Challenging the Current Approaches to Multiple Myeloma-Related Bone Disease: From Bisphosphonates to Target Therapy

Abstract

Bone disease (BD) is the hall-mark clinical feature of multiple myeloma (MM), accounting up to 60% of patients with bone pain at diagnosis and 60% with a pathologic fracture during the course of their disease. Experimental models, which recapitulate in vivo the human bone marrow microenvironment (HBMM) in immunodeficient mice have been recently developed as valuable tool for the study of MM pathophysiology as well as the experimental treatment of BD. At present, bisphosphonates are the mainstay treatment of MM-related BD. The growing information on the cellular and molecular bases of BD as well as the availability of novel anti-resorptive agents, such as the IgG1-anti-RANKL (AMG 161) Denosumab, are now depicting a new scenario where the treatment will be afforded by the use of different agents. Furthermore the availability of highthroughput molecular profiling approaches, including DNA microarrays and proteomics, is likely to provide new platforms for patients stratification and treatment individualization on specific targets. It is now the right time for a therapeutical approach which is rationally based on the complexity of the biopathology of MM-related BD.

miR‐29b negatively regulates human osteoclastic cell differentiation and function: Implications for the treatment of multiple myeloma‐related bone disease

“…MM cells promote bone resorption by stimulating OCLs either by cell‐to‐cell contact or by release of soluble mediators (Tassone et al, 2009). When RPMI‐8226 MM cells, which secrete RANK‐L (data not shown), were seeded on dentin slices, eOCLs generated lacunae without the addition of RANK‐L to culture medium, indicating that MM cells were sufficient to trigger OCL bone resorption (Fig.…”

“…Indeed, the physiological balance between bone apposition and bone resorption is often shifted towards bone resorption resulting in generalized osteoporosis and/or focal lytic lesions of the skeleton. Strategies to hamper osteoclastic activity include the treatment of metastatic disease with cytotoxic agents or directly the use of anti‐resorptive and pro‐apoptotic agents for OCLs (BPs; Shipman et al, 1997; Russell et al, 1999; Tassone et al, 2000, 2002; Marra et al, 2011) or more recently, the use of RANK‐L pathway modulators such as OPG‐Fc and Denosumab (Lewiecki, 2006; Tassone et al, 2009; Goessl et al, 2012). However, in order to produce a clinical benefit, these agents require long‐term clinical use that in turn increases the probability to develop serious adverse events, such as renal failure and osteonecrosis of the jaw, whose risk appears genetically predetermined (Chern et al, 2004; Ludwig and Zojer, 2007; Aapro et al, 2008; Ruggiero and Woo, 2008; Di Martino et al, 2011; McLeod et al, 2012).…”

“…In multiple myeloma (MM), overwhelming OCL activity together with impairment of OBL function is commonly triggered by tumor cells which proliferate in the bone marrow milieu . Current treatment of bone disease (BD) mainly relies on the use of bone modifying agents (BMAs) that promote OCL apoptosis (bisphosphonates, BPs; Rogers et al, 1999; Russell et al, 1999; Marra et al, 2009) or target the Receptor Activator Nuclear Factor Kb Ligand (RANK‐L), as the recently available, Denosumab® monoclonal antibody (Lewiecki, 2006; Tassone et al, 2009; Goessl et al, 2012). However, even when skeletal‐related events (SREs) are significantly prevented and/or delayed in cancer patients, mid‐long‐term treatment with BMAs may be associated with relevant adverse events which limit their long‐term clinical use (Chern et al, 2004; Ludwig and Zojer, 2007; Aapro et al, 2008; Tassone et al, 2009).…”

Mouse Models as a Translational Platform for the Development of New Therapeutic Agents in Multiple Myeloma

“…However, some intrinsic weaknesses remain regarding the use of both subcutaneous and diffuse models for the preclinical evaluation of anti-MM agents. These models are usually based on the use of human plasma cell lines which are often established with primary cells obtained from extramedullary disease of advanced MM patients (peripheral blood or pleural effusion of patients with plasma cell leukemia), and therefore are not fully consistent with the biological behaviour of intramedullary disease in which MM cells closely interact and depend from the huBBM [9, 58]. Moreover, cell lines i ) are unstable over time and acquire additional genetic abnormalities conferring an even more dedifferentiated and aggressive phenotype different from the original disease [58, 59]; ii ) lack the heterogeneity observed in MM patients; iii ) show a higher S-phase fraction of proliferating cells compared to primary MM cells; iv ) sometimes are EBV positive representing a B-lymphoproliferative and not a plasma cell phenotype [58], and v ) produce poorly vascularized xenografts that grow rapidly within few weeks and present wide necrotic areas.…”

“…Despite all recent achievements in the understanding of the pathophysiology of the disease and the availability of new therapeutics, MM remains incurable and runs a progressive and lethal course [1-5]. One of the most important mechanisms involved in the development of MM drug resistance is the block of drug-induced cell death via activation of autocrine or paracrine signaling loops in the context of the human bone marrow microenvironment (huBMM) [6-9]. It appears clear now that the huBMM plays a crucial role in MM cell growth and expansion as well as in tumour cell survival and drug resistance and therefore by itself is one of the most interesting potential targets in MM treatment [6, 7, 10-12].…”