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Biomolecules
Special Issues
Multiple Myeloma: From Pathophysiology to Novel Therapeutic Approaches
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Multiple Myeloma: From Pathophysiology to Novel Therapeutic Approaches

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: 30 April 2026 | Viewed by 2989

Special Issue Editor

Dr. Cirino Botta

E-Mail Website
Guest Editor
Hematology Unit, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90128 Palermo, Italy
Interests: multiple myeloma; tumor immunology; T cell response; immunotherapy; chronic lymphocytic leukemia; monoclonal gammopathy; amyloidosis; CAR-T
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Recent advancements in multiple myeloma (MM) research have significantly transformed patient management, leading to improved survival rates, with a median life expectancy now exceeding 10 years post diagnosis. Innovative diagnostic tools and treatments are enhancing our ability to identify high-risk populations and facilitate timely diagnoses.

Key breakthroughs include the use of single-cell technologies, such as RNA sequencing and flow cytometry, which have deepened our understanding of the MM microenvironment and disease evolution from monoclonal gammopathy of undetermined significance (MGUS) to MM. Mass spectrometry is also emerging as a useful tool to detect M components, while advanced imaging techniques improve bone marrow evaluations.

New immunotherapeutic agents, including CAR-T and bispecific therapies, are rapidly being integrated into clinical practice, prompting discussions on their role alongside traditional treatments like autologous stem cell transplants. Additionally, achieving and maintaining undetectable minimal residual disease (MRD) status is recognized as a crucial prognostic factor for MM patients, raising questions about its potential for guiding treatment decisions and further improving patient outcomes.

In this Special Issue "Multiple Myeloma: From Pathophysiology to Novel Therapeutic Approach", we aim to identify the most important preclinical, diagnostic and therapeutic innovations that shed light on monoclonal gammophaty diagnosis, evolution and treatment. We welcome original research articles, brief reports, and focused reviews—whether solicited or unsolicited—as well as meta-analyses. Your contributions will play an important role in the advancement, understanding and management of this multidisciplinary and complex disease.

Dr. Cirino Botta
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

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. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • multiple myeloma
  • tumor immunology
  • MGUS
  • sMM

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Published Papers (3 papers)

