Breaking through Multiple Myeloma: A Paradigm for a Comprehensive Tumor Ecosystem Targeting

Abstract

Multiple myeloma (MM) is a cancerous condition characterized by the proliferation of plasma cells within the hematopoietic marrow, resulting in multiple osteolytic lesions. MM patients typically experience bone pain, kidney damage, fatigue due to anemia, and infections. Historically, MM was an incurable disease with a life expectancy of around three years after diagnosis. However, over the past two decades, the development of novel therapeutics has significantly improved patient outcomes, including response to treatment, remission duration, quality of life, and overall survival. These advancements include thalidomide and its derivatives, lenalidomide and pomalidomide, which exhibit diverse mechanisms of action against the plasma cell clone. Additionally, proteasome inhibitors such as bortezomib, ixazomib, and carfilzomib disrupt protein degradation, proving specifically toxic to cancerous plasma cells. Recent advancements also involve monoclonal antibodies targeting surface antigens, such as elotuzumab (anti-CS1) and daratumumab (anti-CD38), bispecific t-cell engagers such as teclistamab (anti-BCMA/CD3) and Chimeric antigen receptor T (CAR-T)-based strategies, with a growing focus on drugs that exhibit increasingly targeted action against neoplastic plasma cells and relevant effects on the tumor microenvironment.

Keywords: immunotherapy; microenvironment; monoclonal antibody; multiple myeloma.

Figure 1

Significant advancements have been made in therapeutic approaches for multiple myeloma. These approaches can be broadly categorized into two main strategies: those targeting the toxicity of multiple myeloma cells (represented by the color blue) and those aiming to disrupt the interplay between MM cells and the tumor microenvironment (represented by the color green). MM = Multiple myeloma; TME = Tumor microenvironment; HDAC = Hystone deacetylase; IRF4 = Interferon regulatory factor 4; IMiDs = Immunomodulatory drugs; ACT = adoptive T cells; TCR = T cell receptor; NK = Natural killer; CAR-T = Chimeric antigen receptor T; DC = Dendritic cells; MDSC = Myeloid derived suppressor cells; Treg = T regulatory cells; BMSC = Bone marrow stromal cells; ECM = Extracellular matrix; moAb = Monoclonal antibody; CellMoDs = Cereblon E3 ligase modulators; BiTEs = Bispecific T cell engager. Figure created by BioRender, publication license n. CT25JR89XW.

Figure 2

This figure illustrates the pathomechanisms of multiple myeloma (MM) bone disease characterized by increased osteoclast activity and decreased osteoblast function and resulting in bone destruction and skeletal complications. The figure highlights key factors that contribute to MM bone disease, including: (i) increased osteoclast activity: MM cells produce factors, such as receptor activator of nuclear factor kappa-B ligand (RANKL), that activate osteoclasts and promote bone resorption. This leads to an increase in bone turnover and the release of factors that further stimulate MM cell growth. (ii) Decreased osteoblast function: MM cells and their microenvironment produce factors, such as Dickkopf-1 (DKK1) and sclerostin that inhibit osteoblast differentiation and function, impairing bone formation and repair. (iii) Disruption of bone remodeling: The dysregulation of osteoclast and osteoblast activity in MM leads to an imbalance in bone remodeling, resulting in the accumulation of abnormal bone tissue and the development of lytic lesions, fractures, and bone pain. (iv) immune dysregulation: The immune dysregulation in MM can also contribute to bone disease by promoting osteoclast activation and inhibiting osteoblast function. For example, activated T cells and cytokines, such as interleukin-6 (IL-6), can stimulate osteoclast activity and inhibit osteoblast differentiation. Understanding the pathomechanisms of MM bone disease is crucial for the development of effective therapeutic strategies to prevent and treat skeletal complications. Targeting osteoclast activity, promoting osteoblast function, and restoring immune regulation are promising approaches for the treatment of MM bone disease. Figure created by BioRender, publication license n. QH258ANAV7.

