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

• Published in: Leukemia Vol. 34; no. 7; pp. 1840 - 1852
• Main Authors: Landgren, C. Ola, Chari, Ajai, Cohen, Yael C., Spencer, Andrew, Voorhees, Peter, Estell, Jane A., Sandhu, Irwindeep, Jenner, Matthew W., Williams, Catherine, Cavo, Michele, van de Donk, Niels W. C. J., Beksac, Meral, Moreau, Philippe, Goldschmidt, Hartmut, Kuppens, Steven, Bandekar, Rajesh, Clemens, Pamela L., Neff, Tobias, Heuck, Christoph, Qi, Ming, Hofmeister, Craig C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2020; Nature Publishing Group
• Subjects: 692/699/67/1990/804; 692/700/565/1436/2185; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal - therapeutic use; Antineoplastic Agents - therapeutic use; Cancer Research; Care and treatment; Clinical trials; Confidence intervals; Critical Care Medicine; Development and progression; Fatalities; Female; Follow-Up Studies; Hematology; Humans; Immunotherapy; Intensive; Internal Medicine; Male; Medicine; Medicine & Public Health; Middle Aged; Monoclonal antibodies; Mortality; Multiple myeloma; Oncology; Patients; Pharmaceutical industry; Pharmacokinetics; Product development; Prognosis; Risk; Schedules; Smoldering; Smoldering Multiple Myeloma - drug therapy; Smoldering Multiple Myeloma - pathology; Survival Rate; Switzerland; Targeted cancer therapy; United States; United States; Switzerland
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-020-0718-z

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.