MM) continues to improve, disparities in care are widely prevalent. While sex-based differences in cancer outcomes are apparent in several malignancies, these have not been studied as extensively in MM and consequently, the biology underlying these differences are unknown. Methods We utilized the Multiple Myeloma Research Foundation (MMRF) CoMMpass database (IA11) to evaluate the outcomes of MM by sex. The CoMMpass database includes over 1000 newly-diagnosed MM patients with enriched tumor samples analyzed using RNA sequencing (RNA-seq). Differentially expressed genes (DEGs) were predicted from RNA-seq data using the limma-voom method after TMM normalization, then gene set enrichment analyses using GSEA and WebGestalt and ClueGo were performed to assess for highly enriched pathways. We then performed multiple linear regression analysis using sex as the dependent variable. Other known high-risk prognostic markers were used as independent categorical or numeric variables. Categorical variables included age (&lt;/&gt;65 years), beta2 microglobulin (&gt;5.5 mg/L), elevated LDH (&gt;ULN), presence of del 17p, t(4;14), t(14;16), gain chr 1q, del 1p and hyperdiploid status. Numeric variables included genes from the EMC-92 gene signature. Overall survival (OS) was estimated by Kaplan Meier method and log-rank test. Results Among patients with available data, females accounted for 44% (N=384) and males 56% (N=487) patients. Male sex is associated with inferior overall survival, with median survival (men 55 months vs women NR) (p=0.00024). GSEA detected 310 out of 668 gene sets to be up-regulated in the female cohort of which 69 gene sets were significantly up-regulated (FDR q &lt;25%). While in males, 358 out of the 668 gene sets queried were up-regulated and no gene set was significantly upregulated at FDR q&lt;25%. Compared to males, significantly enriched gene sets in females were those involved oxidative metabolism (oxidative phosphorylation, respiratory electron transfer, and TCA cycle) which have been shown to be a function of B cell differentiation to support increased antibody production and may suggest a more differentiated plasma cell phenotype in women. We then performed WebGestalt over-representation analysis (ORA) using up and down DEGs which showed that cell-cell junction, ECM proteoglycans, IFN gamma signaling, L1CAM interactions and axon guidance pathways were affected when comparing by sex. Using the limma-voom method to predict DEGs (after TMM normalization), the up-regulated genes in women included those involved in protective processes such as inhibition of JAK/STAT mediated signaling (SOCS3), increased glutathione S transferase to detoxify products of oxidative stress (GSTM1), promotion of autophagy (DEPP1) as well as development of long term T cell immunity (TNFRSF4). Downregulated genes in women include those associated with increased proliferative potential such as cell-cell adhesion and signaling (LPHN2, EPHB1, LSAMP, NCAM1, CADM1, CD44, ANK3, CD99), cell cycle regulation (ZNF256, TEAD1, PDGFD), cytoskeletal proteins (MAP9, HYDIN, TMSB4X, TIAM1) and angiogenesis (PDE3B, VASH2). Multiple linear regression analysis with sex as dependent variable showed no differences in the independent categorical variables tested between the male and female groups. 14 genes of the EMC-92 gene signature were also noted to significantly differ between the female and male groups (EHBP1L1, FGFR3, C1S, GRB14, HMGB3, ITM2B, LBR, MRPL41, RAB2A, RPS28, RPS4X, SPATS2L, TOP2A, TMEM97) along with genes expressed in multiple high-risk gene expression profiling signatures (TMEM97, ITM2B). These genes have been associated with cell survival, proliferation, differentiation and angiogenesis which may explain the differences in survival outcomes. Conclusion Female sex was associated with improved overall survival in the MMRF CoMMpass database. Over expression of several protective signatures and under expression of genes associated with increased proliferative signal may explain the differences in disease biology. Validation of these results in an independent cohort will help clarify these interesting and novel findings. Disclosures Girnius: Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees. Landau:Caelum: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Pfizer: 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. Costa:GSK: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; Karyopharm: Consultancy; Fujimoto Pharmaceutical Corporation Japan: Other: Advisor; Janssen: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau.

Two Year Update of Phase II Trial of Pembrolizumab, Lenalidomide and Dexamethasone As Post -Autologous Stem Cell Transplant Consolidation in Patients with High-Risk Multiple Myeloma

Two Year Update of Phase II Trial of Pembrolizumab, Lenalidomide and Dexamethasone As Post -Autologous Stem Cell Transplant Consolidation in Patients with High-Risk Multiple Myeloma