To the Editor:

With the advent of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies (CD38mAbs), the outcomes of transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma (MM) have substantially improved in the last decade.^1-3 Currently, there are two widely accepted standard-of-care regimens in newly diagnosed TIE MM: daratumumab-lenalidomide-dexamethasone (DRd) and bortezomib-lenalidomide-dexamethasone (VRd), based on the MAIA and S0777 trials, respectively, both of which showed significant progression-free survival (PFS) and overall survival (OS) benefit over Rd.^{1, 2, 4, 5} The major toxicity of concern with the addition of CD38mAb is infection and with bortezomib is peripheral neuropathy. While these triplet regimens have been considered the standard of care, two RCTs have been recently reported that compared a quadruplet regimen to these triplet regimens.^{6, 7} The IMROZ phase III trial evaluated the CD38mAb isatuximab on the backbone of bortezomib, lenalidomide, and dexamethasone (Isa-VRd) compared with VRd alone. The IFM-2020/BENEFIT (hereafter, referred to as BENEFIT) trials evaluated Isa-VRd compared with IsaRd alone. Additionally, a third RCT named GEM2017FIT compared the quadruplet regimen daratumumab-carfilzomib-lenalidomide-dexamethasone (Dara-KRd) against KRd and alternating VMP/Rd (VMP: bortezomib-melphalan-prednisone) in this patient population.⁸ The study design and key outcomes of these trials are summarized in Table 1. Here, we will discuss three key aspects of these trials (inclusion criteria, toxicity, and efficacy) and future directions for optimizing therapy for this patient population.

The first key aspect relates to eligibility criteria and the included patient population in these trials. Even though these RCTs were designed for a TIE population, they all had an upper age limit of 80 years, and approximately two-thirds of patients were within the age brackets of 65–75.^6-8 Additionally, the BENEFIT and GEM2017FIT trials specifically excluded frail patients as defined by the IMWG or Geriatric Assessment in Hematology (GAH) frailty scores, respectively. Objective assessment of frailty is critical in older adults, since frailty predicts treatment-related toxicities and OS.⁹ Hence, the external validity of safety and efficacy of quadruplet regimens in patients who are frail or >80 years of age, which constitutes at least ~20% of TIE population,⁹ remain unclear. An ongoing RCT comparing Dara-VRd vs. VRd (CEPHEUS) in TIE patients does not have an upper age limit or exclusion based on frailty and will potentially generate data on the benefit of quadruplets for older patients (NCT03652064). However, it remains to be seen as to what proportion of patients in CEPHEUS trial are frail based on objective criteria. Future RCTs in this population should target specific subgroups such as fit, intermediate fit, and frail rather than arbitrarily defined category based on transplant-eligibility, which may include both patients that are truly not fit for transplant and those in whom either a transplant is deferred or not done due to patient/physician preference.

