Pathogenesis Of Multiple Myeloma Research Articles

The biological and clinical impact of deletions before and after large chromosomal gains in multiple myeloma

AbstractAcquisition of a hyperdiploid (HY) karyotype or immunoglobulin heavy chain (IgH) translocations are considered key initiating events in multiple myeloma (MM). To explore if other genomic events can precede these events, we analyzed whole-genome sequencing data from 1173 MM samples. By integrating molecular time and structural variants within early chromosomal duplications, we indeed identified pregain deletions in 9.4% of patients with an HY karyotype without IgH translocations, challenging acquisition of an HY karyotype as the earliest somatic event. Remarkably, these deletions affected tumor suppressor genes (TSGs) and/or oncogenes in 2.4% of patients with an HY karyotype without IgH translocations, supporting their role in MM pathogenesis. Furthermore, our study points to postgain deletions as novel driver mechanisms in MM. Using multiomics approaches to investigate their biologic impact, we found associations with poor clinical outcome in newly diagnosed patients and profound effects on both the oncogene and TSG activity despite the diploid gene status. Overall, this study provides novel insights into the temporal dynamics of genomic alterations in MM.

Pathogenic Mechanisms Activated by NSD2 Translocations in Multiple Myeloma

The NSD2 gene is overexpressed in multiple cancers and is associated with cancer cell proliferation, invasion, and metastasis. NSD2 gene is universally present in multiple myeloma (MM) patients with t(4;14) (p16;q32) translocation, a high-risk subtype. NSD2 is characterized by different breakpoints. NSD2Δ3 breakpoint is associated with shorter survival than other breakpoints. NSD2Δ3 contains non-coding RNA ACA11 within intron 18. Additionally, 80% of t(4;14) MM patients lack the retinoblastoma tumor suppressor gene (RB1). We hypothesize that ACA11 cooperates with RB1 loss in MM pathogenesis. Also, we hypothesize that NSD2Δ3 increases protein expression driving myeloma growth. To overexpress NSD2WT, snoACA11, and NSD2Δ3 in cells, we cloned NSD2WT, and NSD2Δ3 plasmid constructs in a murine stem cell virus (MSCV)-IRES- GFP vector. We isolated primary B cells from RB1 wild-type and knock-out mice by CD43 microbeads and transduced those cells using a virus containing ACA11 and NSD2WT. ACA11 overexpression significantly increased B cell proliferation in Rb1dKO mice. This hyperproliferative phenotype is induced by reactive oxygen species (ROS) levels. However, we did not find a further increase in B cell proliferation with co-overexpression of NSD2WT and ACA11 in Rb1dKO mice. We demonstrated increased protein stability by finding higher NSD2Δ3 protein expression compared to NSD2WT protein expression in HEK293T cells. These results support our hypothesis and demonstrate oncogenic role of ACA11 in t(4;14) MM. Future work will be done to determine the cell biological effects of NSD2Δ3 and establish its role in myeloma pathogenesis. Completion of this study will advance understanding of this epigenetic NSD2 gene and potentially develop targeted drugs for NSD2, providing more individualized treatment options for these patients. University of Iowa Department of Internal Medicine. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A comparative analysis of transcriptomics of newly diagnosed multiple myeloma: exploring drug repurposing.

Multiple myeloma (MM) is an incurable malignant plasma cell disorder characterized by the infiltration of clonal plasma cells in the bone marrow compartment. Gene Expression Profiling (GEP) has emerged as a powerful investigation tool in modern myeloma research enabling the dissection of the molecular background of MM and allowing the identification of gene products that could potentially serve as targets for therapeutic intervention. In this study we investigated shared transcriptomic abnormalities across newly diagnosed multiple myeloma (NDMM) patient cohorts. In total, publicly available transcriptomic data of 7 studies from CD138+ cells from 281 NDMM patients and 44 healthy individuals were integrated and analyzed. Overall, we identified 28 genes that were consistently differentially expressed (DE) between NDMM patients and healthy donors (HD) across various studies. Of those, 9 genes were over/under-expressed in more than 75% of NDMM patients. In addition, we identified 4 genes (MT1F, PURPL, LINC01239 and LINC01480) that were not previously considered to participate in MM pathogenesis. Meanwhile, by mining three drug databases (ChEMBL, IUPHAR/BPS and DrugBank) we identified 31 FDA-approved and 144 experimental drugs that target 8 of these 28 over/under-expressed MM genes. Taken together, our study offers new insights in MM pathogenesis and importantly, it reveals potential new treatment options that need to be further investigated in future studies.

