Multiple myeloma is one of the most prevalent hematologic malignancies and is often characterized by several comorbid complications, including severe bone disease. Skeletal-related adverse events may present as bone fractures, intense pain, hypercalcemia, or spinal cord compression.  These manifestations negatively affect patient quality of life and overall survival. As a result, the demand for novel treatment strategies to manage bone complications is high.1,2

In a review article published in Pharmaceutics, Sonia Vallet, MD, of the Karl Landsteiner University of Health Sciences in Austria, and colleagues summarized current literature surrounding the management of myeloma bone disease in adults. They also reviewed recent updates regarding disease pathogenesis and discussed recommended treatments for bone complications.

Rebecca Silbermann, MD, MS, of the division of hematology and oncology at the Oregon Health and Science University in Portland, told Hematology Advisor, “Bone disease continues to be one of the most devastating complications of multiple myeloma. Skeletal fragility and myeloma bone lesions persist, even when a patient’s disease is very well controlled.”

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Pathogenesis of Myeloma Bone Disease

In recent years, several major studies have greatly enhanced understanding of the underlying mechanisms of bone complications in patients with myeloma. Researchers have identified key molecular factors that stimulate osteoclast and osteoblast activity, which alter bone resorption and formation pathways. These changes can lead to disruptions in skeletal remodeling and overamplification of protease activity, ultimately resulting in degradation of both organic and inorganic bone matrix.

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The protease RANK plays an important role in regulation of osteocyte activity. Overexpression of the enzyme’s ligand, RANKL, triggers numerous remodeling pathways that can lead to drug resistance, tumor progression, and refractory disease. Consequently, RANKL has become a key molecular target for therapeutic agent development aimed at treating myeloma bone disease.

Treatment of Myeloma Bone Disease

Over the past several years, the mainstay of drug treatment for myeloma bone disease has been bisphosphonates. The therapeutic effect of these agents is largely attributable to their ability to strongly bind hydroxyapatite in bone and produce anticatabolic effects through inhibition of osteoclast differentiation. In addition, these agents exhibit anticancer and immunomodulatory effects on myeloma tumor cells.

The most common bisphosphonates used in the treatment of multiple myeloma are zoledronic acid and pamidronate. These agents are administered as monthly intravenous infusions in patients with active disease plus comorbid osteoporosis or lytic bone lesions but without markers of osteolysis. Results from numerous trials have shown that these injectables can significantly reduce the number of skeletal-related events in patients with multiple myeloma.