First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomized trial.

Abstract

BACKGROUND: Bisphosphonates reducing the risk of skeletal events in patient with malignant bone disease, and zoledronic acid HAS Shown potential anti-cancer effects in preclinical and clinical studies. We aimed to estab whethere bisphosphonates can-affect clinical outcomes in patient with multiple myeloma.

METHODS: Patients 18 years of age or older with newly diagnosed multiple myeloma Were enrolled from 120 centers in the UK. Computer-generated randomisation sequence was Used to Allocate patiënten Equally, through an automated telephone service, to receive 4 mg zoledronic acid as an infusion 3-4 weeks everytime clodronic acid or 1600 mg oral daily. Patients Also Received Intensive or non-intensive induction chemotherapy. No investigators, staff, or patiënten Were masked to treatment allocation, and maintenance therapy and bisphosphonates Continued Until at least disease progression. Were the primary endpoint overall survival, progression-free survival, and overall response rate. We assessed between-group differences with Cox proportional hazards models for progression-free survival and overall survival, and with logistic regression models for overall response rate. Analysis was by intention to treat. This trial is registered, number ISRCTN68454111.

FINDINGS: 1970 patients Were enrolled Between May, 2003, and November, 2007, of Whom 1,960 Were Eligible for intention-to-treat analysis: 981 in the zoledronic acid group (555 on intensive chemotherapy, 426 on non-intensive chemotherapy) and 979 on clodronic acid (556 on intensive chemotherapy, 423 on non-intensive chemotherapy). The treatment cutoff was Oct 5, 2009, with Patients receiving bisphosphonates for a median of 350 days (IQR 137-632) before disease progression, with a median of 3.7 years' follow-up (IQR 2.9 -4 7 ). Zoledronic acid Reduced mortality by 16% (95% CI 4-26) vs. clodronic acid (hazard ratio 0.84 -560 555 688, 95% CI 0.74 -0 ° 96, p = 0.0118), and extended median overall survival by 5.5 months (50.0 months, IQR 21.0 to not Reached vs. 44.5 months, IQR 16.5 to not Reached, p = 0.04). Also zoledronic acid significantly improved progression-free survival by 12% (95% CI 2-20) versus clodronic acid (HR 0.88, 95% CI 0.80 -0 ° 98, p = 0.0179), and median Increased progression-free survival by 2.0 months (19.5 months, IQR 9.0 -38 ° 0 vs. 17.5 months, IQR 8.5 -34 ° 0, p = 0.07). Rates or complete, very good partial, or partial response did not significantly difference Between the zoledronic acid and acid clodronic for Patient groups receiving intensive induction chemotherapy (432 patients [78%] vs 422 [76%], p = 0.43) or non-intensive induction chemotherapy (215 [50%] vs 195 [46%], p = 0.18). Both bisphosphonates Were Generally well tolerated, with similar occurrence of acute renal failure and treatment-emergent serious adverse events, but zoledronic acid was associated with higher rates or CONFIRMED osteonecrosis of the jaw (35 [4%]) Than was clodronic acid (3 [ <1%]).

INTERPRETATIONS: Consistent with the potential anti-cancer activity or zoledronic acid, overall survival improved Independently of prevention or skeletal-related events, showing That HAS zoledronic acid treatment benefits beyond bone health. These Findings support immediate treatment with zoledronic acid in patient with newly diagnosed multiple myeloma, not only for prevention of skeletal-related events, but Also for potential anti-myeloma benefits.

FUNDING: Medical Research Council (London, UK), with unrestricted educational grants from Novartis, Schering Healthcare, Chugai, Pharmion, Celgene, and Ortho Biotech.