Characterization of the biological and transcriptomic landscapes of bone marrow-derived mesenchymal stem cells in patients with multiple myeloma

BackgroundMesenchymal stem/stromal cells (MSCs) have been acknowledged as the most important stromal cells in the bone marrow (BM) microenvironment for physiologic hematopoiesis and the concomitant hematologic malignancies. However, the systematic and detailed dissection of the biological and transcriptomic signatures of BM-MSCs in multiple myeloma (MM) are largely unknown.MethodsIn this study, we isolated and identified BM-MSCs from 10 primary MM patients and 10 healthy donors (HD). On the one hand, we compared the multifaceted biological characteristics of the indicated two BM-MSCs, including biomarker expression pattern, multilineage differentiation potential, stemness and karyotyping, together with the cellular vitality and immunosuppressive property. On the other hand, we took advantage of RNA-SEQ and bioinformatics analysis to verify the similarities and differences at the transcriptomic level between MM-MSCs and HD-MSCs.ResultsAs to biological phenotypes and biofunctions, MM-MSCs revealed conservation in immunophenotype, stemness and differentiation towards adipocytes and chondrocytes with HD-MSCs, whereas with impaired osteogenic differentiation potential, cellular vitality and immunosuppressive property. As to transcriptomic properties, MM-MSCs revealed multidimensional alterations in gene expression profiling and genetic variations.ConclusionsOverall, our date systematic and detailed reflected the multifaceted similarities and variations between MM-MSCs and HD-MSCs both at the cellular and molecular levels, and in particular, the alterations of immunomodulation and cellular viability of MM-MSCs, which wound benefit the further exploration of the pathogenesis and new drug application (NDA) of multiple myeloma from the view of BM-MSCs.

DETERMINATION OF SERUM INTERLEUKIN-36 ALPHA, BETA, GAMMA AND INTERLEUKIN-17 LEVELS IN PATIENTS WITH MULTIPLE MYELOMA

Multiple myeloma (MM) is a hematologic malignancy characterized by bone marrow infiltration of clonal plasma cells. Today, there is no treatment for obtaining a complete cycle for MM. IL-36 is a cytokine composed of three agonists named alpha, beta, and gamma. Its increase in inflammation has been proven in the literature. It is also reported that IL-17 plays a role in some rheumatologic and malignant diseases together with inflammation. 
 The aim of the study is to figure out the roles, if any, of IL-36 and IL-17 in the pathogenesis of multiple myeloma depending on their known physiology and to contribute to the literature to find new treatment options.
 33 newly diagnosed MM patients who had never received any treatment and 33 healthy volunteers were included in the study. Basic laboratory parameters and interleukin levels in myeloma patient group and healthy group were included in the study.
 In the study, it was found that IL-36 alpha, beta, gamma, and IL-17 levels were statistically significantly lower in the disease group when compared to the healthy group. A negative correlation was found between IL-17 measurement and beta-2 microglobulin. Therefore, it was thought that IL-17 may be a marker to predict prognosis.
 In conclusion, we think that IL-36 and IL-17 may play a role in the etiopathogenesis of myeloma and IL-36 alpha and IL-17 may be associated with prognosis. However, there is a need for more comprehensive studies.

