Targeting Bone as a Therapy for Myeloma

Abstract

Myeloma bone disease (BD) not only impairs quality of life, but is also associated with impaired survival. Studies of the biology underlying BD support the notion that the increased osteoclastogenesis and suppressed osteoblastogenesis, is both a consequence and a necessity for tumour growth and clonal expansion. Survival and expansion of the myeloma clone is dependent on its interactions with bone elements, thus targeting these interactions should have antimyeloma activities. Indeed both experimental and clinical findings indicate that bone-targeted therapies not only improve BD, but also create an inhospitable environment for myeloma cell growth and survival, favouring improved clinical outcome. This review summarizes recent progress in our understandings of the biology of myeloma BD, highlighting the role of osteoclasts and osteoblasts in this process and how they can be targeted therapeutically. Unravelling the mechanisms underlying myeloma-bone interactions will facilitate the development of novel therapeutic agents to treat BD, which as a consequence are likely to improve the clinical outcome of myeloma patients.

Preclinical Activity of the Oral Proteasome Inhibitor MLN9708 in Myeloma Bone Disease

“…This highlights the need for supportive bone-targeting treatments besides antimyeloma chemotherapies to reduce the risk of bone complications in multiple myeloma. Moreover, because many of the factors dysregulated in MBD are also important contributors to myeloma progression and chemoresistance, it is expected that restoring bone homeostasis would indirectly and additionally lead to tumor inhibition (42).…”

“…Recent progress in the understanding of the molecular interplayers involved in MBD has stimulated the development alternative bone therapeutic compounds either focusing on osteoclast inhibition, or importantly, on osteoblastogenesis promotion (reviewed in refs. 2,40,42). It is likely that these agents, now at different stages of clinical development, will contribute to a more efficacious and improved management of MBD in the near future.…”

Guest editorial: understanding the pathogenesis and the evolving treatment paradigm for multiple myeloma in the era of novel agents

“…MM cells enhance osteoclastogenesis and stimulate angiogenesis in concert with bone marrow stromal cells and osteoclasts, whereas they suppress osteoblastic differentiation from bone marrow stromal cells, leading to devastating bone destruction and the rapid loss of bone [15,16]. Importantly, osteoclasts, vascular endothelial cells, and bone marrow stromal cells with defective osteoblastic differentiation create a cellular microenvironment suitable for MM growth and survival and confer drug resistance [12,17], in many senses, an ''MM niche'' [15]. This review series provides an overview of the current understanding of the mechanisms underlying the mutual interactions between MM cells and local bone marrow cells leading to the vicious cycle between bone destruction and tumor expansion.…”