Weivoda, Megan

Background: Upfront autologous stem cell transplant (ASCT) is the standard-of-care for newly diagnosed multiple myeloma (MM) patients. However, relapse and the development of therapy-related myeloid neoplasms (t-MN) post ASCT results in considerable morbidity and mortality. We hypothesized that enrichment of abnormal myeloid progenitors and immune effector cells (IEC) in peripheral blood stem cells (PBSCs) of patients with MM is associated with a higher risk of relapse and development of t-MN. Methods: After institutional review board approval, we screened patients with active MM that were evaluated at Mayo Clinic, Rochester, MN between 01/01/2003 and 12/31/2020. Patients that underwent an ASCT and had cryopreserved PBSC product available for research were included. Using mass cytometry, we performed a comprehensive immunophenotyping of mobilized cryopreserved PBSCs from 54 MM patients undergoing 1 st ASCT, using validated antibody panel of 37 lymphoid- and myeloid-based markers each. Flow cytometry standard files were normalized and concatenated using the Fluidigm acquisition software. Flow cytometry standard files were uploaded to the OMIQ software from Dotmatics (www.omiq.ai, www.dotmatics.com), where transformation and cleaning (doublets, debris) were performed. To correct for between-sample technical variations (“batch effects”), we used fdaNorm within the omiq.ai platform. Clustering and visualization of normalized and concatenaded flowcytometry files were performed within the omiq.ai platform using PhenoGraph and UMAP, respectively. We performed principal component analysis (PCA) to identify major immunomic drivers of variability across patients. We explored the associations between immune subsets and the dichotomized clinical outcomes of interest: progression-free (PFS), myeloid neoplasm-free (MNFS) and overall survival (OS) from ASCT. A 2-sided false discovery rate adjusted P-value of <0.05 was considered significant when multiple comparisons were performed; otherwise, a P-value of <0.05 was considered significant. Results: The most abundant cell populations were T-cells (49% of the CD45 +) and myeloid cells (43% of the CD45 + cells). Clustering on the CD45 + cells revealed 30 unique lymphoid clusters and 27 unique myeloid clusters. Subclustering on NK-cells identified an additional 16 NK-cell clusters. On PCA, principal components-1 (PC-1) and 2 (PC-2) explained 15.2% and 12.5% of the variability in the data, respectively. A high PC-2 score was associated with inferior median PFS (20 vs. 52 months; P=0.005, Figure 1A), MNFS (52 vs. 85 months, P=0.03, Figure 1B) and OS (64 vs. 106 months, P=0.01) from ASCT. Immune subsets enriched in the high PC-2 cohort included the ‘NKT-like’ (CD56 +) T-cell subset which expressed the inhibitory CD159a receptor and TIGIT; a terminally differentiated (CD27/CD28 -, CD57/KLRG1 +) and exhausted (TIGIT/PD-1 +) T cell subset, 2 exhausted (TIGIT/PD-1 +) T cell subsets; an immunosenescent (CD27/CD28 -, CD57/KLRG1 +) T cell subset as well as a terminally exhausted (C27/C28 -, KLRG1/PD-1/TIGIT +) TCRgamma-delta subset. Immune subsets with high loadings within PC-1 (associated with improved clinical outcomes) consisted exclusively of CD4 + cells with early memory phenotypes (CD27/CD28/CD127 +). Abnormal expression of CD7 and HLA-DR expression on myeloid progenitor cell subsets was associated with an inferior PFS, MNFS, and OS. A NK-cell subcluster, characterized by an immature (CD56 high), inhibitory (CD159a +, NKG2A) phenotype, was enriched in patients developing t-MN (0.33% vs. 0.17%, P=0.006). Conclusion: We identify abnormal myeloid and immune effector cells in the PBSCs of patients with MM, even prior to ASCT. Patients with a PBSC product that is enriched in immunosuppressive T and myeloid cell subsets, and with a lower proportion of antigen presenting cells, progenitor populations, and anti-tumor macrophages have a shorter PFS and MNFS. This suggests that the predisposition to t-MN and inferior outcomes for MM are possibly determined early in the disease course. These findings need external validation and have the potential to guide sequencing of future treatment modalities.

