Department of Medicine, Myeloma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Leukemia. 2020 Jul;34(7):1840-1852. doi: 10.1038/s41375-020-0718-z. Epub 2020 Feb 5.
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.
目前，冒烟型多发性骨髓瘤（SMM）的指南建议在开始治疗或入组临床试验之前，积极监测直至多发性骨髓瘤（MM）发作。更早的干预可能会延迟进展为 MM。在 CENTAURUS 研究中，123 例中危或高危 SMM 患者被随机分配至达雷妥尤单抗 16mg/kg 静脉输注，分别接受密集型（intense）、延长中间型（intermediate）或短程给药方案。在预设的主要分析（中位随访 15.8 个月）中，完全缓解（CR）率（主要共同终点）分别为 2.4%、4.9%和 0%，密集型、延长中间型和短程给药方案的 CR 率＞15%的主要共同终点未达到。密集型、延长中间型和短程给药方案的进展性疾病（PD）/死亡率（进展或死亡的患者人数除以患者无进展生存时间的总持续时间[以患者年计算]；主要共同终点）分别为 0.055（80%置信区间[CI]，0.014-0.096）、0.102（80%CI，0.044-0.160）和 0.206（80%CI，0.118-0.295），所有臂的中位无进展生存期（PFS）均≥24 个月（均＜0.0001）。随着随访时间的延长（中位随访 25.9 个月），密集型、延长中间型和短程给药方案的 CR 率分别为 4.9%、9.8%和 0%。密集型、延长中间型和短程给药方案的 PD/死亡率分别为 0.059（80%CI，0.025-0.092）、0.107（80%CI，0.058-0.155）和 0.150（80%CI，0.089-0.211），所有臂的中位 PFS 再次均≥24 个月（均＜0.0001）。密集型、延长中间型和短程给药方案的 24 个月 PFS 率分别为 89.9%（90%CI，78.5-95.4%）、82.0%（90%CI，69.0-89.9%）和 75.3%（90%CI，61.1-85.0%）。药代动力学分析表明，密集型给药方案在每周、每 2 周和每 4 周给药期间，大多数患者均维持了目标饱和的谷浓度。未观察到新的安全性信号。这些数据为达雷妥尤单抗在 SMM 中的一项正在进行的 3 期研究提供了依据。
