Role of Bone-Modifying Agents in Multiple Myeloma

Kenneth C. Anderson, MD

Robert A. Kyle, MD

As reported in the Journal of Clinical Oncology by Kenneth C. Anderson, MD, of Dana-Farber Cancer Institute, and colleagues, ASCO has issued a clinical practice guideline update on the role of bone-modifying agents in multiple myeloma.¹ The update was performed by an expert panel systematic literature review including 35 relevant studies. The expert panel was co-chaired by Dr. Anderson and Robert A. Kyle, MD, of the Mayo Clinic, Rochester, Minnesota. Key recommendations are reproduced/summarized here.

Indications to Initiate a Bone-Modifying Agent

• Patients with lytic disease on plain radiographs or other imaging studies. For patients with multiple myeloma who, on plain radiograph(s) or other imaging studies (magnetic resonance imaging or computed tomography scan), have lytic destruction of the bone or compression fracture of the spine from osteopenia, intravenous (IV) pamidronate at 90 mg delivered over at least 2 hours or zoledronic acid at 4 mg delivered over at least 15 minutes every 3 to 4 weeks is recommended. Alternative treatment includes the use of denosumab (Xgeva), a monoclonal antibody that targets receptor activator of nuclear factor kappa-B ligand.
• Patients with solitary plasmacytoma or smoldering (asymptomatic) or indolent myeloma. Starting bisphosphonates in patients with solitary plasmacytoma or smoldering (asymptomatic) or indolent myeloma is not recommended.
• Adjunct to pain control in patients with pain as a result of osteolytic disease and those receiving other interventions for fractures or impending fractures. IV pamidronate or zoledronic acid is recommended for patients with pain as a result of osteolytic disease and as an adjunctive treatment of patients receiving radiation therapy, analgesics, or surgical intervention to stabilize fractures or impending fractures. Denosumab is an additional option.
• Patients with myeloma with normal plain radiograph who have osteopenia. The expert panel supports starting IV bisphosphonates in patients with multiple myeloma with osteopenia (osteoporosis) but no radiographic evidence of lytic bone disease.
• Patients with monoclonal gammopathy of undetermined significance. Starting bisphosphonates in patients with monoclonal gammopathy of undetermined significance is not recommended, unless osteopenia (osteoporosis) exists.

Dosing and Selection of Agents

• As a result of increased concerns over renal adverse events, dosing guidelines for patients with preexisting renal impairment were added to the zoledronic acid package insert. Guidelines recommend that patients with preexisting mild-to-moderate renal impairment—estimated creatinine clearance of 30 to 60 mL/min—should receive a reduced dosage of zoledronic acid. No changes in infusion time or interval are required. Zoledronic acid has not been studied in patients with severe renal impairment and is not recommended for use in these patients. Recent data comparing denosumab with zoledronic acid have demonstrated fewer adverse events related to renal toxicity with denosumab, and this may be preferred in patients with compromised renal function.
• Pamidronate at 90 mg administered over 4 to 6 hours is recommended for patients with extensive bone disease and existing severe renal impairment—serum creatinine level > 3.0 mg/dL (265 mmol/L) or an estimated creatinine clearance of < 30 mL/min. Although no dosing guidelines are available for patients with preexisting renal impairment, the expert panel recommends that clinicians consider reducing the initial pamidronate dose in that setting. Infusion times < 2 hours with pamidronate or < 15 minutes with zoledronic acid should be avoided.

Duration of Therapy

• The expert panel suggests that bone-targeting treatment continue for a period of up to 2 years. Less-frequent dosing has been evaluated and should be considered in patients with responsive or stable disease. In patients who do not have active myeloma and are on maintenance therapy, the physician may consider a 3-month interval of bisphosphonate administration. For those patients for whom bisphosphonates were withdrawn after 2 years, the drug should be resumed upon relapse with new-onset skeletal-related events. Denosumab should not be stopped abruptly, given its reversible mechanism of action.

Monitoring

• The expert panel recommends that serum creatinine should be monitored before each dose of pamidronate or zoledronic acid, in accordance with FDA-approved labeling. 
• In patients who develop renal deterioration without an apparent cause during bisphosphonate therapy, zoledronic acid or pamidronate should be withheld. Bisphosphonate therapy can be resumed at the same dosage as that before treatment interruption, when serum creatinine returns to within 10% of the baseline level. Denosumab requires no dose modification.
• Serum calcium should be monitored regularly, and serum vitamin D levels should be evaluated intermittently. Hypocalcemia is an adverse effect of all bone-resorptive agents and is more pronounced with denosumab. 
• The expert panel also recommends intermittent evaluation—every 3 to 6 months—of all patients receiving pamidronate or zoledronic acid therapy for the presence of albuminuria on a spot urine sample. In patients who experience unexplained albuminuria, a 24-hour urine collection should be obtained to assess for > 500 mg/24 hours of urinary albumin, and discontinuation of the drug is advised until renal problems are resolved. 
• The expert panel supports the use of screening urinalysis for proteinuria but underscores that a 24-hour urine collection for the determination of total protein and electrophoresis is required if the test is positive. Although no similar guidelines are available for zoledronic acid, some expert panel members recommend that zoledronic acid be reinstituted over a longer infusion time (≥ 30 minutes).
• Use of biochemical markers of bone metabolism to monitor bone-modifying therapy use is not suggested for routine care.

Osteonecrosis of the Jaw

• Osteonecrosis of the jaw is an uncommon but potentially serious complication of IV bisphosphonates and denosumab. The expert panel agrees with the recommendations described in the revised FDA label for zoledronic acid and pamidronate. All patients should receive a comprehensive dental examination and appropriate preventive dentistry before bone-modifying therapy. Active oral infections should be treated, and sites that are at high risk for infection should be eliminated. Continuation of a bone-targeting agent in the setting of osteonecrosis of the jaw should be individualized.

For more information, see www.asco.org/guidelineswiki. ■

DISCLOSURE: For full disclosures of the study authors, visit www.ascopubs.org.

REFERENCE

1. Anderson K, Ismaila N, Flynn PJ, et al: ASCO clinical practice guideline update. J Clin Oncol 36:812-818, 2018.