Multiple myeloma: the (r)evolution of current therapy and a glance into future

Gullà, Annamaria; Anderson, Kenneth C.

doi:10.3324/haematol.2020.247015

Cited by 92 publications

(54 citation statements)

References 151 publications

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“…Notably, in a IMiD-conditioned TME, T-cell activation is facilitated, as it no longer requires co-stimulation by antigen-presenting DCs [ 24 , 25 , 26 , 27 ]. In addition, IMiDs trigger caspase-mediated apoptosis in MM cells and impair their interaction with the protective BM stroma [ 28 ]. Efforts are underway to further enhance the clinical potency of IMiDs by combining them with modulators of cereblon E3-ligase, such as iberdomide, that accelerate IMiD-mediated degradation of IKZF1/IKZF3 [ 26 , 27 ].…”

Section: Immunomodulatory Imide Drugs (Imids) To Overcome the Immunosuppressive Tme In MMmentioning

confidence: 99%

Overcoming the Immunosuppressive Tumor Microenvironment in Multiple Myeloma

Uckun

2021

Cancers

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SeverFigurel cellular elements of the bone marrow (BM) microenvironment in multiple myeloma (MM) patients contribute to the immune evasion, proliferation, and drug resistance of MM cells, including myeloid-derived suppressor cells (MDSCs), tumor-associated M2-like, “alternatively activated” macrophages, CD38+ regulatory B-cells (Bregs), and regulatory T-cells (Tregs). These immunosuppressive elements in bidirectional and multi-directional crosstalk with each other inhibit both memory and cytotoxic effector T-cell populations as well as natural killer (NK) cells. Immunomodulatory imide drugs (IMiDs), protease inhibitors (PI), monoclonal antibodies (MoAb), adoptive T-cell/NK cell therapy, and inhibitors of anti-apoptotic signaling pathways have emerged as promising therapeutic platforms that can be employed in various combinations as part of a rationally designed immunomodulatory strategy against an immunosuppressive tumor microenvironment (TME) in MM. These platforms provide the foundation for a new therapeutic paradigm for achieving improved survival of high-risk newly diagnosed as well as relapsed/refractory MM patients. Here we review the scientific rationale and clinical proof of concept for each of these platforms.

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Section: Immunomodulatory Imide Drugs (Imids) To Overcome the Immunosuppressive Tme In MMmentioning

confidence: 99%

Overcoming the Immunosuppressive Tumor Microenvironment in Multiple Myeloma

Uckun

2021

Cancers

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“…11 Compromised immune component of the bone marrow niche including dysregulated regulatory T cells, myeloid derived suppressor cells, Th17 cells, tumor-associated macrophages, mesenchymal stromal cells, and osteoclasts confer immunosuppression and promote tumor immune escape; and therefore represents an ideal target for novel therapeutics. 12,13 Importantly, extensive research has shown the role of plasmacytoid dendritic cells (DCs) in promoting MM cell survival and drug resistance, 14 providing the framework for targeting plasmacytoid DCs/MM cells interaction in novel therapies. 15,16 Similarly, increased expression of immune checkpoints, ie PD-1/PD-L1, in T cells and MM cells, promotes tumor immune evasion and has been also associated to progression from precursor stages.…”

Section: Immune Dysfunction In MMmentioning

confidence: 99%

“…The exceptional sensitivity of MM plasma cells to PI is related to their heightened dependency on the protein quality control system due the high turnover of abnormal immunoglobulins. 12,24 PIs overwhelm proteasome load, increase the accumulation of misfolded and unfolded proteins, thus leading to endoplasmic reticulum stress and eventually cell death. 12 As proteins involved in several biological processes are substrate of the proteasome, its inhibition has multiple downstream effects, including decrease of cell proliferation and apoptosis induction, cell-cycle arrest, deficit in DNA repair mechanisms, and alteration of cellular metabolism.…”