Second, early mortality and cumulative treatment-related toxicity is an important concern in older adults when adding drugs to current backbones, with real-world data showing substantial early mortality even in the modern era.¹⁰ Reassuringly, both IMROZ and BENEFIT trials demonstrated that there was no increase in the risk of early mortality with the addition of 4th drug (isatuximab and bortezomib, respectively).^{6, 7} However, in IMROZ, the cumulative incidence of treatment-related deaths at a median follow-up of ~5 years was approximately 2-fold higher in Isa-VRd versus VRd arm (11% vs. 5.5% respectively), with the most common cause of these deaths being infection.⁶ The increase in these treatment-related deaths in the Isa-VRd arm was largely driven by events beyond 6 months from treatment initiation. This highlights the deleterious impact of prolonged immunosuppression with continuous CD38mAb and dexamethasone until progression. Furthermore, it reiterates the urgent need for de-escalation strategies in frail older adults who particularly value minimizing treatment toxicity and optimizing health-related quality of life (HRQoL).¹¹ De-escalation strategies are currently being explored in two RCTs that are randomizing patients to continuous versus fixed-duration daratumumab in the DRd regimen (NCT05561387 and NCT06182774). In the BENEFIT trial, addition of once-weekly subcutaneous bortezomib increased the risk of Grade ≥2 peripheral neuropathy from 10% in the Isa-Rd arm to 27% in Isa-VRd arm.⁷ However, the incidence of all-grade peripheral neuropathy with Isa-VRd in BENEFIT trial was almost half of that in IMROZ (28% vs. 54.4%, respectively), which is likely due to once-weekly bortezomib in BENEFIT versus once-weekly in IMROZ.^{6, 7} Since bortezomib-induced neuropathy can be reversible in about two-thirds of patients with dose-reduction or dose-discontinuation,¹² it remains to be seen what proportion of these patients develop permanent neuropathy. Nevertheless, close monitoring for new-onset peripheral neuropathy while on bortezomib with prompt dose modification remains paramount if using a bortezomib-containing quadruplet regimen in this age group. Notably, in the GEM2017FIT trial, a substantial increase in toxicity-related deaths in the first 18 months was noted in the quadruplet arm (toxic deaths-4.5%, 3.2%, and 8.5% in VMP/Rd, KRd, and Dara-KRd arms, respectively).⁸ Furthermore, a substantial proportion of patients in the carfilzomib-containing arms (11% in KRd and 14% in Dara-KRd) developed Grade 3–4 cardiac toxicities. This is in line with the GMMG-CONCEPT trial (Isa-KRd) where the incidence of Grade 3–5 cardiac toxicities was ~10× higher in the TIE cohort compared with the TE cohort (20% vs. 2.1%, respectively).¹³ Together, these data imply caution with CD38mAb and carfilzomib-containing quadruplet regimens in older adults, including those who are fit and <80 years old.

Third, all three RCTs met their primary efficacy endpoint (PFS in IMROZ and MRD negativity at 10⁻⁵ by NGS in BENEFIT and GEM2017FIT). However, IMROZ trial has the most mature data thus far with a median follow-up of ~5 years.⁶ Importantly, in the GEM2017FIT trial, the efficacy of Dara-KRd was modulated by frailty status, with 30-month PFS in fitter patients (GAH <20) being 88% and that in patients with GAH >20 being just 71% with Dara-KRd.⁸ Notably, the BENEFIT trial demonstrated a ~2× increase in MRD negativity at 10⁻⁶ with the addition of bortezomib to Isa-Rd. An important caveat is that the MRD-negativity rates at 12 and 18 months were comparable in the Isa-VRd arm of BENEFIT trial, which raises the question whether bortezomib can be limited to 12 months to reduce toxicity without compromising efficacy. Additionally, the time to achievement of very good partial response or better was significantly shorter with Isa-VRd compared with Isa-Rd (2.1 vs. 3.7 mo., respectively; p = 0.0002), which highlights the importance of addition of bortezomib in situations where a rapid reduction in paraprotein is desirable such as myeloma cast nephropathy.¹⁴ Of note, the MRD-negativity rate at 10⁻⁵ (NGS) in the intention-to-treat population was comparable in the Isa-VRd arms of IMROZ and BENEFIT trials (58% vs. 53%, respectively) despite twice-weekly bortezomib in IMROZ and once-weekly in BENEFIT.^{6, 7} Thus far, no difference in PFS or OS has been noted with the addition of bortezomib to Isa-Rd. Unlike IMROZ trial where addition of CD38mAb led to early separation of PFS curves, addition of bortezomib has not led to the separation of PFS curves yet at a median follow-up of ~2 years. In a recent meta-analysis, MRD negativity was shown to have a strong trial-level correlation with PFS (R² = 0.85) and medium trial-level correlation with OS (R² = 0.79) in the TIE cohort,¹⁵ which makes it likely that the benefit in MRD negativity will translate into benefit in PFS and possibly OS with longer follow-up. Nevertheless, due to the trade-off of increased peripheral neuropathy, which has important HRQoL implications in frail older adults, mature data are needed to understand the magnitude of PFS/OS benefit to enable shared decision-making in this population. Of note, IMROZ was the only RCT that had HRQoL as an endpoint, and failed to show superiority of Isa-VRd over VRd in the Global Health Status/Quality of Life domain of EORTC-QLQ-C30 instrument.⁶ In a prospective cohort study in adults with MM over the age of 50, compared with younger adults (50–69 years), older adults (≥70 years) were significantly more likely to prioritize QoL, functional independence, maintaining cognitive ability, and living free from pain compared with longer OS.¹¹ Hence, clinical trials in this population should rigorously measure HRQoL, and clinicians should be cognizant of unique patient preferences in this age group during treatment decision-making.

