Proteasome Inhibitor Research Articles

An adenosinergic positive feedback loop extends pharmacological cardioprotection duration.

Adenosine receptor activation induces delayed, sustained cardioprotection against ischaemia-reperfusion (IR) injury (24-72 h), but the mechanisms underlying extendedcardioprotection duration remain unresolved. We hypothesized that a positive feedback loop involving adenosine receptor-induced proteasomal degradation of adenosine kinase (ADK) and decreased myocardial adenosine metabolism extends the duration of cardioprotection. Mice were administered an ADK inhibitor, ABT-702, to induce endogenous adenosine signalling. Cardiac ADK protein and mRNA levels were analysed 24-120 h later. Theophylline or bortezomib was administered 24 h after ABT-702 to examine the late roles of adenosine receptors or proteasomal activity, respectively, in ADK expression and cardioprotection at 72 h. Coronary flow and IR tolerance were analysed by Langendorff technique. The potential for continuous adenosinergic cardioprotection was examined using heterozygous, cardiac-specific ADK KO (cADK+/-) mice. Cardiac ADK expression was also examined after A1 or A3 receptor agonist, phenylephrine, lipopolysaccharide or sildenafil administration. ABT-702 treatment decreased ADK protein content and provided cardioprotection from 24 to 72 h. ADK mRNA upregulation restored ADK protein after 96-120 h. Adenosine receptor or proteasome inhibition at 24 h reversed ABT-702-induced ADK protein deficit and cardioprotection at 72 h. cADK+/- hearts exhibited continuous cardioprotection. Diverse preconditioning agents also diminished cardiac ADK protein expression. A positive feedback loop driven by adenosine receptor-induced ADK degradation and renewed adenosine signalling extends the duration of cardioprotection by ABT-702 and possibly other preconditioning agents. The therapeutic potential of continuous adenosinergic cardioprotection is demonstrated in cADK+/- hearts.

DBT is a metabolic switch for maintenance of proteostasis under proteasomal impairment

Proteotoxic stress impairs cellular homeostasis and underlies the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). The proteasomal and autophagic degradation of proteins are two major pathways for protein quality control in the cell. Here, we report a genome-wide CRISPR screen uncovering a major regulator of cytotoxicity resulting from the inhibition of the proteasome. Dihydrolipoamide branched chain transacylase E2 (DBT) was found to be a robust suppressor, the loss of which protects against proteasome inhibition-associated cell death through promoting clearance of ubiquitinated proteins. Loss of DBT altered the metabolic and energetic status of the cell and resulted in activation of autophagy in an AMP-activated protein kinase (AMPK)-dependent mechanism in the presence of proteasomal inhibition. Loss of DBT protected against proteotoxicity induced by ALS-linked mutant TDP-43 in Drosophila and mammalian neurons. DBT is upregulated in the tissues of ALS patients. These results demonstrate that DBT is a master switch in the metabolic control of protein quality control with implications in neurodegenerative diseases.

DBT is a metabolic switch for maintenance of proteostasis under proteasomal impairment.

Proteotoxic stress impairs cellular homeostasis and underlies the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). The proteasomal and autophagic degradation of proteins are two major pathways for protein quality control in the cell. Here, we report a genome-wide CRISPR screen uncovering a major regulator of cytotoxicity resulting from the inhibition of the proteasome. Dihydrolipoamide branched chain transacylase E2 (DBT) was found to be a robust suppressor, the loss of which protects against proteasome inhibition-associated cell death through promoting clearance of ubiquitinated proteins. Loss of DBT altered the metabolic and energetic status of the cell and resulted in activation of autophagy in an AMP-activated protein kinase (AMPK)-dependent mechanism in the presence of proteasomal inhibition. Loss of DBT protected against proteotoxicity induced by ALS-linked mutant TDP-43 in Drosophila and mammalian neurons. DBT is upregulated in the tissues of ALS patients. These results demonstrate that DBT is a master switch in the metabolic control of protein quality control with implications in neurodegenerative diseases.

Discovery of Novel Nonpeptidic Proteasome Inhibitors Using Covalent Virtual Screening and Biological Evaluation.

