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Genomic Landscape of Multiple Myeloma with Elevated Lactate Dehydrogenase
Abstracts / Biol Blood Marrow Transplant 25 (2019) S290 S442
fratricide would not occur during expansion. Generation of deltaCS1-CAR-T-CS1 restored CD8+ cells (30%+/-7). Although the percentage of CD8+ increased in delta-CS1-CAR-T-CS1, we observed similar killing to CS1-CAR-Ts in chromium assays. Experiments comparing efficacy of delta-CS1-CAR-T-CS1 vs CS1-CAR-T in vivo are ongoing. We have generated highly effective CAR-T cells targeting CS1, demonstrated by their ability to specifically kill CS1+ myeloma cells in vitro and in vivo. Our work further validates the utility of CS1 as an immunotherapeutic target for myeloma.
Figure 1.
580 Genomic Landscape of Multiple Myeloma with Elevated Lactate Dehydrogenase Susan Bal MD1, Saulius Girnius MD2, Daniel Starczynowski PhD3, Heather Landau MD4, Kwangmin Choi PhD5. 1 Memorial Sloan Kettering Cancer Center, New York, NY; 2 Malignant Hematology and Bone Marrow Transplant, University of Cincinnati, Cincinnati, OH; 3 Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; 4 Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY; 5 Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH Background: Multiple Myeloma (MM) is a malignant clonal plasma cell disorder. Elevated Lactate Dehydrogenase (LDH) has been associated with drug resistance and short survival. The biologic basis of this observation is uncertain. In this study, we sought to define the genomic landscape of MM patients with high LDH. Methods: Utilizing data from the Multiple Myeloma Research Foundation (MMRF) CoMMpass database, we identified a cohort of patients with baseline LDH values and RNA-seq data available for inclusion. The RNA-seq data was analyzed to predict differentially expressed genes. We evaluated for enrichment of high risk cytogenetic changes within the high LDH group. Overall survival (OS) was estimated by Kaplan Meier method and a log-rank test. Results: We identified 871 patients who met inclusion criteria (High LDH N = 143; Normal LDH N = 728). LDH continued to remain a poor prognostic factor consistent with prior literature, with median survival 660 days vs 795 days (p = 0.02852). There was no difference in the non-synchronous mutations between high vs normal LDH group. Hypergeometric test revealed Del(17p13) was significantly enriched (p = 0.011) in the high LDH subset compared to normal LDH. While there was no statistically significant difference in the presence of t(4;14) (p = 0.16) and t(14;16) (p = 0.21).
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GSEA detected 572 gene sets significantly up-regulated in the high LDH group (FDR q < 25%) compared to those with normal LDH including genes involved in the processing of capped intron containing pre-mRNA, recruitment of mitotic centrosome proteins and complexes, mRNA splicing and the proliferation signal in solid tumors leading to metastatic potential. No significantly down-regulated gene set was detected at same significance level. The ClueGO analysis using two separate sets of up-regulated DEGs revealed upregulation of different molecular signatures. The first gene set (fold > 1.5x) showed significant enrichments (p < 0.005) in cell division-related pathways, which provide the myeloma cells with a proliferative advantage. The second gene set (fold > 2x) was strongly associated (p < 0.005) with sympathetic nervous system
S384
Abstracts / Biol Blood Marrow Transplant 25 (2019) S290 S442
development (NELL2, NTRK1, and SOX11) and collagen biosynthesis (ADAMTS family). These genes play a role in lymphocyte differentiation, anti-apoptosis, local invasion, and metastasis. Conclusion: Elevated LDH was confirmed as a poor prognostic factor in the MMRF CoMMpass cohort. Overrepresentation of Del17p likely contributes to poor prognosis. In MM, overexpression of proteolytic and cell adhesion signatures, evasion/ suppression of host immune system along with hyper-proliferative signatures via cell division and RTK pathways in MM patients with high LDH offers insight into the aggressive disease in these patients. Targeting tumor microenvironment and RTK pathways may provide novel therapeutic strategies in this subtype of MM.
RR between HL and NHL (p = 0.5333, p = 1, and p = 0.7287, respectively) or between age < 50 and age 50 (p = 0.5271, p = 1, and p = 1, respectively). BEAM and BEM HDT resulted in similar outcomes with no difference in 100-day mortality and minor differences in 1-year OS and 1-year RR. However, significant differences in age and diagnoses of patients treated with these regimens challenge more direct and applicable comparisons. Further analyses including tighter-matched patient cohorts, prior induction/salvage therapy and treatment-related toxicities would better differentiate these two regimens to provide additional clinical utility. Despite the wider usage of BEAM for auto-HSCT in patients with R/R lymphomas, BEM appears to be an efficacious alternative, and, therefore, warrants further consideration for future studies.
