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Cancers
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Novel Therapeutic Strategies in Multiple Myeloma (MM)
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Novel Therapeutic Strategies in Multiple Myeloma (MM)

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 24750

Special Issue Editor

Dr. Enrique M. Ocio

E-Mail Website
Guest Editor
University Hospital Marqués de Valdecilla (IDIVAL), University of Cantabria, 39008 Santander, Spain
Interests: multiple myeloma; clinical trials; hematology; immunotherapy; novel drugs; preclinical studies

Special Issue Information

Summary: Multiple myeloma (MM) represents a paradigm in the development of novel therapeutic strategies based on the investigation of the pathogenetic mechanisms of the disease. This research has not only focused on the genomic and biological abnormalities inside tumor cells, but also on their interaction with the bone marrow microenvironment and the role of a defective immune system in the disease pathogenesis. This investigation has led to the approval of 12 different novel drugs in the last 20 years for the treatment of these patients. This work still continues, and therefore, the present Special Issue aims at reviewing the most significant novel agents under clinical evaluation for this disease. This includes a 2nd generation of drugs with well-known mechanisms such as alkylators or CelMods (derived from IMiDs); novel mechanisms targeting the tumor cell, such as Bcl-2 family inhibitors, XPO-1 inhibitors or small molecules blocking pathogenetic pathways, genes or proteins (MEK, PIM-K, myc or TP53); and also novel immunotherapeutic strategies such as monoclonal antibodies, antibody–drug conjugates, bispecific antibodies or CAR-T cells. Manuscripts should concisely review the mechanisms of action of these agents as well as the most updated clinical data currently available to have a brief discussion and expert opinion about the potential of the analyzed therapies.

Dr. Enrique M. Ocio
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
  • targeted agents
  • clinical trials
  • novel drugs
  • personalized medicine
  • immunotherapy
  • antibodies
  • small molecules

Published Papers (5 papers)

