An open-label, phase 2 trial of denosumab in the treatment of relapsed or plateau-phase multiple myeloma.

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Am J Hematol. 2009 Oct;84(10):650-6.
An open-label, phase 2 trial of denosumab in the treatment of relapsed or plateau-phase multiple myeloma.
Vij R, Horvath N, Spencer A, Taylor K, Vadhan-Raj S, Vescio R, Smith J, Qian Y, Yeh H, Jun S.
Division of Oncology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

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. (c)
2009 Wiley-Liss, Inc.