Multiple Myeloma (MM) progresses from monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering MM (SMM). Despite similar primary genetic events as MM, MGUS and SMM PCs are non- or low-proliferative. Since oncogene activation and DNA damage drive senescence growth arrest to promote immune clearance of potentially malignant cells, we hypothesized that MGUS and SMM pre-malignant PCs exhibit senescence features. To test this, we performed gene set enrichment analysis (GSEA) of a published human PC gene array dataset (GSE5900) comparing normal, MGUS, and SMM PCs for custom senescence phenotyping gene sets (Senescence Up, SenUp; Senescent Cell Anti-Apoptosis Pathways, SCAPs; Senescence Growth Arrest, SenGA; Inflammatory Senescence Associated Secretory Phenotype, iSASP; Interferon SASP, IFN-SASP) versus biological aging gene sets (SenMayo; CellAge). MGUS and SMM PCs exhibited significant enrichment (NES>1.5, q<0.05) for senescence gene sets SenUp, SenGA, and SCAPs compared to normal PCs, with no enrichment for aging gene sets. MGUS PCs were also enriched for iSASP (NES=1.4, q=0.11), whereas SMM PCs were enriched for IFN-SASP (NES=2.3, q<0.05), characteristic of late-senescence. Thus, both MGUS and SMM PCs show enrichment of senescence gene sets compared to normal PCs with differential SASP profiles. Next, we evaluated MGUS, SMM, and MM patient PCs isolated by magnetic sorting for histological senescence features. PCs were immunostained for LMNB1 and HMGB1, and fluorescent in situ hybridized for α-satellite. Cellular senescence was defined as loss of ≥50% nuclear membrane LMNB1, loss of HMGB1, and ≥2 senescence-associated distensions of satellite (SADS) per nuclei. PCs from MGUS patients (N=12) exhibited increased percentage of senescent PCs (26.9±4.1%, Mean±SEM, p<0.0001) compared to SMM (11.0±1.9%, N=19, p<0.0001) and MM (11.6±1.5%, N=11, p<0.001). A subset analysis of SMM patients for which disease stability was known (≥2 years, N=6-8) showed no differences. These results demonstrate that the percentage of senescent PCs is increased in MGUS but not SMM PCs compared to proliferative disease. To assess PC senescence in the native bone marrow microenvironment (BMME), we evaluated trephine bone biopsies from MGUS and SMM patients that progressed or not to MM ≤10 years, as well as newly diagnosed MM. Biopsies were immunostained for CD138, LMNB1, and HMGB1. Whole biopsy images were analyzed using the artificial intelligence-based software HALO. Cells were classified as senescent if they were double negative and non-senescent if they were double positive for LMNB1 and HMGB1. The percentage of non-senescent PCs increased with progression to MM and positively correlated with total PC burden (R=0.52, p<0.0001), reflective of proliferative disease. Senescent PCs correlated with total senescent BMME (R=0.87, p<0.0001), consistent with a role for senescent cells to drive paracrine senescence. We performed proximity analysis to evaluate the cellular composition within 25um of senescent and non-senescent PCs. As expected, non-senescent PCs exhibited a significantly greater percentage of proximate non-senescent BMME in all groups (p<0.0001). In contrast, senescent PCs in stable MGUS (N=16) and SMM (N=14) were equally surrounded by senescent and non-senescent BMME. In progressing MGUS (N=21) and SMM (N=20), as well as MM (N=18), senescent PCs exhibited significantly reduced senescent BMME in their proximate environment (p<0.05). This suggests that senescent PCs in progressive disease, in contrast to stable disease, fail to drive local paracrine senescence responses. These data demonstrate that PCs from stable MGUS and SMM patients exhibit senescence features, with isolated PCs from stable MGUS showing increased senescence gene expression and histologic features. While stable SMM also exhibits senescence gene expression, they lose morphological features of senescence and show a preferential IFN SASP. Within the bone compartment, senescent PCs in stable MGUS and SMM exhibit the expected proximity to senescent BMME. In contrast, progressing MGUS and SMM, as well as NDMM, show a loss of proximate senescent BMME. Given the role of senescence to drive inflammation to clear potentially tumorigenic cells, these data support that failure to drive paracrine senescence may be key to the immune escape of pre-malignant cells in MGUS and SMM.

