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10 pages, 258 KiB

Open AccessArticle

Clonal Myeloid Dysplasia Following CAR T-Cell Therapy: Chicken or the Egg?

by Vladimir Vainstein, Batia Avni, Sigal Grisariu, Shlomit Kfir-Erenfeld, Nathalie Asherie, Boaz Nachmias, Shlomtzion Auman, Revital Saban, Eran Zimran, Miri Assayag, Kalman Filanovsky, Netanel A. Horowitz, Eyal Lebel, Adir Shaulov, Michal Gur, Chaggai Rosenbluh, Svetlana Krichevsky, Polina Stepensky and Moshe E. Gatt

Cancers 2023, 15(13), 3471; https://doi.org/10.3390/cancers15133471 - 3 Jul 2023

Cited by 12 | Viewed by 2327

Abstract

Multiple myeloma (MM) is characterized by recurrent relapses. Consequently, patients receive multiple therapy lines, including alkylating agents and immune modulators, which have been associated with secondary malignancies such as myelodysplastic syndrome (MDS). Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T cell (CART) therapy [...] Read more.

Multiple myeloma (MM) is characterized by recurrent relapses. Consequently, patients receive multiple therapy lines, including alkylating agents and immune modulators, which have been associated with secondary malignancies such as myelodysplastic syndrome (MDS). Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T cell (CART) therapy is efficacious in patients with relapsed/refractory (R/R) MM. However, the long-term complications, particularly MDS, are not well understood. Whether CART therapy causes or promotes MDS has not been thoroughly investigated. In this study, we explored the causal relationship between MDS and CART therapy. We retrospectively examined the prevalence of MDS-related morphological and mutational changes before and after administration of CART therapy in five patients. Among them, four developed MDS after CART therapy, while one had pre-existing MDS prior to CART. None of the four patients who developed post-CART MDS showed morphological MDS changes prior to CART therapy. However, all four patients exhibited molecular alterations associated with MDS in their pre-CART as well as post-CART therapy bone marrow. No new mutations were observed. Our findings provide initial evidence suggesting that anti-BCMA CART therapy in MM may promote expansion of pre-existing MDS clones rather than causing development of new clones. Full article

(This article belongs to the Special Issue Novel and Personalized Therapies for Multiple Myeloma and Plasma Cell Disorders)

10 pages, 461 KiB

Open AccessArticle

Venetoclax in Relapse/Refractory AL Amyloidosis—A Multicenter International Retrospective Real-World Study

by Eyal Lebel, Efstathios Kastritis, Giovanni Palladini, Paolo Milani, Foteini Theodorakakou, Shlomzion Aumann, Noa Lavi, Liat Shargian, Hila Magen, Yael Cohen, Moshe E. Gatt and Iuliana Vaxman

Cancers 2023, 15(6), 1710; https://doi.org/10.3390/cancers15061710 - 10 Mar 2023

Cited by 15 | Viewed by 2896

Abstract

Therapeutic options in relapsed refractory (R/R) light-chain (AL) amyloidosis patients are limited. Given the encouraging results in t(11;14) multiple myeloma and the high prevalence of t(11;14) in AL amyloidosis, venetoclax is an attractive treatment option in this setting. We report here the results [...] Read more.

Therapeutic options in relapsed refractory (R/R) light-chain (AL) amyloidosis patients are limited. Given the encouraging results in t(11;14) multiple myeloma and the high prevalence of t(11;14) in AL amyloidosis, venetoclax is an attractive treatment option in this setting. We report here the results of a multi-center retrospective study on 26 R/R AL amyloidosis patients treated off-label with venetoclax. The median lines of therapy prior to venetoclax was 3.5 (range 1–7), and 88% of our cohort had t (11;14). Twenty-two patients (85%) were previously treated with daratumumab. The overall hematologic response rate was 88%, 35% achieved a CR, and 35% achieved VGPR. The median event-free survival was 25 months (m) (95% CI 9.7 m-not reached), and the median overall survival was 33 m (95% CI 25.9–39.2 m). Most of the patients in this cohort are in ongoing deep responses and continuing venetoclax therapy. The treatment was relatively safe. One patient died due to infection, and there were two grade 3 infections in our cohort. Tumor lysis syndrome (TLS) was not seen in any patient. Dose reductions were frequent but did not affect the efficacy. These promising results require confirmation in a randomized controlled trial. Full article

