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Blood Cancer Discovery Sep 2023The role of measurable residual disease (MRD) in multiple myeloma patients treated with chimeric antigen receptor (CAR) T cells is uncertain. We analyzed MRD kinetics...
UNLABELLED
The role of measurable residual disease (MRD) in multiple myeloma patients treated with chimeric antigen receptor (CAR) T cells is uncertain. We analyzed MRD kinetics during the first year after idecabtagene vicleucel (ide-cel) infusion in 125 relapsed/refractory multiple myeloma patients enrolled in KarMMa. At month 1 after ide-cel, there were no differences in progression-free survival (PFS) between patients in less than complete response (CR) versus those in CR; only MRD status was predictive of significantly different PFS at this landmark. In patients with undetectable MRD at 3 months and beyond, PFS was longer in those achieving CR versus
plasma cells in MRD-negative patients were associated with inferior PFS. This study unveils different prognostic implications of serological and MRD response dynamics after ide-cel and suggests the potential value of studying the reappearance of normal plasma cells as a surrogate of loss of CAR T-cell functionality. SIGNIFICANCE
This is one of the first studies evaluating the impact of CR and MRD dynamics after CAR T therapy in relapsed/refractory multiple myeloma. These data help interpret the prognostic significance of serological and MRD responses at early and late time points after CAR T-cell infusion. See related commentary by Landgren and Kazandjian, p. 346 . This article is featured in Selected Articles from This Issue, p. 337.
Topics: Humans; Receptors, Chimeric Antigen; Prognosis; Multiple Myeloma; Immunotherapy, Adoptive; Neoplasm, Residual; Neoplasms, Plasma Cell
PubMed: 37486974
DOI: 10.1158/2643-3230.BCD-23-0044 -
EMBO Molecular Medicine Apr 2024B-cell maturation antigen (BCMA), expressed in plasmablasts and plasma cells, could serve as a promising therapeutic target for autoimmune diseases. We reported here...
B-cell maturation antigen (BCMA), expressed in plasmablasts and plasma cells, could serve as a promising therapeutic target for autoimmune diseases. We reported here chimeric antigen receptor (CAR) T cells targeting BCMA in two patients with highly relapsed and refractory myasthenia gravis (one with AChR-IgG, and one with MuSk-IgG). Both patients exhibited favorable safety profiles and persistent clinical improvements over 18 months. Reconstitution of B-cell lineages with sustained reduced pathogenic autoantibodies might underlie the therapeutic efficacy. To identify the possible mechanisms underlying the therapeutic efficacy of CAR-T cells in these patients, longitudinal single-cell RNA and TCR sequencing was conducted on serial blood samples post infusion as well as their matching infusion products. By tracking the temporal evolution of CAR-T phenotypes, we demonstrated that proliferating cytotoxic-like CD8 clones were the main effectors in autoimmunity, whereas compromised cytotoxic and proliferation signature and profound mitochondrial dysfunction in CD8 Te cells before infusion and subsequently defect CAR-T cells after manufacture might explain their characteristics in these patients. Our findings may guide future studies to improve CAR T-cell immunotherapy in autoimmune diseases.
Topics: Humans; Immunotherapy, Adoptive; Multiple Myeloma; B-Cell Maturation Antigen; Cell Lineage; Myasthenia Gravis; T-Lymphocytes; Immunoglobulin G
PubMed: 38409527
DOI: 10.1038/s44321-024-00043-z -
Clinical Cancer Research : An Official... Dec 2023Our preclinical studies showed that the oncolytic reovirus formulation pelareorep (PELA) has significant immunomodulatory anti-myeloma activity. We conducted an...
PURPOSE
Our preclinical studies showed that the oncolytic reovirus formulation pelareorep (PELA) has significant immunomodulatory anti-myeloma activity. We conducted an investigator-initiated clinical trial to evaluate PELA in combination with dexamethasone (Dex) and bortezomib (BZ) and define the tumor immune microenvironment (TiME) in patients with multiple myeloma treated with this regimen.