Abstract 3345: PP1 phosphatase complex at the hub of the integrated stress response: A potential therapeutic target in multiple myeloma

Abstract Protein phosphatase-1 (PP1) is a class of eukaryotic enzyme that catalyzes more than half of the phosphoserine/threonine dephosphorylation reactions, and plays essential roles in cell division, glycogen metabolism and protein synthesis. The substrate specificity of PP1 holoenzyme complex is mediated by PP1-interacting proteins and its catalytic subunits. Of note, PPP1R15B/CReP and PPP1R15A/GADD34 are regulatory subunits of PP1 complex that regulates global protein synthesis and mRNA translation through eIF2α dephosphorylation. Notably, PPP1R15B is constitutively expressed, whereas the expression of PPP1R15A is stress-inducible. Previous studies showed that multiple myeloma (MM), a hematological malignancy arising from immunoglobulin-secreting plasma cells, is characterized by continual ER stress and high dependency on the unfolded protein response (UPR). The integrated stress response (ISR) activated by eIF2α phosphorylation is the fastest reaction pathway of the UPR; however, its functional role and therapeutic potential in MM remains largely unknown. In this study, we performed gene expression analysis and super-enhancer (SE) profiling in MM cell lines, primary patient samples, normal CD138+ plasma cells and memory B cells. we found that PPP1R15B is highly expressed in MM cells as compared to healthy controls, but did not observe significant upregulation of PPP1R15A in MM cells. In addition, higher expression of PPP1R15B predicted poor overall survival of MM patients, suggesting its clinical relevance in MM pathogenesis. Depletion of PPP1R15B significantly reduced cell viability, proliferation and induced G2/M phase cell cycle arrest. Gene Ontology analysis of downregulated genes in response to PPP1R15B knockdown indicates significant association with the UPR pathway. Immunoblot analysis showed activation of ER stress pro-apoptotic executors PUMA, NOXA, and cleavage of caspase-12 in PPP1R15B knockdown cells. Furthermore, we examined the therapeutic effects of eIF2α dephosphorylation inhibitors, Salubrinal and Raphin1, on MM cells. Raphin1 is a selective inhibitor of PPP1R15B that binds strongly to the PPP1R15B-PP1c complex, whereas Salubrinal inhibits both PPP1R15A-PP1c and PPP1R15B-PP1c complex. Our data showed that both Salubrinal and Raphin1 inhibited MM cell proliferation in a dose-dependent manner, while sparing normal plasma cells. MM cell lines with elevated PPP1R15B expression level were more sensitive to Salubrinal or Raphin1 than those with lower PPP1R15B level. Similar changes in the expression patterns of ISR-related genes were observed in response to eIF2α dephosphorylation inhibitors. Taken together, our study suggests that targeting PPP1R15B-PP1c complex or maintaining eIF2α hyperphosphorylation may serve as a new therapeutic approach in MM, which warrants further investigation. Citation Format: Sinan Xiong, Jianbiao Zhou, Tze King Tan, Sabrina Hui-Min Toh, Tae-Hoon Chung, Takaomi Sanda, Wee Joo Chng. PP1 phosphatase complex at the hub of the integrated stress response: A potential therapeutic target in multiple myeloma [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 3345.

Do Alarmins Have a Role in Multiple Myeloma?

Calprotectin (CLP), S100A6, and High Mobility Group Nucleosome-Binding Protein 1 (HMGN1), known as alarmins, are involved in the pathogenesis of many tumors. In this study, we aimed to inve stigate the relationship of serum CLP, S100A6, and HMGN1 levels with clinical and laboratory findings in Multiple Myeloma (MM) patients and their role in the pathogenesis of MM. We measured serum CLP, S100A6, and HMGN1 levels in 55 newly diagnosed patients and 32 healthy controls (HC). We determined significantly decreased serum CLP, S100A6 ve HMGN1 levels in MM patients compared to HC (p=0.012, p=0.001, p=0.030, respectively). ROC analysis was used to determine a diagnostic cut-off value for serum CLP, S100A6 and HMGN1; the cut off value for CLP was <98 ng/ml (AUC = 0.663, 95% CI 0.554-0.761, p=0.009), S100A6 was <1174.5 pg/ml (AUC = 0.706, 95% CI 0.598-0.799, p=0.001), and HMGN1 was <440.18 pg/ml (AUC = 0.640, 95% CI 0.530-0.740, p:0.03). CLP level was found to be statistically significantly in light chain MM patients ( 91.58±22.57) higher than in heavy chain MM patients (79.42±15.83) (p=0.03). A negative correlation was observed between CLP and M protein, IgG, globulin, and beta 2 microglobulin (correlation coefficient: -0,361; -0,370; -0,279; -0,300, p=0,024, p=006, p=0,04, p=0,0033). In this study, we found that serum CLP, S100A6, and HMGN1 levels were statistically lower in newly diagnosed MM patients compared to HC. These results suggest that CLP may binds to the paraprotein produced by heavy chain MM in the blood and therefore its blood levels are found to be low. Additionally, low levels of HMGN1, which is involved in DNA repair, suggest that HMGN1 may contribute to the complex genetic abnormalities found in MM.