In summary, the outcomes of patients with newly diagnosed TIE MM are poised to improve in coming years with the introduction of effective drugs in the frontline setting; however, it remains unclear how we should translate the results of these trials in our routine clinical setting. For healthcare systems that are using VRd as the current standard of care in this population, we believe IMROZ trial provides convincing evidence to add CD38mAb to VRd backbone and should lead to a change in the standard of care. This is particularly important in fit patients and those under the age of 80. Further trials are eagerly awaited investigating the optimal duration of CD38mAb and whether routine quadruplet therapy is feasible and beneficial in frail adults including over the age of 80. However, in settings where CD38mAb + Rd is being currently used as a standard of care, it remains unclear whether addition of bortezomib is essential for all patients since enthusiasm from the benefit in terms of MRD-negativity rate is tempered by the rise in clinically significant peripheral neuropathy, and long-term follow-up will be crucial to understand the magnitude of PFS and potentially OS benefit. We believe that future trials should move away from transplant “ineligibility” as an inclusion criterion given the heterogeneity of this large category and rather focus on frailty-specified subgroups—fit, intermediate fit, and frail. Additionally, incorporating frailty-adapted attenuated dosing strategies and more dynamic fitness measures may allow us to both decrease potential toxicity and improve efficacy, allowing for more personalized treatment strategies in routine clinical practice for this heterogenous group of TIE patients.

 致编辑：

随着蛋白酶体抑制剂 （PI）、免疫调节药物 （IMiD） 和抗 CD38 单克隆抗体 （CD38mAb） 的出现，新诊断的多发性骨髓瘤 （MM） 移植不合格 （TIE） 患者的预后在过去十年中得到了显着改善。^1-3 目前，新诊断的 TIE MM 中有两种被广泛接受的标准护理方案：daratumumab-来那度胺-地塞米松 （DRd） 和硼替佐米-来那度胺-地塞米松 （VRd），分别基于 MAIA 和 S0777 试验，这两项试验均显示无进展生存期 （PFS） 和总生存期 （OS） 优于 ^{Rd.1、2、4、5}添加 CD38mAb 的主要毒性是感染，而硼替佐米是周围神经病变。虽然这些三联方案被认为是标准治疗，但最近报道了两项 RCT，将四联方案与这些三联方案进行了比较。^6、7IMROZ III 期试验评估了 CD38mAb isatuximab 在硼替佐米、来那度胺和地塞米松 （Isa-VRd） 的主干上与单独使用 VRd 的比较。IFM-2020/BENEFIT（以下简称 BENEFIT）试验评估了 Isa-VRd 与单独使用 IsaRd 的比较。此外，名为 GEM2017FIT 的第三项随机对照试验比较了达雷妥尤单抗-卡非佐米-来那度胺-地塞米松 （Dara-KRd） 四联方案与该患者群体中的 KRd 和交替 VMP/Rd （VMP： 硼替佐米-美法仑-泼尼松）。⁸ 表 1 总结了这些试验的研究设计和主要结果。在这里，我们将讨论这些试验的三个关键方面 （纳入标准、毒性和疗效） 以及为该患者群体优化治疗的未来方向。

