Daratumumab monotherapy for patients with intermediate-risk or high-risk smoldering multiple myeloma: a randomized, open-label, multicenter, phase 2 study (CENTAURUS)

Abstract

Current guidelines for smoldering multiple myeloma (SMM) recommend active monitoring until the onset of multiple myeloma (MM) before initiating treatment or enrollment in a clinical trial. Earlier intervention may delay progression to MM. In CENTAURUS, 123 patients with intermediate-risk or high-risk SMM were randomly assigned to daratumumab 16 mg/kg intravenously on extended intense (intense), extended intermediate (intermediate), or short dosing schedules. At the prespecified primary analysis (15.8-month median follow-up), the complete response (CR) rates (co-primary endpoint) were 2.4%, 4.9%, and 0% for intense, intermediate, and short dosing, respectively; the co-primary endpoint of CR rate >15% was not met. Progressive disease (PD)/death rates (number of patients who progressed or died divided by total duration of progression-free survival [PFS] in patient-years; co-primary endpoint) for intense, intermediate, and short dosing were 0.055 (80% confidence interval [CI], 0.014–0.096), 0.102 (80% CI, 0.044–0.160), and 0.206 (80% CI, 0.118–0.295), respectively, translating to a median PFS ≥24 months in all arms (P < 0.0001, <0.0001, and =0.0213, respectively). With longer follow-up (median follow-up, 25.9 months), CR rates were 4.9%, 9.8%, and 0% for intense, intermediate, and short dosing, respectively. PD/death rates for intense, intermediate, and short dosing were 0.059 (80% CI, 0.025–0.092), 0.107 (80% CI, 0.058–0.155), and 0.150 (80% CI, 0.089–0.211), respectively, again translating to a median PFS ≥ 24 months in all arms (P < 0.0001 for all arms). Twenty-four–month PFS rates were 89.9% (90% CI, 78.5–95.4%), 82.0% (90% CI, 69.0–89.9%), and 75.3% (90% CI, 61.1–85.0%) for intense, intermediate, and short dosing, respectively. Pharmacokinetic analyses indicated that intense dosing maintained target-saturating trough concentrations in most patients throughout weekly, every-2-week, and every-4-week dosing periods. No new safety signals were observed. These data provide the basis for an ongoing phase 3 study of daratumumab in SMM.

The Role of Monoclonal Antibodies in Smoldering and Newly Diagnosed Transplant-Eligible Multiple Myeloma

“…A single study tested the efficacy of Dara in delaying progression from high and moderate risk SMM to MM [ 13 ]. The CENTAURUS study (NCT02316106) consisted of a phase 2 randomized study employing 3 different Dara schedules.…”

<p>Evaluating Daratumumab in the Treatment of Multiple Myeloma: Safety, Efficacy and Place in Therapy</p>

“…Interim results suggest that daratumumab does have single-agent activity in this patient population; however, the primary endpoints of CR>15% and median PFS ⩾24 months were not met. 80 A phase II trial from Dana Farber is currently evaluating the efficacy of daratumumab for the treatment of high-risk MGUS or low-risk smoldering MM, following patients for 2 years to see how many will achieve VPGR or better. The active phase III AQUILA (NCT03301220) trial is randomly assigning patients with smoldering MM to either an active monitoring arm without intervention or an experimental arm in which they receive SC daratumumab for 39 cycles or 36 weeks.…”

Treatment of Smoldering Multiple Myeloma: Ready for Prime Time?

“…Daratumumab, an anti-CD-38 monoclonal antibody, is well tolerated and has shown single agent activity with deep and durable responses in both newly diagnosed and heavily pretreated MM patients. This formed the basis for the phase II CENTAURUS study that evaluated daratumumab monotherapy with varying treatment durations in SMM [51]. Patients (N = 123) with intermediate-or high-risk SMM were randomly assigned to one of the three daratumumab arms: Extended intense (progressively extended dosing from weekly, every 2, 4, and 8 weeks up to 20 cycles), extended intermediate (weekly in the first 8-week cycle, then every 8 weeks thereafter up to 20 cycles), and short dosing arms (one 8-week cycle of weekly dosing).…”