SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 30,770 new cases will be diagnosed in 2018 and 12,770 patients are expected to die of the disease. Multiple Myeloma in 2018 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). ASCO recently issued a clinical practice guideline update on the role of Bone-Modifying Agents (BMA) in Multiple Myeloma following a systematic literature review of 35 relevant studies by an expert panel. In the updated guidelines, ASCO has recommended expanding the use of bisphosphonates to include all patients being treated for active Multiple Myeloma. The previous guidelines recommended BMAs only for patients with lytic disease. The new recommendation was based on results from the phase III MRC Myeloma IX Trial, which demonstrated the benefit of bisphosphonate therapy in patients with newly diagnosed multiple myeloma who did not have lytic bone disease.
Indications to initiate a BMA – Key Recommendations
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 (MRI or CT scan), have lytic destruction of the bone or compression fracture of the spine from osteopenia, AREDIA® (Pamidronate) 90 mg IV over at least 2 hours or ZOMETA® (Zoledronic acid) 4 mg IV over at least 15 minutes every 3 to 4 weeks is recommended. Alternative treatment includes the use of XGEVA® (Denosumab), a monoclonal antibody that targets Receptor Activator of Nuclear factor Kappa-B Ligand (RANKL).
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
AREDIA® or ZOMETA® IV 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. XGEVA® is an additional option.
Patients with myeloma with normal plain radiograph or osteopenia in bone mineral density measurements
The Expert Panel supports starting intravenous 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 BMAs
As a result of increased concerns over renal adverse events, Guidelines recommend that patients with preexisting mild to moderate renal impairment (estimated Creatinine Clearance, 30-60 mL/min) should receive a reduced dosage of ZOMETA®. No changes in infusion time or interval are required. ZOMETA® has not been studied in patients with severe renal impairment and is not recommended for use in these patients. Recent data that compare XGEVA® with ZOMETA® has demonstrated fewer adverse events related to renal toxicity with XGEVA®, and this may be preferred in patients with compromised renal function. AREDIA® 90 mg administered over 4-6 hours is recommended for patients with extensive bone disease and existing severe renal impairment (serum creatinine level more than 3.0 mg/dL (265 µmol/L or an estimated Creatinine Clearance of less than 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 AREDIA® dose in that setting. Infusion times less than 2 hours with AREDIA® or less than 15 minutes with ZOMETA® 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. There are no data to support a more precise recommendation for the duration of bisphosphonate therapy in this group of patients. For those patients for whom bisphosphonates were withdrawn after 2 years, the drug should be resumed upon relapse with new-onset Skeletal Related Events. XGEVA® 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 AREDIA® or ZOMETA®, in accordance with FDA-approved labeling. XGEVA® does not require monitoring of renal function. In patients who develop renal deterioration without an apparent cause during bisphosphonate therapy, ZOMETA® or AREDIA® 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. XGEVA® 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 XGEVA®. Patients should be Calcium and Vitamin D repleted. The Expert Panel also recommends intermittent evaluation (every 3-6 months) of all patients receiving AREDIA® or ZOMETA® 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 more than 500 mg/24 hours of urinary albumin, and discontinuation of the drug is advised until renal problems are resolved. These patients should be reassessed every 3-4 weeks with a 24-hour urine collection for total protein and Urine Protein ElectroPhoresis, and AREDIA® should be reinstituted over a longer infusion time (4 hours or more) and at doses not to exceed 90 mg every 4 weeks, when renal function returns to baseline. 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 ZOMETA®, some Expert Panel members recommend that ZOMETA® be reinstituted over a longer infusion time (30 minutes or more).
Biochemical markers
Use of the 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 (ONJ) is an uncommon but potentially serious complication of IV bisphosphonates and XGEVA®. The Expert Panel agrees with the recommendations described in the revised FDA label for ZOMETA® and AREDIA®, Dear Doctor letters, a white paper, and various position papers or statements. 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. While on therapy, patients should maintain excellent oral hygiene and avoid invasive dental procedures, if possible. Continuation of a bone-targeting agent in the setting of ONJ has to be individualized and dependent on a risk-benefit ratio and the severity of bone disease.
Role of bone-modifying agents in multiple myeloma: American Society of Clinical Oncology clinical practice guideline update. Anderson K, Ismaila N, Flynn PJ, et al. J Clin Oncol. 2018;36:812-818.
