Relapsed/Refractory Multiple Myeloma in 2020/2021 and Beyond

Podar, Klaus; Leleu, Xavier

doi:10.3390/cancers13205154

Cited by 38 publications

(25 citation statements)

References 136 publications

(144 reference statements)

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“…The activation of signaling cascades including RAS/RAF/MEK/ERK, PI3K/AKT, NF-κB, and JAK/STAT pathway is considered the main mechanism in the development of MM ( Hu and Hu, 2018 ). Specifically, mutation clusters in RAS/RAF genes are as high as 50% in newly diagnosed MM, rising even to 80% in RRMM, underscoring the promising potential of the RAS/RAF/MEK/ERK signaling pathway–directed therapy ( Podar and Leleu, 2021 ). Unfortunately, treatments targeting the RAS or its downstream/upstream effectors, such as tipifarnib and sorafenib, show limited/no activity in MM ( Lind et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

SHP2 Inhibitors Show Anti-Myeloma Activity and Synergize With Bortezomib in the Treatment of Multiple Myeloma

Zhou

Xiao

et al. 2022

Front. Pharmacol.

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Multiple myeloma (MM) is a plasma cell malignancy that remains incurable. The protein tyrosine phosphatase SHP2 is a central node regulating RAS/mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK) signaling pathway which plays a crucial role in the pathogenesis and proteasome inhibitor (PI) resistance of MM. Several preclinical studies have demonstrated that SHP2 inhibitors exerted antitumor activity in cancer-harboring diverse mutations in the RAS pathway, offering the potential for targeting myeloma. In this study, we showed that pharmacological inhibition of SHP2 activity using SHP099 and RMC-4550 efficiently inhibited the proliferation of MM cells by inducing apoptosis and cell cycle arrest. As per the mechanism, SHP2 inhibitors activated the level of cleaved caspase3, BAK, and P21 and downregulated ERK phosphorylation in MM cells. Moreover, the blockade of SHP2 exhibited anti-myeloma effect in vivo in a mouse xenograft model. In addition, SHP2 inhibitors synergized the antineoplastic effect of bortezomib in bortezomib-sensitive MM cells and showed identical efficacy in targeting bortezomib-resistant MM cells. Overall, our findings suggest that SHP2-specific inhibitors trigger anti-myeloma activity in vitro and in vivo by regulating the ERK pathway and enhancing cytotoxicity of bortezomib, providing therapeutic benefits for both bortezomib naïve and resistant MM.

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Section: Discussionmentioning

confidence: 99%

SHP2 Inhibitors Show Anti-Myeloma Activity and Synergize With Bortezomib in the Treatment of Multiple Myeloma

Zhou

Xiao

et al. 2022

Front. Pharmacol.

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“…The monoclonal CD38-targeting antibodies daratumumab or isatuximab, CS1-targeting elotuzumab, and the B-cell maturation antigen (BCMA)-targeting antibody drug conjugate belantamab mafodotin are approved drugs for the treatment of MM [8][9][10]. In 2021, the Food and Drug Administration (FDA) approved abecma (idecabtagene vicleucel), the first chimeric antigen receptor (CAR) T cell therapy for MM patients [11,12]. Despite the advances in cancer immunotherapy, the majority of patients still relapse, and responses are hampered by immune escape mechanisms and the presence of an immunosuppressive BM microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Dendritic Cell-Based Immunotherapy in Multiple Myeloma: Challenges, Opportunities, and Future Directions

Verheye

Melgar

Deschoemaeker

et al. 2022

IJMS

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Immunotherapeutic approaches, including adoptive cell therapy, revolutionized treatment in multiple myeloma (MM). As dendritic cells (DCs) are professional antigen-presenting cells and key initiators of tumor-specific immune responses, DC-based immunotherapy represents an attractive therapeutic approach in cancer. The past years, various DC-based approaches, using particularly ex-vivo-generated monocyte-derived DCs, have been tested in preclinical and clinical MM studies. However, long-term and durable responses in MM patients were limited, potentially attributed to the source of monocyte-derived DCs and the immunosuppressive bone marrow microenvironment. In this review, we briefly summarize the DC development in the bone marrow niche and the phenotypical and functional characteristics of the major DC subsets. We address the known DC deficiencies in MM and give an overview of the DC-based vaccination protocols that were tested in MM patients. Lastly, we also provide strategies to improve the efficacy of DC vaccines using new, improved DC-based approaches and combination therapies for MM patients.

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“… 4 Isatuximab, a CD38-targeting monoclonal antibody, has been approved by the United States Food and Drug Administration for the treatment of relapsed MM as a combination therapy with pomalidomide and dexamethasone (Isa-Pd) and carfilzomib and dexamethasone (Isa-Kd). 5 …”

Section: Introductionmentioning

confidence: 99%

Isatuximab in the Treatment of Multiple Myeloma: A Review and Comparison With Daratumumab

Shen

2022

Technol Cancer Res Treat

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Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal plasma cells. Although advances in treatment have markedly improved survival outcomes for patients with MM, this disease is still considered incurable owing to its high incidence of relapse and refractoriness. Isatuximab is an anti-CD38 monoclonal antibody that can induce apoptosis in myeloma cells through a variety of mechanisms. Many clinical studies have demonstrated the efficacy and efficiency of isatuximab in both relapsed/refractory multiple myeloma (RRMM) and newly diagnosed multiple myeloma, leading to its approval for the treatment of adults with RRMM in combination therapies. In this review, the structure, mechanisms of action, pharmacokinetics, pharmacogenetics, and safety profile of isatuximab in MM are summarized. Additionally, isatuximab is compared with daratumumab in terms of mechanism and efficacy.

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Relapsed/Refractory Multiple Myeloma in 2020/2021 and Beyond

Cited by 38 publications

References 136 publications

SHP2 Inhibitors Show Anti-Myeloma Activity and Synergize With Bortezomib in the Treatment of Multiple Myeloma

SHP2 Inhibitors Show Anti-Myeloma Activity and Synergize With Bortezomib in the Treatment of Multiple Myeloma

Dendritic Cell-Based Immunotherapy in Multiple Myeloma: Challenges, Opportunities, and Future Directions

Isatuximab in the Treatment of Multiple Myeloma: A Review and Comparison With Daratumumab

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