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Cancers
Special Issues
Immunomodulatory Agents for Multiple Myeloma
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Immunomodulatory Agents for Multiple Myeloma

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

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 12173

Special Issue Editors

Dr. Jiří Minařík

E-Mail Website
Guest Editor
1. Department of Hemato-Oncology, of Medicine and Dentistry, Palacky University Olomouc, 775 20 Olomouc, Czech Republic
2. University Hospital Olomouc, 779 00 Olomouc, Czech Republic
Interests: hemato-oncology; internal medicine; multiple myeloma and other plasma cell dyscrasias
Dr. Sabina Ševčíková

E-Mail Website
Co-Guest Editor
Babak Myeloma Group, Department of Pathological Physiology, Faculty of Medicine, Masaryk University, 625 00 Brno, Czech Republic
Interests: monoclonal gammopathies and their molecular nature
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Immunomodulatory agents (IMiDs) have changed the treatment paradigms in multiple myeloma (MM) and truly improved the survival of multiple myeloma patients. The outcomes of thalidomide-based therapy resulted in the introduction of the first effective drug with a biological mechanism of action in MM. The drug was incorporated into all phases of MM and substantially contributed to the redirection from conventional chemotherapy to immune-mediated therapy.

Lenalidomide and pomalidomide, next-generation IMiDs, have become the backbone of MM treatment and most recently used combined regimens that gain their potential from the accumulative interaction of novel drugs with IMiDs (especially proteasome inhibitors and monoclonal antibodies). A new generation of IMiDs is being tested in both preclinical as well as clinical research.

This Special Issue, “Immunomodulatory Agents for Multiple Myeloma”, aims to clarify the mechanism of action of IMiDs, their position within current strategies of MM therapy, as well as their advantages or pitfalls within routine clinical practice.

We welcome original basic, translational, as well as clinical research articles and review articles leading to a comprehensive overview of IMiD-based therapy in MM.

Dr. Jiří Minařík
Dr. Sabina Ševčíková
Guest Editors

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
  • IMiDs
  • therapy
  • mechanism of action

Published Papers (4 papers)

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Editorial

Jump to: Research, Review

5 pages, 235 KiB  
Editorial
Immunomodulatory Agents for Multiple Myeloma
by Jiří Minařík and Sabina Ševčíková
Cancers 2022, 14(23), 5759; https://doi.org/10.3390/cancers14235759 - 23 Nov 2022
Cited by 1 | Viewed by 1173
Abstract
The treatment of multiple myeloma (MM) has undergone a significant paradigm shift in the last 20 years, from conventional chemotherapy to more tumor-specific treatments, based on the interference with pathogenesis of the malignant clone as well as the bone microenvironment [...] Full article
(This article belongs to the Special Issue Immunomodulatory Agents for Multiple Myeloma)

Research

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13 pages, 1481 KiB  
Article
Ixazomib, Lenalidomide and Dexamethasone in Relapsed and Refractory Multiple Myeloma in Routine Clinical Practice: Extended Follow-Up Analysis and the Results of Subsequent Therapy
by Jiri Minarik, Jakub Radocha, Alexandra Jungova, Jan Straub, Tomas Jelinek, Tomas Pika, Ludek Pour, Petr Pavlicek, Lubica Harvanova, Lenka Pospisilova, Petra Krhovska, Denisa Novakova, Pavel Jindra, Ivan Spicka, Hana Plonkova, Martin Stork, Jaroslav Bacovsky, Vladimir Maisnar and Roman Hajek
Cancers 2022, 14(20), 5165; https://doi.org/10.3390/cancers14205165 - 21 Oct 2022
Cited by 5 | Viewed by 2876
Abstract
Background: We confirmed the benefit of addition of ixazomib to lenalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma (RRMM) in unselected real-world population. We report the final analysis for overall survival (OS), second progression free survival (PFS-2), and the subanalysis [...] Read more.
Background: We confirmed the benefit of addition of ixazomib to lenalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma (RRMM) in unselected real-world population. We report the final analysis for overall survival (OS), second progression free survival (PFS-2), and the subanalysis of the outcomes in lenalidomide (LEN) pretreated and LEN refractory patients. Methods: We assessed 344 patients with RRMM, treated with IRD (N  =  127) or RD (N  = 217). The data were acquired from the Czech Registry of Monoclonal Gammopathies (RMG). With prolonged follow-up (median 28.5 months), we determined the new primary endpoints OS, PFS and PFS-2. Secondary endpoints included the next therapeutic approach and the survival measures in LEN pretreated and LEN refractory patients. Results: The final overall response rate (ORR) was 73.0% in the IRD cohort and 66.8% in the RD cohort. The difference in patients reaching ≥VGPR remained significant (38.1% vs. 26.3%, p = 0.028). Median PFS maintained significant improvement in the IRD cohort (17.5 vs. 12.5 months, p = 0.013) with better outcomes in patients with 1–3 prior relapses (22.3 vs. 12.7 months p = 0.003). In the whole cohort, median OS was for IRD vs. RD patients 40.9 vs. 27.1 months (p = 0.001), with further improvement within relapse 1-3 (51.7 vs. 27.8 months, p ˂ 0.001). The median PFS of LEN pretreated (N = 22) vs. LEN naive (N = 105) patients treated by IRD was 8.7 vs. 23.1 months (p = 0.001), and median OS was 13.2 vs. 51.7 months (p = 0.030). Most patients in both arms progressed and received further myeloma-specific therapy (63.0% in the IRD group and 53.9% in the RD group). Majority of patients received pomalidomide-based therapy or bortezomib based therapy. Significantly more patients with previous IRD vs. RD received subsequent monoclonal antibodies (daratumumab—16.3% vs. 4.3%, p = 0.0054; isatuximab 5.0% vs. 0.0%, p = 0.026) and carfilzomib (12.5 vs. 1.7%, p = 0.004). The median PFS-2 (progression free survival from the start of IRD/RD therapy until the second disease progression or death) was significantly longer in the IRD cohort (29.8 vs. 21.6 months, p = 0.016). There were no additional safety concerns in the extended follow-up. Conclusions: The IRD regimen is well tolerated, easy to administer, and with very good therapeutic outcomes. The survival measures in unsorted real-world population are comparable to the outcomes of the clinical trial. As expected, patients with LEN reatment have poorer outcomes than those who are LEN-naive. The PFS benefit of IRD vs. RD translated into significantly better PFS-2 and OS, but the outcomes must be accounted for imbalances in pretreatment group characteristics (especially younger age and stem cell transplant pretreatment), and in subsequent therapies. Full article
(This article belongs to the Special Issue Immunomodulatory Agents for Multiple Myeloma)
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Review

