Lytic Disease on Plain Radiographs or Imaging
For multiple myeloma patients who have, on plain radiograph(s) or imaging, lytic destruction of bone or compression fracture of the spine from osteopenia, intravenous pamidronate 90 mg delivered over at least 2 hours or zoledronic acid 4 mg delivered over at least 15 minutes every 3 to 4 weeks is recommended. In light of data from showing a 9.5-fold greater risk for the development of osteonecrosis of the jaw (ONJ) with zoledronic acid compared with pamidronate, patients may prefer pamidronate to zoledronic acid until more data become available on this adverse effect of bisphosphonate therapy. Clodronate is an alternative bisphosphonate that has been approved worldwide, except in the United States, for either oral or intravenous administration.
Monitoring
As a result of increased concerns over renal adverse events, new dosing guidelines for patients with preexisting renal impairment were added to the zoledronic acid package insert. The new guidelines recommend that patients with pre-existing mild-to-moderate renal impairment (estimated creatinine clearance, 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. Pamidronate 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 micromol/L] or an estimated creatinine clearance <30 mL/min). Although no dosing guidelines are available for patients with pre-existing renal impairment, the Update Committee recommends that clinicians consider reducing the initial pamidronate dose in that setting.
Infusion times less than 2 hours with pamidronate or less than 15 minutes with zoledronic acid should be avoided. The Update Committee recommends that serum creatinine should be monitored before each dose of pamidronate or zoledronic acid, in accordance with US Food and Drug Administration–approved labeling. In patients who develop renal deterioration with no other 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 the serum creatinine returns to within 10% of the baseline level. Serum calcium, electrolytes, phosphate, magnesium, and hematocrit/hemoglobin should also be monitored regularly, although there is no evidence on which to base a recommendation for time intervals. The Update Committee also recommends intermittent evaluation (every 3 to 6 months) of all patients receiving pamidronate or zoledronic acid therapy for the presence of albuminuria. In patients experiencing unexplained albuminuria (defined as >500 mg/24 hours of urinary albumin), discontinuation of the drug is advised until the renal problems are resolved. When the proteinuria returns to baseline, these patients should be reassessed every 3 to 4 weeks (with a 24-hour urine collection for total protein and urine protein electrophoresis), and pamidronate should be reinstituted over a longer infusion time (>4 hours) and at doses not to exceed 90 mg every 4 weeks. The Update Committee supports the use of screening urinalysis for proteinuria but underscores that a 24-hour urine collection for determination of total protein and electrophoresis is required if the screening test is positive. Although no similar guidelines are available for zoledronic acid, some Update Committee members recommend that zoledronic acid be reinstituted over a longer infusion time (>30 minutes).
Duration of Therapy
A single randomized clinical trial has shown no benefit of monthly bisphosphonates after tandem stem-cell transplantation. There was no difference in the proportion of skeletal events in the pamidronate-containing regimens (21% and 18%) compared with no maintenance (24%) after 29 months of follow-up. Given these data and the best clinical opinion of the Update Committee, we suggest that therapy with bisphosphonates be administered monthly for a period of 2 years. (One trial suggests 1 year if the patient is in a complete response or near complete response after a tandem stem-cell transplantation.) At 2 years, physicians should seriously consider stopping bisphosphonates in patients with responsive or stable disease, but their further use is at the discretion of the treating physician. There are no data to support a more precise recommendation for duration of bisphosphonate therapy in this group of patients. For those patients in whom bisphosphonates are withdrawn after 2 years, the drug should be resumed on relapse with new-onset skeletal-related events.
Myeloma Patients With Osteopenia Based on Normal Plain Radiograph or Bone Mineral Density Measurements
It is reasonable to start intravenous bisphosphonates in multiple myeloma patients with osteopenia but no radiographic evidence of lytic bone disease. Note, patients with nonlytic lesions have been included in selected trials but have not been the primary focus of the trial or of sufficient number to be separately analyzed.
Patients With Solitary Plasmacytoma or Smoldering or Indolent Myeloma Without Documented Lytic Bone Disease
Starting bisphosphonate therapy in patients with solitary plasmacytoma or smoldering (asymptomatic) or indolent myeloma is not recommended.
Patients With Monoclonal Gammopathy of Undetermined Significance
Starting bisphosphonates in patients with monoclonal gammopathy of undetermined significance is not recommended.
Biochemical Markers
The use of biochemical markers of bone metabolism to monitor bisphosphonate use is not suggested for routine care because of a lack of prospective studies validating such an approach.
Role in Pain Control Secondary to Bony Involvement
Intravenous pamidronate or zoledronic acid is recommended for patients with pain caused by osteolytic disease and as an adjunctive treatment for patients receiving radiation therapy, analgesics, or surgical intervention to stabilize fractures or impending fractures.
Safety and Adverse Effects: Osteonecrosis of the Jaw (ONJ)
NOTE. The topic of ONJ as an adverse effect is new to the guideline.
ONJ is an uncommon but potentially serious complication of intravenous bisphosphonates. The Update Committee agrees with the recommendations described in the revised US Food and Drug Administration label for zoledronic acid and pamidronate, Dear Doctor letters, a white paper, and various position papers or statements. All cancer patients should receive a comprehensive dental examination and appropriate preventive dentistry before bisphosphonate therapy. Active oral infections should be treated, and sites at high risk for infection should be eliminated. While on therapy, patients should maintain excellent oral hygiene and avoid invasive dental procedures, if possible.
