From the Guidelines
RANKL is activated in multiple myeloma due to the complex interplay between myeloma cells, bone marrow stromal cells, and the bone microenvironment, leading to an increased RANKL/OPG ratio and subsequent osteoclast activation and bone destruction. This process involves the production of various cytokines, such as interleukin-6 (IL-6), macrophage inflammatory protein-1α (MIP-1α), and tumor necrosis factor-α (TNF-α), which enhance RANKL production and decrease osteoprotegerin (OPG) levels 1. The myeloma cells also directly produce RANKL and stimulate other cells in the bone marrow to increase their RANKL expression, further contributing to the elevated RANKL activity 1.
The increased RANKL/OPG ratio stimulates osteoclast formation, activation, and survival, leading to increased bone resorption and the characteristic osteolytic bone lesions seen in multiple myeloma patients 1. This bone destruction creates a vicious cycle as growth factors released from the degraded bone matrix further promote myeloma cell growth and survival, perpetuating disease progression and bone destruction 1.
Key factors involved in RANKL activation in multiple myeloma include:
- Myeloma cells producing RANKL and stimulating other cells to increase RANKL expression
- Decreased osteoprotegerin (OPG) levels, leading to an increased RANKL/OPG ratio
- Production of cytokines such as IL-6, MIP-1α, and TNF-α, which enhance RANKL production
- Bone destruction and release of growth factors, which promote myeloma cell growth and survival
The most recent and highest quality study, published in 2018, supports the use of bone-modifying agents, such as bisphosphonates and denosumab, to reduce skeletal-related events and improve progression-free survival in multiple myeloma patients 1. Therefore, it is essential to consider the use of these agents in the management of multiple myeloma patients with bone disease or at high risk of skeletal-related events.
From the Research
RANKL Activation in Multiple Myeloma
- RANKL is expressed by primary multiple myeloma cells, and its release is influenced by posttranscriptional/posttranslational regulation 2
- The RANK/RANKL pathway plays a crucial role in bone remodeling and is involved in the pathophysiology of multiple myeloma 3
- RANKL expression is associated with increased serum levels of soluble RANKL and an imbalance in RANKL and osteoprotegerin in patients with multiple myeloma 3
Therapeutic Targeting of RANKL
- Denosumab, a monoclonal antibody targeting RANKL, has been shown to reduce skeletal-related events in patients with multiple myeloma 4, 5, 6
- Denosumab has been demonstrated to be non-inferior to zoledronic acid in preventing skeletal-related events in patients with newly diagnosed multiple myeloma 5
- RANK-Fc fusion proteins with modified Fc moieties have been generated, which can neutralize the effects of RANKL on osteoclastogenesis and stimulate natural killer cell reactivity against RANKL-expressing malignant cells 2
Clinical Implications
- The use of denosumab and bisphosphonates, such as zoledronic acid, can help prevent skeletal complications in patients with multiple myeloma 4, 5, 6
- The choice of therapy may depend on factors such as renal toxicity and the risk of osteonecrosis of the jaw 4, 5, 6
- Further studies are needed to fully understand the role of RANKL in multiple myeloma and to explore the potential of therapeutic targeting of the RANK/RANKL pathway 2, 3