Figure 3

Modern therapy in multiple myeloma. This figure illustrates the pathomechanisms of modern therapeutic approaches for multiple myeloma (MM), which target key pathways involved in MM pathogenesis and progression. The figure highlights the following therapeutic strategies: (i) proteasome inhibitors: Proteasome inhibitors, such as bortezomib and carfilzomib, inhibit the activity of the proteasome complex, leading to the accumulation of misfolded proteins and induction of apoptosis in MM cells. (ii) Immunomodulatory drugs: Immunomodulatory drugs, such as lenalidomide and pomalidomide, modulate the immune microenvironment in MM by inhibiting the production of pro-inflammatory cytokines, enhancing T cell function, and promoting natural killer cell activity. (iii) Monoclonal antibodies: Monoclonal antibodies, such as daratumumab and elotuzumab, target specific antigens on MM cells, leading to their destruction through antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). (iv) Cell-based therapies: Cell-based therapies, such as chimeric antigen receptor (CAR) T cell therapy, involve the engineering of T cells to express CARs that recognize and kill MM cells (v) Targeted therapies: Targeted therapies, such as inhibitors of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway or the B-cell lymphoma-2 (BCL-2), histone deacetylases (HDAC) and Exportin-1 (XPO1) family of proteins, target specific signaling pathways or molecules that are dysregulated in MM cells, leading to their inhibition and apoptosis. MAGE, WT-1, and XBP1 are important targets in myeloma research, offering potential avenues for novel therapies. MAGE (Melanoma-Associated Antigen) and WT-1 (Wilms Tumor 1) are cancer-testis antigens often overexpressed in multiple myeloma, making them attractive targets for immunotherapies like cancer vaccines and adoptive T-cell therapies. Targeting these antigens aims to induce an immune response specifically against myeloma cells, sparing healthy tissues. Additionally, XBP1 (X-Box Binding Protein 1) is a transcription factor critical for plasma cell differentiation and survival. Inhibiting XBP1 holds promise as a therapeutic strategy to disrupt the survival mechanisms of myeloma cells, potentially leading to improved treatment outcomes. Research focusing on these targets shows great potential in advancing precision medicine approaches for multiple myeloma. Finally, novel immunological targeting strategies are represented. Teclistamab: a promising therapy that targets B-cell maturation antigen (BCMA), a cell surface protein highly expressed on multiple myeloma cells. Teclistamab is designed to direct the immune system to attack BCMA-expressing myeloma cells. Elranatamab: an investigational therapy also targeting BCMA, aiming to trigger the immune system to eliminate myeloma cells expressing this antigen. Elranatamab holds potential as a novel treatment for multiple myeloma. REGN5458: another BCMA-targeting therapy that seeks to harness the immune system to target and destroy BCMA-expressing myeloma cells. REGN5458 represents an exciting advancement in the field of multiple myeloma treatment. Talquetamab: an innovative therapy that targets G protein-coupled receptor family C group 5 member D (GPRC5D), a protein found on the surface of myeloma cells. Talquetamab aims to engage the immune system in attacking GPRC5D-expressing myeloma cells. Cevostamab: a potential therapeutic option that targets Fc receptor homolog 5 (FcRH5), a cell surface protein expressed on myeloma cells. Cevostamab aims to induce an immune response against FcRH5-expressing myeloma cells. Idecabtagene vicleucel: an innovative approach using chimeric antigen receptor (CAR) T-cell therapy, specifically Idecabtagene vicleucel, to target and eliminate multiple myeloma cells. This personalized treatment involves modifying patients’ own T-cells to express a CAR that recognizes and attacks myeloma cells. Citacabtagene autoleucel (Cita-cel) is another chimeric antigen receptor (CAR) T-cell therapy used in the treatment of multiple myeloma. It involves engineering a patient’s T-cells to express a CAR that targets BCMA. Understanding the patho-biological mechanism of modern therapeutic approaches for MM is crucial for the development of effective treatment strategies alone and in combination with already approved agents that can improve patient outcomes. Combination therapies that target multiple pathways and mechanisms may offer the best chance for achieving durable responses and long-term disease control in MM [30]. More details are provided in the text. Created by BioRender, publication license n. CW25N085PL.