Many reported proteasome inhibitors, including the three clinically approved inhibitors, bortezomib, carfilzomib, and ixazomib, have peptidic structures. In this study, using a hybrid and versatile strategy for covalent virtual screening by combining warhead screening and preprocessing with GOLD and CovDock software that were applied to the ZINC virtual library, we identified multiple proteasome inhibitors with new nonpeptidic structural scaffolds. Proteasome inhibition assays confirmed the inhibitory activities of these new compounds. These results demonstrate the effectiveness of our computational strategy for large-scale covalent virtual screening. Furthermore, these identified proteasome inhibitors may serve as starting points for the development of a new class of nonpeptidic therapeutic agents.

Promising Therapeutic Strategies for Hematologic Malignancies: Innovations and Potential.

In this review we explore innovative approaches in the treatment of hematologic cancers by combining various therapeutic modalities. We discuss the synergistic potential of combining inhibitors targeting different cellular pathways with immunotherapies, molecular therapies, and hormonal therapies. Examples include combining PI3K inhibitors with proteasome inhibitors, NF-κB inhibitors with immunotherapy checkpoint inhibitors, and neddylation inhibitors with therapies targeting the tumor microenvironment. Additionally, we discuss the potential use of small molecules and peptide inhibitors in hematologic cancer treatment. These multidimensional therapeutic combinations present promising strategies for enhancing treatment efficacy and overcoming resistance mechanisms. However, further clinical research is required to validate their effectiveness and safety profiles in hematologic cancer patients.

Increased RNA and protein degradation is required for counteracting transcriptional burden and proteotoxic stress in human aneuploid cells.

Aneuploidy results in a stoichiometric imbalance of protein complexes that jeopardizes cellular fitness. Aneuploid cells thus need to compensate for the imbalanced DNA levels by regulating their RNA and protein levels, but the underlying molecular mechanisms remain unknown. Here, we dissected multiple diploid vs. aneuploid cell models. We found that aneuploid cells cope with transcriptional burden by increasing several RNA degradation pathways, and are consequently more sensitive to the perturbation of RNA degradation. At the protein level, aneuploid cells mitigate proteotoxic stress by reducing protein translation and increasing protein degradation, rendering them more sensitive to proteasome inhibition. These findings were recapitulated across hundreds of human cancer cell lines and primary tumors, and aneuploidy levels were significantly associated with the response of multiple myeloma patients to proteasome inhibitors. Aneuploid cells are therefore preferentially dependent on several key nodes along the gene expression process, creating clinically-actionable vulnerabilities in aneuploid cells.

Induction prior to autologous haematopoietic cell transplantation in multiple myeloma.

Induction chemotherapy followed by autologous haematopoietic cell transplantation and post-transplant therapy (including maintenance therapy with or without prior consolidation) is still considered as the standard of care for newly diagnosed young and fit multiple myeloma patients. Over the last years, superiority of quadruplet regimens for induction was established, with the addition of an anti-CD38 monoclonal antibody to triplet regimen including a proteasome inhibitor, an IMiD (thalidomide or lenalidomide) or cyclophosphamide, and dexamethasone. Given quadruplet induction regimens are associated with deep response, including a high-rate of sustained measurable residual disease negativity in a significant proportion of patients, they are now recommended for induction chemotherapy when available.

Characterization of driver mutations identifies gene signatures predictive of prognosis and treatment sensitivity in multiple myeloma.

In multiple myeloma (MM), while frequent mutations in driver genes are crucial for disease progression, they traditionally offer limited insights into patient prognosis. This study aims to enhance prognostic understanding in MM by analyzing pathway dysregulations in key cancer driver genes, thereby identifying actionable gene signatures. We conducted a detailed quantification of mutations and pathway dysregulations in 10 frequently mutated cancer driver genes in MM to characterize their comprehensive mutational impacts on the whole transcriptome. This was followed by a systematic survival analysis to identify significant gene signatures with enhanced prognostic value. Our systematic analysis highlighted 2 significant signatures, TP53 and LRP1B, which notably outperformed mere mutation status in prognostic predictions. These gene signatures remained prognostically valuable even when accounting for clinical factors, including cytogenetic abnormalities, the International Staging System (ISS), and its revised version (R-ISS). The LRP1B signature effectively distinguished high-risk patients within low/intermediate-risk categories and correlated with significant changes in the tumor immune microenvironment. Additionally, the LRP1B signature showed a strong association with proteasome inhibitor pathways, notably predicting patient responses to bortezomib and the progression from monoclonal gammopathy of unknown significance to MM. Through a rigorous analysis, this study underscores the potential of specific gene signatures in revolutionizing the prognostic landscape of MM, providing novel clinical insights that could influence future translational oncology research.

