Smoldering multiple myeloma (SMM) is an asymptomatic phase of multiple myeloma (MM) first described in 1980 [1]. It is associated with a yearly risk of progression to MM of approximately 10% in the first 5 years, 3% in the following 5 years, and 1% thereafter [2]. While a watch-and-wait strategy has traditionally been the standard approach for SMM, the notion of early intervention has been under investigation for over three decades [3, 4]. The earliest studies using melphalan in combination with steroids did not demonstrate benefit in terms of response or overall survival (OS) [3, 4]. Subsequently, the use of bisphosphonates was associated with reduction in skeletal-related events without improvement in progression-free survival (PFS) or OS [5]. Upon emergence of evidence for thalidomide activity in MM [6], our group conducted a phase II study of thalidomide in SMM, showing activity in this setting [7]. This was the basis of a phase III randomized trial in 2003, which compared thalidomide (Thal) plus zoledronic acid (ZLD) to ZLD in patients with SMM. In 2013, initial results were published after 6 years of follow-up: patients in the Thal+ZLD arm had longer time-to-progression (TTP) (2.4 vs. 1.2 years, P = 0.02) and 1-year PFS (86% vs. 55%, P = 0.005) compared to the ZLD arm, with progression defined according to the International Myeloma Working Group (IMWG) response criteria [8]. Thal+ZLD was also associated with longer TTP and PFS when progression was defined as “CRAB” features, but these results were not statistically significant [9]. The approval of lenalidomide, which is associated with lower neurotoxicity compared to thalidomide, and emergence of SMM risk stratification systems [10,11,12], shaped the design of subsequent studies, which used lenalidomide-based interventions targeting intermediate- and high-risk SMM patients. In the QuiRedex trial, lenalidomide plus dexamethasone combination was associated with longer TTP and OS compared to active surveillance in high-risk SMM [13]. In the ECOG-ACRIN trial, lenalidomide was associated with improvement in PFS, but not OS, in intermediate- or high-risk patients after a follow-up of 35 months [14]. Given the short follow-up, it remains unclear whether early intervention offers a survival advantage. Thus, we performed an updated analysis of the Thal+ZLD vs. ZLD trial to evaluate OS after approximately 18 years of follow-up. We also evaluated TTP to MM and myeloma-free survival among all patients and in the different risk groups.

This was a randomized phase III clinical trial (NCT00432458) which enrolled patients ≥ 18 years with a new diagnosis of SMM who had measurable disease. The study design has been previously described [9]. Patients with small asymptomatic lytic lesions on plain skeletal survey radiographs were eligible. Based on the initial protocol, ZLD 4 mg was administered every 28 days; the dosing was later changed to every 3 months for the first year, then yearly, to mitigate the risk of osteonecrosis of the jaw. Patients in the Thal+ZLD arm also received Thal 200 mg/day. There was no crossover between the arms. The study enrolled patients at Mayo Clinic and Memorial Sloan Kettering, but this analysis only included Mayo Clinic patients.

冒烟型多发性骨髓瘤 (SMM) 是多发性骨髓瘤 (MM) 的无症状阶段，于 1980 年首次被描述[1]。前 5 年进展为 MM 的年风险约为 10%，接下来 5 年为 3%，此后为 1% [2]。虽然观察等待策略历来是 SMM 的标准方法，但早期干预的概念已经被研究了三十多年 [3, 4]。最早使用美法仑与类固醇联合使用的研究并未证明在反应或总生存 (OS) 方面有益处 [3, 4]。随后，双磷酸盐的使用与骨骼相关事件的减少相关，但无进展生存期 (PFS) 或 OS 没有改善 [5]。在出现沙利度胺在 MM 中活性的证据后 [6]，我们的小组进行了沙利度胺在 SMM 中的 II 期研究，显示了沙利度胺在这种情况下的活性 [7]。这是 2003 年一项 III 期随机试验的基础，该试验比较了沙利度胺 (Thal) 加唑来膦酸 (ZLD) 与 ZLD 在 SMM 患者中的治疗效果。2013 年，经过 6 年随访后公布了初步结果：Thal+ZLD 组患者的疾病进展时间 (TTP) 更长（2.4 年 vs. 1.2 年，P  = 0.02）和 1 年 PFS（86 % vs. 55%，P  = 0.005）与 ZLD 组相比，进展根据国际骨髓瘤工作组 (IMWG) 反应标准定义 [8]。当进展被定义为“CRAB”特征时，Thal+ZLD 也与更长的 TTP 和 PFS 相关，但这些结果没有统计学意义 [9]。来那度胺的批准与沙利度胺相比具有较低的神经毒性，以及 SMM 风险分层系统的出现[10,11,12]，塑造了后续研究的设计，这些研究使用基于来那度胺的针对中危和高风险的干预措施SMM患者。在 QuiRedex 试验中，与高危 SMM 的主动监测相比，来那度胺加地塞米松组合与更长的 TTP 和 OS 相关 [13]。在 ECOG-ACRIN 试验中，在 35 个月的随访后，来那度胺与中危或高危患者的 PFS 改善相关，但与 OS 无关[14]。鉴于随访时间较短，目前尚不清楚早期干预是否能提供生存优势。因此，我们对 Thal+ZLD 与 ZLD 试验进行了更新分析，以评估大约 18 年随访后的 OS。我们还评估了所有患者和不同风险组的从 TTP 到 MM 的生存率以及无骨髓瘤生存率。

这是一项随机 III 期临床试验 (NCT00432458)，招募了 18 岁以上、新诊断为 SMM、患有可测量疾病的患者。该研究设计先前已描述过[9]。骨骼平扫X光片上有小的无症状溶解性病变的患者符合条件。根据最初的方案，每 28 天给予 ZLD 4 mg；后来，第一年的剂量改为每三个月一次，然后每年一次，以降低颌骨坏死的风险。Thal+ZLD 组的患者还接受了 200 毫克/天的 Thal 治疗。手臂之间没有交叉。该研究招募了梅奥诊所和纪念斯隆凯特琳医院的患者，但本次分析仅包括梅奥诊所的患者。