The Effect of Belantamab Mafodotin on Primary Myeloma–Stroma Co-Cultures: Asymmetrical Mitochondrial Transfer between Myeloma Cells and Autologous Bone Marrow Stromal Cells

Matula, Zsolt; Uher, Ferenc; Vályi‐Nagy, István; Mikala, Gábor

doi:10.3390/ijms24065303

Cited by 5 publications

(4 citation statements)

References 47 publications

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“…A potential mechanism of belantamab mafodotin was recently reported by Matula et al, who assessed the effect of belantamab mafodotin on primary myeloma-stroma co-cultures [ 15 ]. It was noticed that the MM BCMA expression level positivity varies between 31% and 96% among patients, and inadequate expression is associated with extremely high resistance to belantamab mafodotin.…”

Section: Discussionmentioning

confidence: 99%

Explosive Disease Progression After Single-Agent B-cell Maturation Antigen-Targeted Treatment in Multiple Myeloma: A Report of Three Cases in Sheikh Shakhbout Medical City

Jaber,

Abdaljalil,

Ali

et al. 2023

Cureus

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Patients with “penta-refractory” multiple myeloma (MM) are challenging to treat given the limited treatment options available to them. Belantamab mafodotin is the first B-cell maturation antigen (BCMA)-targeting antibody-drug conjugate approved for the treatment of relapsed/refractory MM (RRMM). In this case report, we reviewed in detail three female patients who were diagnosed with MM international scoring system (ISS)-3 and were heavily pretreated, and refractory to CD38 monoclonal antibodies, two proteasome inhibitors, and two immunomodulatory agents. These patients were started on belantamab mafodotin and experienced rapid and explosive clinical, biochemical, and extramedullary disease progression within a short period of time. All three patients experienced worsening cytopenia, increased transfusion requirement, severe uncontrolled bony pain, recurrent infections, and frequent hospital admissions. Two of them passed away due to disease progression complications within a few months of starting belantamab mafodotin. Although belantamab mafodotin as a single agent was withdrawn from the market after the DREAMM-3 trial failed to achieve its primary endpoint in late RRMM, BCMA-targeted therapy may still be a promising treatment approach, and the role of belantamab mafodotin is yet to be revealed in combination therapy in early RRMM.

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Section: Discussionmentioning

confidence: 99%

Explosive Disease Progression After Single-Agent B-cell Maturation Antigen-Targeted Treatment in Multiple Myeloma: A Report of Three Cases in Sheikh Shakhbout Medical City

Jaber,

Abdaljalil,

Ali

et al. 2023

Cureus

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“…The uptake of functional mitochondria from MM-MSCs occurs through several mechanisms, including tunneling nanotubes, CD38 [177], and EVs, as well as cell-to-cell contact and the CXCL12/CXCR4 axis [55]. This mitochondrial trafficking supports the oxidative metabolism of tumor PCs, favoring cancer growth and drug resistance [55,[178][179][180][181].…”

Section: Role Of Mscs In In Multiple Myelomamentioning

confidence: 99%

Engagement of Mesenchymal Stromal Cells in the Remodeling of the Bone Marrow Microenvironment in Hematological Cancers

Giallongo,

Duminuco,

Dulcamare

et al. 2023

Biomolecules

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Mesenchymal stromal cells (MSCs) are a subset of heterogeneous, non-hematopoietic fibroblast-like cells which play important roles in tissue repair, inflammation, and immune modulation. MSCs residing in the bone marrow microenvironment (BMME) functionally interact with hematopoietic stem progenitor cells regulating hematopoiesis. However, MSCs have also emerged in recent years as key regulators of the tumor microenvironment. Indeed, they are now considered active players in the pathophysiology of hematologic malignancies rather than passive bystanders in the hematopoietic microenvironment. Once a malignant event occurs, the BMME acquires cellular, molecular, and epigenetic abnormalities affecting tumor growth and progression. In this context, MSC behavior is affected by signals coming from cancer cells. Furthermore, it has been shown that stromal cells themselves play a major role in several hematological malignancies’ pathogenesis. This bidirectional crosstalk creates a functional tumor niche unit wherein tumor cells acquire a selective advantage over their normal counterparts and are protected from drug treatment. It is therefore of critical importance to unveil the underlying mechanisms which activate a protumor phenotype of MSCs for defining the unmasked vulnerabilities of hematological cancer cells which could be pharmacologically exploited to disrupt tumor/MSC coupling. The present review focuses on the current knowledge about MSC dysfunction mechanisms in the BMME of hematological cancers, sustaining tumor growth, immune escape, and cancer progression.

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“…This suggests that multiple myeloma cells resist chemical drugs by plundering mitochondria from stromal cells [72,73]. It has also been shown that multiple myeloma cells can resist belamaf (a monoclonal antibody conjugated with microtubule-disrupting agent monomethyl auristatin-F (MMAF)) through this mechanism, thus avoiding apoptosis [74]. In ALL, mitochondrial transfer occurs more frequently, and traditional chemotherapy drugs like AraC and DNR always fail to completely eliminate tumor cells [75].…”

Section: Mitochondrial Transfer Promotes Tumor Resistance To Chemothe...mentioning

confidence: 99%

Mitochondrial transfer in tunneling nanotubes—a new target for cancer therapy

Guan,

Wu,

Zhou

et al. 2024

J Exp Clin Cancer Res

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A century ago, the Warburg effect was first proposed, revealing that cancer cells predominantly rely on glycolysis during the process of tumorigenesis, even in the presence of abundant oxygen, shifting the main pathway of energy metabolism from the tricarboxylic acid cycle to aerobic glycolysis. Recent studies have unveiled the dynamic transfer of mitochondria within the tumor microenvironment, not only between tumor cells but also between tumor cells and stromal cells, immune cells, and others. In this review, we explore the pathways and mechanisms of mitochondrial transfer within the tumor microenvironment, as well as how these transfer activities promote tumor aggressiveness, chemotherapy resistance, and immune evasion. Further, we discuss the research progress and potential clinical significance targeting these phenomena. We also highlight the therapeutic potential of targeting intercellular mitochondrial transfer as a future anti-cancer strategy and enhancing cell-mediated immunotherapy. Graphical Abstract

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The Effect of Belantamab Mafodotin on Primary Myeloma–Stroma Co-Cultures: Asymmetrical Mitochondrial Transfer between Myeloma Cells and Autologous Bone Marrow Stromal Cells

Cited by 5 publications

References 47 publications

Explosive Disease Progression After Single-Agent B-cell Maturation Antigen-Targeted Treatment in Multiple Myeloma: A Report of Three Cases in Sheikh Shakhbout Medical City

Explosive Disease Progression After Single-Agent B-cell Maturation Antigen-Targeted Treatment in Multiple Myeloma: A Report of Three Cases in Sheikh Shakhbout Medical City

Engagement of Mesenchymal Stromal Cells in the Remodeling of the Bone Marrow Microenvironment in Hematological Cancers

Mitochondrial transfer in tunneling nanotubes—a new target for cancer therapy

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