Cilia defects upon loss of WDR4 are linked to proteasomal hyperactivity and ubiquitin shortage

The WD repeat-containing protein 4 (WDR4) has repeatedly been associated with primary microcephaly, a condition of impaired brain and skull growth. Often, faulty centrosomes cause microcephaly, yet aberrant cilia may also be involved. Here, we show using a combination of approaches in human fibroblasts, zebrafish embryos and patient-derived cells that WDR4 facilitates cilium formation. Molecularly, we associated WDR4 loss-of-function with increased protein synthesis and concomitant upregulation of proteasomal activity, while ubiquitin precursor pools are reduced. Inhibition of proteasomal activity as well as supplementation with free ubiquitin restored normal ciliogenesis. Proteasome inhibition ameliorated microcephaly phenotypes. Thus, we propose that WDR4 loss-of-function impairs head growth and neurogenesis via aberrant cilia formation, initially caused by disturbed protein and ubiquitin homeostasis.

EP4 receptor agonist CAY10598 upregulates ROS-dependent Hsp90 cleavage in colorectal cancer cells

Prostaglandin E2 (PGE2) interacts with four specific G protein-coupled receptors, namely EP1, EP2, EP3, and EP4, playing a pivotal role in determining the fate of cells. Our previous findings highlighted that stimulating the EP4 receptor with its agonist, CAY10598, triggers apoptosis in colon cancer HCT116 cells via the production of reactive oxygen species (ROS). This process also reduces the phosphorylation of the oncogenic protein JAK2 and leads to its degradation in these cells. In this study, our goal was to explore the pathways through which CAY10598 leads to JAK2 degradation. We focused on Hsp90, a heat shock protein family member known for its role as a molecular chaperone maintaining the stability of several key proteins including EGFR, MET, Akt, and JAK2. Our results show that CAY10598 decreases the levels of client proteins of Hsp90 in HCT116 cells, an effect reversible by pretreatment with the ROS scavenger N-acetyl cysteine (NAC) or the proteasome inhibitor MG132, indicating that the degradation is likely driven by ROS. Furthermore, we observed that CAY10598 cleaves both α and β isoforms of Hsp90, the process inhibited by NAC. Inhibition of EP4 with the antagonist GW627368x not only prevented the degradation of Hsp90 client proteins but also the cleavage of Hsp90 itself in CAY10598-treated HCT116 cells. Additionally, CAY10598 suppressed the growth of HCT116 cells implanted in mice. Our findings reveal that CAY10598 induces apoptosis in cancer cells by a novel mechanism involving the ROS-dependent cleavage of Hsp90, thereby inhibiting the function of crucial Hsp90 client proteins.

The Proteasome and Cul3-Dependent Protein Ubiquitination Is Required for Gli Protein-Mediated Activation of Gene Expression in the Hedgehog Pathway.

Many cellular processes are regulated by proteasome-mediated protein degradation, including regulation of signaling pathways and gene expression. Among the pathways regulated by the ubiquitin-proteasome system is the Hedgehog pathway and its downstream effectors, the Gli transcription factors. Here we provide evidence that proteasomal activity is necessary for maintaining the activation of the Hedgehog pathway, and this crucial event takes place at the level of Gli proteins. We undertook extensive work to demonstrate the specificity of the observed phenomenon by ruling out the involvement of primary cilium, impaired nuclear import, failed dissociation from Sufu, microtubule stabilization, and stabilization of Gli repressor forms. Moreover, we showed that proteasomal-inhibition-mediated Hedgehog pathway downregulation is not restricted to the NIH-3T3 cell line. We demonstrated, using CRISPR/Ca9 mutagenesis, that neither Gli1, Gli2, nor Gli3 are solely responsible for the Hedgehog pathway downregulation upon proteasome inhibitor treatment, and that Cul3 KO renders the same phenotype. Finally, we report two novel E3 ubiquitin ligases, Btbd9 and Kctd3, known Cul3 interactors, as positive Hedgehog pathway regulators. Our data pave the way for a better understanding of the regulation of gene expression and the Hedgehog signaling pathway.

