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PRIORITY PRESS - 52nd Annual Meeting and Exposition of the American Society of Hematology

Orlando, Florida / December 4-7, 2010

Bisphosphonates are known to prevent bone loss and are used to prevent and treat bone lesions in myeloma and other cancers. However, the different mechanisms of action of each bisphosphonate could result in different effects on disease state and survival among cancer patients, noted Prof. Gareth Morgan, Institute of Cancer Research, London, UK.

Nitrogen-containing zoledronic acid induces cell death in osteoclasts, whereas the non-nitrogen bisphosphonate clodronic acid targets bone-destroying cells with cytotoxic compounds. In preclinical models of myeloma, zoledronic acid significantly improved survival, independent of its effects on bone disease (Croucher et al. J Bone Miner Res 2003;18:482-92, Guenther et al. Int J Cancer Res 2010;126:239-46).

Until now, how bisphosphonates improved survival in clinical myeloma remained unclear. No clinical study had demonstrated improved survival with bisphosphonate therapy in a cancer-patient population. However, certain subgroups of patients appeared to derive a survival benefit. For example, a study of clodronic acid in myeloma and bone metastases showed an improvement in overall survival (OS) vs. placebo in patients who had no history of fracture at entry (McCloskey et al. Br J Haematol 2001;21:2188-94).

Resolving the Uncertainty

In an effort to resolve the uncertainty surrounding bisphosphonate effect on survival in myeloma, Prof. Morgan and colleagues enrolled 1970 patients with newly diagnosed myeloma. Patients were randomized to intravenous (i.v.) zoledronic acid (4 mg every 3 to 4 weeks) or to oral clodronic acid 1600 mg/day.

Patients received intensive or non-intensive induction chemotherapy. Intensive induction therapy consisted of 4 to 6 21-day cycles of CVAD (cyclophosphamide/vincristine/doxorubicin/dexamethasone) or CTD (cyclophosphamide/thalidomide/dexamethasone). Non-intensive induction therapy consisted of 6 to 9 28-day cycles of melphalan/prednisolone chemotherapy or an attenuated CTD regimen.

Some 555 patients received zoledronic acid plus intensified chemotherapy; 556 patients received clodronic acid plus intensified therapy; 426 received non-intensive therapy plus zoledronic acid; and 423 received non-intensive therapy and clodronic acid.

Median treatment duration with both bisphosphonates was 350 days and the median follow-up was 3.7 years. The primary end points were OS, progression-free survival (PFS) and overall response rate. Secondary end points included skeletal-related events (SREs) and toxicity.

In the final analysis, patients randomized to zoledronic acid had a median OS of 50 months vs. 44.5 months with clodronic acid (P=0.04). Additionally, treatment with zoledronic acid was associated with a statistically significant 16% reduction in the mortality hazard (P=0.0118) and a 12% improvement in PFS (P=0.0179). It remained significant after adjusting for SREs with a 15% reduction (P=0.0178) (Figure 1).

Figure 1.

Consistent Benefits

The analysis showed no interaction with treatment assignment (intensive vs. non-intensive), lending further support to a survival benefit attributable to zoledronic acid. “These findings support immediate treatment with zoledronic acid in patients with newly diagnosed multiple myeloma, not only for prevention of SREs, but also for potential antimyeloma benefits,” Prof. Morgan told delegates.

“The advantage in favour of zoledronic acid was consistent across all subgroups analyzed,” he added. “Patients who received thalidomide-containing regimens and zoledronic acid had the best clinical outcomes, including complete and very good partial responses, OS and reduction in SREs.”

Overall response rates (complete, very good and partial responses combined) were substantially higher with intensive induction therapy (77% vs. ~50% with non-intensive therapy). Patients allocated to zoledronic acid and non-intensive therapy had a significantly higher rate of complete and very good partial response compared with clodronic acid (P=0.018).

Zoledronic acid significantly reduced the risk of SREs vs. clodronic acid (P=0.0004) and reduced the risk of all types of SREs vs. clodronic acid, regardless of bone-disease status at presentation, Prof. Morgan reported.

The frequency and intensity of toxicity were generally similar between the two bisphosphonates. Osteonecrosis of the jaw, a known potential effect of zoledronic acid, occurred in 4% of patients vs. 1% of those treated with clodronic acid (P<0.0001). Serious adverse events (SAEs) occurred more often in patients treated with zoledronic acid, but the frequency of treatment-emergent SAEs did not differ between treatment groups.

The findings were published simultaneously online in The Lancet. In an accompanying commentary, Dr. Vincent Rajkumar, Mayo Clinic, Rochester, Minnesota, noted the findings support the concept that nitrogen-containing bisphosphonates might have direct anti-myeloma effects.

Timing, Relative Efficacy, Cost

Other studies reported here at the hematology conference provided additional insights into the role of bisphosphonates in the management of multiple myeloma. Investigators in one study examined the relationship between the timing of therapy initiation with zoledronic acid and subsequent effect on SRE risk. They retrospectively reviewed medical records of 312 patients with newly diagnosed multiple myeloma and categorized initiation of treatment with zoledronic acid as early (<60 days after diagnosis) or delayed (=60 days).

The review showed that 126 patients started treatment with zoledronic acid early (median of 25 days from diagnosis of myeloma) and 186 patients had delayed initiation (median of 242 days from diagnosis). Patients who began treatment early had significant prolongation of the time for a first SRE. Two years after myeloma diagnosis, 74.6% of the early-initiation group vs. 56.5% of the delayed-initiation group remained free of SREs (P=0.005), reported Dr. Andrew Peng Yu, Analysis Group Inc., Boston, Massachusetts.

After adjustment for differences in baseline characteristics, early initiation of zoledronic acid remained superior with respect to the SRE-free rate (HR 0.625, P=0.029).

The timing of treatment initiation also influenced discontinuation, Dr. Yu found. After 2 years of follow-up, 9.6% of the early-initiation group had discontinued therapy vs. 16.4% of patients who had delayed initiation (P=0.032). “These results indicate that early initiation of zoledronic acid therapy may have important clinical implications in multiple myeloma,” Dr. Yu concluded.

The comparative effectiveness of bisphosphonates in myeloma was the subject of a meta-analysis reported here at ASH. Investigators analyzed 18 randomized clinical trials involving almost 5000 patients with myeloma. For the outcome of OS, zoledronic acid had a significant advantage over clodronic acid (HR 0.83, 0.73-0.94) and etidronate (HR 0.48, 0.31-0.71) but not pamidronate (HR 0.84, 0.61-1.13) or ibandronate (HR 0.70, 0.42-1.11).

Zoledronic acid demonstrated superiority to clodronic acid for the outcome of PFS (HR 0.88, 0.78-0.99). The analysis showed better outcomes with zoledronic acid with respect to SREs compared with clodronic acid (HR 0.75, 0.64-0.88), pamidronate (HR 0.65, 0.42-0.95) and ibandronate (HR 0.44, 0.26-0.72).

The analysis revealed no significant adverse effects associated with administration of bisphosphonates. However, the incidence of osteonecrosis of the jaw was higher with zoledronic acid compared with clodronic acid.

Finally, a cost-effectiveness analysis based on data from the Canadian health system compared quality-adjusted life-years (QALY) and other outcomes in models of treatment with zoledronic acid vs. clodronic acid. The analysis favoured zoledronic acid with 85% probability when a QALY threshold of $50,000 was used, increasing to 98% probability with a threshold of $100,000 per QALY, reported Thomas E. Delea, Policy Analysis Inc., Brookline, Massachusetts.