Multiple Myeloma Derived Extracellular Vesicle Uptake by Monocyte Cells Stimulates IL-6 and MMP-9 Secretion and Promotes Cancer Cell Migration and Proliferation.

Multiple Myeloma (MM) is an incurable haematological malignancy caused by uncontrolled growth of plasma cells. MM pathogenesis is attributed to crosstalk between plasma cells and the bone marrow microenvironment, where extracellular vesicles (EVs) play a role. In this study, EVs secreted from a panel of MM cell lines were isolated from conditioned media by ultracentrifugation and fluorescently stained EVs were co-cultured with THP-1 monocyte cells. MM EVs from three cell lines displayed a differential yet dose-dependent uptake by THP-1 cells, with H929 EVs displaying the greatest EV uptake compared to MM.1s and U266 EVs suggesting that uptake efficiency is dependent on the cell line of origin. Furthermore, MM EVs increased the secretion of MMP-9 and IL-6 from monocytes, with H929 EVs inducing the greatest effect, consistent with the greatest uptake efficiency. Moreover, monocyte-conditioned media collected following H929 EV uptake significantly increased the migration and proliferation of MM cells. Finally, EV proteome analysis revealed differential cargo enrichment that correlates with disease progression including a significant enrichment of spliceosome-related proteins in H929 EVs compared to the U266 and MM.1s EVs. Overall, this study demonstrates that MM-derived EVs modulate monocyte function to promote tumour growth and metastasis and reveals possible molecular mechanisms involved.

Decreased circulating myeloid-derived suppressor cell count at the engraftment is one of the risk factors for multiple myeloma relapse after autologous hematopoietic stem cell transplantation

Recent studies demonstrated that myeloid-derived suppressor cells (MDSCs) are involved in the pathogenesis and progression of multiple myeloma (MM). Nevertheless, data on the quantitative and functional changes in MDSCs during standard MM treatment remain poorly understood. Here, we determined that monocytic MDSCs (M-MDSC; CD14+HLA-DRlow/–) and granulocytic MDSCs (PMN-MDSC; Lin–HLA-DR–CD33+CD66b+) in MM patients in remission following induction therapy (IT) were significantly increased, while early MDSCs (E-MDSCs; Lin–HLA-DR–CD33+CD66b–) were decreased compared to the donor group. In progression, MM patients had the most pronounced decrease in E-MDSCs and enhanced levels of PMN-MDSCs. IT was accompanied with a decrease in the expression of arginase-1 (Arg-1). In MM patients with relapse or resistance to IT, Arg-1+ cell frequency in M-MDSCs and E-MDSCs, as well as PD-L1+ M-MDSCs, was increased, which may facilitate tumor immunosuppression. G-CSF administration led to a significant increment in the MDSC subsets. At the engraftment, circulating M-MDSC and PMN-MDSCs were temporarily increased, with a gradual decline to the pre-transplant levels in 12 months. The percentage of E-MDSCs was decreased at the leukocyte recovery. Patients with a higher (>Me) M-MDSC count at the engraftment had a shorter post-transplant leukopenia duration (Me 11 vs. 13 days; pU = 0.0086). The advanced MM stage, depth of response, and lower relative count of circulating E-MDSCs at the engraftment were independent risk factors associated with a lower progression-free survival.The obtained data allow us to hypothesize that MDSCs may play a positive role at the stage of leukocyte recovery by ameliorating the long-term anti-tumor response in MM.