LYMPHOMA/MYELOMA - CLINICAL
581
Table 1 Baseline Characteristics.
A Comparison between BEAM and BEM Conditioning Regimens for Autologous Hematopoietic Stem Cell Transplantation in Relapsed Lymphoma: A Retrospective Analysis Kevin Yen BA1, Lan Y. Wang MD2, Mindy Hsiao MD3, Kum Ja Lee PharmD1, Mojtaba Akhtari MD4. 1 University of Southern California School of Pharmacy, Los Angeles, CA; 2 Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA; 3 Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA; 4 Hematology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA High dose chemotherapy (HDT) followed by autologous hematopoietic cell transplantation (auto-HCT) is an effective treatment for relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Historically, carmustine, etoposide, cytarabine, and melphalan (BEAM) has been shown to improve progression free survival (PFS) and overall survival (OS) with relatively low toxicity. However, high doses of carmustine and etoposide with melphalan (BEM) has also demonstrated efficacy as a more intensive regimen tolerated in younger patients. We performed a single institution retrospective study to compare outcomes of lymphoma patients treated with either BEAM or BEM and auto-HSCT. We identified 65 patients treated at USC Norris Comprehensive Cancer Center for R/R NHL or HL with HDT and auto-HCT between 2013 and 2018. 14 patients were excluded from statistical analysis due to insufficient data. The primary outcome was 1-year OS and the secondary outcomes were 100-day mortality and 1-year relapse rate (RR). BEAM consisted of carmustine 150 mg/m2, etoposide 200 mg/m2, cytarabine 200 mg/m2, and melphalan 140 mg/m2, while BEM was carmustine 12 mg/kg, etoposide 60 mg/kg, and melphalan 140 mg/m2. The T-test and Fisher’s exact test were used to describe groups with continuous and categorical outcomes respectively. A p-value of < 0.05 was considered statistically significant. 22 BEM patients and 29 BEAM patients were included for statistical analysis. Baseline characteristics are shown in Table 1. There was an insignificant trend towards increased 1-year OS (100% vs. 93.10%; p = 0.4996) but a higher 1-year RR (35.29% vs. 33.33%; p = 0.77) in BEM than BEAM. No difference in 100-day mortality was observed between BEAM and BEM. Notable differences in demographics between BEAM and BEM patients were in age and diagnosis. Compared to BEAM, BEM was utilized more in younger patients (mean age at transplant 41.7 vs. 58.6 years old; p < 0.0001) with a larger percentage of HL diagnoses (48.28% vs. 5.56%; p = 0.0001). There was no significant difference in 1-year OS, 100-day mortality or 1-year
Abbreviations: HL = Hodgkin lymphoma; NHL = Non-Hodgkin lymphoma
582 A New Prognostic Score Using Lymphocyte to Monocyte Ratio and Immunoglobulin Levels to Predict Progression in Multiple Myeloma Patients Undergoing Autologous Transplant Karen Sweiss1, Jonathan Lee2, Gregory Calip3, Dolores Mahmud PhD4, Nadim Mahmud MD, PhD5, Damiano Rondelli6, Pritesh Patel6. 1 Pharmacy Practice, University of Illinois at Chicago, Chicago, IL; 2 College of Medicine, University of Illinois at Chicago, Chicago, IL; 3 Center for Pharmacoepidemiology and Pharmacoeconomic Research, University of Illinois at Chicago, Chicago, IL; 4 Division of Hematology/Oncology, University of Illinois at Chicago, Chicago, IL; 5 Division of Hematology/Oncology, Dept. of Medicine, University of Illinois College of Medicine, Chicago, Chicago, IL; 6 Division of Hematology/Oncology, University of Illinois at Chicago, Chicago, IL Introduction: Although autologous stem cell transplant (ASCT) prolongs progression free survival (PFS) in multiple myeloma (MM), prediction of outcomes is challenging due to wide variability in post-transplant survival. MM is an immune suppressive disease characterized by the development of a microenvironment that promotes disease progression and resistance to treatment. Clinical surrogates of immune suppression such as the lymphocyte to monocyte ratio (LMR) have predicted outcome in other cancers. Objectives: We hypothesized that clinically available surrogates for immune suppression may predict survival after ASCT.