A substantial subset of follicular lymphoma (FL) patients has an early relapse with a poor outcome. We showed that this unfavorable group displays increased expression of IRF4, dysregulated immune signaling and an immunosuppressive microenvironment. At the molecular level, IRF4 controls expression of antigen presentation and immune molecules (e.g. HLA-DR, CD40, PDL1). Furthermore, silencing of IRF4 triggers anti-lymphoma immunity ( Mondello P et al, Blood 2022;140 Suppl 1:168-169). However, little is known on the molecular mechanisms whereby IRF4 controls the crosstalk between B and T cells. To address this question, first we performed RNA-seq, ATAC-seq and CUT&TAG of active (H3K27Ac, H3K4me3) and repressive (H3K27me3, H3K4me1) histone marks in TMD8 and HBL1 (lymphoma cells with high IRF4 expression) transfected with two pairs of siIRF4 or siCtr for 72 hours. Gene expression revealed a broad change in transcription, with 432 upregulated genes and 136 downregulated genes in siIRF4 compared to siCtr. Notably, the genes with increased expression following IRF4 silencing coded for antigen presentation, immune molecules and cytokines (e.g. HLA-DR, CD86, IL6, IL10). Accordingly, we observed significant enrichment of antigen presentation, interferon and immune response signatures ( Fig 1A). Integrating RNA-seq with chromatin accessibility showed a significant shift towards transcriptional upregulation at genes nearest to upregulated ATAC peaks, with significant enrichment at enhancers (n=771). Conversely, transcriptional suppression was enriched at enhancers (n=2,458) of downregulated peaks. k-means analyses of all union peaks, generated by merging ATAC with CUT&TAG peaks, revealed a significant gain of H3K4me3, with concordant loss of H3K4me1 at enhancers with upregulated gene expression. In contrast, H3K4me3 was severely decreased at suppressed peaks. TF motif analysis revealed an enrichment for PU.1 and E2A at IRF4-bound regions, suggesting their cooperation in regulating immune signaling. Since antigen presentation and other immune molecules are critical components of the immune synapse, we explored the role of IRF4 on the interaction between germinal center (GC) B and T cells by crossing irf4 fl/fl mice with conditional deletion of irf4 ( Klein et al, Nat Immunol 2006) and Cγ 1cre mice ( Cγ 1cre; irf4 fl/fl) to induce recombination in GC B cells. After 10 days of immunization (GC reaction peak), Cγ 1cre; irf4 fl/fl and Cγ 1cre; irf4 fl/+ GC B cells showed significant increase of HLA-DR and CD40 expression compared to WT. As expected, Cγ 1cre; irf4 fl/fl mice displayed a significantly skewed light-zone:dark-zone ratio in favor of increased dark-zone, which are the cells that most reflect the action of BCL6, with concordant suppression of plasma cells. Additionally, we observed a significant increase of CD4 + T cells after partial or complete deletion of irf4, with upregulation of T FH cells and decrease of T reg cells ( Fig 1B). Notably, mice with loss of irf4 showed a significant decrease in exhausted T FH cells. To test if this effect was dependent on MHC:TCR interaction, we cocultured CD4 + T cells with TMD8 cells transfected with two siIRF4 or siCtr in presence of blocking antibodies for MHC class I, MHC class II or both. Blocking one or the other MHC class I or II partially rescued the IRF4 effect on T reg and T FH cells respectively as well as reduced anti-lymphoma cytotoxicity. Further experiments blocking IRF4-dependent IL6 and IL10 identified these two cytokines as responsible for the additional effects on T cells. To confirm this as an antigen-dependent immune response we coculture sorted GC B cells from NP-OVA-immunized Cγ 1cre; irf4 fl/fl, Cγ 1cre; irf4 fl/+ and WT mice with CSFE-labeled OVA-specific OT-II CD4 + T cells at a ratio of 2:1 in an organoid system for 5 days. We observed induced antigen specific proliferation of CD4 + T cells in the presence of Cγ 1cre; irf4 fl/fl and Cγ 1cre; irf4 fl/+ GC B cellscompared to WT,as indicated by decrease in CSFE expression . We confirmed an increase of T FH cells and a decrease of T reg cells, supporting the conclusion that IRF4 directly controls the antigen-dependent immune response . In summary, IRF4 expression in GC and lymphoma B cells regulates immune signaling with PU.1 and E2A, thereby modulating antigen-dependent immune responses with potential implications for lymphomagenesis. Future studies investigating targeting of IRF4 in lymphoma are warranted.