Preclinical and clinical evaluation of the Janus Kinase inhibitor ruxolitinib in multiple myeloma.

Multiple myeloma (MM) is the most common primary malignancy of the bone marrow. No established curative treatment is currently available for patients diagnosed with MM. In recent years, new and more effective drugs have become available for the treatment of this B-cell malignancy. These new drugs have often been evaluated together and in combination with older agents. However, even these novel combinations eventually become ineffective; and, thus, novel therapeutic approaches are necessary to help overcome resistance to these treatments. Recently, the Janus Kinase (JAK) family of tyrosine kinases, specifically JAK1 and JAK2, has been shown to have a role in the pathogenesis of MM. Preclinical studies have demonstrated a role for JAK signaling in direct and indirect growth of MM and downregulation of anti-tumor immune responses in these patients. Also, inhibition of JAK proteins enhances the anti-MM effects of other drugs used to treat MM. These findings have been confirmed in clinical studies which have further demonstrated the safety and efficacy of JAK inhibition as a means to overcome resistance to currently available anti-MM therapies. Additional studies will provide further support for this promising new therapeutic approach for treating patients with MM.

Research Progress on the Mechanism of PI3K/AKT/mTOR Signaling Pathway in Multiple Myeloma --Review

PI3K/AKT/mTOR signaling pathway is of great significance in the development and prognosis of tumors, and is closely related to the pathogenesis of multiple myeloma (MM). PI3K/AKT/mTOR signaling pathway can participate in the regulation of MM through multichannel and multitarget, such as regulating the tumor microenvironment of MM cells survival, affecting tumor development and migration, regulating the proliferation, apoptosis and autophagy of MM cells. It have shown that after the PI3K/AKT/mTOR signaling pathway is inhibited, the apoptosis and autophagy of MM cells are activated, which promote the death of MM cells and inhibit the metastasis and recurrence of MM cells. Therefore, indepth study of the mechanism of PI3K/AKT/mTOR signaling pathway in MM is helpful to elucidate the pathogenesis and prognosis of MM.

Inhibition of Ephrin B2 Reverse Signaling Abolishes Multiple Myeloma Pathogenesis.

Ephrin B2 reverse signaling mediated by endothelial cells directly regulates multiple myeloma progression and treatment resistance, which can be overcome through targeted inhibition of ephrin B2 to abolish myeloma.

CRIP1 involves the pathogenesis of multiple myeloma via dual-regulation of proteasome and autophagy

Multiple myeloma (MM) is an incurable hematological malignancy of the plasma cells. The maintenance of protein homeostasis is critical for MM cell survival. Elevated levels of paraproteins in MM cells are cleared by proteasomes or lysosomes, which are independent but inter-connected with each other. Proteasome inhibitors (PIs) work as a backbone agent and successfully improved the outcome of patients; however, the increasing activity of autophagy suppresses the sensitivity to PIs treatment. The transcription levels of CRIP1 were explored in plasma cells obtained from healthy donors, patients with newly diagnosed multiple myeloma (NDMM), and relapsed/refractory multiple myeloma (RRMM) using Gene expression omnibus datasets. Doxycycline-inducible CRIP1-shRNA and CRIP1 overexpressed MM cell lines were constructed to explore the role of CRIP1 in MM pathogenesis. Proliferation, invasion, migration, proteasome activity and autophagy were examined in MM cells with different CRIP1 levels. Co-immunoprecipitation (Co-IP) with Tandem affinity purification/Mass spectrum (TAP/MS) was performed to identify the binding proteins of CRIP1. The mouse xenograft model was used to determine the role of CRIP1 in the proliferation and drug-resistance of MM cells. High CRIP1 expression was associated with unfavorable clinical outcomes in patients with MM and served as a biomarker for RRMM with shorter overall survival. Invitro and invivo studies showed that CRIP1 plays a critical role in protein homeostasis via the dual regulation of the activities of proteasome and autophagy in MM cells. A combined analysis of RNA-seq, Co-IP and TAP/MS demonstrated that CRIP1 promotes proteasome inhibitors resistance in MM cells by simultaneously binding to de-ubiquitinase USP7 and proteasome coactivator PA200. CRIP1 promoted proteasome activity and autophagosome maturation by facilitating the dequbiquitination and stabilization of PA200. Our findings clarified the pivotal roles of the CRIP1/USP7/PA200 complex in ubiquitin-dependent proteasome degradation and autophagy maturation involved in the pathogenesis of MM. A full list of funding sources can be found in the acknowledgements section.