PATIENTS AND METHODS
Patients with relapsed/refractory multiple myeloma (n = 14) were enrolled in a phase Ib clinical trial (ClinicalTrials.gov: NCT02514382) of three escalating PELA doses administered on Days 1, 2, 8, 9, 15, and 16. Patients received 40 mg Dex and 1.5 mg/m2 BZ on Days 1, 8, and 15. Cycles were repeated every 28 days. Pre- and posttreatment bone marrow specimens (IHC, n = 9; imaging mass cytometry, n = 6) and peripheral blood samples were collected for analysis (flow cytometry, n = 5; T-cell receptor clonality, n = 7; cytokine assay, n = 7).
RESULTS
PELA/BZ/Dex was well-tolerated in all patients. Treatment-emergent toxicities were transient, and no dose-limiting toxicities occurred. Six (55%) of 11 response-evaluable patients showed decreased paraprotein. Treatment increased T and natural killer cell activation, inflammatory cytokine release, and programmed death-ligand 1 expression in bone marrow. Compared with nonresponders, responders had higher reovirus protein levels, increased cytotoxic T-cell infiltration posttreatment, cytotoxic T cells in significantly closer proximity to multiple myeloma cells, and larger populations of a novel immune-primed multiple myeloma phenotype (CD138+ IDO1+HLA-ABCHigh), indicating immunomodulation.
CONCLUSIONS
PELA/BZ/Dex is well-tolerated and associated with anti-multiple myeloma activity in a subset of responding patients, characterized by immune reprogramming and TiME changes, warranting further investigation of PELA as an immunomodulator.
Topics: Humans; Multiple Myeloma; Oncolytic Virotherapy; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Cytokines; Tumor Microenvironment
PubMed: 37812476
DOI: 10.1158/1078-0432.CCR-23-0229 -
Autophagy Apr 2024Glycosphingolipids (GSLs) are key constituents of membrane bilayers playing a role in structural integrity, cell signalling in microdomains, endosomes and lysosomes, and...
Glycosphingolipids (GSLs) are key constituents of membrane bilayers playing a role in structural integrity, cell signalling in microdomains, endosomes and lysosomes, and cell death pathways. Conversion of ceramide into GSLs is controlled by GCS (glucosylceramide synthase) and inhibitors of this enzyme for the treatment of lipid storage disorders and specific cancers. With a diverse range of functions attributed to GSLs, the ability of the GSC inhibitor, eliglustat, to reduce myeloma bone disease was investigated. In pre-clinical models of multiple myeloma, osteoclast-driven bone loss was reduced by eliglustat in a mechanistically separate manner to zoledronic acid, a bisphosphonate that prevents osteoclast-mediated bone destruction. Autophagic degradation of TNF receptor-associated factor 3 (TRAF3), a key step for osteoclast differentiation, was inhibited by eliglustat as evidenced by TRAF3 lysosomal and cytoplasmic accumulation. By altering GSL composition, eliglustat prevented lysosomal degradation whilst exogenous addition of missing GSLs rescued TRAF3 degradation to restore osteoclast formation in bone marrow cells from myeloma patients. This work highlights the clinical potential of eliglustat as a therapy for myeloma bone disease. Furthermore, using eliglustat as a lysosomal inhibitor in osteoclasts may widen its therapeutic uses to other bone disorders such as bone metastasis, osteoporosis and inflammatory bone loss.
Topics: Osteoclasts; Autophagy; Multiple Myeloma; Animals; Humans; Glycosphingolipids; Bone Diseases; Lysosomes; Mice; Pyrrolidines; Zoledronic Acid; Glucosyltransferases
PubMed: 37771244
DOI: 10.1080/15548627.2023.2208931 -
Cancer Research Communications Dec 2023Clonal hematopoiesis (CH) at time of autologous stem cell transplant (ASCT) has been shown to be associated with decreased overall survival (OS) and progression-free...
