Biological relationship between bone and myeloma cells

Introduction

Multiple myeloma (MM) is a cancer of differentiated B lymphocytes, known as plasma cells, which clonally proliferate in the bone marrow (BM). MM is characterized by the production of monoclonal immunoglobulins (known as a paraprotein or M-spike) and by the uncoupling of the dynamic process of bone remodeling. MM is classified using the CRAB criteria (hyper C alcemia, R enal impairment, A nemia, and B one disease) [ ] and accounts for 1% of all new cancers worldwide. It is the second most common hematological malignancy and has a low 5-year survival rate (53.2%) [ ]. Myeloma-induced bone disease (MBD) is present in approximately 70% of patients at diagnosis and 80%–90% of patients develop MBD at some stage during their disease course [ ]. This is because MM cell growth can significantly disrupt normal bone function by factors that promote osteoclastic bone resorption and inhibit osteoblastic bone formation. These changes can lead to the development of osteolytic lesions, hypercalcemia, susceptibility to pathological bone fractures, spinal cord compression, and pain, collectively referred to as skeletal-related events (SREs), which contribute to a significantly reduced quality of life (QoL). Although there has been a substantial increase in MM patient overall survival in the past 10 years, due to the development of more effective anti-MM therapies, the management of MBD largely remains the same. In this chapter we will discuss the biological relationship between the bone marrow microenvironment (BMME) and MM cells ( Fig. 68.1 ), and current therapies to treat MBD.

Myeloma-induced bone disease

Under normal physiological conditions, skeletal health is maintained by a dynamic balance between bone formation and bone resorption, leading to remineralization of the skeleton (approximately every 7 years) and its ability to respond appropriately to physiological stresses. In MM, this balance is uncoupled, with an increase in the number and activity of osteoclasts and a decrease in osteoblasts, leading to accelerated osteoporosis and the development of osteolytic lesions [ ].

Osteoclast-activating factors (OAFs) are produced by MM cells or other tumor-activated cells in the BMME (osteocytes, adipocytes, immune cells, etc.), causing an increase in osteoclastic bone resorption ( Table 68.1 ). OAFs that were identified early include RANKL [ , ], chemokine (C–C motif) ligands (CCLs) [ ], various interleukins (ILs) [ , , , , , ], transforming growth factor beta (TGF-β) [ , ], and tumor necrosis factor alpha (TNF-α) [ , ]. In more recent years this has expanded to include microRNA-21 (miR-21) [ , ], X-box-binding protein 1 (XBP1) [ ], B-cell-activating factor (BAFF) [ , ], syndecan-1 [ , ], notch signaling mediators, osteopontin (OPN) [ , , ], sequestosome-1 (p62) [ , ], and C-X-C motif chemokine 12 (CXCL12) [ , ]. Many of the more recently identified OAFs act as upstream or downstream mediators of signaling pathways previously known to stimulate osteoclastogenesis and osteolysis (e.g., RANKL) and potentially offer new therapeutic targets for treatment of MBD.

The simultaneous secretion of osteoblast-inhibitory factors (OIFs) exacerbates MBD further by impairing bone formation. OIFs include members of the Wnt signaling pathway, dickkopf-1 (DKK1) [ ], and soluble frizzled-related protein-2 (sFRP-2) [ ]; members of the TGF-β superfamily, activin A [ ], and TGF-β [ ]; and the osteocyte-derived factor sclerostin [ , ]; hepatocyte growth factor (HGF) has also been implicated [ , ]. OIFs are expressed by MM cells and other cells in the BMME which suppress bone formation by inhibiting osteoblast progenitor recruitment and osteoblast differentiation. For example, osteocytes release paracrine factors, such as sclerostin and RANKL, which inhibit osteoblasts and enhance osteoclasts, respectively [ , ]. TGF-β is released from the bone matrix during resorption, promoting osteoclastogenesis and preventing osteoblast progenitor differentiation into mature osteoblasts [ ]. TGF-β also acts on osteoblasts and BM stromal cells (BMSCs) to stimulate release of protumorigenic factors (e.g., IL-6) creating what is termed the “vicious cycle” of bone destruction and tumor growth [ , ].

Other cells within the BMME can modulate osteoclasts, osteoblasts, and MM cell survival and growth. For example, bone marrow adipocytes (BMAds) have been shown to support MM growth and survival, promote drug resistance, and contribute to MBD [ ]. Similarly, osteocytes are known to promote MBD via secretion of sclerostin and RANKL, and to support MM growth via bidirectional Notch signaling [ , ]. While not the focus of this chapter, immune cells are increasingly recognized for their contribution to MBD. Immune dysfunction is a feature of MM progression, and T cells are known to express high levels of RANKL supporting osteoclastogenesis in MM [ ].

Following diagnosis MM patients typically undergo induction chemotherapy, which debulks the majority of tumor load. However, not all tumor is cleared and the remaining tumor, which can lead to disease relapse, is known as minimal residual disease (MRD) [ ]. MRD is a major problem that has prevented the development of curative treatments for MM patients and is due to the presence of chemoresistant and/or dormant tumor cells. In murine models, MM cell dormancy has been demonstrated to be a reversible state that is switched “on” by engagement with bone-lining cells or osteoblasts, and switched “off” by increased osteoclastic bone resorption using RANKL [ ]. Therefore, emerging bone anabolic therapies that may have potential use to treat MBD, to promote bone formation and repair damaged bones [ , , ], may also prevent tumor regrowth by retaining MM cell dormancy by bone-lining cell/osteoblast engagement.