Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Instituto de Biología Molecular y Celular del Cáncer, Salamanca, Spain.
Hospital Universitario de Canarias, Tenerife, Spain.
Lancet Oncol. 2016 Aug;17(8):1127-1136. doi: 10.1016/S1470-2045(16)30124-3. Epub 2016 Jul 9.
The standard of care for smouldering multiple myeloma is observation. We did the QuiRedex study to compare early treatment with lenalidomide plus dexamethasone with observation in patients with high-risk smouldering multiple myeloma. Here we report the long-term follow-up results of the trial.
We did this open-label, randomised, controlled phase 3 study at 19 centres in Spain and three centres in Portugal. Patients aged 18 years or older with high-risk smouldering multiple myeloma were randomly assigned (1:1), via a computerised random number generator, to receive either early treatment with lenalidomide plus dexamethasone or observation, with dynamic balancing to maintain treatment balance within the two groups. Randomisation was stratified by time from diagnosis of smouldering multiple myeloma to study enrolment (≤6 months vs >6 months). Patients in the treatment group received nine 4-week induction cycles (lenalidomide 25 mg per day on days 1-21, plus dexamethasone 20 mg per day on days-1-4 and days 12-15), followed by maintenance therapy (lenalidomide 10 mg per day on days 1-21 of each 28-day cycle) up to 2 years. Group allocation was not masked from study investigators or patients. The primary endpoint was time from randomisation to progression to symptomatic myeloma. The primary analysis was based on the per-protocol population, restricted to patients who fulfilled the protocol in terms of eligibility. Safety assessments were based on the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00480363.
Between Nov 8, 2007, and June 9, 2010, 125 patients were enrolled and underwent randomisation. 119 patients comprised the per-protocol population and were randomly assigned to receive either lenalidomide plus dexamethasone (n=57) or observation (n=62). The cutoff date for this update was June 30, 2015. Median follow-up for surviving patients was 75 months (IQR 67-85). Lenalidomide plus dexamethasone continued to provide a benefit on time to progression compared with observation (median time to progression not reached [95% CI 47 months-not reached] vs 23 months [16-31]; hazard ratio [HR] 0·24 [95% CI 0·14-0·41]; p<0·0001). Progression to multiple myeloma occurred in 53 (86%) of 62 patients in the observation group compared with 22 (39%) of 57 patients in the treatment group. At data cutoff, ten (18%) patients had died in the treatment group and 22 (36%) patients had died in the observation group; median overall survival from the time of study entry had not been reached in either group (95% CI 65 months-not reached vs 53 months-not reached; HR 0·43 [95% CI 0·21-0·92], p=0·024). Survival in patients who had received subsequent treatments at the time of progression to active disease did not differ between groups (HR 1·34 [95% CI 0·54-3·30]; p=0·50). The most frequently reported grade 3 adverse events in patients given lenalidomide plus dexamethasone were infection (four [6%]), asthenia (four [6%]), neutropenia (three [5%]), and skin rash (two [3%]); these events all occurred during induction therapy. No grade 4 adverse events occurred, but one (2%) patient in the lenalidomide plus dexamethasone group died from a respiratory infection during induction therapy The frequency of second primary malignancies was higher in patients in the treatment group than in those in the observation group (six [10%] of 62 patients vs one [2%] of 63 patients), but the cumulative risk of development did not differ significantly between the groups (p=0·070).
This study is, to our knowledge, the first randomised trial in which early treatment has been assessed in selected patients with high-risk smouldering multiple myeloma. Positive results from ongoing trials would support the use of early treatment for patients with high-risk disease in the near future.
Pethema (Spanish Program for the Treatment of Hematologic Diseases).
冒烟型多发性骨髓瘤的标准治疗方法是观察。我们开展了 QuiRedex 研究，旨在比较来那度胺联合地塞米松早期治疗与高危冒烟型多发性骨髓瘤患者观察等待的疗效。现将该试验的长期随访结果报道如下。
我们在西班牙的 19 个中心和葡萄牙的 3 个中心开展了这项开放标签、随机、对照的 3 期研究。年龄在 18 岁及以上、具有高危冒烟型多发性骨髓瘤的患者，按计算机生成的随机数字，以 1:1 的比例，通过动态平衡以维持两组之间的治疗平衡，随机分配接受来那度胺联合地塞米松早期治疗或观察等待。随机分组根据从冒烟型多发性骨髓瘤诊断到研究入组的时间（≤6 个月 vs. >6 个月）进行分层。治疗组患者接受 9 个为期 4 周的诱导周期（来那度胺 25 mg/d，第 1-21 天；地塞米松 20 mg/d，第-1-4 天和第 12-15 天），随后进行维持治疗（来那度胺 10 mg/d，每 28 天周期的第 1-21 天），持续 2 年。研究人员和患者对分组情况均不知情。主要终点是从随机分组到进展为有症状多发性骨髓瘤的时间。主要分析基于方案人群，仅限于符合方案入组标准的患者。安全性评估基于意向治疗人群。该试验在 ClinicalTrials.gov 注册，编号为 NCT00480363。
2007 年 11 月 8 日至 2010 年 6 月 9 日期间，共纳入 125 名患者并进行随机分组。119 名患者符合方案人群，随机分配接受来那度胺联合地塞米松（n=57）或观察等待（n=62）。本次更新的截止日期为 2015 年 6 月 30 日。对存活患者进行中位随访 75 个月（IQR 67-85）。与观察等待相比，来那度胺联合地塞米松持续显示出对进展时间的获益（中位无进展时间未达到[95%CI 47 个月-未达到] vs. 23 个月[16-31]；风险比[HR]0.24[95%CI 0.14-0.41]；p<0.0001）。在观察等待组中，62 名患者中有 53 名（86%）进展为多发性骨髓瘤，而在治疗组中，57 名患者中有 22 名（39%）进展为多发性骨髓瘤。在数据截止时，治疗组中有 10 名（18%）患者死亡，观察等待组中有 22 名（36%）患者死亡；两组的中位总生存期均未达到（95%CI 65 个月-未达到 vs. 53 个月-未达到；HR 0.43[95%CI 0.21-0.92]，p=0.024）。在进展为活动性疾病时接受后续治疗的患者中，两组的生存情况无差异（HR 1.34[95%CI 0.54-3.30]；p=0.50）。接受来那度胺联合地塞米松治疗的患者最常见的 3 级不良事件为感染（4 例[6%]）、乏力（4 例[6%]）、中性粒细胞减少（3 例[5%]）和皮疹（2 例[3%]）；这些事件均发生在诱导治疗期间。未发生 4 级不良事件，但治疗组中有 1 例（2%）患者在诱导治疗期间死于呼吸道感染。治疗组的第二原发恶性肿瘤发生率高于观察等待组（62 名患者中有 6 例[10%] vs. 63 名患者中有 1 例[2%]），但两组之间的累积发病风险差异无统计学意义（p=0.070）。
就我们所知，这是第一项在具有高危的冒烟型多发性骨髓瘤患者中评估早期治疗的随机试验。正在进行的试验的阳性结果将支持在不久的将来对高危疾病患者进行早期治疗。
Pethema（西班牙血液疾病治疗计划）。