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Research

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17 pages, 3501 KiB  
Article
Myc-Related Mitochondrial Activity as a Novel Target for Multiple Myeloma
by Alejandra Ortiz-Ruiz, Yanira Ruiz-Heredia, María Luz Morales, Pedro Aguilar-Garrido, Almudena García-Ortiz, Antonio Valeri, Carmen Bárcena, Rosa María García-Martin, Vanesa Garrido, Laura Moreno, Alicia Gimenez, Miguel Ángel Navarro-Aguadero, María Velasco-Estevez, Eva Lospitao, María Teresa Cedena, Santiago Barrio, Joaquín Martínez-López, María Linares and Miguel Gallardo
Cancers 2021, 13(7), 1662; https://doi.org/10.3390/cancers13071662 - 1 Apr 2021
Cited by 11 | Viewed by 3197
Abstract
Mitochondria are involved in the development and acquisition of a malignant phenotype in hematological cancers. Recently, their role in the pathogenesis of multiple myeloma (MM) has been suggested to be therapeutically explored. MYC is a master regulator of b-cell malignancies such as multiple [...] Read more.
Mitochondria are involved in the development and acquisition of a malignant phenotype in hematological cancers. Recently, their role in the pathogenesis of multiple myeloma (MM) has been suggested to be therapeutically explored. MYC is a master regulator of b-cell malignancies such as multiple myeloma, and its activation is known to deregulate mitochondrial function. We investigated the impact of mitochondrial activity on the distinct entities of the disease and tested the efficacy of the mitochondrial inhibitor, tigecycline, to overcome MM proliferation. COXII expression, COX activity, mitochondrial mass, and mitochondrial membrane potential demonstrated a progressive increase of mitochondrial features as the disease progresses. In vitro and in vivo therapeutic targeting using the mitochondrial inhibitor tigecycline showed promising efficacy and cytotoxicity in monotherapy and combination with the MM frontline treatment bortezomib. Overall, our findings demonstrate how mitochondrial activity emerges in MM transformation and disease progression and the efficacy of therapies targeting these novel vulnerabilities. Full article
(This article belongs to the Special Issue Novel Therapeutic Strategies in Multiple Myeloma (MM))
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21 pages, 2543 KiB  
Article
Aminopeptidase Expression in Multiple Myeloma Associates with Disease Progression and Sensitivity to Melflufen
by Juho J. Miettinen, Romika Kumari, Gunnhildur Asta Traustadottir, Maiju-Emilia Huppunen, Philipp Sergeev, Muntasir M. Majumder, Alexander Schepsky, Thorarinn Gudjonsson, Juha Lievonen, Despina Bazou, Paul Dowling, Peter O`Gorman, Ana Slipicevic, Pekka Anttila, Raija Silvennoinen, Nina N. Nupponen, Fredrik Lehmann and Caroline A. Heckman
Cancers 2021, 13(7), 1527; https://doi.org/10.3390/cancers13071527 - 26 Mar 2021
Cited by 31 | Viewed by 5433
Abstract
Multiple myeloma (MM) is characterized by extensive immunoglobulin production leading to an excessive load on protein homeostasis in tumor cells. Aminopeptidases contribute to proteolysis by catalyzing the hydrolysis of amino acids from proteins or peptides and function downstream of the ubiquitin–proteasome pathway. Notably, [...] Read more.
Multiple myeloma (MM) is characterized by extensive immunoglobulin production leading to an excessive load on protein homeostasis in tumor cells. Aminopeptidases contribute to proteolysis by catalyzing the hydrolysis of amino acids from proteins or peptides and function downstream of the ubiquitin–proteasome pathway. Notably, aminopeptidases can be utilized in the delivery of antibody and peptide-conjugated drugs, such as melflufen, currently in clinical trials. We analyzed the expression of 39 aminopeptidase genes in MM samples from 122 patients treated at Finnish cancer centers and 892 patients from the CoMMpass database. Based on ranked abundance, LAP3, ERAP2, METAP2, TTP2, and DPP7 were highly expressed in MM. ERAP2, XPNPEP1, DPP3, RNPEP, and CTSV were differentially expressed between relapsed/refractory and newly diagnosed MM samples (p < 0.05). Sensitivity to melflufen was detected ex vivo in 11/15 MM patient samples, and high sensitivity was observed, especially in relapsed/refractory samples. Survival analysis revealed that high expression of XPNPEP1, RNPEP, DPP3, and BLMH (p < 0.05) was associated with shorter overall survival. Hydrolysis analysis demonstrated that melflufen is a substrate for aminopeptidases LAP3, LTA4H, RNPEP, and ANPEP. The sensitivity of MM cell lines to melflufen was reduced by aminopeptidase inhibitors. These results indicate critical roles of aminopeptidases in disease progression and the activity of melflufen in MM. Full article
(This article belongs to the Special Issue Novel Therapeutic Strategies in Multiple Myeloma (MM))
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Review