fratricide would not occur during expansion. Generation of deltaCS1-CAR-T-CS1 restored CD8+ cells (30%+/-7). Although the percentage of CD8+ increased in delta-CS1-CAR-T-CS1, we observed similar killing to CS1-CAR-Ts in chromium assays. Experiments comparing efficacy of delta-CS1-CAR-T-CS1 vs CS1-CAR-T in vivo are ongoing. We have generated highly effective CAR-T cells targeting CS1, demonstrated by their ability to specifically kill CS1+ myeloma cells in vitro and in vivo. Our work further validates the utility of CS1 as an immunotherapeutic target for myeloma.
Figure 1.
580 Genomic Landscape of Multiple Myeloma with Elevated Lactate Dehydrogenase Susan Bal MD1, Saulius Girnius MD2, Daniel Starczynowski PhD3, Heather Landau MD4, Kwangmin Choi PhD5. 1 Memorial Sloan Kettering Cancer Center, New York, NY; 2 Malignant Hematology and Bone Marrow Transplant, University of Cincinnati, Cincinnati, OH; 3 Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; 4 Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY; 5 Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH Background: Multiple Myeloma (MM) is a malignant clonal plasma cell disorder. Elevated Lactate Dehydrogenase (LDH) has been associated with drug resistance and short survival. The biologic basis of this observation is uncertain. In this study, we sought to define the genomic landscape of MM patients with high LDH. Methods: Utilizing data from the Multiple Myeloma Research Foundation (MMRF) CoMMpass database, we identified a cohort of patients with baseline LDH values and RNA-seq data available for inclusion. The RNA-seq data was analyzed to predict differentially expressed genes. We evaluated for enrichment of high risk cytogenetic changes within the high LDH group. Overall survival (OS) was estimated by Kaplan Meier method and a log-rank test. Results: We identified 871 patients who met inclusion criteria (High LDH N = 143; Normal LDH N = 728). LDH continued to remain a poor prognostic factor consistent with prior literature, with median survival 660 days vs 795 days (p = 0.02852). There was no difference in the non-synchronous mutations between high vs normal LDH group. Hypergeometric test revealed Del(17p13) was significantly enriched (p = 0.011) in the high LDH subset compared to normal LDH. While there was no statistically significant difference in the presence of t(4;14) (p = 0.16) and t(14;16) (p = 0.21).
S383
GSEA detected 572 gene sets significantly up-regulated in the high LDH group (FDR q < 25%) compared to those with normal LDH including genes involved in the processing of capped intron containing pre-mRNA, recruitment of mitotic centrosome proteins and complexes, mRNA splicing and the proliferation signal in solid tumors leading to metastatic potential. No significantly down-regulated gene set was detected at same significance level. The ClueGO analysis using two separate sets of up-regulated DEGs revealed upregulation of different molecular signatures. The first gene set (fold > 1.5x) showed significant enrichments (p < 0.005) in cell division-related pathways, which provide the myeloma cells with a proliferative advantage. The second gene set (fold > 2x) was strongly associated (p < 0.005) with sympathetic nervous system
S384
Abstracts / Biol Blood Marrow Transplant 25 (2019) S290 S442
development (NELL2, NTRK1, and SOX11) and collagen biosynthesis (ADAMTS family). These genes play a role in lymphocyte differentiation, anti-apoptosis, local invasion, and metastasis. Conclusion: Elevated LDH was confirmed as a poor prognostic factor in the MMRF CoMMpass cohort. Overrepresentation of Del17p likely contributes to poor prognosis. In MM, overexpression of proteolytic and cell adhesion signatures, evasion/ suppression of host immune system along with hyper-proliferative signatures via cell division and RTK pathways in MM patients with high LDH offers insight into the aggressive disease in these patients. Targeting tumor microenvironment and RTK pathways may provide novel therapeutic strategies in this subtype of MM.
RR between HL and NHL (p = 0.5333, p = 1, and p = 0.7287, respectively) or between age < 50 and age 50 (p = 0.5271, p = 1, and p = 1, respectively). BEAM and BEM HDT resulted in similar outcomes with no difference in 100-day mortality and minor differences in 1-year OS and 1-year RR. However, significant differences in age and diagnoses of patients treated with these regimens challenge more direct and applicable comparisons. Further analyses including tighter-matched patient cohorts, prior induction/salvage therapy and treatment-related toxicities would better differentiate these two regimens to provide additional clinical utility. Despite the wider usage of BEAM for auto-HSCT in patients with R/R lymphomas, BEM appears to be an efficacious alternative, and, therefore, warrants further consideration for future studies.
