Background Multiple myeloma (MM) patients often develop bone disease, predisposing them to skeletal-related events (SREs). Renal impairment (RI), a cardinal feature of MM, further complicates treatment strategies. Denosumab, a bone-directed agent, has demonstrated non-inferiority to zoledronic acid but its efficacy and safety in patients with severe RI remains underexplored.

Methods The IMWG Bone Subcommittee conducted a retrospective study to evaluate denosumab efficacy and safety in MM patients with severe RI (eGFR based on CKD-EPI <30 ml/min/1.73m2). A multi-institutional chart review was performed and data from patients diagnosed with symptomatic MM and RI, under active treatment and denosumab, were analyzed.

Results This analysis included 118 MM patients: 61 (51.7%) newly-diagnosed (NDMM) and 57 (48.3%) relapsed/refractory (RRMM; median lines of prior treatment: 5); median age 70 years (range 28 – 92); 61 (51.7%) patients were females. All patients had bone disease at the time of denosumab initiation and all but two RRMM patients had been given zoledronic acid previously. Median eGFR was 23.75 (4.4-30.0) ml/min/1.73m2. Twenty-nine patients (24.6%) were on dialysis. RI was due to underlying MM in 87 (73.7%) patients; concomitant hypercalcemia was present in 18 (15.3%) patients. The median follow-up was 19.2 (5.5-22.4) months. 101 (85.6%) patients received denosumab at a dose of 120 mg monthly, while 17 (14.4%) at a dose of 60mg monthly.

Best response to MM treatment for the whole cohort was as follows: 10 (8.5%) patients achieved ≥CR, 42 (35.6%) vgPR and 29 (24.6%) PR; median time to response was 42 (28-90) days. Regarding best renal response, 11 (9.3%) patients achieved CRrenal, 15 (12.7%) PRrenal and 37 (31.4%) MRrenal; median time to renal response was 30 (20-42) days.

At the time of this report, 50 patients (42.4%) are still receiving denosumab, while 68 (57.6%) have discontinued.Reasons for treatment discontinuation included mainly disease progression (58.5%), side-effects – mainly hypocalcemia (28.0%) and death. There were 51 recorded deaths (43.2%), mostly attributed to disease progression (88.2%).

Sixty-five (55.1%) patients in our cohort developed hypocalcemia [23 grade 1 (35.4%), 16 grade 2 (24.6%), 22 grade 3 (33.8%) and 4 grade 4 (6.2%)]; almost four times higher than the reported incidence for patients with normal renal function or mild/moderate RI. Lower baseline calcium levels (Point-Biserial, coeff.=-0.39, p<0.001) and higher denosumab dose (120 vs. 60 mg; Fisher's, p=0.022) were associated with hypocalcemia. There were 4 (3.9%) cases of osteonecrosis of the jaw and one case of new SRE (fracture) during the follow-up period.

Conclusions Overall, our findings suggest that denosumab is effective and safe for MM patients with severe RI, provided that prevention measures are taken to mitigate hypocalcemia. Denosumab 60 mg, monthly, seems to be sufficient to prevent both SREs and hypocalcemia. However, further prospective research with larger cohort and longer follow-up period will confirm these results and refine treatment guidelines.

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2025
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