Randomized Clinical Trial of Zoledronic Acid in Multiple Myeloma Patients Undergoing High-Dose Chemotherapy and Stem-Cell Transplantation

Background: A growing body of evidence is demonstrating that the nitrogen-containing bisphosphonate zoledronic acid (zol) improves clinical outcomes in various cancer settings, including multiple myeloma. Those findings provided the rationale for conducting an open-label randomized controlled phase iii trial to evaluate the effect of zol on overall survival (os) and progression-free survival (pfs) in patients with previously untreated high-risk multiple myeloma. Methods: The trial randomly assigned 308 adult patients less than 65 years of age with previously untreated symptomatic multiple myeloma (1:1) to receive zol 4 mg intravenously once every 28 days for 24 months (n = 151) or no zol (n = 157). Before autologous stem-cell transplantation (asct), all patients received a high-dose noncytotoxic induction regimen of dexamethasone, all-trans-retinoic acid, and interferon alpha 2b. Results: After a median follow-up of 69.8 months (range: 36.5–96 months), the 10-year pfs (66% vs. 52%, p < 0.001) and os (67% vs. 48%, p < 0.001) rates were significantly higher in treated patients than in control patients. Overall response (77% zol vs. 75% control), complete response (52% vs. 46%), and very good partial response (25% vs. 29%) rates were similar between the groups. Treatment was generally well tolerated, with no reports of renal impairment or osteonecrosis of the jaw. Conclusions: In symptomatic previously untreated multiple myeloma patients, zol combined with high-dose therapy followed by asct improved os and pfs without appreciable toxicity. These findings provide additional evidence of the meaningful anticancer activity of zol in this patient population.