LYMPHOMA/MYELOMA - CLINICAL
581
Table 1 Baseline Characteristics.
A Comparison between BEAM and BEM Conditioning Regimens for Autologous Hematopoietic Stem Cell Transplantation in Relapsed Lymphoma: A Retrospective Analysis Kevin Yen BA1, Lan Y. Wang MD2, Mindy Hsiao MD3, Kum Ja Lee PharmD1, Mojtaba Akhtari MD4. 1 University of Southern California School of Pharmacy, Los Angeles, CA; 2 Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA; 3 Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA; 4 Hematology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA High dose chemotherapy (HDT) followed by autologous hematopoietic cell transplantation (auto-HCT) is an effective treatment for relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Historically, carmustine, etoposide, cytarabine, and melphalan (BEAM) has been shown to improve progression free survival (PFS) and overall survival (OS) with relatively low toxicity. However, high doses of carmustine and etoposide with melphalan (BEM) has also demonstrated efficacy as a more intensive regimen tolerated in younger patients. We performed a single institution retrospective study to compare outcomes of lymphoma patients treated with either BEAM or BEM and auto-HSCT. We identified 65 patients treated at USC Norris Comprehensive Cancer Center for R/R NHL or HL with HDT and auto-HCT between 2013 and 2018. 14 patients were excluded from statistical analysis due to insufficient data. The primary outcome was 1-year OS and the secondary outcomes were 100-day mortality and 1-year relapse rate (RR). BEAM consisted of carmustine 150 mg/m2, etoposide 200 mg/m2, cytarabine 200 mg/m2, and melphalan 140 mg/m2, while BEM was carmustine 12 mg/kg, etoposide 60 mg/kg, and melphalan 140 mg/m2. The T-test and Fisher’s exact test were used to describe groups with continuous and categorical outcomes respectively. A p-value of < 0.05 was considered statistically significant. 22 BEM patients and 29 BEAM patients were included for statistical analysis. Baseline characteristics are shown in Table 1. There was an insignificant trend towards increased 1-year OS (100% vs. 93.10%; p = 0.4996) but a higher 1-year RR (35.29% vs. 33.33%; p = 0.77) in BEM than BEAM. No difference in 100-day mortality was observed between BEAM and BEM. Notable differences in demographics between BEAM and BEM patients were in age and diagnosis. Compared to BEAM, BEM was utilized more in younger patients (mean age at transplant 41.7 vs. 58.6 years old; p < 0.0001) with a larger percentage of HL diagnoses (48.28% vs. 5.56%; p = 0.0001). There was no significant difference in 1-year OS, 100-day mortality or 1-year
Abbreviations: HL = Hodgkin lymphoma; NHL = Non-Hodgkin lymphoma
582 A New Prognostic Score Using Lymphocyte to Monocyte Ratio and Immunoglobulin Levels to Predict Progression in Multiple Myeloma Patients Undergoing Autologous Transplant Karen Sweiss1, Jonathan Lee2, Gregory Calip3, Dolores Mahmud PhD4, Nadim Mahmud MD, PhD5, Damiano Rondelli6, Pritesh Patel6. 1 Pharmacy Practice, University of Illinois at Chicago, Chicago, IL; 2 College of Medicine, University of Illinois at Chicago, Chicago, IL; 3 Center for Pharmacoepidemiology and Pharmacoeconomic Research, University of Illinois at Chicago, Chicago, IL; 4 Division of Hematology/Oncology, University of Illinois at Chicago, Chicago, IL; 5 Division of Hematology/Oncology, Dept. of Medicine, University of Illinois College of Medicine, Chicago, Chicago, IL; 6 Division of Hematology/Oncology, University of Illinois at Chicago, Chicago, IL Introduction: Although autologous stem cell transplant (ASCT) prolongs progression free survival (PFS) in multiple myeloma (MM), prediction of outcomes is challenging due to wide variability in post-transplant survival. MM is an immune suppressive disease characterized by the development of a microenvironment that promotes disease progression and resistance to treatment. Clinical surrogates of immune suppression such as the lymphocyte to monocyte ratio (LMR) have predicted outcome in other cancers. Objectives: We hypothesized that clinically available surrogates for immune suppression may predict survival after ASCT.