Role of Natural Killer T (NKT) Cells in Myeloma Biology and Therapy.

Natural Killer T (NKT) cells are distinct innate lymphocytes that recognize lipid antigens in the context of nonpolymorphic molecule CD1d. Multiple myeloma (MM) is a hematologic malignancy wherein malignant plasma cells express CD1d and are sensitive to lysis by NKT cells. Progressive malignancy in MM is characterized by NKT cell dysfunction. Several studies have tried to harness the anti-tumor properties of NKT cells in MM to mediate tumor regression. NKT cells are also attractive targets for approaches at immune redirection in MM with chimeric-antigen receptor NKT (CAR-NKT) and bispecific antibodies. In addition to the commonly studied invariant-NKT (iNKT) cells, MM patients often also exhibit alterations in type-II NKT cells and their ligands. In patients and mouse models with Gaucher disease (GD), an inherited lipid-storage disorder with markedly increased risk for MM, distinct type-II NKT cells exhibit a T-follicular helper (NKT-TFH) phenotype and provide help to lipid-specific B cells. Chronic immune activation in this setting eventually sets the stage for malignancy, which can be targeted in both mouse models and GD patients by reducing the underlying antigen. NKT cells are thus integrally linked to MM pathogenesis and an attractive target for MM immunotherapy.

Myeloma Cast Nephropathy Complicating Multiple Myeloma Associated with Kaposi Sarcoma: Is This a New Victim of Human Herpes Virus Type 8? Case Report

Kaposi sarcoma (KS) is an angiogenic neoplasia characterized primarily by purplish to brownish skin lesions. Most often linked to infection by human herpes virus type 8 (HHV8), it affects men more than women and has especially been found in elderly people around the Mediterranean. Classic Kaposi sarcoma is rare and the association with multiple myeloma (or Kahler's disease) remains exceptional with a few cases sporadically described in the literature. We report a new case illustrating this association. This is a 70-year-old patient in whom classic Kaposi disease was recently diagnosed by skin biopsy with positive HHV8 serology. He was subsequently referred to the Department of Nephrology due to the fortuitous discovery of severe kidney failure with a renal biopsy in favour of myeloma light chain cast nephropathy. The hypothesis incriminating an HHV8 variant in the pathogenesis of multiple myeloma is known in the literature but not yet elucidated. It is therefore of great interest that clinicians be sensitized about this association in order to progress in research and improve treatment and prognosis.

Germline genetic variants in Turkish familial multiple myeloma/monoclonal gammopathy of undetermined significance cases.

Multiple myeloma (MM) is a haematological malignancy primarily affecting the elderly, with a striking male predilection and ethnic disparities in incidence. Familial predisposition to MM has long been recognized, but the genetic underpinnings remain elusive. This study aimed to investigate germline variants in Turkish families with recurrent MM cases. A total of 37 MM-affected families, comprising 77 individuals, were included. Targeted next-generation sequencing analysis yielded no previously reported rare variants. Whole exome sequencing analysis in 11 families identified rare disease-causing variants in various genes, some previously linked to familial MM and others not previously associated. Notably, genes involved in ubiquitination, V(D)J recombination and the PI3K/AKT/mTOR pathway were among those identified. Furthermore, a specific variant in BNIP1 (rs28199) was found in 13 patients across nine families, indicating its potential significance in MM pathogenesis. While this study sheds light on genetic variations in familial MM in Turkey, its limitations include sample size and the absence of invivo investigations. In conclusion, familial MM likely involves a polygenic inheritance pattern with rare, disease-causing variants in various genes, emphasizing the need for international collaborative efforts to unravel the intricate genetic basis of MM and develop targeted therapies.

