New Guidelines for Multiple Myeloma-Related Bone Disease

Laurie Barclay, MD

May 30, 2013

New guidelines for the management of bone disease in all patients with multiple myeloma, issued by the International Myeloma Working Group, were published online May 20 in the Journal of Clinical Oncology.

"Bisphosphonates (zoledronic acid or pamidronate) should be considered in all myeloma patients receiving frontline antimyeloma therapy, regardless of the presence of osteolytic bone lesions on conventional radiography," said lead author Evangelos Terpos, MD, PhD, from the Department of Clinical Therapeutics at the University of Athens School of Medicine and the Alexandra General Hospital in Greece.

"Previously, the recommendation was only for patients who had myeloma-related bone disease," Dr. Terpos told Medscape Medical News. However, it is not clear whether bisphosphonates offer any advantage for patients with no evidence of bone disease on magnetic resonance imaging (MRI) or positron emission tomography/computed tomography (PET/CT), he explained.

Despite the introduction of novel agents that have led to improved survival, multiple myeloma is still an incurable plasma cell malignancy. At diagnosis, 70% to 80% of patients have osteolytic lesions, which increase the risk for skeletal-related events (pathologic fractures, spinal cord compression, or surgery or palliative radiotherapy to bone).

"I believe that the widespread implementation of these guidelines will help in the management of patients with myeloma and prevent skeletal-related events, improve quality of life, and reduce the cost of treatment," Dr. Terpos said.

The International Myeloma Working Group convened an interdisciplinary panel of clinical experts to develop practice guidelines for the management of multiple myeloma–related bone disease, after reviewing data published up to August 2012. Panel members assigned and approved levels of evidence and grades of recommendations. For situations lacking sufficient published evidence, the panel relied on expert consensus.

In these guidelines, the previous recommendations of various organizations for the use of bisphosphonates in patients with multiple myeloma have been updated.

New Recommendations for Bisphosphonates

Patients newly diagnosed with multiple myeloma who require antimyeloma treatment should receive intravenous bisphosphonates, regardless of bone status.
Bisphosphonates should be given monthly during initial therapy and thereafter in patients who are not in remission.
After 2 years, patients who have achieved a complete or very good partial response should discontinue bisphosphonates, but those who have achieved a partial response or less should continue bisphosphonate therapy.
Patients should undergo monthly monitoring of creatinine clearance.
First-line bisphosphonate therapy is zoledronic acid; second-line therapy is pamidronate.
Clodronate should be used only in patients who cannot come to the hospital, have severe disabilities, or who have contraindications for zoledronic acid and pamidronate.

"Zoledronic acid is preferred over oral clodronate in newly diagnosed myeloma patients because of its potential antimyeloma effects and survival benefits. Clodronate is currently not recommended, with specific exceptions," Dr. Terpos said.

Previous recommendations have supported bisphosphonate therapy for 2 years. "We suggest that zoledronic acid or pamidronate be continued in patients with active disease and, if discontinued in patients in complete remission or very good partial remission after antimyeloma therapy, be resumed after disease relapse."

Recommendation Highlights

Bisphosphonates should be considered for all patients receiving first-line treatment for multiple myeloma, regardless of whether osteolytic bone lesions are evident on conventional radiography.
It is not clear whether bisphosphonates provide additional advantage over first-line antimyeloma therapy in patients with no evidence of bone disease on MRI or PET/CT.
Intravenous zoledronic acid or pamidronate are recommended to prevent skeletal-related events.
In patients newly diagnosed with multiple myeloma, zoledronic acid is preferred over oral clodronate because of its potential antimyeloma effects and survival benefits. Zoledronic acid, pamidronate, and clodronate all reduce skeletal-related events and control bone pain, compared with placebo. However, zoledronic acid is associated with longer survival than clodronate, and with fewer skeletal-related events.
During initial treatment, patients should receive intravenous bisphosphonates every 3 to 4 weeks.
Patients with active disease should continue receiving zoledronic acid or pamidronate.
Patients should receive zoledronic acid until disease progression, except those who have achieved a complete or very good partial response; there are no data indicating a survival advantage for zoledronic acid in these patients.
There are no data showing a survival advantage for pamidronate, which can be administered for up to 2 years and continued in a patient with active myeloma.
In patients who achieve a complete or very good partial response and then discontinue zoledronic acid or pamidronate, the therapy should resume after disease relapse.
Although bisphosphonates are well tolerated overall, strategies are required to prevent renal toxicity or osteonecrosis of the jaw.
Clinicians should consider balloon kyphoplasty in patients with symptomatic and/or painful vertebral compression fractures.
Low-dose radiation therapy can help mitigate uncontrolled pain, impending pathologic fracture, or spinal cord compression.
Long-bone fractures, spinal cord compression, and vertebral column instability require orthopedic consultation.

"Zoledronic acid improves overall survival and reduces skeletal-related events better than clodronate in patients who received treatment for more than 2 years. Therefore, it should be given until disease progression in patients not in complete remission or very good partial remission and continued at relapse (grade B)," Dr. Terpos reported. "There is not similar evidence for pamidronate, but it can be continued in patients with active disease at the physician's discretion (grade D), and should be resumed after disease relapse (grade D)."

Some of the guidelines authors report financial relationships with Novartis, Amgen, Millennium Pharmaceuticals–Takeda, Neotope, Celgene, Onyx Pharmaceuticals, Merck, Janssen-Cilag, Pfizer, Janssen-Cilag, and/or LeoPharma.

J Clin Oncol. Published online May 20, 2013. Abstract


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