UNLABELLED
Clonal hematopoiesis (CH) at time of autologous stem cell transplant (ASCT) has been shown to be associated with decreased overall survival (OS) and progression-free survival (PFS) in patients with multiple myeloma not receiving immunomodulatory drugs (IMiD). However, the significance of CH in newly diagnosed patients, including transplant ineligible patients, and its effect on clonal evolution during multiple myeloma therapy in the era of novel agents, has not been well studied. Using our new algorithm to differentiate tumor and germline mutations from CH, we detected CH in approximately 10% of 986 patients with multiple myeloma from the Clinical Outcomes in MM to Personal Assessment of Genetic Profile (CoMMpass) cohort (40/529 transplanted and 59/457 non-transplanted patients). CH was associated with increased age, risk of recurrent bacterial infections and cardiovascular disease. CH at time of multiple myeloma diagnosis was not associated with inferior OS or PFS regardless of undergoing ASCT, and all patients benefited from IMiD-based therapies, irrespective of the presence of CH. Serial sampling of 52 patients revealed the emergence of CH over a median of 3 years of treatment, increasing its prevalence to 25%, mostly with DNMT3A mutations.
SIGNIFICANCE
Using our algorithm to differentiate tumor and germline mutations from CH mutations, we detected CH in approximately 10% of patients with newly diagnosed myeloma, including both transplant eligible and ineligible patients. Receiving IMiDs improved outcomes irrespective of CH status, but the prevalence of CH significantly rose throughout myeloma-directed therapy.
Topics: Humans; Multiple Myeloma; Clonal Hematopoiesis; Transplantation, Autologous; Stem Cell Transplantation; Progression-Free Survival
PubMed: 38019104
DOI: 10.1158/2767-9764.CRC-23-0093 -
Journal of Hematology & Oncology Jul 2023Treatment of relapsed and/or refractory multiple myeloma (RRMM) utilizing the novel therapeutic target of the B-cell maturation antigen (BCMA) has demonstrated...
Treatment of relapsed and/or refractory multiple myeloma (RRMM) utilizing the novel therapeutic target of the B-cell maturation antigen (BCMA) has demonstrated incredible results, leading to regulatory approval of BCMA-targeted chimeric antigen receptor (CAR)-T cell therapies in RRMM. With now two approved BCMA-targeted CAR-T cell therapies, investigators globally are working to build off and improve upon BCMA-targeted therapies. We discuss long-term data from the pivotal study that led to CAR-T approval, a phase 3 trial supporting their use in earlier lines, and novel manufacturing platforms to decrease vein-to-vein time. We highlight five key abstracts from the 2023 ASCO Annual Meeting that showcase these exciting updates in BCMA-directed CAR-T cell therapies in RRMM.
Topics: Humans; Multiple Myeloma; B-Cell Maturation Antigen; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; T-Lymphocytes
PubMed: 37507805
DOI: 10.1186/s13045-023-01479-5 -
Cell Reports. Medicine Oct 2023Multiple myeloma (MM) growth is supported by an immune-tolerant bone marrow microenvironment. Here, we find that loss of Never in mitosis gene A (NIMA)-related kinase 2...
Multiple myeloma (MM) growth is supported by an immune-tolerant bone marrow microenvironment. Here, we find that loss of Never in mitosis gene A (NIMA)-related kinase 2 (NEK2) in tumor microenvironmental cells is associated with MM growth suppression. The absence of NEK2 leads to both fewer tumor-associated macrophages (TAMs) and inhibitory T cells. NEK2 expression in myeloid progenitor cells promotes the generation of functional TAMs when stimulated with MM conditional medium. Clinically, high NEK2 expression in MM cells is associated with increased CD8 T effector memory cells, while low NEK2 is associated with an IFN-γ gene signature and activated T cell response. Inhibition of NEK2 upregulates PD-L1 expression in MM cells and myeloid cells. In a mouse model, the combination of NEK2 inhibitor INH154 with PD-L1 blockade effectively eliminates MM cells and prolongs survival. Our results provide strong evidence that NEK2 inhibition may overcome tumor immune escape and support its further clinical development.
