An Open-Label, Phase 2 Trial of Denosumab in the Treatment of Relapsed (R) or Plateau-Phase (PP) Multiple Myeloma (MM).

Denosumab is a fully human monoclonal antibody that inhibits RANKL, an essential mediator of osteoclast (OC) formation, function, and survival. Denosumab is being investigated in a phase 3 study to delay skeletal-related events in patients (pts) with MM. Preclinical data suggest that OCs may interact either directly with MM cells or indirectly through a “vicious cycle” of bone destruction that releases factors promoting myeloma cell growth. In a mouse MM model, RANKL inhibition reduced OC number, osteolysis, serum paraprotein levels, and prolonged survival. In this single-arm, proof-of-concept study of denosumab in pts with R (≥ 2 prior therapies and relapse after a response to most recent therapy) or PP (response to the most recent therapy and stable, detectable serum M-protein for ≥3 mos) MM, we report efficacy data on pts who could have completed 6 mos of treatment; for the R cohort, this represented a complete analysis and for the PP cohort, this was an interim analysis. Eligible MM pts (age ≥18 yrs; measurable M-protein; ECOG of 0 or 1; life expectancy >3mos) were given subcutaneous injections of denosumab 120mg monthly with additional loading doses on days 8 and 15 of mo 1. Pts were instructed to take calcium 500mg and Vit D 400 IU daily. The primary endpoint was the % of pts with complete response (CR) or partial response (PR), which included serum M-protein reductions ≥50%. Pt incidence of adverse events (AEs) was measured. 52 pts in R (13 women, 39 men) and 33 pts in PP (20 women, 13 men) received 1 to 12 mos of denosumab. The median ages of the R and PP cohorts were 63 and 62 yrs. 79% of the R cohort, and 58% in PP had ≥3 prior therapies. In R, the median on-study follow up time was 3.1 mos; 85% of pts who discontinued denosumab was due to disease progression. In PP, the median on-study follow up time was 8.1 mos; 81% of pts who discontinued treatment was due to disease progression. No objective CR or PR was observed in either cohort. In R, 13 pts (25%) had stable disease for >6 mos; maximum reductions of ≥25% in serum M-protein levels were seen in 3 pts (6%) and <25% in 19 pts (37%). In PP, 19 pts (59%) had stable disease for >6 mos; maximum reductions of ≥25% in serum M-protein levels were seen in 4 pts (13%) and <25% in 18 pts (56%). In R, the median % change from baseline in serum C-telopeptide (sCTx) and bone serum alkaline phosphatase (BSAP) levels at 4 mos was −70% and −33%. In PP, the median % change from baseline in sCTx and BSAP levels at 4 mos was −52% and −16%. The most common AEs were anemia, upper respiratory tract infection, and fatigue (in R); and upper respiratory tract infection, diarrhea, fatigue, headache, peripheral edema, and pain in extremity (in PP). 3 cases of grade 2 hypocalcemia (1 in R, 2 in PP) and 1 case of grade 3 hypocalcemia (in PP) were observed. Of the 19 pts who reported serious AEs across both R and PP, the most common were 2 cases each of thrombocytopenia, pneumonia, relapsed MM, and renal failure. 4 deaths (2 disease progression, 2 pneumonia) occurred on-study, which were not considered to be treatment-related. The stable disease observed in some MM pts in the R and PP cohorts may reflect an inhibitory effect of denosumab on myeloma cell growth and warrants further study.