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Multiple Myeloma—Biology, Diagnosis, Treatment and Prognosis
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Multiple Myeloma—Biology, Diagnosis, Treatment and Prognosis

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Causes, Screening and Diagnosis".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 9307

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; smoldering multiple myeloma; tumor immunology; T cell response; immunotherapy; monoclonal gammopathies; amyloidosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Advancements in the deep understanding of multiple myeloma (MM) biology, coupled with the development of novel diagnostic tools and ever more effective drugs, have opened the way to the tremendous revolution we are experiencing in the management of MM patients. Indeed, survival rates have significantly improved in the last years, with a current median life expectancy (since diagnosis) exceeding 10 years. Innovative approaches significantly impacted many areas of MM research and clinical practice, and many others are ready to “translate” from the bench to bedside. Along the same line, many new technologies are now ready to reach our “ordinary” work and will produce profound changes in our patient-management workflow. These effects are more visible in specific fields of MM research: MM biology was recently “shocked”  by the introduction of single-cell technologies (RNAseq, ATACseq, CITEseq, multiparametric spectral and traditional flow cytometry), which helped to characterize the microenvironment as well as the transcriptome of MM cell at an unprecedent detail level; the diagnostic of MM is facing the introduction of mass spectrometry for the detection of M component as well as the development of improved imaging strategies for the study of bone marrow involvement; innovative immunotherapeutic agents, including CAR-T and bispecific agents are finally ready to enter current clinical practice, and their correct positioning is still matter of important debates (Will there be still a role for autologous stem cell transplant? Are there new mechanisms of resistance?); the achievement and maintenance of undetectable minimal residual disease (MRD) status is considered the most important prognostic factor for MM patients, but is there still room for improvements? Could we use MRD for treatment guidance?   

On these bases, this Special Issue aims to provide an overview of the current advances in the field of biology, innovative diagnostic and prognostic approaches (including immunomonitoring and MRD detection) and the development of novel treatment strategies for MM patients.

We are pleased to invite you to submit original research articles as well as reviews focusing on the biology/pathology, diagnosis, treatment and prognosis of MM. Topics related to basic, clinical as well as translational research are welcome.

I look forward to receiving your contributions.

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 100 words) can be sent to the Editorial Office for announcement on this website.

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. Cancers is an international peer-reviewed open access semimonthly 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 2900 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
  • bone marrow microenvironment
  • minimal residual disease
  • mass spectrometry
  • flow cytometry
  • CAR-T
  • bispecific agents
  • genomic alterations

Published Papers (7 papers)

