Bone health is critical in patients with multiple myeloma, since up to 85% will suffer bone damage. Options for management include two FDA-approved bisphosphonates—pamidronate and zoledronic acid—and possibly the RANK-L inhibitor denosumab (Xgeva, investigational use).
Importance of Supportive Care
“With modern treatments, multiple myeloma has become a chronic disease, but it can have potentially devastating effects on bone. Oncologists need to give attention to supportive care, which includes bone health,” said Noopur Raje, MD, Associate Professor of Medicine at Dana-Farber/Harvard Cancer Center and Director of the Multiple Myeloma Program at Massachusetts General Hospital, Boston. Dr. Raje spoke at the NCCN 8th Annual Congress on Hematologic Malignancies.1
Recent studies suggest that pamidronate and zoledronic acid are equivalent in preventing skeletal-related events in multiple myeloma, and that zoledronic acid may have a survival advantage. Studies using the bone biomarker N-telopeptide (NTx) suggest that it is possible to dose zoledronic acid less frequently after 2 years of regular bisphosphonate therapy, reducing the risk of concerning side effects unrelated to multiple myeloma that include spontaneous fracture and osteonecrosis of the jaw.
“We don’t have all of the answers when it comes to bone disease. We don’t know how long to treat with bisphosphonates, nor do we know how frequently to treat,” said Dr. Raje.
Denosumab is not FDA-approved for reducing skeletal-related events in multiple myeloma but has approval for that indication in some solid tumors. An international randomized trial is currently comparing denosumab vs zoledronic acid in multiple myeloma patients.
Bone remodeling is a constant and dynamic process in the human body, Dr. Raje explained. “In multiple myeloma, the balance is tilted. The osteoblasts are hyperactive, leading to thinning of the bone, and osteoblasts that re-form the bone are dysfunctional. This results in sequelae associated with significant morbidity and mortality. About 50% of patients with multiple myeloma who are not treated for their disease will develop some form of skeletal-related event within the first year. Pathologic fracture is the most common symptom, and patients with fracture have double the mortality,” she continued.
The goal in treating multiple myeloma patients with bone-targeted agents is to avoid skeletal-related events, especially vertebral compression fractures, which occur in 3% to 4% of patients. These fractures are extremely painful and interfere with daily activities.
NCCN guidelines recommend a skeletal survey annually throughout a patient’s lifetime, but x-rays fail to identify clinically silent skeletal-related events in about 30% of patients. She advised having a lower threshold for use of MRI and PET scans in patients with multiple myeloma, especially those with back pain.
Treatment Recommendations
Recommended management of multiple myeloma includes bisphosphonates, vertebroplasty and kyphoplasty for vertebral fractures, limited use of radiation, and treatment for the myeloma itself. “I cannot overemphasize the importance of treating multiple myeloma. These treatments can mitigate bone problems,” Dr. Raje stated.
Several large, randomized studies have demonstrated the efficacy of zoledronic acid in this setting, she continued. These studies suggest that all patients being treated with multiple myeloma should also receive zoledronic acid to reduce the incidence of new osteolytic lesions.2
“Studies show for the first time that a nonmyeloma approach (ie, zoledronic acid) can affect the microenvironment and improve overall survival,” Dr. Raje said.
It is important for patients taking bisphosphonates to have good oral hygiene and to be sure their dentists know they are taking that drug. Also, tooth extraction is not recommended during bisphosphonate treatment.
Toxicity Considerations
Osteonecrosis of the jaw and stress fractures unrelated to myeloma are concerns with bisphosphonates, but Dr. Raje believes this is probably a consequence of overtreatment. Thus, it is important to determine the optimal duration of treatment with bisphosphonates.
Patients usually receive bisphosphonates every 4 weeks. A study by Dr. Raje and colleagues suggested that less frequent dosing of a bisphosphonate is feasible, based on measurements of bone marker (NTx) levels.3 In this study of multiple myeloma patients with up to 2 years of prior bisphosphonate treatment, treatment every 12 weeks for an additional 2 years was feasible (up to 4 years of bisphosphonate treatment). The rate of skeletal-related events was about 4% in this study, and the rate of osteonecrosis of the jaw was about 3%.
Looking Ahead
Future directions of research in this field include combining drugs that target the osteoblasts and osteoclasts, and combining other drugs with bisphosphonate. Also, use of imaging and incorporation of biomarkers will be refined, said Dr. Raje.
“As more patients with multiple myeloma are living longer, the disease is becoming more chronic. And the majority of patients have bone damage, whether it is evident on imaging or not,” said conference Chair Andrew D. Zelenetz, MD, of Memorial Sloan-Kettering Cancer Center, New York. “As Dr. Raje explained, the most important thing to do for newly diagnosed patients is to treat the myeloma first and also treat them upfront with bisphosphonates.” ■
Disclosure: Drs. Raje and Zelenetz reported no potential conflicts of interest.
Reference
1. Raje N: Management of bone health in multiple myeloma. NCCN 8th Annual Congress: Hematologic Malignancies. Presented September 21, 2013.
3. Raje N, Vescio R, Montgomery CW, et al: Bone marker directed dosing of zoledronic acid for the prevention of skeletal complications in patients with multiple myeloma: Primary analysis results of the Z-MARK study. Blood 118(ASH Annual Meeting Abstracts):Abstract 5122, 2011.