mentioning

confidence: 99%

“…12,24 PIs overwhelm proteasome load, increase the accumulation of misfolded and unfolded proteins, thus leading to endoplasmic reticulum stress and eventually cell death. 12 As proteins involved in several biological processes are substrate of the proteasome, its inhibition has multiple downstream effects, including decrease of cell proliferation and apoptosis induction, cell-cycle arrest, deficit in DNA repair mechanisms, and alteration of cellular metabolism. Proteasome inhibition affects both cellular and non cellular components of the host microenvironment via decreasing the expression of several adhesion molecules (such as ICAM1 and VCAM1), disrupting the interaction of MM cells with bone marrow accessory cells, inhibiting the secretion of cytokines (such as IL-6, VEGF, IGF-1) and angiogenesis, and modifying bone turnover and osteoclast activity.…”

mentioning

confidence: 99%

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<p>Immunotherapeutic and Targeted Approaches in Multiple Myeloma</p>

Nadeem

Tai

Anderson

2020

ITT

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The multiple myeloma (MM) therapeutic landscape has evolved significantly with the approval of numerous novel agents, including next generation proteasome inhibitors (PIs), immunomodulatory agents (IMIDs), and monoclonal antibodies (MoABs) targeting CD38 and SLAMF7. While these discoveries have led to an unprecedented improval in patient outcomes, the disease still remains incurable. Immunotherapeutic approaches have shown substantial promise in recent studies of chimeric antigen receptor T-cell (CAR T-cell) therapy, bispecific antibodies, and antibody drug conjugates targeting B-cell maturation antigen (BCMA). This review will highlight these novel and targeted therapies in MM, with particular focus on PIs, IMIDs, MoAb and BCMA-directed immunotherapy.

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“…An equally important yet tumor cellextrinsic driver of RRMM pathophysiology is the tumor microenvironment (TME), which provides myeloma-promoting interactions with resident BM cells, including specimens of the innate and adaptive immune system (8). Enhanced understanding of immune regulation of the BM microenvironment (BMME) has not only shed light on pathways of myeloma progression but also greatly advanced myeloma treatment over the past decade (9).…”

Section: Introductionmentioning

confidence: 99%

Laboratory Mice – A Driving Force in Immunopathology and Immunotherapy Studies of Human Multiple Myeloma

et al. 2021

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Mouse models of human cancer provide an important research tool for elucidating the natural history of neoplastic growth and developing new treatment and prevention approaches. This is particularly true for multiple myeloma (MM), a common and largely incurable neoplasm of post-germinal center, immunoglobulin-producing B lymphocytes, called plasma cells, that reside in the hematopoietic bone marrow (BM) and cause osteolytic lesions and kidney failure among other forms of end-organ damage. The most widely used mouse models used to aid drug and immunotherapy development rely on in vivo propagation of human myeloma cells in immunodeficient hosts (xenografting) or myeloma-like mouse plasma cells in immunocompetent hosts (autografting). Both strategies have made and continue to make valuable contributions to preclinical myeloma, including immune research, yet are ill-suited for studies on tumor development (oncogenesis). Genetically engineered mouse models (GEMMs), such as the widely known Vκ*MYC, may overcome this shortcoming because plasma cell tumors (PCTs) develop de novo (spontaneously) in a highly predictable fashion and accurately recapitulate many hallmarks of human myeloma. Moreover, PCTs arise in an intact organism able to mount a complete innate and adaptive immune response and tumor development reproduces the natural course of human myelomagenesis, beginning with monoclonal gammopathy of undetermined significance (MGUS), progressing to smoldering myeloma (SMM), and eventually transitioning to frank neoplasia. Here we review the utility of transplantation-based and transgenic mouse models of human MM for research on immunopathology and -therapy of plasma cell malignancies, discuss strengths and weaknesses of different experimental approaches, and outline opportunities for closing knowledge gaps, improving the outcome of patients with myeloma, and working towards a cure.

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Multiple myeloma: the (r)evolution of current therapy and a glance into future

Cited by 92 publications

References 151 publications

Overcoming the Immunosuppressive Tumor Microenvironment in Multiple Myeloma

Overcoming the Immunosuppressive Tumor Microenvironment in Multiple Myeloma

<p>Immunotherapeutic and Targeted Approaches in Multiple Myeloma</p>

Laboratory Mice – A Driving Force in Immunopathology and Immunotherapy Studies of Human Multiple Myeloma

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