(This article belongs to the Special Issue Novel and Personalized Therapies for Multiple Myeloma and Plasma Cell Disorders)

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21 pages, 3505 KiB

Open AccessArticle

Inhibition of PI3K Class IA Kinases Using GDC-0941 Overcomes Cytoprotection of Multiple Myeloma Cells in the Osteoclastic Bone Marrow Microenvironment Enhancing the Efficacy of Current Clinical Therapeutics

by Hugh Kikuchi, Eunice Amofa, Maeve Mcenery, Steve Arthur Schey, Karthik Ramasamy, Farzin Farzaneh and Yolanda Calle

Cancers 2023, 15(2), 462; https://doi.org/10.3390/cancers15020462 - 11 Jan 2023

Cited by 1 | Viewed by 3068

Abstract

Osteoclasts contribute to bone marrow (BM)-mediated drug resistance in multiple myeloma (MM) by providing cytoprotective cues. Additionally, 80% of patients develop osteolytic lesions, which is a major cause of morbidity in MM. Although targeting osteoclast function is critical to improve MM therapies, pre-clinical [...] Read more.

Osteoclasts contribute to bone marrow (BM)-mediated drug resistance in multiple myeloma (MM) by providing cytoprotective cues. Additionally, 80% of patients develop osteolytic lesions, which is a major cause of morbidity in MM. Although targeting osteoclast function is critical to improve MM therapies, pre-clinical studies rarely consider overcoming osteoclast-mediated cytoprotection within the selection criteria of drug candidates. We have performed a drug screening and identified PI3K as a key regulator of a signalling node associated with resistance to dexamethasone lenalidomide, pomalidomide, and bortezomib mediated by osteoclasts and BM fibroblastic stromal cells, which was blocked by the pan-PI3K Class IA inhibitor GDC-0941. Additionally, GDC-0941 repressed the maturation of osteoclasts derived from MM patients and disrupted the organisation of the F-actin cytoskeleton in sealing zones required for bone degradation, correlating with decreased bone resorption by osteoclasts. In vivo, GDC-0941 improved the efficacy of dexamethasone against MM in the syngeneic GFP-5T33/C57-Rawji mouse model. Taken together, our results indicate that GDC-0941 in combination with currently used therapeutic agents could effectively kill MM cells in the presence of the cytoprotective BM microenvironment while inhibiting bone resorption by osteoclasts. These data support investigating GDC-0941 in combination with currently used therapeutic drugs for MM patients with active bone disease. Full article

(This article belongs to the Special Issue Novel and Personalized Therapies for Multiple Myeloma and Plasma Cell Disorders)

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16 pages, 1242 KiB

Open AccessArticle

Liquid Biopsy-Derived DNA Sources as Tools for Comprehensive Mutation Profiling in Multiple Myeloma: A Comparative Study

by Robbe Heestermans, Wouter De Brouwer, Ken Maes, Isabelle Vande Broek, Freya Vaeyens, Catharina Olsen, Ben Caljon, Ann De Becker, Marleen Bakkus, Rik Schots and Ivan Van Riet

Cancers 2022, 14(19), 4901; https://doi.org/10.3390/cancers14194901 - 7 Oct 2022

Cited by 5 | Viewed by 2723

Abstract

The analysis of bone marrow (BM) samples in multiple myeloma (MM) patients can lead to the underestimation of the genetic heterogeneity within the tumor. Blood-derived liquid biopsies may provide a more comprehensive approach to genetic characterization. However, no thorough comparison between the currently [...] Read more.

The analysis of bone marrow (BM) samples in multiple myeloma (MM) patients can lead to the underestimation of the genetic heterogeneity within the tumor. Blood-derived liquid biopsies may provide a more comprehensive approach to genetic characterization. However, no thorough comparison between the currently available circulating biomarkers as tools for mutation profiling in MM has been published yet and the use of extracellular vesicle-derived DNA for this purpose in MM has not yet been investigated. Therefore, we collected BM aspirates and blood samples in 30 patients with active MM to isolate five different DNA types, i.e., cfDNA, EV-DNA, BM-DNA and DNA isolated from peripheral blood mononucleated cells (PBMNCs-DNA) and circulating tumor cells (CTC-DNA). DNA was analyzed for genetic variants with targeted gene sequencing using a 165-gene panel. After data filtering, 87 somatic and 39 germline variants were detected among the 149 DNA samples used for sequencing. cfDNA showed the highest concordance with the mutation profile observed in BM-DNA and outperformed EV-DNA, CTC-DNA and PBMNCs-DNA. Of note, 16% of all the somatic variants were only detectable in circulating biomarkers. Based on our analysis, cfDNA is the preferable circulating biomarker for genetic characterization in MM and its combined use with BM-DNA allows for comprehensive mutation profiling in MM. Full article

