Osteonecrosis of the Jaw in Myeloma Patients Receiving Denosumab or Zoledronic Acid. Comment on Pivotal Trial by Raje et al. Published on Lancet Oncology

Abstract

The recent randomized trial, published by Raje et al., on Lancet Oncology is potentially practice changing. It proposes that denosumab is a valid alternative to zoledronic acid in the treatment of myeloma patients. However, several points need further data and more details, such as information on incidence, diagnosis, and follow-up of osteonecrosis of the jaw (ONJ) cases, observed among treated patients. Adopted definition to adjudicate ONJ cases, type of registration of potential ONJ cases, length of observation are possible causes of potential underestimation of ONJ incidence in their study. Future updated evaluations with longer follow-up, and including actuarial estimation, are required for final judgment on ONJ risk in myeloma patients receiving denosumab, and comparison with ONJ risk by zoledronic acid.

Reply to Comment—Osteonecrosis of the Jaw in Myeloma Patients Receiving Denosumab or Zoledronic Acid. Comment on Pivotal Trial by Raje et al. Published in Lancet Oncology

“…Consistent with this observation, median exposure to denosumab and zoledronic acid was longer in our study (15.8 and 14.8 months, respectively) [2] than that reported in the integrated dataset from pivotal denosumab registrational studies in solid tumor patients (12.0 and 11.1 months, respectively) [6,21]. The data presented in Fusco et al [1] compare cumulative incidence of ONJ across the various trials. Because cumulative incidence depends on the patient characteristics, treatment characteristics, and time period of follow-up, it is difficult to compare or summarize the cumulative incidences in a single summary risk estimate across studies.…”

“…Once receiving treatment, patients need to be monitored for ONJ symptoms and should avoid invasive dental procedures. We have addressed as many of the concerns that were raised by Fusco et al [1] as is possible, and again thank them for their comments and observations on our study results.…”

“…We believe that the information reported in the Saad et al 2012 study may have been misinterpreted by Fusco et al [1]. In that study, all of the oral adverse events (AEs) were referred to the independent ONJ adjudication committee and, of those, one third of the cases evaluated were found to be positively-adjudicated ONJ.…”

“…We read the comment by Fusco et al [1] in response to our recent article in Lancet Oncology titled “Denosumab Versus Zoledronic Acid in Bone Disease Treatment of Newly Diagnosed Multiple Myeloma: An International, Double-Blind, Double-Dummy, Randomised, Controlled, Phase 3 Study” [2], and want to thank the authors for their interest and review of our study report. We would like to respond to their comment as follows.…”

Comment on Medication-Related Osteonecrosis of the Jaw: MASCC/ISOO/ASCO Clinical Practice Guideline Summary

“…These possible nonexposed MRONJ patients are still excluded from the definition of an MRONJ patient, and they contribute to the perceived underestimation of the disease burden. 18,19 In several recently published randomized controlled trials comparing the efficacy of denosumab and zoledronic acid in the cancer setting, a consistent number of patients receiving BMAs developed signs and symptoms that are compatible with exposed or nonexposed MRONJ during the study (ie, "potential" MRONJ patients), [20][21][22][23][24] of whom only a few were confirmed by the adjudication committees, based on the AAOMS 2009 and 2014 definitions 3 (Table 1). Unfortunately, neither clinical nor radiologic data for patients who were not adjudicated have been reported so far.…”