Background: Frailty is a state of decreased reserve affecting multiple organ systems, thereby increasing vulnerability to stressors. Several tools have been proposed to measure frailty in multiple myeloma (MM), such as the IMWG frailty index, and the Revised Myeloma Comorbidity Index. However, these are based on clinical trial datasets, and include chronological age as one of the indicators of frailty. A frailty index based on the principle of accumulation of health deficits (Rockwood doi:10.1093/gerona/62.7.738), provides a measure of physiologic age. This index can be readily calculated using various combinations of health deficits and has been shown to predict outcomes in several populations. Social support has been associated with improved outcomes in various populations, however its impact on survival in patients with MM has not been well studied. The objective of this study was to assess the impact of frailty measured by a deficit accumulation frailty index and the impact of relationship status on outcomes in patients with newly diagnosed MM. Methods: This is a retrospective study including patients diagnosed with MM between January 6 th, 2005, and September 19 th, 2018. We calculated a deficit accumulation frailty index using previously published methods (McNallan et. al doi.org/10.1016/j.ahj.2013.07.008, Searle et al. doi.org/10.1186/1471-2318-8-24). We used the electronic medical record system at Mayo Clinic in Rochester, MN, to extract data on activities of daily living (14 items) provided by patient-completed questionnaires, and data on comorbidities as recorded by treating providers (16 items), within 6 months prior to diagnosis. Each item was scored as 0, 0.5, or 1, with 1 indicating the presence of deficit (Table 1). The frailty index was defined as the sum of individual scores divided that by the total number of non-missing items. Patients who had N >2 missing items were excluded. Patients with a frailty index ≥0.15 were considered frail. We also extracted data on self-reported relationship status within 6 months prior to diagnosis. Variables were compared between groups using Fisher's exact test and Wilcoxon signed-rank test for categorical and continuous variables, respectively. Univariate and multivariate analysis were performed using Cox proportional hazard models. Overall survival (OS) was estimated using the Kaplan-Meier method and compared between groups using the Log-rank test. P values <0.05 were considered statistically significant. Results: We included 578 patients. Median age was 67 (interquartile range: 59-74) years, and 40% were female. Among all patients, 226 (39%) were frail. Compared to fit patients, patients who were frail were older (median age: 70 vs. 65 years, P<0.001) and more likely to have International Staging System (ISS) III (vs. I/II) disease (47% vs. 27%, P<0.001) and ECOG performance status ≥2 (vs. 0 or 1) (45% vs. 17%, P<0.001). There was no difference in R-ISS III disease or presence of high-risk cytogenetic abnormalities between fit and frail patients. Median OS was 7.6 and 4.1 years in fit and frail patient, respectively (P<0.001). Physician assessed ECOG performance status was available for 268 patients. Among patients with ECOG performance status 0 or 1 (193 patients), 136 (70%) were fit, and 57 (30%) were frail. The OS was 8.3 and 4.6 years in the 2 groups, respectively (P=0.006) (table 2). On multivariate analysis including age, frailty status, and R-ISS stage (III vs. I/II), all were associated with OS with frailty's hazard ratio (HR): 1.4 (95%CI [1.1-1.8]), P=0.004; the HR was 1.4 (95%CI [1.1-1.9]), P=0.02, when analysis was restricted to patients ≥60 years. Among all patients, those who were married or in a committed relationship (474 patients) had improved survival (median OS: 7.0 vs. 3.7 years, respectively, P<0.001) compared to patients who were divorced/separated, widowed, or single (96 patients). On multivariate analysis, which included age, R-ISS III, frailty status, and relationship status, all were associated with OS. The HR for relationship status was 1.4 (95%CI [1.0-1.8]), P=0.0465. Conclusion: Frailty, defined by the deficit accumulation frailty index, is independently associated with decreased survival in patients with newly diagnosed MM. Being married or in a committed relationship is associated with improved survival independent of age, disease stage, and frailty.