Signal mining of adverse events of proteasome inhibitors in multiple myeloma based on FAERS.

To mine and analyze adverse events (AEs) related to proteasome inhibitors in multiple myeloma based on the FDA Adverse Event Reporting System (FAERS), providing references for rational clinical medication. AE data related to multiple myeloma proteasome inhibitors were collected from the FAERS from the first quarter of 2010 to the first quarter of 2024. Signal mining of AEs was conducted using the reporting odds ratio method and Bayesian confidence propagation neural network method. A total of 8,805 reports for bortezomib, 5,264 for carfilzomib, and 8,771 for ixazomib were collected, with corresponding AE signals of 474, 279, and 287, respectively, involving 23, 21, and 22 System Organ Classes (SOCs). The report information for the three drugs tended to be consistent: more cases were reported in males than in females; the majority of patients were 65 years and over; AEs mostly occurred within 6months of medication; the outcomes primarily consisted of hospitalization, prolonged hospital stay, and other serious adverse events; the primary reporting country was the United States. The most affected SOCs were infections and infestations, general disorders and administration site conditions, and blood and lymphatic system disorders. The overall distribution of AEs for the three multiple myeloma proteasome inhibitors was consistent, but there were certain differences in specific AE signal characteristics, which should be noted in clinical applications.

Discovery of novel 20S proteasome subunit β5 PROTAC degraders as potential therapeutics for pharyngeal carcinoma and Bortezomib-resistant multiple myeloma

Resistance to proteasome inhibitors like Bortezomib is a major challenge in the treatment of multiple myeloma (MM). Proteolysis targeting chimeras (PROTACs), an emerging therapeutic approach that induces selective degradation of target proteins, offer a promising solution to overcome drug resistance. In this study, we designed and synthesized novel small-molecule PROTACs that induce 20S proteasome subunit β5 degradation as a strategy to overcome Bortezomib resistance. These 20S proteasome subunit β5 PROTACs demonstrated considerable binding affinity to 20S proteasome subunit β5 and cereblon (CRBN), effectively induced 20S proteasome subunit β5 degradation, and exhibited potent antiproliferative activity against a panel of cancer cell lines. Notably, PROTACs 12f and 14 displayed robust antitumor effects against both the pharyngeal carcinoma cell line FaDu and the Bortezomib-resistant MM cell line KM3/BTZ in vitro and in vivo with excellent safety profiles. Taken together, our findings highlight the potential of PROTACs 12f and 14 as novel 20S proteasome subunit β5-degrading agents for the treatment of pharyngeal carcinoma and overcoming Bortezomib resistance in MM.

Phase 1b study of the anti-CD38 antibody mezagitamab in patients with relapsed/refractory multiple myeloma

AbstractThis phase 1b trial aimed to determine the safety, tolerability, and preliminary efficacy of mezagitamab, a subcutaneously administered anti-CD38 monoclonal antibody, in patients with relapsed/refractory multiple myeloma (RRMM). Eligible patients had received ≥3 prior lines of treatment, including an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and a steroid, or ≥2 prior lines in which 1 included a PI + IMiD, and were refractory or intolerant to ≥1 IMiD and ≥1 PI. Fifty patients were enrolled: 44 received mezagitamab monotherapy (dose-escalating cohorts at 45-1200 mg) and 6 received mezagitamab 300 mg in combination with pomalidomide plus dexamethasone. Patients received mezagitamab weekly for 8 doses, every other week for 8 doses, and monthly thereafter. No dose-limiting toxicities were reported with single-agent mezagitamab, and the recommended phase 2 dose was determined as 600 mg. The most common drug-related treatment-emergent adverse events (TEAEs) were fatigue in the monotherapy cohort (9/44 patients) and neutropenia in the combination cohort (4/6 patients); neutropenia was the only drug-related grade ≥3 TEAE to occur in >1 patient. No infusion reactions occurred, and 4 injection-site reactions were reported. Three patients discontinued treatment due to TEAEs. Among the 22 patients receiving 600 mg mezagitamab, the overall response rate was 47%, and the median duration of response was 22.1 months. Mezagitamab had a manageable safety profile and activity in patients with RRMM, with comparable outcomes to those reported with other anti-CD38 therapies in patients with advanced RRMM. Further development of mezagitamab in myeloma is not planned, but given its encouraging safety, studies are underway in autoimmune conditions with underlying abnormal autoantibodies. This trial was registered at www.ClinicalTrials.gov as #NCT03439280.

