Management of Myeloma Bone Lesions

Abstract

Multiple myeloma (MM) is a B-cell neoplasm characterized by clonal plasma–cell proliferation. The survival and prognosis of this condition have been significantly improved by treatment with active anti-MM drugs such as bortezomib or lenalidomide. Further, the discovery of novel agents has recently paved the way for new areas of investigation. However, MM, including myeloma-related bone diseases, remains fatal. Bone disease or bone destruction in MM is a consequence of skeletal involvement with bone pain, spinal cord compression, and bone fracture resulting from osteolytic lesions. These consequences affect disease outcomes, including patients’ quality of life and survival. Several studies have sought to better understand MM bone disease (MBD) through the classification of its molecular mechanisms, including osteoclast activation and osteoblast inhibition. Bisphosphonates and the receptor activator of the nuclear factor-kappa B (NF-κB) ligand (RANKL) inhibitor, denosumab, prevent skeletal-related events in MM. In addition, several other bone-targeting agents, including bone-anabolic drugs, are currently used in preclinical and early clinical evaluations. This review summarizes the current knowledge of the pathogenesis of MBD and discusses novel agents that appear very promising and will soon enter clinical development.

Pathogenesis and Treatment of Myeloma-Related Bone Disease

“…The FDA-approved BPs for MBD are zoledronic acid and pamidronate [ 103 ]. Clodronate (oral non-nitrogenous BP), which is used for reducing SREs in MM patients, yielded inferior survival outcomes compared with zoledronic acid in the Myeloma IX trial [ 104 , 105 , 106 ]. Zolendronic acid may have an anti-myeloma effect through the inhibition of protein prenylation and the inhibition of antiangiogensis or by the indirect downregulation of BMSC-related adhesion molecules and the blocking of osteoclast activation [ 8 , 107 , 108 ].…”

Four and a Half LIM Domains Protein 2 Mediates Bortezomib-Induced Osteogenic Differentiation of Mesenchymal Stem Cells in Multiple Myeloma Through p53 Signaling and β-Catenin Nuclear Enrichment

“…The specific probes for FISH are as follows: del(13q) abnormality was assessed with LSI 13q34 (specific for the 13q34 locus, Abbott Laboratories); del (17p13) was assessed with LSI p53 (specific for the 17p13. 1…”

“…Multiple myeloma (MM)-related bone disease (MBD), characterized by lytic bone lesions, fracture, hypercalcemia, and severe pain, is the most common and life-threatening complication in MM patients ( 1 , 2 ). The pathophysiology of MBD has been widely studied.…”

“…In addition to its anti-MM activity, preclinical and clinical data have shown that Bzb can inhibit osteoclast activity (7-10) and stimulate osteoblast activity (8)(9)(10)(11)(12)(13)(14), thus potentially exerting positive effects on bone metabolism (15,16) independent of its effects on MM. Such induction of osteoblast differentiation may be mediated via bcatenin/T-cell factor TCF pathway and the modulation of Runx-2 (1,17,18). Further defining molecular mechanism of Bzbenhanced bone formation in MM will be beneficial for the treatment of myeloma patients (5)(6)(7)(8).…”

Therapeutic targeting of PFKFB3 and PFKFB4 in multiple myeloma cells under hypoxic conditions

“…Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells due to the accumulation of abnormal plasma cells in the bone marrow and monoclonal protein in the serum and/or urine [1]. The plasma cells proliferate in the bone marrow and can result in extensive skeletal destruction with osteolytic lesions, osteopenia, and/or pathologic fractures [2]. MM often progresses from a premalignant state called monoclonal gammopathy of undetermined signi cance (MGUS) [3].…”