Denosumab in multiple myeloma patients with severe renal impairment: a multicenter phase 2 study

Lytic bone lesions are a defining characteristic of multiple myeloma (MM) and one of its most significant clinical consequences. Bone-modifying agents, including the bisphosphonates zoledronic acid and pamidronate, as well as the receptor activator of nuclear factor-κB ligand (RANKL) monoclonal antibody denosumab, are a mainstay of bone supportive care [ 1 , 2 ]. However, a major limitation of zoledronic acid and pamidronate is nephrotoxicity, with guidelines recommending caution in patients with creatinine clearance <30 mL/min [ 3 ]. This is particularly relevant in MM where renal dysfunction is common at presentation and at relapse [ 4 ]. In contrast, denosumab has a significantly lower risk of kidney injury compared with zoledronic acid in a large, randomized study in MM that led to its approval [ 5 ]. However, patients with creatinine clearance <30 mL/min were excluded from this trial, limiting application of these findings to this subgroup. Given the unmet need for bone supportive care in MM patients with renal impairment, we conducted a prospective, multicenter, phase 2 trial of denosumab in this patient population (NCT02833610).