IMPORTANCE High-risk smoldering myeloma has a 5-year risk of progression to symptomatic multiple myeloma of approximately 75%. Treatment with lenalidomide decreases the risk of progression; however, novel triplet regimens are superior, and earlier disease may be more treatment sensitive. OBJECTIVE To evaluate the use of carfilzomib, lenalidomide, and dexamethasone (KRd) with lenalidomide maintenance therapy as early intervention in high-risk smoldering myeloma and to determine the rates of minimal residual disease (MRD)-negative complete response (CR). DESIGN, SETTING, AND PARTICIPANTS In this single-arm, single-center, phase 2 nonrandomized controlled trial, responses were evaluated at every cycle during KRd treatment and every 3 cycles subsequently. Bone marrow biopsies and imaging were performed by cycle 8 and then annually. The study enrolled patients from May 29, 2012, to July 23, 2020, at the National Institutes of Health Clinical Center, a highly specialized tertiary cancer center. Patient key eligibility criteria included a diagnosis of high-risk smoldering myeloma based on the Mayo Clinic, Spanish, and/or Rajkumar, Mateos, and Landgren criteria. INTERVENTIONS Patients received eight 4-week cycles of intravenous carfilzomib 36 mg/m2 (first 2 doses, 20 mg/m2), dexamethasone (20 mg, cycles 1-4; 10 mg, cycles 5-8 twice weekly), and lenalidomide 25 mg (days 1-21) followed by twenty-four 28-day cycles of maintenance lenalidomide 10 mg (days 1-21). Stem cell harvest and storage were optional. MAIN OUTCOMES AND MEASURES The primary outcome was the MRD-negative CR rate. Key secondary outcomes included duration of MRD-negative CR and progression to multiple myeloma. RESULTS A total of 54 patients (median age, 59 years [range, 40-79 years]; 30 men [55.6%]; and 2 Asian [3.7%], 15 Black [27.8%], 1 Hispanic [1.9%], and 36 White [66.7%] patients) were enrolled, with a median potential follow-up time of 31.9 months (range, 6.7-102.9 months). The MRD-negative CR rate was 70.4% (95% CI, 56.4%-82.0%), with a median sustained duration of 5.5 years (95% CI, 3.7 years to not estimable). The 8-year probability of being free from progression to multiple myeloma was 91.2% (95% CI, 67.4%-97.9%), and no deaths occurred. Nonhematologic grade 3 adverse events occurred in 21 patients (38.9%) and included thromboembolism, rash, and lung infection, with no grade 4 events. CONCLUSIONS AND RELEVANCE Results of this phase 2 nonrandomized controlled trial suggest that treatment of high-risk smoldering myeloma with novel triplet regimens, such as KRd and lenalidomide maintenance therapy, may alter the natural history of smoldering myeloma by significantly delaying development of end-organ disease. Randomized clinical trials are needed to confirm this favorable benefit-to-risk profile. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01572480.

中文翻译：

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卡非佐米、来那度胺和地塞米松继以来那度胺维持治疗预防高危冒烟型骨髓瘤患者出现症状性多发性骨髓瘤：2 期非随机对照试验。

重要性 高危冒烟型骨髓瘤在 5 年内进展为症状性多发性骨髓瘤的风险约为 75%。来那度胺治疗可降低进展风险；然而，新的三联方案更胜一筹，早期疾病可能对治疗更敏感。目的 评估卡非佐米、来那度胺和地塞米松 (KRd) 联合来那度胺维持治疗作为高危冒烟型骨髓瘤的早期干预，并确定微小残留病 (MRD) 阴性完全缓解 (CR) 的发生率。设计、设置和参与者 在这项单臂、单中心、2 期非随机对照试验中，在 KRd 治疗期间的每个周期以及随后的每 3 个周期评估反应。骨髓活检和成像在第 8 个周期进行，然后每年进行一次。该研究在 2012 年 5 月 29 日至 2020 年 7 月 23 日期间在高度专业化的三级癌症中心美国国立卫生研究院临床中心招募了患者。患者的关键资格标准包括根据 Mayo Clinic、西班牙和/或 Rajkumar、Mateos 和 Landgren 标准诊断为高危冒烟型骨髓瘤。干预 患者接受 8 个 4 周周期的静脉卡非佐米 36 mg/m2（前 2 剂，20 mg/m2）、地塞米松（20 mg，第 1-4 周期；10 mg，第 5-8 周期，每周两次）和来那度胺 25 mg（第 1-21 天），然后是 24 个 28 天周期的维持性来那度胺 10 mg（第 1-21 天）。干细胞收获和储存是可选的。主要结果和措施 主要结果是 MRD 阴性 CR 率。关键的次要结局包括 MRD 阴性 CR 的持续时间和进展为多发性骨髓瘤。结果 共有 54 名患者（中位年龄，59 岁 [范围，40-79 岁]；30 名男性 [55.6%]；2 名亚洲人 [3.7%]，15 名黑人 [27.8%]，1 名西班牙裔 [1.9%]，和 36 名白人 [66.7%] 患者）入组，中位潜在随访时间为 31.9 个月（范围为 6.7-102.9 个月）。MRD 阴性 CR 率为 70.4%（95% CI，56.4%-82.0%），中位持续时间为 5.5 年（95% CI，3.7 年至无法估计）。8 年内无进展为多发性骨髓瘤的概率为 91.2%（95% CI，67.4%-97.9%），无死亡发生。21 名患者 (38.9%) 发生了非血液学 3 级不良事件，包括血栓栓塞、皮疹和肺部感染，没有 4 级事件。结论和相关性 该 2 期非随机对照试验的结果表明，采用新型三联方案（如 KRd 和来那度胺维持治疗）治疗高危冒烟型骨髓瘤可能会通过显着延缓终末器官疾病的发展来改变冒烟型骨髓瘤的自然史. 需要进行随机临床试验来确认这种有利的风险收益比。试验注册 ClinicalTrials.gov 标识符：NCT01572480。