International Journal of Molecular Sciences

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Special Issue Editor

Dr. Catarina Geraldes

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Guest Editor

1. Laboratory of Oncobiology and Hematology (LOH), University Clinic of Hematology, Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal
2. Coimbra Institute for Clinical and Biomedical Research (iCBR)—Group of Environmental Genetics of Oncobiology (CIMAGO), FMUC, University of Coimbra, 3000-548 Coimbra, Portugal
3. Hematology Service, Centro Hospitalar e Universitário de Coimbra (CHUC), 3000-061 Coimbra, Portugal
Interests: multiple myeloma; autologous stem cell transplantation; immunotherapy; CAR-T cell therapy; bispecific antibodies; monoclonal antibodies; antibody–drug conjugates; resistance mechanisms; cellular and molecular alterations in multiple myeloma

Special Issue Information

Dear Colleagues,

In the last few years, there have been remarkable advances in the knowledge of the molecular and cellular mechanisms involved in multiple myeloma (MM) development and progression, leading to new therapies, particularly in the field of immunotherapy. Some of these advances are related to immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, which have both direct anti-MM effects and immunostimulatory properties. Additionally, they relate to monoclonal antibodies (mAbs), targeting specific proteins on the surface of myeloma cells, such as CD38 (daratumumab, isatuximab) and SLAMF7 (elotuzumab), or more recently, antibody–drug conjugates (ADCs), which combine the specificity of mAbs with the cytotoxic effect of chemotherapy drugs and bispecific antibodies (BiTEs) that bind to both MM cells and immune cells to enhance the immune response against cancer cells. Belantamab mafodotin is an ADC that targets BCMA and BiTEs, targeting different antigens, such as BCMA (teclistamab) and GPRC5D (talquetamab), which have shown promising results in clinical trials and have been approved. Chimeric antigen receptor (CAR) T cell therapy uses patient's own genetically modified T cells to recognize specific antigen on cancer cells and has received FDA and EMA approval for the treatment of RRMM.

This Special Issue aims to publish current research related to the discovery of novel biomarkers and targets for immunotherapies in MM as well as the mechanism related with resistance to this kind of therapy. Original research articles and review articles covering these knowledge fields are strongly invited, including: cellular and molecular mechanisms; genomic, proteomic, and metabolic profiles; biomarkers of prognosis; therapy monitoring; and drug response and resistance.

Dr. Catarina Geraldes
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

multiple myeloma
immunotherapy
CAR-T cell therapy
bispecific antibodies
monoclonal antibodies
antibody–drug conjugates
resistance mechanisms

Published Papers (2 papers)

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Research

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16 pages, 3980 KiB

Open AccessArticle

Tinostamustine (EDO-S101), an Alkylating Deacetylase Inhibitor, Enhances the Efficacy of Daratumumab in Multiple Myeloma by Upregulation of CD38 and NKG2D Ligands

by Andrea Díaz-Tejedor, Javier Rodríguez-Ubreva, Laura Ciudad, Mauro Lorenzo-Mohamed, Marta González-Rodríguez, Bárbara Castellanos, Janet Sotolongo-Ravelo, Laura San-Segundo, Luis A. Corchete, Lorena González-Méndez, Montserrat Martín-Sánchez, María-Victoria Mateos, Enrique M. Ocio, Mercedes Garayoa and Teresa Paíno

Int. J. Mol. Sci. 2024, 25(9), 4718; https://doi.org/10.3390/ijms25094718 - 26 Apr 2024

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Abstract

Multiple myeloma is a malignancy characterized by the accumulation of malignant plasma cells in bone marrow and the production of monoclonal immunoglobulin. A hallmark of cancer is the evasion of immune surveillance. Histone deacetylase inhibitors have been shown to promote the expression of silenced molecules and hold potential to increase the anti-MM efficacy of immunotherapy. The aim of the present work was to assess the potential effect of tinostamustine (EDO-S101), a first-in-class alkylating deacetylase inhibitor, in combination with daratumumab, an anti-CD38 monoclonal antibody (mAb), through different preclinical studies. Tinostamustine increases CD38 expression in myeloma cell lines, an effect that occurs in parallel with an increment in CD38 histone H3 acetylation levels. Also, the expression of MICA and MICB, ligands for the NK cell activating receptor NKG2D, augments after tinostamustine treatment in myeloma cell lines and primary myeloma cells. Pretreatment of myeloma cell lines with tinostamustine increased the sensitivity of these cells to daratumumab through its different cytotoxic mechanisms, and the combination of these two drugs showed a higher anti-myeloma effect than individual treatments in ex vivo cultures of myeloma patients’ samples. In vivo data confirmed that tinostamustine pretreatment followed by daratumumab administration significantly delayed tumor growth and improved the survival of mice compared to individual treatments. In summary, our results suggest that tinostamustine could be a potential candidate to improve the efficacy of anti-CD38 mAbs. Full article

(This article belongs to the Special Issue Recent Advances in Immunotherapy of Multiple Myeloma)

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Review

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25 pages, 5855 KiB

Open AccessReview

An Assessment of the Effectiveness and Safety of Chimeric Antigen Receptor T-Cell Therapy in Multiple Myeloma Patients with Relapsed or Refractory Disease: A Systematic Review and Meta-Analysis

by Rita Pereira and Rui Bergantim

Int. J. Mol. Sci. 2024, 25(9), 4996; https://doi.org/10.3390/ijms25094996 - 3 May 2024

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Abstract

Multiple myeloma (MM), the second most common hematologic malignancy, remains incurable, and its incidence is rising. Chimeric Antigen Receptor T-cell (CAR-T cell) therapy has emerged as a novel treatment, with the potential to improve the survival and quality of life of patients with relapsed/refractory multiple myeloma (rrMM). In this systematic review and meta-analysis, conducted in accordance with PRISMA guidelines, we aim to provide a concise overview of the latest developments in CAR-T therapy, assess their potential implications for clinical practice, and evaluate their efficacy and safety outcomes based on the most up-to-date evidence. A literature search conducted from 1 January 2019 to 12 July 2023 on Medline/PubMed, Scopus, and Web of Science identified 2273 articles, of which 29 fulfilled the specified criteria for inclusion. Our results offer robust evidence supporting CAR-T cell therapy’s efficacy in rrMM patients, with an encouraging 83.21% overall response rate (ORR). A generally safe profile was observed, with grade ≥ 3 cytokine release syndrome (CRS) at 7.12% and grade ≥ 3 neurotoxicity at 1.37%. A subgroup analysis revealed a significantly increased ORR in patients with fewer antimyeloma regimens, while grade ≥ 3 CRS was more common in those with a higher proportion of high-risk cytogenetics and prior exposure to BCMA therapy. Full article

(This article belongs to the Special Issue Recent Advances in Immunotherapy of Multiple Myeloma)

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