(This article belongs to the Special Issue Novel and Personalized Therapies for Multiple Myeloma and Plasma Cell Disorders)

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Review

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18 pages, 1654 KiB

Open AccessReview

Novel Developments in the Treatment of Multiple Myeloma-Associated Bone Disease

by Martin Johansen, Mette Bøegh Levring, Kasper Stokbro, Marta Diaz-delCastillo, Abdul Ahad Khan, Line Adsbøll Wickstroem, Michael Tveden Gundesen, Ida Bruun Kristensen, Charlotte Guldborg Nyvold, Mikkel Østerheden Andersen, Thomas Levin Andersen, Niels Abildgaard and Thomas Lund

Cancers 2023, 15(23), 5585; https://doi.org/10.3390/cancers15235585 - 25 Nov 2023

Cited by 3 | Viewed by 2891

Abstract

Osteolytic bone disease is present in about 80% of patients with multiple myeloma at the time of diagnosis. Managing bone disease in patients with multiple myeloma is a challenge and requires a multi-faceted treatment approach with medication, surgery, and radiation. The established treatments [...] Read more.

Osteolytic bone disease is present in about 80% of patients with multiple myeloma at the time of diagnosis. Managing bone disease in patients with multiple myeloma is a challenge and requires a multi-faceted treatment approach with medication, surgery, and radiation. The established treatments with intravenous or subcutaneous antiresorptives can cause debilitating adverse events for patients, mainly osteonecrosis of the jaw, which, traditionally, has been difficult to manage. Now, oral surgery is recommended and proven successful in 60–85% of patients. Patients with spinal involvement may benefit from surgery in the form of vertebroplasty and kyphoplasty for pain relief, improved mobility, and reestablished sagittal balance, as well as the restoration of vertebral height. These procedures are considered safe, but the full therapeutic impact needs to be investigated further. Ixazomib, the first oral proteasome inhibitor, increases osteoblast differentiation, and recently published preliminary results in patients treated with Ixazomib maintenance have promisingly shown increased trabecular volume caused by prolonged bone formation activity. Other novel potential treatment strategies are discussed as well. Full article

(This article belongs to the Special Issue Novel and Personalized Therapies for Multiple Myeloma and Plasma Cell Disorders)

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17 pages, 1111 KiB

Open AccessReview

Bispecific Antibodies in Multiple Myeloma: Opportunities to Enhance Efficacy and Improve Safety

by Dawn Swan, Philip Murphy, Siobhan Glavey and John Quinn

Cancers 2023, 15(6), 1819; https://doi.org/10.3390/cancers15061819 - 17 Mar 2023

Cited by 27 | Viewed by 7486

Abstract

Multiple myeloma (MM) is the second most common haematological neoplasm of adults in the Western world. Overall survival has doubled since the advent of proteosome inhibitors (PIs), immunomodulatory agents (IMiDs), and monoclonal antibodies. However, patients with adverse cytogenetics or high-risk disease as determined [...] Read more.

Multiple myeloma (MM) is the second most common haematological neoplasm of adults in the Western world. Overall survival has doubled since the advent of proteosome inhibitors (PIs), immunomodulatory agents (IMiDs), and monoclonal antibodies. However, patients with adverse cytogenetics or high-risk disease as determined by the Revised International Staging System (R-ISS) continue to have poorer outcomes, and triple-refractory patients have a median survival of less than 1 year. Bispecific antibodies (BsAbs) commonly bind to a tumour epitope along with CD3 on T-cells, leading to T-cell activation and tumour cell killing. These treatments show great promise in MM patients, with the first agent, teclistamab, receiving regulatory approval in 2022. Their potential utility is hampered by the immunosuppressive tumour microenvironment (TME), a hallmark of MM, which may limit efficacy, and by undesirable adverse events, including cytokine release syndrome (CRS) and infections, some of which may be fatal. In this review, we first consider the means of enhancing the efficacy of BsAbs in MM. These include combining BsAbs with other drugs that ameliorate the effect of the immunosuppressive TME, improving target availability, the use of BsAbs directed against multiple target antigens, and the optimal time in the treatment pathway to employ BsAbs. We then discuss methods to improve safety, focusing on reducing infection rates associated with treatment-induced hypogammaglobulinaemia, and decreasing the frequency and severity of CRS. BsAbs offer a highly-active therapeutic option in MM. Improving the efficacy and safety profiles of these agents may enable more patients to benefit from these novel therapies and improve outcomes for patients with high-risk disease. Full article