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Research

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16 pages, 6744 KiB  
Article
BR109, a Novel Fully Humanized T-Cell-Engaging Bispecific Antibody with GPRC5D Binding, Has Potent Antitumor Activities in Multiple Myeloma
by Ying Liu, Ya-Qiong Zhou, Lei Nie, Shan-Shan Zhu, Na Li, Zhen-Hua Wu, Qi Wang, Jian Qi, Bing-Yuan Wu, Shu-Qing Chen and Hai-Bin Wang
Cancers 2023, 15(24), 5774; https://doi.org/10.3390/cancers15245774 - 9 Dec 2023
Viewed by 1376
Abstract
At present, multiple myeloma (MM) is still an essentially incurable hematologic malignancy. Although BCMA-targeted therapies have achieved remarkable results, BCMA levels were found to be downregulated in patients with MM who relapsed after these treatments. Therefore, the search for other antigens specific to [...] Read more.
At present, multiple myeloma (MM) is still an essentially incurable hematologic malignancy. Although BCMA-targeted therapies have achieved remarkable results, BCMA levels were found to be downregulated in patients with MM who relapsed after these treatments. Therefore, the search for other antigens specific to MM has become a priority. Independently of BCMA expression, G-protein-coupled receptor family C group 5 member D (GPRC5D) is mainly expressed in the plasma cells of MM patients, while it is expressed in a limited number of normal tissues. Combining MM-specific antigen GPRC5D and T-cell-mediated therapies would be a promising therapeutic strategy for MM. Recently, we constructed a new anti-GPRC5D × anti-CD3 T-cell-engaging bispecific antibody (TCB), BR109, which was capable of binding to human GPRC5D and human CD3ε. Moreover, BR109 was proven to have relatively good stability and antitumor activity. BR109 could specifically trigger T-cell-mediated cytotoxicity against many GPRC5D-positive MM cells in vitro. Meanwhile, antitumor activity was demonstrated in MM cell line xenograft mouse models with human immune cell reconstitution. These preclinical studies have formed a solid foundation for the evaluation of MM treatment efficacy in clinical trials. Full article
(This article belongs to the Special Issue Multiple Myeloma—Biology, Diagnosis, Treatment and Prognosis)
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19 pages, 3996 KiB  
Article
The MYC-Regulated RNA-Binding Proteins hnRNPC and LARP1 Are Drivers of Multiple Myeloma Cell Growth and Disease Progression and Negatively Predict Patient Survival
by Marcel Seibert, Sebastian E. Koschade, Verena Stolp, Björn Häupl, Frank Wempe, Hubert Serve, Nina Kurrle, Frank Schnütgen and Ivana von Metzler
Cancers 2023, 15(23), 5508; https://doi.org/10.3390/cancers15235508 - 21 Nov 2023
Viewed by 1130
Abstract
Multiple myeloma (MM) is a malignant plasma cell disorder in which the MYC oncogene is frequently dysregulated. Due to its central role, MYC has been proposed as a drug target; however, the development of a clinically applicable molecule modulating MYC activity remains an [...] Read more.
Multiple myeloma (MM) is a malignant plasma cell disorder in which the MYC oncogene is frequently dysregulated. Due to its central role, MYC has been proposed as a drug target; however, the development of a clinically applicable molecule modulating MYC activity remains an unmet challenge. Consequently, an alternative is the development of therapeutic options targeting proteins located downstream of MYC. Therefore, we aimed to identify undescribed MYC-target proteins in MM cells using Stable Isotope Labeling with Amino Acids in Cell Culture (SILAC) and mass spectrometry. We revealed a cluster of proteins associated with the regulation of translation initiation. Herein, the RNA-binding proteins Heterogeneous Nuclear Ribonucleoprotein C (hnRNPC) and La Ribonucleoprotein 1 (LARP1) were predominantly downregulated upon MYC depletion. CRISPR-mediated knockout of either hnRNPC or LARP1 in conjunction with redundant LARP family proteins resulted in a proliferative disadvantage for MM cells. Moreover, high expression levels of these proteins correlate with high MYC expression and with poor survival and disease progression in MM patients. In conclusion, our study provides valuable insights into MYC’s role in translation initiation by identifying hnRNPC and LARP1 as proliferation drivers of MM cells and as both predictive factors for survival and disease progression in MM patients. Full article
(This article belongs to the Special Issue Multiple Myeloma—Biology, Diagnosis, Treatment and Prognosis)
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10 pages, 6516 KiB  
Article
CD46–ADC Reduces the Engraftment of Multiple Myeloma Patient-Derived Xenografts
by Michael J. VanWyngarden, Zachary J. Walker, Yang Su, Olivia Perez de Acha, Brett M. Stevens, Peter A. Forsberg, Tomer M. Mark, William Matsui, Bin Liu and Daniel W. Sherbenou
Cancers 2023, 15(22), 5335; https://doi.org/10.3390/cancers15225335 - 9 Nov 2023
Cited by 3 | Viewed by 1226
Abstract
An antibody–drug conjugate (ADC) targeting CD46 conjugated to monomethyl auristatin has a potent anti-myeloma effect in cell lines in vitro and in vivo, and patient samples treated ex vivo. Here, we tested if CD46–ADC may have the potential to target MM-initiating cells (MM-ICs). [...] Read more.
An antibody–drug conjugate (ADC) targeting CD46 conjugated to monomethyl auristatin has a potent anti-myeloma effect in cell lines in vitro and in vivo, and patient samples treated ex vivo. Here, we tested if CD46–ADC may have the potential to target MM-initiating cells (MM-ICs). CD46 expression was measured on primary MM cells with a stem-like phenotype. A patient-derived xenograft (PDX) model was implemented utilizing implanted fetal bone fragments to provide a humanized microenvironment. Engraftment was monitored via serum human light chain ELISA, and at sacrifice via bone marrow and bone fragment flow cytometry. We then tested MM regeneration in PDX by treating mice with CD46–ADC or the nonbinding control–ADC. MM progenitor cells from patients that exhibit high aldehyde dehydrogenase activity also have a high expression of CD46. In PDX, newly diagnosed MM patient samples engrafted significantly more compared to relapsed/refractory samples. In mice transplanted with newly diagnosed samples, CD46–ADC treatment showed significantly decreased engraftment compared to control–ADC treatment. Our data further support the targeting of CD46 in MM. To our knowledge, this is the first study to show preclinical drug efficacy in a PDX model of MM. This is an important area for future study, as patient samples but not cell lines accurately represent intratumoral heterogeneity. Full article
(This article belongs to the Special Issue Multiple Myeloma—Biology, Diagnosis, Treatment and Prognosis)
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17 pages, 3462 KiB  
Article
Non-Toxicological Role of Aryl Hydrocarbon Receptor in Obesity-Associated Multiple Myeloma Cell Growth and Survival
by Jonathan D. Diedrich, Craig E. Cole, Matthew J. Pianko, Justin A. Colacino and Jamie J. Bernard
Cancers 2023, 15(21), 5255; https://doi.org/10.3390/cancers15215255 - 1 Nov 2023
Viewed by 1094
Abstract