Topics: Mice; Animals; Multiple Myeloma; B7-H1 Antigen; T-Lymphocytes; Cell Line, Tumor; Myeloid Progenitor Cells; Tumor Microenvironment
PubMed: 37794587
DOI: 10.1016/j.xcrm.2023.101214 -
Leukemia Jun 2024Extramedullary multiple myeloma (EMM) is an aggressive form of multiple myeloma (MM). This study represents the most comprehensive next-generation sequencing analysis of...
Extramedullary multiple myeloma (EMM) is an aggressive form of multiple myeloma (MM). This study represents the most comprehensive next-generation sequencing analysis of EMM tumors (N = 14) to date, uncovering key molecular features and describing the tumor microenvironment. We observed the co-occurrence of 1q21 gain/amplification and MAPK pathway mutations in 79% of EMM samples, suggesting that these are crucial mutational events in EMM development. We also demonstrated that patients with mutated KRAS and 1q21 gain/amplification at the time of diagnosis have a significantly higher risk of EMM development (HR = 2.4, p = 0.011) using data from a large CoMMpass dataset. We identified downregulation of CXCR4 and enhanced cell proliferation, along with reduced expression of therapeutic targets (CD38, SLAMF7, GPRC5D, FCRH5), potentially explaining diminished efficacy of immunotherapy. Conversely, we identified significantly upregulated EZH2 and CD70 as potential future therapeutic options. For the first time, we report on the tumor microenvironment of EMM, revealing CD8+ T cells and NK cells as predominant immune effector cells using single-cell sequencing. Finally, this is the first longitudinal study in EMM revealing the molecular changes from the time of diagnosis to EMM relapse.
Topics: Humans; Multiple Myeloma; High-Throughput Nucleotide Sequencing; Tumor Microenvironment; Mutation; Biomarkers, Tumor; Male; Female; Middle Aged; Aged; Bone Marrow; Prognosis
PubMed: 38493239
DOI: 10.1038/s41375-024-02206-w -
International Journal of Molecular... Mar 2024Multiple myeloma (MM) is a plasma cell disorder representing the second most common blood cancer [...].
Multiple myeloma (MM) is a plasma cell disorder representing the second most common blood cancer [...].
Topics: Humans; Multiple Myeloma; Paraproteinemias; Hematologic Neoplasms; Neoplasms, Second Primary
PubMed: 38612612
DOI: 10.3390/ijms25073799 -
Scientific Reports Nov 2023Previous studies have shown that metabolites play an important role in phenotypic regulation. However, the causal relationship between metabolites and multiple myeloma...
Previous studies have shown that metabolites play an important role in phenotypic regulation. However, the causal relationship between metabolites and multiple myeloma has not been adequately investigated. Here, we attempt to explore the causal effects of genetically determined blood metabolites on multiple myeloma. The large-scale public blood metabolites and multiple myeloma datasets from independently published genome-wide association studies (GWAS) were used to explore the causal relationship between each genetically determined blood metabolite and multiple myeloma through inverse variance weighted (IVW), weighted median, MR-Egger and mode-based estimation methods. Sensitivity tests were performed to evaluate the stability and reliability of the results by MR-Egger regression and leave-one-out methods. Metabolic pathway analysis was further explored using filtered data. Statistical analyses were all performed in R. Among 452 metabolites, ten known metabolites and three unknown metabolites had significant causal relationship with multiple myeloma (P < 0.05). Four known metabolites, 3-methyl-2-oxovalenate, oxidized bilirubin, isovalerylcarnitine and glutamine carnitine, reached statistical significance in IVW models. Metabolic pathways analysis identified four significant pathways. The occurrence of multiple myeloma may have a causal relationship with these four metabolites, and there are four metabolic pathways that are also related to the occurrence of multiple myeloma. This can provide new ideas for exploring early screening and treatment of multiple myeloma.
Topics: Humans; Genome-Wide Association Study; Mendelian Randomization Analysis; Multiple Myeloma; Reproducibility of Results; Bilirubin
PubMed: 37914749
DOI: 10.1038/s41598-023-45801-0