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19 pages, 6731 KB  
Article
Phosphoproteomic Profiling of Multiple Myeloma Based on Ex Vivo Drug Sensitivity Resistance Testing Identifies Phosphorylation Signatures Associated with Drug Response
by Katie Dunphy, Ellen Purcell, Caroline A. Heckman, Paul Dowling, Despina Bazou and Peter O’Gorman
Biomolecules 2026, 16(2), 323; https://doi.org/10.3390/biom16020323 - 19 Feb 2026
Viewed by 549
Abstract
Multiple myeloma (MM) is characterised by the clonal expansion of plasma cells in the bone marrow followed by end-organ damage. Despite a significant increase in the five-year survival rate in recent years, MM is still considered an incurable disease as patients will repeatedly [...] Read more.
Multiple myeloma (MM) is characterised by the clonal expansion of plasma cells in the bone marrow followed by end-organ damage. Despite a significant increase in the five-year survival rate in recent years, MM is still considered an incurable disease as patients will repeatedly relapse and develop resistance to standard-of-care therapies. A central theme for the personalization of MM therapy is understanding the biological mechanisms of drug resistance and identifying clinically relevant biomarkers of therapeutic response. Highly effective protocols for the enrichment of phosphorylated peptides followed by high-resolution mass spectrometry makes possible the quantitation of thousands of site-specific phosphorylation events, principally on serine, threonine or tyrosine residues. In this study, phosphoproteomic analysis of 20 MM patient cell lysates was performed, stratified based on their ex vivo drug response profiles to Bortezomib and Lenalidomide, two of the most foundational therapeutic agents in the management of MM. In this study, patients who are highly sensitive to these drugs show increased phosphorylation of proteins concerned with translation and RNA processing including the spliceosome, RNA transport and RNA binding pathways, while highly resistant patients demonstrated an increased phosphorylation of proteins involved with tight junctions, the Rap1 signalling pathway and the phosphatidylinositol signalling system. This study has established a phosphoproteomic dataset displaying unique phosphorylation signatures associated with drug sensitivity in MM patient plasma cells. The identification of phosphorylation signatures associated with drug resistance provides the foundation for further exploration of these mechanisms and associated signalling pathways to further characterise drug resistance mechanisms in MM and identify promising biomarkers of therapeutic response and targets for drug re-sensitization in MM. Full article
(This article belongs to the Special Issue Multiple Myeloma: From Pathophysiology to Novel Therapeutic Approaches)
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19 pages, 7178 KB  
Article
Humanized Bone Model Identifies BMP6 as a Multifunctional Regulator in Myeloma Bone Disease
by Jiaxian Wang, Thomas Baardemans, Ricardo de Matos Simoes, Willy Noort, Ruud W. J. Ruiter, Henk-Jan Prins, Susan E. van Hal-van Veen, Huipin Yuan, Joost D. de Bruijn, Anton C. M. Martens, Constantine S. Mitsiades, Sonja Zweegman, Maria Themeli and Richard W. J. Groen
Biomolecules 2025, 15(12), 1747; https://doi.org/10.3390/biom15121747 - 18 Dec 2025
Cited by 1 | Viewed by 782
Abstract
Multiple myeloma (MM) is a plasma cell malignancy that disrupts bone homeostasis by suppressing osteogenesis and promoting osteoclast activity. While most therapeutic interventions to date have focused on targeting tumor cells and reducing osteolysis, we investigate whether osteoinductive strategies can restore bone formation [...] Read more.
Multiple myeloma (MM) is a plasma cell malignancy that disrupts bone homeostasis by suppressing osteogenesis and promoting osteoclast activity. While most therapeutic interventions to date have focused on targeting tumor cells and reducing osteolysis, we investigate whether osteoinductive strategies can restore bone formation and counteract disease progression. Using a human bone marrow-like scaffold model that enables direct in vivo evaluation of tumor–stroma interactions and human bone formation, we demonstrate that MM-derived mesenchymal stromal cells (MSCs) retain osteogenic potential but are functionally suppressed by MM cells. Transcriptomic profiling of MM-primed MSCs revealed the downregulation of small leucine-rich proteoglycans (SLRPs), ASPN, OGN, and OMD, key mediators of bone morphogenetic protein (BMP) signaling, which governs osteoblast differentiation. Among the BMPs analyzed, BMP6 emerged as a potent inducer of osteogenesis and regulator of the expression of these SLRPs. Notably, BMP6 selectively promoted bone formation without enhancing osteoclastogenesis and attenuated inflammatory and tumor-supportive MSC phenotypes. BMP6 also directly inhibited MM cell proliferation and suppressed IL6-induced growth. These findings highlight BMP6 as a distinct multifunctional regulator warranting further investigation as a potential therapeutic approach, while establishing the humanized model as a valuable platform for dissecting tumor–bone interactions in MM. Full article
(This article belongs to the Special Issue Multiple Myeloma: From Pathophysiology to Novel Therapeutic Approaches)
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13 pages, 1088 KB  
Article
Inflammatory Biomarkers for Thrombotic Risk Assessment in Multiple Myeloma Patients on IMiD/aCD38-Based Regimens: Insights from a Prospective Observational Study
by Cirino Botta, Anna Maria Corsale, Claudia Cammarata, Fabiana Di Fazio, Emilia Gigliotta, Andrea Rizzuto, Manuela Ingrascì, Maria Speciale, Cristina Aquilina, Marta Biondo, Andrea Romano, Mariasanta Napolitano, Marta Mattana and Sergio Siragusa
Biomolecules 2025, 15(11), 1533; https://doi.org/10.3390/biom15111533 - 31 Oct 2025
Viewed by 1000
Abstract
Thrombosis is a common complication in multiple myeloma (MM) patients treated with immunomodulatory drugs (IMiDs), including thalidomide, lenalidomide, and pomalidomide. When combined with anti-CD38 monoclonal antibodies, these agents are highly effective but may increase thrombotic events (TE), potentially delaying therapy. This exploratory, hypothesis-generating [...] Read more.
Thrombosis is a common complication in multiple myeloma (MM) patients treated with immunomodulatory drugs (IMiDs), including thalidomide, lenalidomide, and pomalidomide. When combined with anti-CD38 monoclonal antibodies, these agents are highly effective but may increase thrombotic events (TE), potentially delaying therapy. This exploratory, hypothesis-generating analysis, conducted within the MMVision mono-institutional prospective study, included 53 MM patients who initiated IMiD plus anti-CD38 therapy between May 2021 and December 2022 (median follow-up: 18 months). Treatment regimens comprised lenalidomide (n = 36) or thalidomide (n = 15) with daratumumab, and pomalidomide (n = 2) with isatuximab. Most patients (n = 38) received frontline therapy, and all were given thromboprophylaxis according to guidelines, mainly aspirin (73%). Five patients (9.4%) developed VTE after a median of 48 days, managed with short-term low-molecular-weight heparin (LMWH). Exploratory analysis of 27 clinical/laboratory parameters suggested possible associations between VTE and low levels of beta-2 microglobulin, ferritin, intact/free lambda light chains, and monocyte-to-lymphocyte ratio. Notably, four of the five VTEs occurred in patients without lytic bone disease, typically associated with bone-driven inflammation in MM. Although all patients received aspirin prophylaxis from treatment initiation, it remains unclear whether thrombosis would also have occurred among those with higher inflammatory burden. These preliminary observations may indicate that in patients with relatively lower inflammation, aspirin prophylaxis could be less effective, potentially favoring VTE onset. In two VTE cases, cytokine profiling showed decreased M-CSF, SCLF-β, and MIP-1α, with increased G-CSF, raising the hypothesis of distinct immune-inflammatory pathways contributing to TEs. Given the limited number of patients and thrombotic events, and the cytokine data available for only two VTE cases, these associations should be regarded as exploratory and interpreted with caution. Overall, these exploratory findings warrant validation in larger, independent cohorts and may help generate hypotheses on how inflammatory signatures influence thrombotic risk and prophylaxis efficacy in MM patients receiving IMiD/anti-CD38-based regimens. Full article
(This article belongs to the Special Issue Multiple Myeloma: From Pathophysiology to Novel Therapeutic Approaches)
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