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19 pages, 1718 KiB  
Review
Lenalidomide in Multiple Myeloma: Review of Resistance Mechanisms, Current Treatment Strategies and Future Perspectives
by Piotr Kulig, Sławomir Milczarek, Estera Bakinowska, Laura Szalewska, Bartłomiej Baumert and Bogusław Machaliński
Cancers 2023, 15(3), 963; https://doi.org/10.3390/cancers15030963 - 02 Feb 2023
Cited by 6 | Viewed by 3997
Abstract
Multiple myeloma (MM) is the second most common hematologic malignancy, accounting for approximately 1% of all cancers. Despite the initial poor prognosis for MM patients, their life expectancy has improved significantly with the development of novel agents. Immunomodulatory drugs (IMiDs) are widely used [...] Read more.
Multiple myeloma (MM) is the second most common hematologic malignancy, accounting for approximately 1% of all cancers. Despite the initial poor prognosis for MM patients, their life expectancy has improved significantly with the development of novel agents. Immunomodulatory drugs (IMiDs) are widely used in MM therapy. Their implementation has been a milestone in improving the clinical outcomes of patients. The first molecule belonging to the IMiDs was thalidomide. Subsequently, its novel derivatives, lenalidomide (LEN) and pomalidomide (POM), were implemented. Almost all MM patients are exposed to LEN, which is the most commonly used IMiD. Despite the potent anti-MM activity of LEN, some patients eventually relapse and become LEN-resistant. Drug resistance is one of the greatest challenges of modern oncology and has become the main cause of cancer treatment failures. The number of patients receiving LEN is increasing, hence the problem of LEN resistance has become a great obstacle for hematologists worldwide. In this review, we intended to shed more light on the pathophysiology of LEN resistance in MM, with particular emphasis on the molecular background. Moreover, we have briefly summarized strategies to overcome LEN resistance and we have outlined future directions. Full article
(This article belongs to the Special Issue Immunomodulatory Agents for Multiple Myeloma)
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16 pages, 1351 KiB  
Review
CRL4CRBN E3 Ligase Complex as a Therapeutic Target in Multiple Myeloma
by Joanna Barankiewicz, Aleksander Salomon-Perzyński, Irena Misiewicz-Krzemińska and Ewa Lech-Marańda
Cancers 2022, 14(18), 4492; https://doi.org/10.3390/cancers14184492 - 16 Sep 2022
Cited by 12 | Viewed by 3681
Abstract
Multiple myeloma (MM) is the second most common hematological malignancy with a recurrent clinical course. The introduction of immunomodulatory drugs (IMiDs) was one of the milestones in MM therapy leading to a significant improvement in patients’ prognosis. Currently, IMiDs are the backbone of [...] Read more.
Multiple myeloma (MM) is the second most common hematological malignancy with a recurrent clinical course. The introduction of immunomodulatory drugs (IMiDs) was one of the milestones in MM therapy leading to a significant improvement in patients’ prognosis. Currently, IMiDs are the backbone of MM therapy in newly diagnosed and relapsed/refractory settings. It is now known that IMiDs exert their anti-myeloma activity mainly by binding cereblon (CRBN), the substrate receptor protein of the CRL4 E3 ubiquitin ligase (CRL4CRBN) complex. By binding CRBN, IMiDs alter its substrate specificity, leading to ubiquitination and proteasomal degradation of proteins essential for MM cell survival. Following the success of IMiDs, it is not surprising that the possibility of using the CRL4CRBN complex’s activity to treat MM is being further explored. In this review, we summarize the current state of knowledge about novel players in the MM therapeutic landscape, namely the CRBN E3 ligase modulators (CELMoDs), the next generation of IMiDs with broader biological activity. In addition, we discuss a new strategy of tailored proteolysis called proteolysis targeting chimeras (PROTACs) using the CRL4CRBN to degrade typically undruggable proteins, which may have relevance for the treatment of MM and other malignancies in the future. Full article
(This article belongs to the Special Issue Immunomodulatory Agents for Multiple Myeloma)
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