The role of the bone microenvironment in regulating myeloma residual disease and treatment

Abstract

Multiple myeloma is an incurable haematological cancer. The increase in targeted therapies has improved the number of myeloma patients achieving a complete response and improved progression-free survival following therapy. However, a low level of disease or minimal residual disease (MRD) still persists which contributes to the inevitable relapse in myeloma patients. MRD has been attributed to the presence of dormant myeloma cells and their subsequent reactivation, which is controlled by the microenvironment and specialised niches within the bone marrow. This contributes to the evasion of the immune system and chemotherapy, eventually leading to relapse. The growth of myeloma tumours are heavily dependent on environmental stimuli from the bone marrow microenvironment, and this plays a key role in myeloma progression. The bone microenvironment also plays a critical role in myeloma bone disease and the development of skeletal-related events. This review focuses on the bone marrow microenvironment in relation to myeloma pathogenesis and cancer dormancy. Moreover, it reviews the current therapies targeting the bone microenvironment to treat myeloma and myeloma bone disease. Lastly, it identifies novel therapeutic targets for myeloma treatment and the associated bone disease.

Novel Developments in the Treatment of Multiple Myeloma-Associated Bone Disease

“…But, since the incidence Importantly, the sum of the described MM-induced alterations to the bone marrow microenvironment drives the production of anti-apoptotic cytokines and suppresses antitumor responses, resulting in an environment supporting MM cells' growth, survival, and resistance to therapy-termed "the MM niche". This niche plays a pivotal role in the induction of MM dormancy [142,143], a state of quiescent growth arrest that allows MM cells to become unavailable to anti-myeloma therapy. Here, osteoblastic cells may control dormancy induction, while osteoclastic bone remodeling may promote dormancy escape and consequent disease relapse [144].…”

Targeting CAM-DR and Mitochondrial Transfer for the Treatment of Multiple Myeloma

“…The HSC niche can regulate the dormancy of tumor cells [ 21 ]. In MM, dormancy occurs when tumor cells enter a quiescent state (G0), in which they are under reversible growth arrest [ 70 , 71 ]. Importantly, dormant MM cells can be induced to re-enter the cell cycle in response to extrinsic stimuli from the microenvironment or various therapeutic agents, including bortezomib [ 71 , 72 ].…”

“…In MM, dormancy occurs when tumor cells enter a quiescent state (G0), in which they are under reversible growth arrest [ 70 , 71 ]. Importantly, dormant MM cells can be induced to re-enter the cell cycle in response to extrinsic stimuli from the microenvironment or various therapeutic agents, including bortezomib [ 71 , 72 ]. Drug-resistant dormant MM cells residing in skeletal endosteal niches are thought to mediate disease relapse.…”

Inhibition of PI3K Class IA Kinases Using GDC-0941 Overcomes Cytoprotection of Multiple Myeloma Cells in the Osteoclastic Bone Marrow Microenvironment Enhancing the Efficacy of Current Clinical Therapeutics

“…The development of specific supportive conditions in the BM microenvironment through the interaction of MM cells with the BM stroma are critical for MM-cell growth, survival, enhanced MM invasive capacity, and resistance to therapy [6][7][8]. The effects of the newer drugs in MM have been related, in part, to their direct impact not only on MM viability, but also on the protective BM cells [1,6,8].…”

“…The development of specific supportive conditions in the BM microenvironment through the interaction of MM cells with the BM stroma are critical for MM-cell growth, survival, enhanced MM invasive capacity, and resistance to therapy [6][7][8]. The effects of the newer drugs in MM have been related, in part, to their direct impact not only on MM viability, but also on the protective BM cells [1,6,8]. However, MM tumours eventually become resistant to these treatments and the exact signalling pathways or the specific cellular or molecular cytoprotective BM niches involved in this process remain elusive [2,5,9,10].…”