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.
Highlights
Multiple myeloma (MM) evolves from a premalignant, asymptomatic precursor stage known as smoldering MM
We hypothesized that daratumumab monotherapy could delay progression from intermediate-risk or high-risk smoldering multiple myeloma (SMM) to MM compared with historical observations [19]
The primary analysis of Progressive disease (PD)/ death rate, defined as the number of patients who progressed to MM or died divided by the total duration of progressionfree survival (PFS) for all patients, in patient-years, was conducted 12 months after the last patient was randomized
Summary
Multiple myeloma (MM) evolves from a premalignant, asymptomatic precursor stage known as smoldering MM. The phase 3 QuiRedex study of lenalidomide/dexamethasone (Rd) in patients with SMM, which was conducted before the definition of MM was revised to include validated biomarkers to allow earlier MM diagnosis [6], showed that Rd decreased the proportion of patients who developed MM (39 vs 86%), and improved overall survival (OS), albeit with treatment-related toxicities (one patient died due to treatment) [7, 8] These findings suggest that intercepting high-risk or intermediate-risk SMM may yield clinical benefit, and that finding a less toxic intervention is an unmet need. In the GEN501 and SIRIUS studies, daratumumab monotherapy induced deep and durable responses and had a favorable safety profile in patients with heavily pretreated relapsed and/or refractory MM (RRMM) [17, 18] Based on these findings, we hypothesized that daratumumab monotherapy could delay progression from intermediate-risk or high-risk SMM to MM compared with historical observations [19]. We initiated this phase 2 study of daratumumab monotherapy in patients with intermediate-risk or high-risk SMM
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