Multiple myeloma

Donk, Niels W.C.J. van de; Pawlyn, Charlotte; Yong, Kwee

doi:10.1016/s0140-6736(21)00135-5

Cited by 413 publications

(397 citation statements)

References 148 publications

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Section: Introductionmentioning

confidence: 99%

“…Multiple myeloma (MM) is a plasma cell malignancy that accounts for approximately 10% of all hematological malignancies [1][2][3]. Currently, there is no curative therapy for this disease, which is accompanied by symptoms including renal failure, anemia, hypercalcemia, and skeletal destruction [2]. However, the response rate in patients with MM has been improved by the introduction of various novel drugs available for MM treatment, including monoclonal antibodies (mAbs) such as daratumumab [4] and elotuzumab [5].…”

Section: Introductionmentioning

confidence: 99%

“…Most patients, including those that responded to these drugs, developed drug resistance; therefore, it is essential to overcome this issue to improve survival. Among the novel drugs described, IMiDs are supposed to be key drugs as partners of PIs and mAbs for use in combination therapy [2]. Cereblon (CRBN) is a component of the CUL4 E3 ligase complex that serves as the primary target of IMiDs [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

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Small-molecule HDAC and Akt inhibitors suppress tumor growth and enhance immunotherapy in multiple myeloma

Hirano

Imai

Kaito

et al. 2021

J Exp Clin Cancer Res

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Background Multiple myeloma (MM) is an incurable disease. The acquisition of resistance to drugs, including immunomodulatory drugs (IMiDs), has a negative effect on its prognosis. Cereblon (CRBN) is a key mediator of the bioactivities of IMiDs such as lenalidomide. Moreover, genetic alteration of CRBN is frequently detected in IMiD-resistant patients and is considered to contribute to IMiD resistance. Thus, overcoming resistance to drugs, including IMiDs, is expected to improve clinical outcomes. Here, we examined potential mechanisms of a histone deacetylase (HDAC) inhibitor and Akt inhibitor in relapsed/refractory MM patients. Methods We established lenalidomide-resistant cells by knocking down CRBN with RNAi-mediated downregulation or knocking out CRBN using CRISPR-Cas9 in MM cells. Additionally, we derived multi-drug (bortezomib, doxorubicin, or dexamethasone)-resistant cell lines and primary cells from relapsed/refractory MM patients. The effects of HDAC and Akt inhibitors on these drug-resistant MM cells were then observed with a particular focus on whether HDAC inhibitors enhance immunotherapy efficacy. We also investigated the effect of lenalidomide on CRBN-deficient cells. Results The HDAC inhibitor suppressed the growth of drug-resistant MM cell lines and enhanced the antibody-dependent cellular cytotoxicity (ADCC) of therapeutic antibodies by upregulating natural killer group 2D (NKG2D) ligands in MM cells. CRBN-deficient cells showed lenalidomide-induced upregulation of phosphorylated glycogen synthase kinase-3 (p-GSK-3) and c-Myc phosphorylation. Moreover, HDAC and Akt inhibitors downregulated c-Myc by blocking GSK-3 phosphorylation. HDAC and Akt inhibitors also exhibited synergistic cytotoxic and c-Myc-suppressive effects. The dual HDAC and PI3K inhibitor, CUDC-907, exhibited cytotoxic and immunotherapy-enhancing effects in MM cells, including multi-drug-resistant lines and primary cells from lenalidomide-resistant patients. Conclusions The combination of an HDAC and an Akt inhibitor represents a promising approach for the treatment of relapsed/refractory MM.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Small-molecule HDAC and Akt inhibitors suppress tumor growth and enhance immunotherapy in multiple myeloma

Hirano

Imai

Kaito

et al. 2021

J Exp Clin Cancer Res

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“…Younger transplant-eligible patients with newly diagnosed disease are frequently treated with high-dose melphalan and autologous stem cell transplantation. Prior to high-dose therapy, these patients receive induction therapy, typically a bortezomib-based triplet such as bortezomib-lenalidomide-dexamethasone (VRD), bortezomib-thalidomidedexamethasone (VTD), or bortezomib-cyclophosphamide-dexamethasone (VCD) [34]. Because of the favorable activity and safety profile of CD38-targeting antibodies, several studies have evaluated or are currently evaluating the value of adding a CD38-targeting antibody to these triplets (Table 3).…”

Section: Cd38-targeting Antibody Based Quadrupletsmentioning

confidence: 99%

Immunotherapy with Antibodies in Multiple Myeloma: Monoclonals, Bispecifics, and Immunoconjugates

Verkleij¹,

Bruins²,

Donk³

2021

Hemato

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In the 2010s, immunotherapy revolutionized the treatment landscape of multiple myeloma. CD38-targeting antibodies were initially applied as monotherapy in end-stage patients, but are now also approved by EMA/FDA in combination with standards-of-care in newly diagnosed disease or in patients with early relapse. The approved SLAMF7-targeting antibody can also be successfully combined with lenalidomide or pomalidomide in relapsed/refractory myeloma. Although this has resulted in improved clinical outcomes, there remains a high unmet need in patients who become refractory to immunomodulatory drugs, proteasome inhibitors and CD38-targeting antibodies. Several new antibody formats, such as antibody–drug conjugates (e.g., belantamab mafodotin, which was approved in 2020 and targets BCMA) and T cell redirecting bispecific antibodies (e.g., teclistamab, talquetamab, cevostamab, AMG-420, and CC-93269) are active in these triple-class refractory patients. Based on their promising efficacy, it is expected that these new antibody formats will also be combined with other agents in earlier disease settings.

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“…Several strategies are currently used in the treatment of MM. The standard of care [4,5] includes a high dose of melphalan followed by autologous stem cell transplantation in eligible patients. Induction therapy before transplantation consists in a combined treatment with bortezomib-thalidomide or lenalidomide-dexamethasone for 4-6 cycles.…”

Section: Introductionmentioning

confidence: 99%

Oncolytic Virotherapy and Microenvironment in Multiple Myeloma

Marchica

Costa

Donofrío

et al. 2021

IJMS

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Multiple myeloma (MM) is a hematologic malignancy characterized by the accumulation of bone marrow (BM) clonal plasma cells, which are strictly dependent on the microenvironment. Despite the improvement of MM survival with the use of new drugs, MM patients still relapse and become always refractory to the treatment. The development of new therapeutic strategies targeting both tumor and microenvironment cells are necessary. Oncolytic virotherapy represent a promising approach in cancer treatment due to tumor-specific oncolysis and activation of the immune system. Different types of human viruses were checked in preclinical MM models, and the use of several viruses are currently investigated in clinical trials in MM patients. More recently, the use of alternative non-human viruses has been also highlighted in preclinical studies. This strategy could avoid the antiviral immune response of the patients against human viruses due to vaccination or natural infections, which could invalid the efficiency of virotherapy approach. In this review, we explored the effects of the main oncolytic viruses, which act through both direct and indirect mechanisms targeting myeloma and microenvironment cells inducing an anti-MM response. The efficacy of the oncolytic virus-therapy in combination with other anti-MM drugs targeting the microenvironment has been also discussed.

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Multiple myeloma

Cited by 413 publications

References 148 publications

Small-molecule HDAC and Akt inhibitors suppress tumor growth and enhance immunotherapy in multiple myeloma

Small-molecule HDAC and Akt inhibitors suppress tumor growth and enhance immunotherapy in multiple myeloma

Immunotherapy with Antibodies in Multiple Myeloma: Monoclonals, Bispecifics, and Immunoconjugates

Oncolytic Virotherapy and Microenvironment in Multiple Myeloma

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