Efficacy of CARVYKTI in CARTITUDE-4 versus other conventional treatment regimens for lenalidomide-refractory multiple myeloma using inverse probability of treatment weighting.

Aim: The phase III randomized controlled trial (RCT) CARTITUDE-4 (NCT04181827) demonstrated superiority of CARVYKTI (ciltacabtagene autoleucel; cilta-cel) over daratumumab, pomalidomide and dexamethasone (DPd) and pomalidomide, bortezomib and dexamethasone (PVd) for relapsed/refractory multiple myeloma (RRMM) patients who have received one to three prior line(s) of therapy (LOT[s]) including an immunomodulatory agent and a proteasome inhibitor, and are refractory to lenalidomide. These analyses estimate the relative efficacy between cilta-cel and other common treatment regimens, for which no direct comparative evidence is available. Materials & methods: Patient data were available from the CARTITUDE-4, CASTOR, CANDOR and APOLLO RCTs. Imbalances between cohorts on key patient characteristics were adjusted for using inverse probability of treatment weighting (IPTW). Relative efficacies were estimated with response rate ratios (RRs) and 95% confidence intervals (CIs) for overall response rate (ORR), very good partial response or better rate (≥VGPR) and complete response or better rate (≥CR), and with hazard ratios (HRs) and 95% CIs for progression-free survival (PFS). Sensitivity analyses using different analytical methods and additional covariates were explored. Results: Key characteristics were well balanced across cohorts after IPTW. Cilta-cel showed statistically significant benefit in PFS (HRs: 0.11-0.51), ≥VGPR (RRs: 1.51-5.13) and ≥CR (RRs: 2.90-35.24) versus all comparators, and statistically significant improvements in ORR over most comparator regimens (RRs: 1.22-1.90). Results were consistent across sensitivity analyses. Conclusion: Cilta-cel demonstrated benefit over other common treatment regimens, highlighting its potential to become a new standard of care option for lenalidomide-refractory RRMM patients with one to three prior LOT(s). These comparisons help to demonstrate the improved efficacy of cilta-cel in countries where the standard of care may differ from DPd/PVd.

Addition of Elotuzumab to Backbone Treatment Regimens for Multiple Myeloma: An Updated Meta-Analysis of Randomized Clinical Trials

BackgroundThe efficacy of elotuzumab, an anti-SLAMF7 monoclonal antibody, in treating relapsed/refractory multiple myeloma (RRMM) and newly-diagnosed multiple myeloma (NDMM) has varied in randomized controlled trials (RCTs). Moreover, there is limited data on its real-world application. Patients and MethodsWe conducted a systematic review and meta-analysis of RCTs investigating the addition of elotuzumab to backbone antimyeloma regimens. The primary outcome of interest was progression-free survival (PFS). Secondary efficacy outcomes included overall survival (OS), overall response rate (ORR), and rates of very good partial response or better (VGPR). Key toxicities were also evaluated. ResultsThree RRMM trials (n = 915) and 5 NDMM trials (n = 1790) were included, with 50% of the 2705 patients receiving elotuzumab-containing triplets or quadruplets. In RRMM settings, elotuzumab use significantly improved PFS (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.60-0.82; P < .001; I² = 0%). This benefit was consistent among patients with high-risk cytogenetics (HR, 0.62; 95% CI, 0.43-0.90; P = .01; I² = 0%) and was particularly evident in those previously treated with proteasome inhibitors (PIs) or immunomodulatory drugs (IMiDs). The RRMM cohort also demonstrated better OS, ORR, and ≥VGPR rate. However, the NDMM cohort showed no significant improvements in any efficacy outcomes. Despite an increase in severe (grade ≥3) infections, elotuzumab use did not adversely affect rates of severe cytopenias, severe cardiac disorders, or second primary malignancies. ConclusionOur results suggest that elotuzumab-containing regimens represent valuable therapeutic options for PI/IMiD-exposed patients with RRMM. In contrast, elotuzumab's role in frontline settings remains limited.