(This article belongs to the Special Issue Novel and Personalized Therapies for Multiple Myeloma and Plasma Cell Disorders)

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18 pages, 943 KiB

Open AccessReview

Approach to Contemporary Risk Assessment, Prevention and Management of Thrombotic Complications in Multiple Myeloma

by Despina Fotiou, Meletios Athanasios Dimopoulos and Efstathios Kastritis

Cancers 2022, 14(24), 6216; https://doi.org/10.3390/cancers14246216 - 16 Dec 2022

Cited by 12 | Viewed by 3190

Abstract

Multiple myeloma (MM) is associated with an increased risk of thrombotic complications, which remains substantial despite the implementation of thromboprophylaxis. The procoagulant state that characterizes the disease is multifactorial, and a greater understanding of the underlying pathophysiology is required to inform appropriate thrombosis [...] Read more.

Multiple myeloma (MM) is associated with an increased risk of thrombotic complications, which remains substantial despite the implementation of thromboprophylaxis. The procoagulant state that characterizes the disease is multifactorial, and a greater understanding of the underlying pathophysiology is required to inform appropriate thrombosis prevention. Currently, there is a shift towards using direct oral anticoagulants (DOACs) in this setting; head-to-head comparisons in the context of controlled clinical trials between class agents are still missing. MM-specific VTE risk assessment scores have been developed to optimize management and minimize the associated mortality/morbidity. Their clinical utility remains to be evaluated. The value of adding biomarkers to clinical scores to optimize their performance and increase their discriminatory power is also under assessment. Full article

(This article belongs to the Special Issue Novel and Personalized Therapies for Multiple Myeloma and Plasma Cell Disorders)

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23 pages, 1096 KiB

Open AccessReview

Monoclonal Gammopathies of Clinical Significance: A Critical Appraisal

by Rafael Ríos-Tamayo, Bruno Paiva, Juan José Lahuerta, Joaquín Martínez López and Rafael F. Duarte

Cancers 2022, 14(21), 5247; https://doi.org/10.3390/cancers14215247 - 26 Oct 2022

Cited by 12 | Viewed by 4477

Abstract

Monoclonal gammopathies of clinical significance (MGCSs) represent a group of diseases featuring the association of a nonmalignant B cells or plasma cells clone, the production of an M-protein, and singularly, the existence of organ damage. They present a current framework that is difficult [...] Read more.

Monoclonal gammopathies of clinical significance (MGCSs) represent a group of diseases featuring the association of a nonmalignant B cells or plasma cells clone, the production of an M-protein, and singularly, the existence of organ damage. They present a current framework that is difficult to approach from a practical clinical perspective. Several points should be addressed in order to move further toward a better understanding. Overall, these entities are only partially included in the international classifications of diseases. Its definition and classification remain ambiguous. Remarkably, its real incidence is unknown, provided that a diagnostic biopsy is mandatory in most cases. In fact, amyloidosis AL is the final diagnosis in a large percentage of patients with renal significance. On the other hand, many of these young entities are syndromes that are based on a dynamic set of diagnostic criteria, challenging a timely diagnosis. Moreover, a specific risk score for progression is lacking. Despite the key role of the clinical laboratory in the diagnosis and prognosis of these patients, information about laboratory biomarkers is limited. Besides, the evidence accumulated for many of these entities is scarce. Hence, national and international registries are stimulated. In particular, IgM MGCS deserves special attention. Until now, therapy is far from being standardized, and it should be planned on a risk and patient-adapted basis. Finally, a comprehensive and coordinated multidisciplinary approach is needed, and specific clinical trials are encouraged. Full article

(This article belongs to the Special Issue Novel and Personalized Therapies for Multiple Myeloma and Plasma Cell Disorders)

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