DENOSUMAB: COMBINING INHIBITION OF OSTEOCLASTOGENESIS WITH ANTI-MYELOMA ACTIVITY AND AN IMPROVED SIDE-EFFECT PROFILE
Denosumab is a fully human monoclonal antibody that binds and inhibits RANKL and is administered subcutaneously. Unlike BPs, denosumab does not accumulate or persist in bone and is cleared through the reticuloendothelial system hence not dependent on renal clearance. Denosumab has a half-life of approximately 26 days.97 The positive effect of denosumab on bone remodeling was initially demonstrated in the treatment of osteoporosis. A phase III trial of 7886 women with osteoporosis demonstrated that denosumab (60mg given subcutaneously every 6 months) was superior to placebo in reducing the risk of vertebral, nonvertebral and hip fractures.98
Two clinical trials have evaluated the efficacy of denosumab for the prevention of SRE in MM (Table 1).
The first double-blind study which evaluated the efficacy of denosumab in MM was the 244 study which compared denosumab 120mg subcutaneously vs ZA 4mg IV every 4 weeks.99 This study excluded breast and prostate cancer patients and the largest proportion of patients had lung cancer (40%) and MM (10%). The median time to first SRE was longer with denosumab compared to ZA (20.6 vs 16.3 months, p=0.06). Denosumab improved quality of life and also reduced the need for radiation and preventing worsening of pain.100 When all patients in the 244 study were analyzed together, there was no difference in overall survival. However, in the MM cohort (n=180), patients treated with denosumab had a worse overall survival (HR=2.26). Due to the small number of MM patients, the 244 study had many limitations and confounding factors that favored the ZA arm; the denosumab arm had more patients with renal dysfunction (which confers a worse prognosis) and the patients in the ZA arm received more intensive treatment with newer agents and high dose melphalan and ASCT. In addition, there was more censoring from early withdrawal in the ZA arm.
To address the limitations of the 244 study, a large phase III study was carried out randomizing 1718 patients with newly diagnosed MM with at least one bone lesion to either denosumab 120mg subcutaneously vs ZA 4mg IV every 4 weeks.25 The primary end point of the study was time to SRE, defined in the trial as pathologic fracture, need for radiation therapy or bone surgery or spinal cord compression. Denosumab was non-inferior to ZA in time to SRE (22.83 vs 23.98 months; HR=0.98 [0.84–1.14]; p=0.01 for non-inferiority) and OS was similar in both arms, (49.5 months vs not reached; HR=0.90 [0.70–1.16]; p=0.41). PFS survival was longer in the denosumab arm compared with the ZA arm (46 vs 35.4 months; HR=0.82 [0.68–0.99], p=0.036).
ONJ was reported in 4.1% of patients in the denosumab arm and in 2.8% of patients in the ZA arm, though the difference was not statistically significant (p=0.147). Renal toxicity was significantly lower in the denosumab arm compared to the ZA arm, 10 vs 17.1% (p=<0.001) respectively. This difference in renal toxicity was highlighted in patients with renal insufficiency at baseline (creatinine clearance ≤ 60ml/min) where renal toxicity was reduced by half with denosumab compared with ZA; 12.9 vs 26.4% respectively. Fewer acute phase reactions were noted in the denosumab group (5.4%) compared to the ZA group (8.7%). Hypocalcemia occurred in 16.9% of patients in the denosumab arm compared to 12.4% in the ZA arm. Grade 3–4 hypocalcemia was uncommon, occurring in 0.9% of patients in the denosumab arm and 0.2% of patients in the ZA arm. On the basis of these findings, the FDA and the European Medicines Agency approved denosumab for the prevention of SRE in patients with MM.101,102
In a large series of 1027 patients with newly diagnosed MM, half of the patients were found to have an elevated creatinine and 20% had a serum creatinine >2 mg/dl.103 Given these findings and the fact that renal dysfunction often presents a major barrier to effective and continued use of osteoclast-targeted therapy with BPs, denosumab is an ideal agent for preventing SRE in patients with MM and renal disease as its dosing does not depend on creatinine clearance. The improved PFS noted in the denosumab group compared to the ZA group warrants further investigation. Given the key role of RANKL in osteoclastogenesis and the importance of osteoclast cytokine signaling crucial for MPC survival, it is possible that denosumab’s anti-myeloma effects arises from its interference of the crosstalk between osteoclasts and MPC via RANKL.18 The first therapeutic study on RANKL blockade in an animal model of myeloma bone disease revealed that RANKL inhibition markedly reduced tumor burden assessed histologically and by serum paraprotein in the SCID-hu-MM mice.24 In a phase II study of single-agent denosumab in the treatment of 93 relapsed or plateau-phase multiple myeloma patients, treatment with denosumab did not result in reduction of serum monoclonal protein level in the range of complete response, partial response or minimal response.104 However, eleven subjects (21%) with myeloma who entered the study with progressive disease maintained stable disease for a maximum of 16.5 months (median duration: 2.6 months) and 19 subjects (46%) with plateau-phase myeloma maintained stable disease for a maximum of 18.3 months (median duration: 10.2 months). It is important to consider that this study was dealing with a relatively-drug resistant population which may have made it difficult to detect an anti-myeloma effect with single agent denosumab. The stabilization of disease observed in some subjects raises the possibility that cytostatic effects through alteration of the BMME could influence the growth of MPC. Further research into the anti-neoplastic role of RANKL inhibition and its clinical benefit is merited, especially in the context of recent therapeutic advances in the treatment of MM.
As noted above, the toxicity profile of denosumab is fairly established. Hypocalcemia and ONJ are important acute and long term toxicities, respectively. One of the major concerns of denosumab treatment is the increased risk of vertebral fractures when the drug is discontinued. Multiple case reports of vertebral fractures, including multiple vertebral fractures, soon after discontinuation of denosumab in osteoporosis patients have been published.105,106 A post hoc analysis of postmenopausal women with osteoporosis discontinuing denosumab in the FREEDOM trial revealed evidence of increased vertebral fractures.107 The risk of multiple vertebral fractures was 3.4% after stopping denosumab and 2.2% after stopping placebo (p = 0.049), with the risk being 3.9 (95% CI 2.1–7.2) times higher in those with a prior vertebral fracture before or during treatment compared with those having no prior vertebral fracture. Treating with BPs after stopping denosumab can prevent rebound fractures. Limited evidence suggests that ZA given 7–8 months after the last dose of denosumab may be the preferred clinical strategy.108 Further evaluation of denosumab discontinuation and fracture risk in MM patients is warranted.
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