Th9/IL-9 may participate in the pathogenesis of multiple myeloma.

This research is aimed to evaluate the correlation between Th9-associated cytokine levels in MM patients, clinical features, and therapy. Peripheral blood samples were taken in 52 MM patients and 20 healthy volunteers matched by sex and age. The patients with MM were separated into two groups: the untreated group (27) and the remission group (25). An enzyme-linked immunosorbent assay (ELISA) was used to measure the IL-9 plasma levels. The levels of Th9-associated cytokines' mRNA expression (IL-9, PU.1, and IRF4) were measured in RT-qPCR. We also analyzed the correlations between the IL-9 plasma levels and the clinical parameters of newly diagnosed MM patients. The IL-9 plasma levels and the Th9-associated cytokines (IL-9, PU.1, and IRF4) mRNA levels in newly diagnosed MM patients were significantly elevated than those in healthy volunteers and significantly decreased after achieving remission. Moreover, PU.1 and IRF4 had a positive correlation with the IL-9 mRNA expression. Then, we found that the upregulation of IL-9 plasma levels correlates with the severity of anemia and decreased albumin Levels. The results demonstrate that Th9/IL-9 may be involved in the pathogenesis of MM and is correlated with worse patient conditions such as lower hemoglobin and serum albumin. More work is necessary to confirm whether they might serve as a useful therapeutic target and prognostic marker for MM.

Use of daratumumab drug formulation for subcutaneous administration in multiple myeloma therapy: Literature review and clinical observation

Study of the molecular pathogenesis of multiple myeloma led to development and introduction of antitumor agents with new mechanisms of action and their combinations into clinical practice. According to several trials, use of anti-CD38 monoclonal antibody daratumumab as part of triplet therapies at an early stage leads to deep and long-term antitumor response, achievement of MRD-negative status, and, as a result, increased survival and improved prognosis in all patient subgroups. High effectiveness of daratumumab subcutaneous formulation close to intravenous formulation has favorable safety profile, short administration time and low rate of infusion reactions which improves patients’ quality of life, affects their treatment compliance, and decreases healthcare costs.We present a clinical observation of a 60-year-old patient with newly diagnosed multiple myeloma who previously underwent treatment for another lymphoproliferative disorder which included autologous hematopoietic stem cell transplantation leading to complete and long-term remission. After 9 intravenous daratumumab infusions (with recommended dose of 16 mg/kg) in accordance to the D-Rd regimen, evaluation of antitumor effect and consideration of socially active lifestyle of the patient, daratumumab formulation for intravenous administration was replaced with subcutaneous formulation of fixed dose 1800 mg. Further deepening of the antitumor response was observed along with manageable safety profile and absence of significant adverse events which allowed to maintain intercourse intervals and improve the patient’s quality of life.

Abstract B056: Inflammatory dietary pattern and risk of multiple myeloma in US Black women

