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.