ABSTRACT Estrogen regulates bone mass in women and men, but the underlying cellular mechanisms of estrogen action on bone remain unclear. Although both estrogen receptor (ER)α and ERβ are expressed in bone cells, ERα is the dominant receptor for skeletal estrogen action. Previous studies using either global or cell‐specific ERα deletion provided important insights, but each of these approaches had limitations. Specifically, either high circulating sex steroid levels in global ERα knockout mice or the effects of deletion of ERα during growth and development in constitutive cell‐specific knockout mice have made it difficult to clearly define the role of ERα in specific cell types in the adult skeleton. We recently generated and characterized mice with tamoxifen‐inducible ERα deletion in osteocytes driven by the 8‐kb Dmp1 promoter (ERαΔOcy mice), revealing detrimental effects of osteocyte‐specific ERα deletion on trabecular bone volume (−20.1%) and bone formation rate (−18.9%) in female, but not male, mice. Here, we developed and characterized analogous mice with inducible ERα deletion in osteoclasts using the Cathepsin K promoter (ERαΔOcl mice). In a study design identical to that with the previously described ERαΔOcy mice, adult female, but not male, ERαΔOcl mice showed a borderline (−10.2%, p = 0.084) reduction in trabecular bone volume, no change in osteoclast numbers, but a significant increase in serum CTx levels, consistent with increased osteoclast activity. These findings in ERαΔOcl mice differ from previous studies of constitutive osteoclast‐specific ERα deletion, which led to clear deficits in trabecular bone and increased osteoclast numbers. Collectively, these data indicate that in adult mice, estrogen action in the osteocyte is likely more important than via the osteoclast and that ERα deletion in osteoclasts from conception onward has more dramatic skeletal effects than inducible osteoclastic ERα deletion in adult mice. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

ABSTRACT Bone remodeling in the adult skeleton facilitates the removal and replacement of damaged and old bone to maintain bone quality. Tight coordination of bone resorption and bone formation during remodeling crucially maintains skeletal mass. Increasing evidence suggests that many cell types beyond osteoclasts and osteoblasts support bone remodeling, including macrophages and other myeloid lineage cells. Herein, we discuss the origin and functions for macrophages in the bone microenvironment, tissue resident macrophages, osteomacs, as well as newly identified osteomorphs that result from osteoclast fission. We also touch on the role of macrophages during inflammatory bone resorption. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Abstract Multiple myeloma (MM) is a clonal plasma cell (PC) cancer that is preceded by the benign conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM). While MGUS/SMM PCs are not proliferative, many of the oncogenes and chromosomal abnormalities in MM PCs are also present in MGUS/SMM. Since oncogenic stress is known to induce cellular senescence, we hypothesized that MGUS/SMM PCs may be in a senescent-like state. Our analysis of a published human dataset (GSE5900) revealed that compared to healthy PCs, MGUS/SMM PCs had significantly increased expression of senescence markers CDKN1A and GADD45A (FDR<0.05). Gene Set Enrichment Analysis (GSEA) showed significant enrichment in MGUS/SMM PCs of our customized senescence phenotyping gene sets (q<0.25). We next evaluated the KaLwRij MGUS mouse model. 10-mo-old female KaLwRij mice were treated with placebo or senolytics (dasatinib+quercetin, D+Q). D+Q treatment significantly reduced PCs compared to placebo, while restoring B cell number and functional gene expression. PCs isolated from D+Q-treated KaLwRij mice exhibited significant reductions in Myc and Il1b expression (p<0.05) versus placebo and a trend towards reduced Trp53 expression (p=0.13), supporting that senescent PCs are targeted by D+Q. Single-cell RNA-seq and single sample (ss)GSEA of 24-mo-old KaLwRij PCs revealed a PC subset enriched for the ‘Plasma Cell Senescence’ gene set, which included genes from our customized gene sets that were differentially expressed in the human PCs dataset GSE5900. Notably, PCs in this subset showed enrichment for ‘Inflammatory SASP’ (median: 15.26%) and ‘Interferon (IFN) SASP’ (39.36%) gene sets. The IFN-SASP is characteristic of late senescence, driven by the accumulation of transposable elements. In the GSE5900 dataset, we found significant enrichment of ‘IFN-SASP’ in SMM (q<0.25) but not MGUS PCs. Further, whole transcriptome RNA-sequencing showed that SMM PCs had increased expression of LINE1 retrotransposon L1HS in relation to normal PCs (FDR<0.1), but not MGUS (FDR=0.83) or MM (FDR=0.5) PCs. Immunostaining confirmed increased cytosolic DNA:RNA hybrids in SMM (median frequency of cells exceeding the intensity threshold = 33%) versus MGUS (16.4%), MM (4.4%), and healthy PCs (1.5%), which is consistent with cytosolic DNA-mediated activation of the IFN SASP in SMM PCs. When these same patients were redistributed according to disease progression, L1HS was higher in patients with progressing SMM and newly diagnosed MM (NDMM) (FDR<0.1) versus patients with stable MGUS (FDR=0.56) or advanced MM (FDR=0.38). Increased DNA:RNA staining was observed in progressing SMM PCs (median frequency = 41%), but the results for NDMM patients (4.4%) and advanced MM (3%) were comparable to healthy or stable patients (3.5%). These data demonstrate that MGUS and SMM PCs exhibit senescence features, suggest mechanisms that may contribute to MM tumorigenesis, and show that pharmacological ablation of senescent cells may prevent progression from MGUS/SMM to MM. Citation Format: Gabriel Alvares Borges, Angelo Jose Guilatco, Christine M. Hachfeld, Ming Ruan, Sonya Royzenblat, Ming Xu, Claire M. Edwards, Marta Diaz-delCastillo, Thomas L. Andersen, Taxiarchis Kourelis, Tamar Tchkonia, James L. Kirkland, Matthew T. Drake, Megan Weivoda. Pre-malignant plasma cells exhibit a senescence-like phenotype and accumulation of transposable elements [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr PR012.

