Evaluation of the Safety and Efficacy of Denosumab in Patients with Multiple Myeloma and Severe Renal Impairment; Results from an IMWG Bone Subcommittee Study

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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 immunotherapy, has demonstrated non-inferiority to zoledronic acid but its efficacy and safety in patients with severe RIremains underexplored. Methods IMWG Bone Subcommittee designed 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 antimyeloma treatment and concurrent denosumab, were analyzed. Results This analysis included 98 MM patients: 51 (52%) with newly-diagnosed (NDMM) and 47 (48%) with relapsed/refractory MM (RRMM; median lines of prior treatment: 5); median age 69 years (IRQ 58.0-77.0); 50 (51.0%) patients were females. All patients had bone disease at the time of denosumab initiation and all RRMM patients had been given zoledronic acid previously. Regarding concomitant anti-myeloma treatments, 23/98 (23.5%) of the patients were receiving bortezomib, cyclophosphamide and dexamethasone (VCd), whereas 32/98 (32.7%) were receiving anti-CD38-based therapies. Median eGFR was 24.0 (16.1-28.0) ml/min/1.73m2. Twenty patients (20.4%) were on dialysis. RI was due to underlying MM in 72 (73.5%) patients; concomitant hypercalcemia was present in 15 (15.3%) patients. The median follow-up was 12.1 (3.3-17.5) months. Eighty-four (85.7%) patients received denosumab at a dose of 120 mgmonthly, while 14 (14.3%) at a dose of 60mg monthly. Best response to MM treatment for the whole cohort was as follows: 8 (8.2%) patients achieved ≥CR, 35 (35.7%) vgPR and 24 (24.5%) PR; median time to response was 42 (28-90) days. Regarding best renal response, 9 (9.2%) patients achieved CRrenal, 12 (12.2%) PRrenal and 31 (31.6%) MRrenal; median time to renal response was 30 (20-42) days. At the time of this report, 44 patients (44.9%) are still receiving denosumab, while 54 (55.1%) have discontinued. The median follow-up after denosumab discontinuation was 1 month. Reasons for treatment discontinuation included mainly disease progression (58.2%), side-effects - mainly hypocalcemia (19.4%) and death. There were 42 recorded deaths (42.9%), mostly attributed to disease progression (88.1%). Fifty-one (52.0%) patients in our cohort developed hypocalcemia [18 grade 1 (35.3%), 13 grade 2 (25.5%), 17 grade 3 (33.3%) and 3 grade 4 (5.9%)]; 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.=-0.43, p<0.001) and higher denosumab dose (120 vs. 60 mg; Fisher's, p=0.016) were associated with hypocalcemia. There were 3 (3.1%) cases of osteonecrosis of the jaw and no case of new SRE during the follow-up period. Conclusions Overall, our findings suggest that denosumab is effective and safe for MM patients with severe RI, provided that proactive measures are taken to mitigate hypocalcemia. Possibly 60 mg, monthly, is sufficient for these patients 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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