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Perspectives
Osteoprotective medication in the era of novel agents: a European perspective on values, risks and future solutions
Monika Engelhardt,1,2 Georg W. Herget,3 Giulia Graziani,1,2 Gabriele Ihorst,4 Heike Reinhardt,1,2 Stefanie Ajayi,1,2 Stefan Knop5 and Ralph Wasch1,2
1Department of Medicine I, Hematology, Oncology & Stem Cell Transplantation, Medical Center, University of Freiburg; 2Comprehensive Cancer Center Freiburg (CCCF), Medical Center, University of Freiburg; 3Department of Orthopedics and Trauma Surgery, Medical Center, University of Freiburg; 4Clinical Trials Unit, Medical Center, University of Freiburg and 5Hematology, Oncology, Gastroenterology, University of Würzburg, Germany
E-mail: monika.engelhardt@uniklinik-freiburg.de doi:10.3324/haematol.2018.188516
Osteolytic bone disease is one of the most promi- nent features of multiple myeloma (MM) and is
1 present in up to 80% of patients at diagnosis.
Bone destruction leads to skeletal-related events (i.e. verte- bral and other pathological fractures) and/or spinal cord compression. MM is mainly due to an increase in osteo- clastic activity which is accompanied by low osteoblastic function.1 Bisphosphonates and other bone-targeting agents (such as denosumab which inhibits RANKL and osteoclast function and is not renally cleared), effective anti-myeloma treatment, radiotherapy and surgery are the main therapies used for the management of bone disease in MM.1–3 Regarding the definition of MM-defining events, there are important studies which suggest that asympto- matic patients with more than one focal lesion detectable by magnetic resonance imaging have a higher risk of pro- gression to symptomatic MM (>70% within 2 years).1,4–6 These patients have been described by international myeloma experts as having symptomatic disease.5,6
Based on phase 3 studies, the bisphosphonates, pamidronate and zoledronic acid, have been found to reduce skeletal-related events compared to placebo.7–9 Three randomized studies have compared the effect of different bisphosphonates or different dosages of the same bisphosphonate. In the first study, zoledronic acid was as effective as pamidronate in reducing skeletal-relat- ed events in the era of conventional chemotherapy.9,10 In the second, two doses of intravenous pamidronate (30 versus 90 mg) showed comparable results regarding time to skeletal-related events and survival time free of such events.11 The limitation of this study was that it was pow- ered to show differences in quality of life and not in skeletal-related events.11 The third study compared intra- venous (i.v.) zoledronic acid with oral clodronate and showed that zoledronic acid reduced the risk of skeletal- related events compared to clodronate in all MM patients, irrespective of the presence of lytic lesions at diagnosis, and improved overall survival by 10 months in patients with lytic lesions at diagnosis.12,13 These effects continued in patients who received zoledronic acid for >2 years.14 There was no sub-analysis according to the response sta- tus of the patients, thus it is not clear whether the contin- uous use of zoledronic acid produces similar results in patients who have achieved excellent responses (≥very good partial response). A meta-analysis was unable to confirm superiority of zoledronic acid over pamidronate, but revealed a survival advantage from zoledronic acid versus placebo.15 This analysis also determined that in
order to prevent one skeletal-related event, 6-15 MM patients need to be treated.15
The European Myeloma Network (EMN) and International Myeloma Working Group (IMWG) have therefore recommended that all MM patients with ade- quate renal function (creatinine clearance >30 mL/min) and osteolytic disease at diagnosis should be treated with zoledronic acid [4 mg i.v. infusion, over at least 15 min, every 4 weeks (Q4W) or pamidronate (90 mg, in a 3-hour infusion, Q4W], in addition to specific anti-myeloma therapy (grade 1A; definition of evidence levels: Online Supplementary Table S1). Symptomatic patients, without bone disease assessed by conventional radiography, can be treated with zoledronic acid (grade 1B). The advantage is not clear for patients without detectable bone involve- ment on magnetic resonance imaging or positron emis- sion tomography/computed tomography. Bisphosphonates are not routinely recommended in smoldering MM (grade 1A); but in cases of osteoporosis or vertebral fractures that are not due to the MM, bispho- sphonates should be given at the doses given for osteo- porosis (5 mg zoledronic acid/year). For high-risk smol- dering MM, the treating physician should consider using the bisphosphonate doses and schedules typically used to treat symptomatic MM (grade 1B). Zoledronic acid should be given continuously (grade 1B). It is debatable whether patients who achieve a very good partial response or better have benefits from the continuous use of zoledronic acid. Regarding pamidronate, there are no data to support its continuous use; thus it should be given for 2 years and then at the physician’s discretion (grade 2C).1,2 Of note, bisphosphonates are now available as generic drugs, whereas denosumab has just been approved by the Food and Drug Administration for use in MM (January 2018; likewise anticipated in Europe) and is patent-protected. This approval was based on the results of a large phase III study comparing denosumab with zoledronic acid, in which the efficacy and safety of the drugs were assessed in newly diagnosed MM. Eligible patients were randomized 1:1 to denosumab 120 mg sub- cutaneously Q4W or zoledronic acid 4 mg (with dose adjustments according to renal function) i.v. Q4W along with anti-myeloma therapy. The primary objective was non-inferiority of denosumab to zoledronic acid with respect to time to first on-study skeletal-related event. Overall survival was a secondary endpoint; progression- free survival was an exploratory endpoint. The 1718 patients enrolled were randomized into two arms, each
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