Abstract Multiple myeloma (MM) is an incurable plasma cell cancer. Therapeutic advances have greatly improved patient survival; however, all patients are expected to relapse. New treatments are critically needed to overcome relapse and provide durable response. There is evidence that dormant MM cells exist in the bone marrow, where they exhibit reduced proliferative capacity and resistance to treatment. These cells are present over extended periods of time and may regain proliferative capacity to drive relapse. Tumor dormancy shares features with senescence, a state of stress-induced growth arrest. Chemotherapies, including those used in the treatment of MM, have been shown to cause therapy-induced senescence in a variety of tissues. Dormant MM cells have been shown to be maintained in their non-proliferative state by interactions with bone lining cells. Interestingly, matrix signaling has also been shown to protect against chemotherapy-induced apoptosis in an in vitro ovarian cancer organoid model. Taken together, this suggests that interaction of MM cells with the bone niche maintains growth arrest and survival. We hypothesize that therapy-induced senescence drives dormancy in MM cells that depends on interactions with the mesenchymal bone niche. GFP-expressing 5TGM1 mouse MM cells were treated with vehicle or melphalan for 48 hours and then cultured in the presence or absence of ex vivo mouse bone marrow stromal cells (BMSCs). Cells were maintained for 12 additional days to allow for the development of senescence after the initial stress response. Cells were imaged and quantified during media replacements to assess adherence/survival. Cells were then fixed and stained for nuclei, phospho-γH2AX, and telomeres by immunofluorescence/fluorescence in-situ hybridization (IF/FISH). Melphalan-treated 5TGM1 cells cultured with BMSCs were significantly growth arrested over 2 weeks compared to vehicle-treated cells. Co-culture with BMSCs significantly enhanced melphalan-treated 5TGM1 adherence compared to culture without BMSCs during media replacement. Of note, melphalan-treated 5TGM1 did not survive in the absence of BMSCs after a week in culture. Melphalan-treated 5TGM1 also exhibited significantly greater adherence with BMSCs than vehicle-treated cells. Melphalan-treated 5TGM1 were significantly larger than vehicle-treated cells and exhibited both heterochromatin foci and persistent DNA damage foci associated with telomeres, which are all markers of cellular senescence. Our findings suggest that interactions with BMSCs promote the survival of melphalan-treated MM tumor cells. The enhanced adherence of these cells also suggests that current methods for minimal residual disease assessment may be inadequate, as rare populations of MM cells adhered to the marrow stroma may not be captured by routine bone marrow aspiration. These cells exhibit features of therapy-induced senescence which may be key to MM dormancy. Thus, targeting senescence survival pathways via senolytic therapy may be a novel approach to eliminate dormant MM cells and prevent disease relapse. Citation Format: Angelo J. Guilatco, Gabriel Alvares Borges, Tamar Tchkonia, James L. Kirkland, Taxiarchis Kourelis, Matthew T. Drake, Megan Weivoda. Enhanced survival and adherence of melphalan-induced senescent-like dormant multiple myeloma cells co-cultured with bone marrow stromal cells [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B023.

Abstract This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Short Talks from Proffered Abstracts section (PR012) of the Conference Proceedings. Citation Format: Gabriel Alvares Borges, Angelo Jose Guilatco, Christine M. Hachfeld, Ming Ruan, Sonya Royzenblat, Ming Xu, Claire M. Edwards, Marta Diaz-delCastillo, Thomas L. Andersen, Taxiarchis Kourelis, Tamar Tchkonia, James L. Kirkland, Matthew T. Drake, Megan Weivoda. Pre-malignant plasma cells exhibit a senescence-like phenotype and accumulation of transposable elements [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B020.