Denosumab for smoldering multiple myeloma: Rates of osteoporosis and change in lowest T-score after 12 months of treatment.
Authors: Lipof Jodi , Baran Andrea M. , Passero Frank Charles , Burrows Kaitlyn , Lipe Brea 
Published: June 2023

e20057 Background: Smoldering multiple myeloma (SMM) is a plasma cell precursor disease with variable risk of progression to multiple myeloma (MM). The standard of care for the treatment of SMM remains observation. Numerous clinical trials have sought to determine optimal treatment for SMM but have either failed to demonstrate efficacy, or resulted in unacceptable toxicity for the treatment of a disease that may not lead to progression in some patients. Denosumab is a human monoclonal IgG2 antibody directed against RANKL, that has demonstrated non-inferiority to zoledronic acid for the prevention of lytic bone lesions in MM patients. We are investigating the use of denosumab in patients with SMM and hypothesize that it will lead to decreased rates of progression to MM and increased bone mineral density. In this report, we describe the rates of osteoporosis and change in T scores for patients that received all 12 planned treatment doses. Methods: This is a single-center, open-label, phase II single-arm trial of denosumab in patients with SMM, with at least 1 high-risk feature for progression. All patients received denosumab 120 mg administered by subcutaneous injection every 4 weeks for a total of 12 cycles. Patients underwent bone mineral density analysis by dual-energy X-ray absorptiometry (DEXA) scan at enrollment and after completing study treatment at 13 months. Results: Target enrollment of 20 patients has been reached with a median age of 73 (38-82), 55% of participants being male and 90% identifying as Caucasian/white. At enrollment, 15% of patients were classified as osteoporotic and 40% were classified as osteopenic. Of the 15/20 (75%) of patients that completed all 12 doses of denosumab, 12 had an increase or no change in their lowest t-score [80%, 95% CI = (51.9, 95.7%)]. Only 1 of 15 patients that completed all doses changed classification from osteoporotic to osteopenic. Of the 5 patients that did not complete all 12 doses of denosumab, 3 stopped treatment due to biochemical progression of disease, and 2 patients withdrew from study. One patient withdrew due to COVID-19 concerns and another withdrew due to extensive dental work required during the treatment period. None of the patients have responded to treatment and 6/20 (30%) have progressed. Three of those patients progressed while on treatment and 3 progressed after completing study treatment. All progression of disease has been biochemical and there have been no skeletal-related events recorded at the time of this report. Conclusions: While there appears to be minimal disease response of SMM to denosumab, there does appear to be either stable or increased bone mineral density in the majority of patients that have completed therapy. All patients that have progressed since initiation of the study experienced biochemical progression and no patients have had skeletal-related events at the time of this report. Clinical trial information: NCT03839459 .