Vertebral Fragility in Monoclonal Gammopathy of Undetermined Significance Despite Denosumab: Lessons From a Case

Evidence on antiosteoporotic therapies in patients with precursor stages of myeloma remains rare.Denosumab (DMAb) use in this setting is extrapolated from postmenopausal osteoporosis trials.We present an 81-year-old woman with known high-risk IgG/κ monoclonal gammopathy of undetermined significance (MGUS) who transitioned to low-risk smoldering multiple myeloma (SMM) and developed multiple vertebral fractures while receiving DMAb 60 mg.The patient presented two months after an L4 spontaneous fracture, with severe low back pain impairing mobilization.Ten months earlier, she had sustained an L3 refracture.The fractures occurred at six months post-DMAb injections that were sequentially delayed by approximately seven to 10 weeks, respectively.Her disease had been reclassified as low-risk SMM 18 months earlier (bone marrow plasma cells 15%).At presentation, M-protein (1.93 g/dL) and free light chain (FLC) ratio (5.11) were rising but below the 20/2/20 thresholds.A new lumbar spine CT revealed L1 collapse with vacuum cleft and showed progression of the L4 fracture and the L3 refracture.DMAb was already 10 weeks delayed.S-NTx (13.5 nmBCE) and S-PINP (40.4 ng/mL) were elevated above the median premenopausal values (12.6 nmBCE and 37.5 ng/mL, respectively), consistent with the rebound phenomenon.Given the prolonged DMAb exposure (four years), the delayed timing of the switch (8.5 months after the last dose), and the very high imminent fracture risk, resumption of DMAb was considered preferable to transition to zoledronate.Multilevel percutaneous balloon kyphoplasty was performed at L1, L4, and L3 refracture to reduce pain and preserve or gain height where possible.Intraoperative biopsies were received from L1, L2, and iliac bone.Adjacent fractures with cement, along with poor bone quality, indicated prophylactic cementation of L2.Biopsies confirmed L1 osteonecrosis and showed no evidence of myeloma.Despite the fracture burden and lack of a whole-body MRI, the patient remained under surveillance, since she was classified as having low-to-intermediate risk SMM.Administering DMAb at approximately six months + 6.9 weeks of DMAb delay did not prevent the L3 refracture six months later.Thus, DMAb was given at shortened intervals (three months, then every four months) for one year and was monitored with S-NTx and PINP.This regimen attenuated bone resorption (S-NTx (7.5 to 8.4 nmBCE)) but did not suppress it below the lower premenopausal level before the next injection.PINP decreased below the median premenopausal value after one year of therapy.Postkyphoplasty, a new L2 superior end plate fracture occurred within six months.At nine-month follow-up, a new bone marrow biopsy showed 10% bone marrow clonal plasma cells (BMPCs), and whole-body low-dose CT was negative for lytic lesions.L1 retropulsion progressed without neurologic symptoms.After three years on DMAb 60 mg every six months, no new fractures or neurologic complications occurred.This case highlights the clinical ambiguity when increasing disease burden in patients with MGUS/SMM overlaps with the DMAb-related rebound phenomenon.Additionally, it underscores the gap in evidencebased treatment strategies for osteoporosis in SMM.Percutaneous kyphoplasty combined with monitored denosumab may be a viable option for patients with MGUS/SMM, very high imminent fracture risk and no neurologic deficits, if intervention is indicated.