Novel Developments in the Treatment of Multiple Myeloma-Associated Bone Disease

Abstract

Osteolytic bone disease is present in about 80% of patients with multiple myeloma at the time of diagnosis. Managing bone disease in patients with multiple myeloma is a challenge and requires a multi-faceted treatment approach with medication, surgery, and radiation. The established treatments with intravenous or subcutaneous antiresorptives can cause debilitating adverse events for patients, mainly osteonecrosis of the jaw, which, traditionally, has been difficult to manage. Now, oral surgery is recommended and proven successful in 60-85% of patients. Patients with spinal involvement may benefit from surgery in the form of vertebroplasty and kyphoplasty for pain relief, improved mobility, and reestablished sagittal balance, as well as the restoration of vertebral height. These procedures are considered safe, but the full therapeutic impact needs to be investigated further. Ixazomib, the first oral proteasome inhibitor, increases osteoblast differentiation, and recently published preliminary results in patients treated with Ixazomib maintenance have promisingly shown increased trabecular volume caused by prolonged bone formation activity. Other novel potential treatment strategies are discussed as well.

Keywords: antiresorptive agents; bone marrow microenvironment; kyphoplasty; multiple myeloma; osteonecrosis of the jaw; vertebroplasty.

Figure 1

(A) Clinical presentation of medication-related osteonecrosis of the jaw (MRONJ). The stage 3 osteonecrosis in the anterior part of the mandible is clinically visible as grey bone protruding through the inflamed gingiva. (B) MRONJ. The figure shows the area of necrosis and the suggested resection area for resection. The edges are slightly rounded to avoid sharp edges that may perforate the gingiva during healing. (C) Surgical treatment with submandibular incision to access the necrotic bone. A wide incision is necessary to ensure that all necrotic bone is removed, and the mandible can subsequently be restored by a reconstruction plate. Blue line marks the extention of visible osteonecrosis. Yellow line marks the intermediate, sclerotic zone.

Figure 2

Lateral standing X-ray images before (left) and after (right) wedge osteotomy in a patient with MM with multiple vertebral lesions treated with vertebroplasty. Note the correction of the sagittal profile.

Figure 3

Current therapies in myeloma bone disease. MM cells interact with their surrounding bone marrow microenvironment, including vasculature/innervation, SSPCs, and adipocytes, which, in turn, promote MM cell survival and proliferation. Upon disruption of the bone remodeling compartment (BRC) canopy, MM cells enter into direct contact with osteoclasts, osteoblasts, and osteoprogenitor cells, uncoupling the bone resorption and formation and inducing osteolytic disease. Bisphosphonates bind the bone surface and promote osteoclast apoptosis and Dmab binds RANKL, thereby decreasing osteoclast differentiation. Ixazomib, a proteasome inhibitor, decreases osteoclast activity and simultaneously promotes longer bone formation events by osteoblasts, resulting in net bone gain.