Oxygen-dependent regulation of F-box proteins in Toxoplasma gondii is mediated by Skp1 glycosylation

A dynamic proteome is required for cellular adaption to changing environments including levels of O2, and the SKP1/CULLIN-1/F-box protein/RBX1 (SCF) family of E3 ubiquitin ligases contributes importantly to proteasome-mediated degradation. We examine, in the apicomplexan parasite Toxoplasma gondii, the influence on the interactome of SKP1 by its novel glycan attached to a hydroxyproline generated by PHYa, the likely ortholog of the HIFα PHD2 oxygen-sensor of human host cells. Strikingly, the representation of several putative F-box proteins (FBPs) is substantially reduced in PHYaΔ parasites grown in fibroblasts. One, FBXO13, is a predicted lysyl hydroxylase related to the human JmjD6 oncogene except for its F-box domain. The abundance of FBXO13, epitope-tagged at its genetic locus, was reduced in PHYaΔ parasites thus explaining its diminished presence in the SKP1 interactome. A similar effect was observed for FBXO14, a cytoplasmic protein of unknown function that may have co-evolved with PHYa in apicomplexans. Similar findings in glycosylation-mutant cells, rescue by proteasomal inhibitors, and unchanged transcript levels, suggested the involvement of the SCF in their degradation. The effect was selective, because FBXO1 was not affected by loss of PHYa. These findings are physiologically significant because the effects were phenocopied in parasites reared at 0.5% O2. Modest impact on steady-state SKP1 modification levels suggests that effects are mediated during a lag phase in hydroxylation of nascent SKP1. The dependence of FBP abundance on O2-dependent SKP1 modification likely contributes to the reduced virulence of PHYaΔ parasites owing to impaired ability to sense O2 as an environmental signal.

B cell targeting in IgA nephropathy.

The "multi-hit theory/4-hit theory" pathogenesis hypothesis is widely accepted and IgA nephropathy (IgAN) is understood to be a disease originating from Hit 1, galactose deficient IgA1 (GdIgA1). The chronic repetitive activation of the complement pathway (alternative and lectin pathways) and the subsequent inflammation results in progressive glomerular damage that spills over into increased intraglomerular pressure and other hemodynamic changes, increased urinary protein, glomerulosclerosis, and tubulointerstitial fibrosis. The basic pathophysiology of this disease is the progression of a mixture of such acute and chronic pathologies. Currently, a number of new drugs has emerged as promising agents, such as complement regulators, endothelin receptor antagonists, and SGLT2 inhibitors, which are associated with each pathological step after glomerular deposition of GdIgA1/immune complexes. On the other hand, the molecular mechanisms of GdIgA1 production are gradually being elucidated, and the development of several novel therapeutic agents targeting the responsible B cells and their international clinical trials are progressing. These agents that inhibit or control the production of the Hit1, GdIgA1, are highly expected as essential therapies for this disease. The large body of clinical and basic research findings to date strongly suggest that nephritogenic GdIgA1 is a polymeric IgA1 of mucosal origin. In addition, the B cells involved in its nephritogenic GdIgA1 production are mainly differentiated mature B cells such as plasma cells, which may migrate to the bone marrow as well as the mucosa. The innate immune system in the mucosa, especially Toll-like receptors (TLRs), is thought to be involved in their production. Among TLRs, TLT9 and TLR7, which recognize bacterial and viral unmethylated DNA and RNA, have been reported to be involved. The mucosal activation of these TLRs is associated with the production of APRIL (A Proliferation Inducing Ligand) and BAFF (B cell activating factor), which are TNF superfamily cytokines involved in B cell maturation, survival, and IgA class switching, and may also be involved in the production of nephritogenic GdIgA1. It is still inconclusive whether APRIL or BAFF is more closely involved in the production of nephritogenic GdIgA1. Phenotypes in transgenic animal models suggest BAFF involvement, however, a genome wide association study (GWAS) analysis of human IgAN has identified APRIL, not BAFF, as a candidate gene. Based on the above background, several international clinical trials are underway for drugs such as TLR regulators (hydroxychloroquine), anti-APRIL drugs, anti-BAFF drugs, APRIL/BAFF receptor (TACI) binding inhibitors, and cytoreductive drugs (proteasome inhibitors, anti-CD38 antibodies) to inhibit nephritogenic GdIgA1 production in responsible B cells. This session will provide an overview of the responsible B cells, their GdIgA1 production mechanism, and ongoing drugs.