第一个关键方面与纳入这些试验的合格标准和纳入的患者群体有关。尽管这些 RCT 是为 TIE 人群设计的，但它们的年龄上限均为 80 岁，大约三分之二的患者年龄在 65-75 岁之间。^6-8 此外，BENEFIT 和 GEM2017FIT 试验分别明确排除了 IMWG 或血液学老年评估 （GAH） 衰弱评分定义的虚弱患者。客观评估衰弱对老年人至关重要，因为衰弱可以预测与治疗相关的毒性和 ^OS.9 因此，四联方案在虚弱或 >80 岁患者中的安全性和有效性的外部有效性，至少占 TIE 人群的 ~20%，⁹ 仍不清楚。一项正在进行的 RCT 在 TIE 患者中比较 Dara-VRd 与 VRd （CEPHEUS） 没有年龄上限或基于虚弱的排除，并且可能会生成有关四胞胎对老年患者益处的数据 （NCT03652064）。然而，根据客观标准，CEPHEUS 试验中有多少比例的患者虚弱还有待观察。未来针对该人群的 RCT 应针对特定的亚组，例如适合、中等适合和虚弱，而不是根据移植资格任意定义的类别，其中可能包括确实不适合移植的患者以及由于患者/医生偏好而推迟或未进行移植的患者。

其次，早期死亡率和累积治疗相关毒性是老年人在当前主干网络中添加药物时的一个重要问题，真实世界数据显示，即使在现代，早期死亡率也很高。¹⁰ 令人欣慰的是，IMROZ 和 BENEFIT 试验都表明，添加第 4 种药物（分别为 isatuximab 和 bortezomib）后，早期死亡风险没有增加。^6、7然而，在 IMROZ 中，中位随访 ~5 年时，Isa-VRd 组与治疗相关死亡的累积发生率约为 VRd 组的 2 倍（分别为 11% 和 5.5%），这些死亡的最常见原因是感染。⁶ Isa-VRd 组这些治疗相关死亡的增加主要是由治疗开始后 6 个月以上的事件驱动的。这突出了持续使用 CD38mAb 和地塞米松进行长期免疫抑制直至进展的有害影响。此外，它重申了对虚弱老年人降级策略的迫切需求，他们特别重视最大限度地减少治疗毒性和优化与健康相关的生活质量 （HRQoL）。¹¹ 目前正在两项随机对照试验中探索降级策略，这些随机对照试验将患者随机分配到 DRd 方案中连续与固定持续时间的 daratumumab 组 （NCT05561387 和 NCT06182774）。在 BENEFIT 试验中，添加每周一次的皮下硼替佐米使 ≥2 级周围神经病变的风险从 Isa-Rd 组的 10% 增加到 Isa-VRd 组的 27%。⁷ 然而，在 BENEFIT 试验中，Isa-VRd 的所有级别周围神经病变的发生率几乎是 IMROZ 的一半（28% 对 54。4%），这可能是由于 BENEFIT 每周一次的硼替佐米与 IMROZ 的每周一次。^6、7由于硼替佐米诱导的神经病变在约三分之二的剂量减少或停药患者中是可逆的，¹² 这些患者中发展为永久性神经病变的比例还有待观察。然而，如果在该年龄组使用含硼替佐米的四联方案，在服用硼替佐米并及时调整剂量时密切监测新发的周围神经病变仍然至关重要。值得注意的是，在 GEM2017FIT 试验中，四联组在前 18 个月内与毒性相关的死亡人数显著增加（VMP/Rd、KRd 和 Dara-KRd 组的毒性死亡分别为 -4.5%、3.2% 和 8.5%）。⁸ 此外，含卡非佐米的组中很大一部分患者（KRd 组为 11%，Dara-KRd 组为 14%）出现 3-4 级心脏毒性。这与 GMMG-CONCEPT 试验 （Isa-KRd） 一致，其中 TIE 队列的 3-5 级心脏毒性发生率比 TE 队列高 ~10×（分别为 20% 和 2.1%）。¹³ 总之，这些数据表明在老年人（包括身体健康和 <80 岁的人）中谨慎使用含 CD38mAb 和卡非佐米的四联方案。