Obesity is not only a risk factor for multiple myeloma (MM) incidence, but it is also associated with an increased risk of progression from myeloma precursors—monoclonal gammopathy of undetermined significance—and smoldering myeloma. Adipocytes in the bone marrow (BMAs) microenvironment have been shown to [...] Read more.
Obesity is not only a risk factor for multiple myeloma (MM) incidence, but it is also associated with an increased risk of progression from myeloma precursors—monoclonal gammopathy of undetermined significance—and smoldering myeloma. Adipocytes in the bone marrow (BMAs) microenvironment have been shown to facilitate MM cell growth via secreted factors, but the nature of these secreted factors and their mechanism of action have not been fully elucidated. The elevated expression of aryl hydrocarbon receptor (AhR) is associated with a variety of different cancers, including MM; however, the role of AhR activity in obesity-associated MM cell growth and survival has not been explored. Indeed, this is of particular interest as it has been recently shown that bone marrow adipocytes are a source of endogenous AhR ligands. Using multiple in vitro models of tumor–adipocyte crosstalk to mimic the bone microenvironment, we identified a novel, non-toxicological role of the adipocyte-secreted factors in the suppression of AhR activity in MM cells. A panel of six MM cell lines were cultured in the presence of bone marrow adipocytes in (1) a direct co-culture, (2) a transwell co-culture, or (3) an adipocyte-conditioned media to interrogate the effects of the secreted factors on MM cell AhR activity. Nuclear localization and the transcriptional activity of the AhR, as measured by CYP1A1 and CYP1B1 gene induction, were suppressed by exposure to BMA-derived factors. Additionally, decreased AhR target gene expression was associated with worse clinical outcomes. The knockdown of AhR resulted in reduced CYP1B1 expression and increased cellular growth. This tumor-suppressing role of CYP1A1 and CYP1B1 was supported by patient data which demonstrated an association between reduced target gene expression and worse overall survival. These data demonstrated a novel mechanism by which bone marrow adipocytes promote MM progression. Full article
(This article belongs to the Special Issue Multiple Myeloma—Biology, Diagnosis, Treatment and Prognosis)
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12 pages, 528 KiB  
Article
Neuroimaging and Neurocognitive Outcomes in Older Patients with Multiple Myeloma Treated with Chemotherapy and Autologous Stem Cell Transplantation
by Denise D. Correa, Behroze A. Vachha, Raymond E. Baser, Adrian Koch, Phillip Wong, Suril Gohel, Sergio Giralt and James C. Root
Cancers 2023, 15(18), 4484; https://doi.org/10.3390/cancers15184484 - 8 Sep 2023
Viewed by 980
Abstract
There is a paucity of research on treatment-related neurotoxicity in older adults with multiple myeloma (MM) treated with high-dose chemotherapy (HDC) and autologous SCT (HDC/ASCT), despite the increasing use of this regimen. We examined resting state functional connectivity (RSFC), gray matter (GM) volume, [...] Read more.
There is a paucity of research on treatment-related neurotoxicity in older adults with multiple myeloma (MM) treated with high-dose chemotherapy (HDC) and autologous SCT (HDC/ASCT), despite the increasing use of this regimen. We examined resting state functional connectivity (RSFC), gray matter (GM) volume, neurocognitive function (NF), and proinflammatory cytokines (PCy) in older patients with MM pre- and post-HDC/ASCT. Eighteen patients underwent MRI, NF tests, and serum PCy measurements prior to HDC/ASCT, and fifteen patients completed a follow up five-months post-HDC/ASCT. There were significant decreases in RSFC post-HDC/ASCT in (1) the central executive network (CEN) involving the left dorsolateral prefrontal cortex and right posterior parietal cortex (p = 0.022) and (2) the CEN involving the right posterior parietal cortex and the salience network involving the right dorsal anterior cingulate cortex (p = 0.029). There were no significant changes in GM or NF, except for improvements in attention (Digit Span Backward, p = 0.03). There were significant increases in several PCy post-HDC/ASCT (p ≤ 0.05). In conclusion, RSFC decreased in frontal, parietal, and cingulate cortices post-HDC/ASCT, NF was relatively stable, and several PCy increased. These findings are congruent with other studies in cancer patients and provide supporting evidence for the vulnerability of frontoparietal regions to chemotherapy’s adverse effects. Full article
(This article belongs to the Special Issue Multiple Myeloma—Biology, Diagnosis, Treatment and Prognosis)
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13 pages, 1754 KiB  
Article
Analysis of High-Risk Extramedullary Relapse Factors in Newly Diagnosed MM Patients
by Xiaoyan Yue, Donghua He, Gaofeng Zheng, Yang Yang, Xiaoyan Han, Yi Li, Yi Zhao, Wenjun Wu, Qingxiao Chen, Enfang Zhang, Zhen Cai and Jingsong He
Cancers 2022, 14(24), 6106; https://doi.org/10.3390/cancers14246106 - 12 Dec 2022
Cited by 3 | Viewed by 1172
Abstract
Extramedullary relapse of multiple myeloma (MM) is often resistant to existing treatments, and has an extremely poor prognosis, but our understanding of extramedullary relapse is still limited. The incidence, clinical characteristics, impact on the prognosis of extramedullary relapse, and the risk factors for [...] Read more.
Extramedullary relapse of multiple myeloma (MM) is often resistant to existing treatments, and has an extremely poor prognosis, but our understanding of extramedullary relapse is still limited. The incidence, clinical characteristics, impact on the prognosis of extramedullary relapse, and the risk factors for extramedullary relapse in NDMM patients were analyzed. Among the 471 NDMM patients, a total of 267 patients had disease relapse during follow-up, including 64 (24.0%) patients with extramedullary relapse. Extramedullary relapse was more common in patients with younger age, IgD subtype, elevated LDH, extensive osteolytic lesions, extramedullary involvement, and spleen enlargement at the time of MM diagnosis. Survival analysis showed that extramedullary relapse patients had significantly worse median OS than patients with relapse but without extramedullary involvement (30.8 months vs. 53.6 months, p = 0.012). Multivariate analysis confirmed that elevated LDH (OR = 2.09, p = 0.023), >2 osteolytic lesions (OR = 3.70, p < 0.001), extramedullary involvement (OR = 3.48, p < 0.001) and spleen enlargement (OR = 2.27, p = 0.011) at the time of MM diagnosis were independent risk factors for extramedullary relapse in NDMM patients. Each of the above four factors was assigned a value of 1 to form the extramedullary relapse prediction score, and the 3-year extramedullary relapse rates of patients in the 0–2 and 3–4 score groups were 9.0 % and 76.7 %, respectively. This study suggested that extramedullary relapse was associated with poor clinical characteristics and poor prognosis in NDMM patients. The extramedullary relapse prediction score model composed of LDH, osteolytic lesions, extramedullary involvement and spleen enlargement has a better ability to predict extramedullary relapse than the existing ISS and R-ISS stages. Full article
(This article belongs to the Special Issue Multiple Myeloma—Biology, Diagnosis, Treatment and Prognosis)
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Review