Real-Life Management of Patients Aged 80 Years Old and Over With Multiple Myeloma: Results of the EMMY Cohort

Multiple myeloma patients aged 80 years and older are a population more prone to comorbidities and frailty. We aim to describe the real-life management and outcomes of this population. EMMY is a descriptive large-scale study. Between 2017 and 2021 we included 4383 patients of which 894 (20.3%) were aged ≥ 80 years. Four cohorts of patients aged ≥ 80 years were analysed: line 1 (L1), line 2 (L2), line 3 (L3) or line 4+ (L4+).The proportion of patients ≥ 80 years old was 20.8% in L1, 21.3% in L2, 20.9% in L3 and 17.8% in L4+. L1 patients received more treatment including a proteasome inhibitor (PI) (42.9%), L2 patients received mainly an immunomodulator (IMID) (65.9%) or an anti-CD38 (31.5%). For L3, IMID was used in 71.4% than an anti-CD38 (33.5%). L4+ patients received a PI (40.6%), IMID (33.2%) or an anti-CD38 (29.1%). Regarding efficacy, the median progression-free survival was 18.4 months in L1, 15.1 months in L2, 10.4 months in L3 and 6.5 months in L4+. The median overall survival was 49 months in L1, 31.3 months in L2, 21.4 months in L3 and 13.6 months in L4+.EMMY cohort confirmed that patients ≥ 80 years of age represent an important proportion of MM patients, in the de novo or relapse setting. This study is an important step in improving our comprehension and management of treatment in elderly patients.

Nitrogen mustard induces dynamic nuclear protein spectrum change and DNA-protein crosslinking, with p97 mediating repair

Nitrogen mustard (NM) is a chemotherapeutic agent capable of alkylating nucleophilic proteins and DNA, causing severe cell damage. However, no reports have been on the dynamic changes in proteomics induced by NM. In this study, we established a model of acute exposure to NM for 1 h and a continuous cultured model for 24 h after NM removal (repair stage) using 16HBE cells. The nuclear protein spectrum and nuclear proteins crosslinked with DNA were analyzed, and the function of p97 during NM damage was examined. An hour of NM exposure resulted in severe changes in the nuclear protein spectrum and protein into the cell nucleus, which is mainly involved in nuclear acid-related issues. After 24 h, the return to normal process of the types and amounts of differentially expressed proteins was inhibited by si-p97. The main processes involved in si-p97 intervention were nucleocytoplasmic transport, processing in the endoplasmic reticulum, metabolic abnormalities, and DNA-response; however. An hour of exposure to NM increased DNA-protein crosslinking (DPC), total-H2AX, and p-H2AX. In contrast, si-p97 only further increased or maintained their levels at 24 h yet not at 1 h. The effect of the proteasome inhibitor, MG132, was similar to that of si-p97. The siRNA of DVC1, a partner of p97, also increased the DPC content. Both si-p97 and si-DVC1 increased the cytoplasmic levels of the proteasome (PSMD2). These results suggest acute NM exposure induces severe nuclear protein spectral changes, rapid protein influx into the nucleus, DPC formation, and DNA double-strand breaks. Furthermore, our data indicated that p97 is involved in normal protein spectrum maintenance and DPC removal after NM withdrawal, requiring the participation of DVC1 and the proteasome.