Abstract Background: Multiple myeloma (MM) takes a disproportionate toll on Black Americans compared to non-Hispanic whites, yet factors related to these disparities remain poorly understood. In a prior analysis of two prospective cohort studies examining diet and MM, a dietary inflammatory pattern was significantly associated with MM risk. Here, we investigate the association between dietary inflammatory index (DII) score and MM incidence in a cohort of US Black women. Methods: The Black Women’s Health Study (BWHS) is a prospective cohort study that enrolled 59,000 US self-identified Black women age 21-69 at entry in 1995. Incident cases of MM, identified among BWHS participants followed by biennial questionnaires, were confirmed via medical record review or linkage with cancer registries. We analyzed food frequency questionnaire (FFQ) data collected in 1995, excluding participants with implausible or missing FFQ data. We also excluded women diagnosed with cancer (other than non-melanoma skin cancer) prior to baseline. FFQ data were used to create a dietary inflammatory index (DII) for each person. The DII score includes total fat and cholesterol as pro-inflammatory dietary contributors, and n-3 PUFAs, selenium, and vitamin D as anti-inflammatory contributors. The DII has been previously associated with six inflammatory markers (CRP, IL-1b, IL-4, IL-6, IL-10, TNF-a). We evaluated associations of DII score quintile with MM incidence using Cox proportional hazards regression, adjusted for age, body mass index (BMI), and total energy intake (kcal/day). Results: Among 55,276 BWHS participants eligible for this analysis, we confirmed 313 incident cases of MM over 26 years of follow-up. Median age at baseline was 38 years old and median BMI was 26.6 kg/m2. The multivariable hazard ratio for women in the top quintile of DII (most pro-inflammatory diet) relative to the lowest quintile (most anti-inflammatory diet) was 0.71 (95% confidence interval: 0.43, 1.16). Conclusions: Overall, DII score was not associated with MM incidence in this cohort of US Black women. Ongoing analyses of markers of dietary inflammation and specific food groups may clarify the possible role of dietary components in MM pathogenesis. Cumulative time-varying models of DII score may also offer more robust conclusions in future analyses. Citation Format: Anisha V. Patel, Julie R. Palmer, Jessica L. Petrick, Kimberly A. Bertrand. Inflammatory dietary pattern and risk of multiple myeloma in US Black women [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B056.

Levels of Individual Mid and Long Chain Polyunsaturated Triacylglycerols (TAGs) Are Different between the Bone Marrow Microenvironment of Patients with Multiple Myeloma (MM) and Monoclonal Gammopathy of Unknown Significance (MGUS)

Background: It has been recently demonstrated that altered lipid metabolism involving increased free fatty acids (FFAs) uptake supports the growth and proliferation of MM cells (Panaroni et al. Blood 2022; Farell et al. Elife 2023). Whether the availability of FFAs in the bone marrow (BM) microenvironment is associated with the pathogenesis of MM from MGUS has not been previously evaluated. Thus, we evaluated if individual species of FAs or FA-containing lipids such as triacylglycerols (TAGs), diacylglycerols (DAGs), and monoacylglycerols (MAGs) are differentially present between the BM microenvironment of MGUS and MM patients. Methods: Lipid profiles of BM plasma samples (reflective of the BM microenvironment) from patients with a spectrum of plasma cell disorders (22 MGUS and 24 MM (15 newly diagnosed and 9 relapsed/refractory)) were acquired by liquid chromatography (LC)/tandem mass spectrometry (MS), and individual lipid species were quantified based on single-point quantification using 55 isotopically labeled internal standards. Concentration-based lipid species data was analyzed by the web-based tool MetaboAnalyst 5.0. Data was normalized by quantile normalization, log transformed and scaled by Pareto scaling. p values &amp;lt;0.05 were considered significant. Results: A total of 993 distinct lipid species were quantified by the MS-based targeted lipidomics assessment. Of these lipid species, the levels of individual mid-chain (≤50 carbon chain length) and long-chain (≥52 carbon chain length) polyunsaturated TAGs were the most differentially present in the BM plasma of MM compared to MGUS patients (Figure 1A). Even though a principal component analysis (PCA) involving all lipid species showed moderate separation of MM from MGUS patients, five MGUS patients (categorized as MGUS-other (MGO)) who clustered more towards MM patients compared to the remaining MGUS patients had a distinct pattern of individual mid and long-chain polyunsaturated TAG levels that were comparable to MM patients (Figure 1B). Furthermore, the proliferation rate of clonal plasma cells in the BM of these MM and MGUS as measured by the S-phase% was found to be directly correlated with the level of long-chain polyunsaturated TAGs. Conclusions: Mid and long-chain polyunsaturated TAGs are present in lower and higher levels, respectively, in the BM microenvironment of MM compared to MGUS patients. These findings continue to support the importance of FA-containing TAGs and other lipids in the pathogenesis of MM. Future confirmatory studies evaluating the biological significance of these differences are required to determine if they can be exploited for diagnostic and therapeutic purposes.