Treatment of relapsed multiple myeloma: Evidence-based recommendations

Durer, Ceren; Durer, Seren; Lee, Sarah; Chakraborty, Rajshekhar; Malik, Mustafa Nadeem; Rafae, Abdul; Zar, Muhammad Abu; Kamal, Ahmad; Rosko, Nathaniel; Samaras, Christy; Valent, Jason; Chaulagain, Chakra P; Anwer, Faiz

doi:10.1016/j.blre.2019.100616

Cited by 48 publications

(53 citation statements)

References 131 publications

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“…Prof. Claire Edwards (University of Oxford, Oxford, UK). The 5TGM1 cells expressing both green fluorescent protein (GFP) and firefly luciferase were generated using the retroviral expression vector NES-TGL [ 48 ], and a new clonal subline that exhibits consistent bone tropism (5TGM1.Bmx1) was established [ 48 ]. The 5TGM1 cells were maintained in Iscove’s Modified Eagle’s Medium.…”

Section: Methodsmentioning

confidence: 99%

Targeted Disruption of Bone Marrow Stromal Cell-Derived Gremlin1 Limits Multiple Myeloma Disease Progression In Vivo

Clark

Hewett

Panagopoulos

et al. 2020

Cancers

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In most instances, multiple myeloma (MM) plasma cells (PCs) are reliant on factors made by cells of the bone marrow (BM) stroma for their survival and growth. To date, the nature and cellular composition of the BM tumor microenvironment and the critical factors which drive tumor progression remain imprecisely defined. Our studies show that Gremlin1 (Grem1), a highly conserved protein, which is abundantly secreted by a subset of BM mesenchymal stromal cells, plays a critical role in MM disease development. Analysis of human and mouse BM stromal samples by quantitative PCR showed that GREM1/Grem1 expression was significantly higher in the MM tumor-bearing cohorts compared to healthy controls (p < 0.05, Mann–Whitney test). Additionally, BM-stromal cells cultured with 5TGM1 MM PC line expressed significantly higher levels of Grem1, compared to stromal cells alone (p < 0.01, t-test), suggesting that MM PCs promote increased Grem1 expression in stromal cells. Furthermore, the proliferation of 5TGM1 MM PCs was found to be significantly increased when co-cultured with Grem1-overexpressing stromal cells (p < 0.01, t-test). To examine the role of Grem1 in MM disease in vivo, we utilized the 5TGM1/KaLwRij mouse model of MM. Our studies showed that, compared to immunoglobulin G (IgG) control antibody-treated mice, mice treated with an anti-Grem1 neutralizing antibody had a decrease in MM tumor burden of up to 81.2% (p < 0.05, two-way ANOVA). The studies presented here demonstrate, for the first time, a novel positive feedback loop between MM PCs and BM stroma, and that inhibiting this vicious cycle with a neutralizing antibody can dramatically reduce tumor burden in a preclinical mouse model of MM.

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Section: Methodsmentioning

confidence: 99%

Targeted Disruption of Bone Marrow Stromal Cell-Derived Gremlin1 Limits Multiple Myeloma Disease Progression In Vivo

Clark

Hewett

Panagopoulos

et al. 2020

Cancers

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“…The binding to cereblon modulates the stability of cereblon-interacting molecules [36] and thereby promotes apoptosis by activating caspase-8 [38]. However, the clinical evidence suggests that there are important pharmacological differences among IMiDs, and resistance against one IMiD does not exclude a response to another IMiD [39]. In the present study we investigated how IMiDs differ in their effects on normal monocytes.…”

Section: Discussionmentioning

confidence: 98%

Immunomodulatory Drugs Alter the Metabolism and the Extracellular Release of Soluble Mediators by Normal Monocytes

et al. 2020

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Immunomodulatory drugs (IMiDs) are used in the treatment of hematological malignancies, especially multiple myeloma. IMiDs have direct anticancer effects but also indirect effects via cancer-supporting stromal cells. Monocytes are a stromal cell subset whose metabolism is modulated by the microenvironment, and they communicate with neighboring cells through extracellular release of soluble mediators. Toll-like receptor 4 (TLR4) is then a common regulator of monocyte metabolism and mediator release. Our aim was to investigate IMiD effects on these two monocyte functions. We compared effects of thalidomide, lenalidomide, and pomalidomide on in vitro cultured normal monocytes. Cells were cultured in medium alone or activated by lipopolysaccharide (LPS), a TLR4 agonist. Metabolism was analyzed by the Seahorse XF 96 cell analyzer. Mediator release was measured as culture supernatant levels. TLR4 was a regulator of both monocyte metabolism and mediator release. All three IMiDs altered monocyte metabolism especially when cells were cultured with LPS; this effect was strongest for lenalidomide that increased glycolysis. Monocytes showed a broad soluble mediator release profile. IMiDs decreased TLR4-induced mediator release; this effect was stronger for pomalidomide than for lenalidomide and especially thalidomide. To conclude, IMiDs can alter the metabolism and cell–cell communication of normal monocytes, and despite their common molecular target these effects differ among various IMiDs.

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“…Overall, these regimens showed also impressive anti myeloma activity and improved results over standard strategies. All these rescue combinations are widely used in clinical practice and their results have been extensively reviewed elsewhere [58][59][60][61], thus they will not be discussed here (Table 3). However, as lenalidomide has been progressively incorporated into the front-line regimens used for the treatment of patients with NDMM, these "first generation" combinations become no longer useful in an important number of patients.…”

Section: Treatment Of Early Relapsementioning

confidence: 99%

Recent Advances in the Treatment of Patients with Multiple Myeloma

Legarda

Cejalvo

Rubia

2020

Cancers

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In the past 20 years, few diseases have seen as great progress in their treatment as multiple myeloma. With the approval of many new drugs and the limited availability of clinical trials comparing head-to-head the different possible combinations, the choice of the best treatments at each stage of the disease becomes complex as well as crucial since multiple myeloma remains incurable. This article presents a general description of the novelties of the whole treatment of multiple myeloma, from induction in the newly diagnosed patient through the role of hematopoietic stem cell transplantation and maintenance treatment until early and late relapses, including a section on recently approved drugs as well as novel drugs and immunotherapy in advanced stages of research, and that will surely play a relevant role in the treatment of this devastating disease in the coming years.

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Treatment of relapsed multiple myeloma: Evidence-based recommendations

Cited by 48 publications

References 131 publications

Targeted Disruption of Bone Marrow Stromal Cell-Derived Gremlin1 Limits Multiple Myeloma Disease Progression In Vivo

Targeted Disruption of Bone Marrow Stromal Cell-Derived Gremlin1 Limits Multiple Myeloma Disease Progression In Vivo

Immunomodulatory Drugs Alter the Metabolism and the Extracellular Release of Soluble Mediators by Normal Monocytes

Recent Advances in the Treatment of Patients with Multiple Myeloma

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