Update on Bone Disease in Multiple Myeloma

Asher Chanan-Khan, MD

Bone disease in patients with multiple myeloma should not be taken lightly, stated Asher Chanan-Khan, MD, the new chair of the Division of Hematology/Oncology at the Mayo Clinic in Jacksonville, Florida. Chanan-Khan updated attendees on management of bone disease in patients with multiple myeloma during the NCCN 6th Annual Congress on Hematologic Malignancies.

Bone disease occurs in about 84% of patients with multiple myeloma and is responsible for a great deal of morbidity, including pain, hypercalcemia, compromised quality of life, and pathological fracture. Patients with bone disease typically sustain a skeletal-related event (SRE) within the first year of having bone disease.

Patients with smoldering multiple myeloma should be monitored with an annual x-ray, while those with active symptomatic disease should be monitored as needed to confirm response, determine relapse, and evaluate symptoms. Tools for evaluating bone disease include x-rays for lytic lesions, bone density tests to detect osteoporosis, and noncontrast CT scans to identify vertebral fractures.

Patients with established bone disease should incorporate lifestyle modifications, which include exercise, calcium supplementation, and reducing the risk of falls in their environment.

“The need to reduce risk of falls may be overlooked, but educating patients about this is very important,” said Chanan-Khan. Treatment of bone disease includes radiotherapy to the bone or surgery (either vertebroplasty or kyphoplasty). Chanan-Khan prefers kyphoplasty to vertebroplasty, noting that this procedure relieves pain, restores 34% to 54% of vertebral height, and results in better quality of life than vertebroplasty.

Pharmacologic management of bone disease includes vitamin D supplementation, although the optimal way to replenish vitamin D is still under study; bisphosphonate therapy with either zoledronic acid or pamidronate; and treatment of the underlying myeloma.

A recent study of 900 patients with multiple myeloma with or without bone disease [Morgan GJ et al. Lancet. 2010;376(9757):1989-1999] found that zoledronic acid was superior to clodronate. At a median follow-up of 3.7 years, zoledronic acid reduced SREs from 35% with clodronate to 27% (P = .0004) and improved overall survival by 5.5 months versus clodronate (P = .05), independent of time to first SRE. Osteonecrosis of the jaw (ONJ) was increased in patients treated with zoledronic acid (3.5% vs 0% with clodronate).

“Although the authors of this study suggested that zoledronic acid should be considered in all patients with newly diagnosed multiple myeloma regardless of the presence of bone disease for its presumed antimyeloma effect, no improvement in survival or progression-free survival was observed in patients with no bone disease,” said Chanan-Khan. Thus, at present he does not recommend bisphosphonate therapy until bone disease emerges.

ONJ has been reported in 3.5% to 10% of patients treated with bisphosphonates. Risk factors include time on bisphosphonate therapy, dental extraction, older age, and longer time from diagnosis of multiple myeloma. If ONJ occurs, stop the bisphosphonate and perform surgical debridement, Chanan-Khan advised. Before initiating bisphosphonate therapy, a dental consult and necessary dental extractions should be performed to reduce the risk of ONJ.

Novel agents being studied for bone disease in multiple myeloma include the anti-RANK ligand denosumab (which is not approved for multiple myeloma). Anti-DKK1 therapy is in early trials for multiple myeloma and bone disease, and this therapy is potentially usable over longer periods of time than a bisphosphonate. ACE-011 is another novel therapy that targets activin A.

A number of questions remain. It is not clear whether all myeloma patients should be treated with a bisphosphonate. If complete remission is achieved on bisphosphonate therapy, Chanan-Khan advised withholding the bisphosphonate if the bone marrow is clear, and reinitiating the drug at the time of need. It is not clear how long bisphosphonate therapy should be given, nor is it clear if the novel agents will be more effective and have less toxicity with prolonged use than existing bisphosphonates.