ASCO Panel Sees Greater Utility for Bone-Modifying Agents in Myeloma

Kenneth C. Anderson, MD

In updated guidelines exploring the role of bone-modifying agents, the American Society of Clinical Oncology (ASCO) has recommended expanding the use of bisphosphonates to include all patients being treated for active multiple myeloma.¹

The previous guidelines recommended bone-modifying agents only for patients with lytic disease, said Kenneth C. Anderson, MD, program director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at Dana-Farber Cancer Institute, Boston. Anderson served as co-chair of the ASCO expert panel that wrote these new guidelines.

Anderson said the recommendation was based on results from the phase III MRC Myeloma IX Trial, which demonstrated the benefit of bisphosphonate therapy in patients with newly diagnosed multiple myeloma who did not have lytic bone disease.

At first randomization, patients were assigned to 4 mg of zoledronic acid (Zometa) as an infusion every 3 to 4 weeks or 1600 mg of oral clodronic acid (Clodronate) daily from May 2003 to November 2007. Patients also received intensive or nonintensive induction chemotherapy. The zoledronic acid group included 555 patients on intensive chemotherapy and 426 on nonintensive chemotherapy.²

A total of 1960 patients were included in the intention-to-treat analysis. The treatment cutoff was October 5, 2009, with patients receiving bisphosphonates for a median of 350 days (interquartile range, 137-632) before disease progression.

At a median follow-up of 3.7 years, zoledronic acid reduced mortality by 16% (95% CI, 4%-26%) versus clodronic acid (HR, 0.84; 95% CI, 0.74-0.96; P = .0118), and it extended median overall survival (OS) by 5.5 months (50.0 vs 44.5 months; P = .04). Zoledronic acid also significantly improved progression-free survival (PFS) by 12% (95% CI, 2%-20%) versus clodronic acid (HR, 0.88; 95% CI, 0.80-0.98; P = .0179), and it increased median PFS by 2.0 months (19.5 vs 17.5 months; P = .07).

Table. Denosumab Demonstrates Noninferiority to Zoledronic Acid in Time to First Skeletal Event⁵

Dosing Changes Discussed

Rates of complete, very good partial, or partial response did not differ significantly between the zoledronic acid and clodronic acid groups for patients receiving intensive induction chemotherapy (78% vs 76%; P = .43) or nonintensive induction chemotherapy (50% vs 46%; P = .18). In long-term follow-up results (median, 5.9 years), zoledronic acid was associated with significantly improved PFS (HR, 0.89; P = .02) and OS (HR, 0.86; P = .01) compared with clodronic acid.³The updated guidelines also discuss the feasibility of less-frequent dosing of bone-targeted treatments in selected patients, given the risk of osteonecrosis of the jaw (ONJ) associated with bone-targeting agents. Study results have shown that less-frequent dosing can reduce the risk.

For patients without active multiple myeloma who are receiving maintenance therapy, receiving bisphosphonates every 3 months, rather than monthly, is an option. Data from the single-arm Z-MARK study associated less-frequent dosing of zoledronic acid with a low incidence of skeletal-related events (SREs). Results from that study showed that patients treated with zoledronic acid every 12 weeks were not at increased risk for SREs. Incidence of SREs was 5.8% at year 1 and 4.9% at year 2.⁴

Incidence of ONJ was 3.3% beyond 3 years. Z-MARK investigators noted that the finding was consistent with the incidence of ONJ (≤5%) reported in long-term studies in patients receiving monthly zoledronic acid treatment for more than 2 years.

“In terms of duration of therapy, previous guidelines had suggested continuing bisphosphonates for 2 years, after which point discontinuation should be considered and further use should be left up to the physician’s discretion,” Anderson said. “Recent data suggest a potential benefit with continued dosing beyond 2 years, although this has not been evaluated in a randomized study. The new guidelines note that there are insufficient data to recommend a specific duration of bisphosphonate therapy. Therefore, it is recommended that bone-targeted treatments are continued for up to 2 years, resuming monthly treatment upon relapse with new-onset SREs.”

The updated guidelines recommend denosumab (Xgeva), a RANK ligand inhibitor, as an alternative to zoledronic acid, but note that denosumab is substantially more expensive. The 4-week cost is $399 for intravenous (IV) pamidronate; $697 for IV zoledronic acid; and $25,941 for denosumab.¹ The FDA approved denosumab for the prevention of SREs in patients with multiple myeloma in January 2018 based on data from the phase III 482 study.⁵

In that trial, denosumab demonstrated noninferiority to zoledronic acid (Zometa) at delaying the time to the first SRE in patients with multiple myeloma (HR, 0.98; 95% CI, 0.85-1.14; P = .01).

The median time to first on-study SRE was similar between the treatments, at 22.8 months with denosumab versus 24.0 months with zoledronic acid (TABLE). The median PFS was 10.7 months higher in the denosumab arm (HR, 0.82; 95% CI, 0.68-0.99; P = .036). There was also a nonstatistically significant trend in OS favoring denosumab (HR, 0.90; 95% CI, 0.70-1.16; P = .41).

As noted in the guidelines, the risk for ONJ appears to increase with the use of more potent bisphosphonates, such as pamidronate (Aredia) and zoledronic acid. It has also been observed in patients undergoing treatment with denosumab.

The guidelines advise that patients undergo a comprehensive dental examination with appropriate preventive measures before starting bone-modifying therapy. Active oral infections should be treated and high-risk sites should be eliminated. Clinicians should talk with patients about the importance of oral hygiene and of avoiding invasive dental procedures if possible.

References

1. Anderson K, Ismaila N, Flynn PJ, et al. Role of bone-modifying agents in multiple myeloma: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2018;36(8):812-818. doi: 10.1200/JCO.2017.76.6402.
2. Morgan GJ, Davies FE, Gregory WM, et al; National Cancer Research Institute Haematological Oncology Clinical Study Group. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet. 2010;376(9757):1989-1999. doi: 10.1016/S0140-6736(10)62051-X.
3. Morgan GJ, Davies FE, WM Gregory, et al. Long-term follow-up of MRC Myeloma IX trial: survival outcomes with bisphosphonate and thalidomide treatment. Clin Cancer Res. 2013;19(21):6030-6038. doi: 10.1158/1078-0432.CCR-12-3211.
4. Raje N, Vescio R, Montgomery CW, et al. Bone marker-directed dosing of zoledronic acid for the prevention of skeletal complications in patients with multiple myeloma: results of the Z-MARK study. Clin Cancer Res. 2016;22(6);1378-1384. doi: 10.1158/1078-0432.CCR-15-1864.
5. Raje N, Terpos E, Willenbacher W, et al. Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study. Lancet Oncol. 2018;19(3):370-381. doi: 10.1016/ S1470-2045(18)30072-X.