title: An open-label, phase 2 trial of denosumab in the treatment of relapsed or plateau-phase multiple myeloma.
abstract: RANKL is a key mediator of osteoclast differentiation, activation, and survival. Preclinical data suggest that aberrant production and activation of osteoclasts may influence proliferation of multiple myeloma (MM) cells in the bone marrow. Reports have also shown that inhibiting RANKL may have a direct effect on RANK-expressing myeloma cells and a therapeutic role in treating the disease. In mouse myeloma models, inhibition of RANKL led to reduced serum paraprotein levels and tumor burden. Based on this hypothesis, this proof-of-concept, single-arm study investigated whether RANKL inhibition with denosumab could reduce serum M-protein levels in relapsed or plateau-phase myeloma subjects. All subjects received denosumab monthly, with loading doses on days 8 and 15 of month one, until disease progression or subject discontinuation. Results of this ongoing study demonstrated that no subjects in either cohort met the protocol-defined objective response criteria of complete response (CR) or partial response (PR), but that denosumab effectively inhibited the RANKL pathway regardless of previous exposure to bisphosphonates, as evidenced by suppressed levels of the bone turnover marker, serum C-terminal telopeptide of type 1 collagen (sCTx). Eleven (21%) subjects who relapsed within 3 months before study entry maintained stable disease for up to 16.5 months. Nineteen (46%) subjects with plateau-phase myeloma maintained stable disease for up to 18.3 months. The adverse event (AE) profile for denosumab and its dosing schedule in these populations was consistent with that for advanced cancer patients receiving systemic therapy. Additional controlled clinical studies of denosumab in subjects with both relapsed and plateau-phase MM are warranted.
authors.affiliation: Division of Oncology, Washington University School of Medicine, St. Louis, Missouri 63110, USA. rvij@dom.wustl.edu
authors.forename: Ravi
authors.initials: R
authors.lastname: Vij
authors.forename: Noemi
authors.initials: N
authors.lastname: Horvath
authors.forename: Andrew
authors.initials: A
authors.lastname: Spencer
authors.forename: Kerry
authors.initials: K
authors.lastname: Taylor
authors.forename: Saroj
authors.initials: S
authors.lastname: Vadhan-Raj
authors.forename: Robert
authors.initials: R
authors.lastname: Vescio
authors.forename: Judy
authors.initials: J
authors.lastname: Smith
authors.forename: Yi
authors.initials: Y
authors.lastname: Qian
authors.forename: Howard
authors.initials: H
authors.lastname: Yeh
authors.forename: Susie
authors.initials: S
authors.lastname: Jun
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001315:Australia; D001862:Bone Resorption / Q000517:prevention & control; D015331:Cohort Studies; D000069448:Denosumab; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D053245:RANK Ligand / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012008:Recurrence; D014481:United States
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007136:Immunoglobulins; C009823:M-proteins (Myeloma); D053245:RANK Ligand; D000069448:Denosumab