Effects of zoledronic acid versus clodronic acid on skeletal morbidity in patients with newly diagnosed multiple myeloma (MRC Myeloma IX): secondary outcomes from a randomised controlled trial

Abstract

SummaryBackgroundBisphosphonates are the standard of care for reducing the risk of skeletal-related events in patients with bone lesions from multiple myeloma. The MRC Myeloma IX study was designed to compare the effects of zoledronic acid versus clodronic acid in newly diagnosed patients with multiple myeloma. Here, we report the secondary outcomes relating to skeletal events.MethodsPatients (≥18 years) with newly diagnosed multiple myeloma were enrolled from 120 centres in the UK and received intensive or non-intensive antimyeloma treatment. A computer-generated randomisation sequence was used to allocate patients in a 1:1 ratio, through an automated telephone service to intravenous zoledronic acid (4 mg every 21–28 days) or oral clodronic acid (1600 mg/day), and the drugs were continued at least until disease progression. No investigators, staff, or patients were masked to treatment allocation. The primary endpoints—overall survival, progression-free survival, and overall response rate—and adverse events have been reported previously. We assessed between-group differences with Cox proportional hazards models for time to first skeletal-related event and incidence of skeletal-related events. These were defined as fractures, spinal cord compression, radiation or surgery to bone, and new osteolytic lesions. Data were analysed until disease progression. Analyses were by intention to treat. This trial is registered, number ISRCTN68454111.Findings1960 patients were randomly assigned and analysed—981 in the zoledronic acid group and 979 in the clodronic acid group. This trial is fully enrolled, and follow-up continues. At a median follow-up of 3·7 years (IQR 2·9–4·7), patients in the zoledronic acid group had a lower incidence of skeletal-related events than did those in the clodronic acid group (265 [27%] vs 346 [35%], respectively; hazard ratio 0·74, 95% CI 0·62–0·87; p=0·0004). Zoledronic acid was also associated with a lower risk of any skeletal-related event in the subsets of patients with (233 [35%] of 668 vs 292 [43%] of 682 with clodronic acid; 0·77, 0·65–0·92; p=0·0038) and without bone lesions at baseline (29 [10%] of 302 vs 48 [17%] of 276 with clodronic acid; 0·53, 0·33–0·84; p=0·0068). Fewer patients in the zoledronic acid group had vertebral fractures than did those in the clodronic acid group (50 [5%] in the zoledronic acid group vs 88 [9%] in the clodronic acid group; p=0·0008), other fractures (45 [5%] vs 66 [7%]; p=0·04), and new osteolytic lesions (46 [5%] vs 95 [10%]; p<0·0001).InterpretationThe results of this study support the early use of zoledronic acid rather than clodronic acid in patients with newly diagnosed multiple myeloma for the prevention of skeletal-related events, irrespective of bone disease status at baseline.FundingMedical Research Council (London, UK), Novartis, Schering Health Care, Chugai, Pharmion, Celgene, and Ortho Biotech.

A Study of Clinical Profile and Biochemical Parameters in Multiple Myeloma

“…The mean age of the study group was 61.4±7.6 yrs with 35 (53.8%) patients in the age group of >60yrs.The median age of diagnosis of multiple myeloma is 70 yrs and it is said to be uncommon <40yrs according to literature, in accordance with a study by Won Jin Chang et al the age group of > 60yrs included only 11.1% patients 15 .In a study by P.kaur et al the age range of patients with myeloma was from 27 to 81 years and the mean age was 57.8 years 16 . In the MRC myeloma IX trial by Gareth J. Morgan et al the median age of myeloma was 73 yrs and a study by Ping Wu et al had a median age of diagnosis of 57yrs 17 .The percentage of males and females were comparable in our study -49.2% males and 50.8% females, this was in accordance with other similar studies.…”

Management of older adults with multiple myeloma

“…Zoledronic acid reduced skeletal-related events more than clodronic acid, with the advantage of longer PFS and OS. [85] and [86] Both zoledronic and pamidronic acid are effective in decreasing skeletal-related events 87 ; recently, no efficacy difference was seen with pamidronate administered at either 30 or 90 mg. In patients with mild to moderate renal impairment (30-60 mL/min of creatinine clearance), dose reductions of zoledronic acid are recommended; in case of severe renal impairment (< 30 mL/min of creatinine clearance), pamidronic acid should be preferred.…”

Myelosuppressive Therapies Significantly Increase Pro-Inflammatory Cytokines and Directly Cause Bone Loss

“…(1,2,5,6) Strategies are required to reduce or prevent skeletal-related events (SREs) in order to improve the quality and potentially duration of life of patients. (7) Bone remodeling, the process whereby old or damaged bone is removed by osteoclasts and replaced by new bone by osteoblasts, is essential for maintaining bone homeostasis. This process takes place at discrete sites throughout the skeleton with bone resorption and formation equal, except during growth and throughout aging.…”