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25 pages, 1097 KiB  
Review
p38 Molecular Targeting for Next-Generation Multiple Myeloma Therapy
by Mario Morales-Martínez and Mario I. Vega
Cancers 2024, 16(2), 256; https://doi.org/10.3390/cancers16020256 - 6 Jan 2024
Cited by 1 | Viewed by 1556
Abstract
Resistance to therapy and disease progression are the main causes of mortality in most cancers. In particular, the development of resistance is an important limitation affecting the efficacy of therapeutic alternatives for cancer, including chemotherapy, radiotherapy, and immunotherapy. Signaling pathways are largely responsible [...] Read more.
Resistance to therapy and disease progression are the main causes of mortality in most cancers. In particular, the development of resistance is an important limitation affecting the efficacy of therapeutic alternatives for cancer, including chemotherapy, radiotherapy, and immunotherapy. Signaling pathways are largely responsible for the mechanisms of resistance to cancer treatment and progression, and multiple myeloma is no exception. p38 mitogen-activated protein kinase (p38) is downstream of several signaling pathways specific to treatment resistance and progression. Therefore, in recent years, developing therapeutic alternatives directed at p38 has been of great interest, in order to reverse chemotherapy resistance and prevent progression. In this review, we discuss recent findings on the role of p38, including recent advances in our understanding of its expression and activity as well as its isoforms, and its possible clinical role based on the mechanisms of resistance and progression in multiple myeloma. Full article
(This article belongs to the Special Issue Multiple Myeloma—Biology, Diagnosis, Treatment and Prognosis)
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