第三，所有 3 项 RCT 均达到其主要疗效终点（IMROZ 的 PFS 和 NGS 在 BENEFIT 和 GEM2017FIT 中的 MRD 阴性为 ^10-5）。然而，IMROZ 试验拥有迄今为止最成熟的数据，中位随访时间为 ~5 年。⁶ 重要的是，在 GEM2017FIT 试验中，Dara-KRd 的疗效受虚弱状态的调节，更健康的患者 （GAH <20） 的 30 个月 PFS 为 88%，而 GAH >20 患者的 Dara-KRd 仅为 71%。⁸ 值得注意的是，BENEFIT 试验表明，在 Isa-Rd 中加入硼替佐米后，MRD 阴性在 ^10-6 时增加了 ~2×。一个重要的警告是，在 BENEFIT 试验的 Isa-VRd 组中，12 个月和 18 个月的 MRD 阴性率相当，这提出了一个问题，是否可以将硼替佐米限制在 12 个月以降低毒性而不影响疗效。此外，与 Isa-Rd 相比，Isa-VRd 达到非常好的部分反应或更好的时间显著缩短（分别为 2.1 个月和 3.7 个月;p = 0.0002），这强调了在需要快速减少副蛋白的情况下（例如骨髓瘤管型肾病）添加硼替佐米的重要性。¹⁴ 值得注意的是，意向治疗人群中 ^10-5 （NGS） 的 MRD 阴性率在 IMROZ 和 BENEFIT 试验的 Isa-VRd 组中是相当的（分别为 58% 和 53%），尽管 IMROZ 每周两次硼替佐米和 BENEFIT 每周一次。^6、7到目前为止，在 Isa-Rd 中加入硼替佐米后，PFS 或 OS 没有差异。 与 IMROZ 试验不同，在IMROZ试验中，添加CD38mAb会导致PFS曲线的早期分离，而在中位随访~2年时，添加硼替佐米尚未导致PFS曲线的分离。在最近的一项荟萃分析中，MRD 阴性与 TIE 队列中的 PFS （R² = 0.85） 具有很强的试验水平相关性，与 OS （R² = 0.79） 具有中等试验水平相关性，¹⁵ 这使得 MRD 阴性的益处可能会转化为 PFS 的益处，并且可能转化为随访时间延长的 OS。然而，由于周围神经病变增加的权衡，这对虚弱的老年人具有重要的 HRQoL 影响，因此需要成熟的数据来了解 PFS/OS 获益的大小，以便能够在该人群中做出共同决策。值得注意的是，IMROZ 是唯一以 HRQoL 为终点的 RCT，在 EORTC-QLQ-C30 仪器的全球健康状况/生活质量领域未能显示 Isa-VRd 优于 VRd。⁶ 在一项针对 50 岁以上 MM 成人的前瞻性队列研究中，与年轻人（50-69 岁）相比，老年人（≥70 岁）明显更有可能优先考虑 QoL、功能独立性、保持认知能力和无痛生活。^因此，在该人群中进行的临床试验应严格测量 HRQoL， 临床医生在做出治疗决策时应认识到该年龄组患者的独特偏好。

总之，随着在一线环境中引入有效药物，新诊断的 TIE MM 患者的预后有望在未来几年得到改善;然而，目前尚不清楚我们应该如何在常规临床环境中转化这些试验的结果。对于使用 VRd 作为该人群当前护理标准的医疗保健系统，我们认为 IMROZ 试验提供了令人信服的证据，可以将 CD38mAb 添加到 VRd 骨架中，并应该会导致护理标准的变化。这对于身体健康的患者和 80 岁以下的患者尤其重要。热切期待进一步的试验，调查 CD38mAb 的最佳持续时间，以及常规四联疗法对包括 80 岁以上在内的虚弱成年人是否可行和有益。然而，在目前将 CD38mAb + Rd 用作标准治疗的环境中，目前尚不清楚是否对所有患者都有必要添加硼替佐米，因为 MRD 阴性率方面的好处的热情被临床显着周围神经病变的增加所缓和，长期随访对于了解 PFS 的大小和潜在的 OS 益处至关重要。鉴于这一大类的异质性，我们认为未来的试验应该从移植“不合格”作为纳入标准，而是关注虚弱特定的亚组——适合、中等适合和虚弱。此外，结合虚弱适应的减毒给药策略和更动态的健身措施可能使我们能够降低潜在毒性并提高疗效，从而在常规临床实践中为这一异质性 TIE 患者群体提供更加个性化的治疗策略。