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20 pages, 519 KiB  
Review
Current and Novel Alkylators in Multiple Myeloma
by Fredrik Schjesvold and Albert Oriol
Cancers 2021, 13(10), 2465; https://doi.org/10.3390/cancers13102465 - 18 May 2021
Cited by 10 | Viewed by 4115
Abstract
A large number of novel treatments for myeloma have been developed and approved; however, alkylating drugs continue to be part of standard regimens. Additionally, novel alkylators are currently being developed. We performed a non-systematized literary search for relevant papers and communications at large [...] Read more.
A large number of novel treatments for myeloma have been developed and approved; however, alkylating drugs continue to be part of standard regimens. Additionally, novel alkylators are currently being developed. We performed a non-systematized literary search for relevant papers and communications at large conferences, as well as exploiting the authors’ knowledge of the field, to review the history, current use and novel concepts around the traditional alkylators cyclophosphamide, bendamustine and melphalan and current data on the newly developed pro-drug melflufen. Even in the era of targeted treatment and personalized medicine, alkylating drugs continue to be part of the standard-of-care in myeloma, and new alkylators are coming to the market. Full article
(This article belongs to the Special Issue Novel Therapeutic Strategies in Multiple Myeloma (MM))
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19 pages, 1944 KiB  
Review
Pathway-Directed Therapy in Multiple Myeloma
by Lukas John, Maria Theresa Krauth, Klaus Podar and Marc-Steffen Raab
Cancers 2021, 13(7), 1668; https://doi.org/10.3390/cancers13071668 - 1 Apr 2021
Cited by 19 | Viewed by 3807
Abstract
Multiple Myeloma (MM) is a malignant plasma cell disorder with an unmet medical need, in particular for relapsed and refractory patients. Molecules within deregulated signaling pathways, including the RAS/RAF/MEK/ERK, but also the PI3K/AKT-pathway belong to the most promising evolving therapeutic targets. Rationally derived [...] Read more.
Multiple Myeloma (MM) is a malignant plasma cell disorder with an unmet medical need, in particular for relapsed and refractory patients. Molecules within deregulated signaling pathways, including the RAS/RAF/MEK/ERK, but also the PI3K/AKT-pathway belong to the most promising evolving therapeutic targets. Rationally derived compounds hold great therapeutic promise to target tumor-specific abnormalities rather than general MM-associated vulnerabilities. This paradigm is probably best depicted by targeting mutated BRAF: while well-tolerated, remarkable responses have been achieved in selected patients by inhibition of BRAFV600E alone or in combination with MEK. Targeting of AKT has also shown promising results in a subset of patients as monotherapy or to resensitize MM-cells to conventional treatment. Approaches to target transcription factors, convergence points of signaling cascades such as p53 or c-MYC, are emerging as yet another exciting strategy for pathway-directed therapy. Informed by our increasing knowledge on the impact of signaling pathways in MM pathophysiology, rationally derived Precision-Medicine trials are ongoing. Their results are likely to once more fundamentally change treatment strategies in MM. Full article
(This article belongs to the Special Issue Novel Therapeutic Strategies in Multiple Myeloma (MM))
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24 pages, 1283 KiB  
Review
Monoclonal Antibodies and Antibody Drug Conjugates in Multiple Myeloma
by Jakub Radocha, Niels W. C. J. van de Donk and Katja Weisel
Cancers 2021, 13(7), 1571; https://doi.org/10.3390/cancers13071571 - 29 Mar 2021
Cited by 23 | Viewed by 7442
Abstract
Multiple myeloma is the second most common hematologic malignancy. Current treatment strategies are mainly based on immunomodulatory drugs, proteasome inhibitors or combination of both. Novel agents added to these backbone treatments represent a promising strategy in treatment of newly diagnosed as well as [...] Read more.
Multiple myeloma is the second most common hematologic malignancy. Current treatment strategies are mainly based on immunomodulatory drugs, proteasome inhibitors or combination of both. Novel agents added to these backbone treatments represent a promising strategy in treatment of newly diagnosed as well as relapsed and refractory multiple myeloma patients. In this respect, the incorporation of monoclonal antibodies into standard-of-care regimens markedly improved prognosis of myeloma patients during the last years. More specifically, monoclonal anti-CD38 antibodies, daratumumab and isatuximab, have been implemented into treatment strategies from first-line treatment to refractory disease. In addition, the monoclonal anti-SLAM-F7 antibody elotuzumab in combination with immunomodulatory drugs has improved the clinical outcomes of patients with relapsed/refractory disease. Belantamab mafodotin is the first approved antibody drug conjugate directed against B cell maturation antigen and is currently used as a monotherapy for patients with advanced disease. This review focuses on clinical efficacy and safety of monoclonal antibodies as well as antibody drug conjugates in multiple myeloma. Full article
(This article belongs to the Special Issue Novel Therapeutic Strategies in Multiple Myeloma (MM))
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