Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
Lancet Haematol. 2023 Nov;10(11):e890-e901. doi: 10.1016/S2352-3026(23)00236-3. Epub 2023 Sep 27.
For patients with newly diagnosed multiple myeloma, reaching minimal residual disease (MRD) negativity after treatment is associated with improved outcomes; however, the use of MRD to modulate therapy remains elusive. We present the final analysis of the MASTER trial of daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) therapy in patients with newly diagnosed multiple myeloma, in which MRD status is used to modulate treatment duration and cessation.
MASTER was a multicentre, single-arm, phase 2 trial conducted in five academic medical centres in the USA. Eligible participants were 18 years or older with newly diagnosed multiple myeloma (measurable by serum or urine protein electrophoresis or serum free light chains), a life expectancy of at least 12 months, and an Eastern Cooperative Oncology Group performance status of 0-2, and had received no previous treatment for multiple myeloma except up to one cycle of therapy containing bortezomib, cyclophosphamide, and dexamethasone. The study was enriched for participants with high-risk chromosome abnormalities (HRCAs). During the induction phase, participants received four 28-day cycles of Dara-KRd, each comprising daratumumab (16 mg/kg intravenously on days 1, 8, 15, and 22), carfilzomib (56 mg/m intravenously on days 1, 8, and 15), lenalidomide (25 mg orally on days 1-21), and dexamethasone (40 mg orally or intravenously on days 1, 8, 15, and 22); induction was followed by autologous haematopoietic stem-cell transplantation and up to two phases of consolidation with Dara-KRd. We assessed MRD by next-generation sequencing after or during each phase. The primary endpoint was reaching MRD negativity (<10). Participants who reached MRD negativity after or during two consecutive phases stopped treatment and began observation with MRD surveillance (MRD-SURE); participants who did not reach two consecutive MRD-negative results received maintenance lenalidomide. Secondary endpoints included progression-free survival and cumulative incidence of progression. All analyses were conducted in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03224507, and is complete.
Between Mar 21, 2018, and Oct 23, 2020, 123 participants were recruited to the study, of whom 70 (57%) were men, 53 (43%) were women, 94 (76%) were non-Hispanic White, 25 (20%) were non-Hispanic Black, and four (3%) were of another race or ethnicity. The median age of participants was 61 years (IQR 55-68), and 24 (20%) were aged 70 years or older. The median duration of follow up was 42·2 months (IQR 34·5-46·0). Of the 123 participants, 53 (43%) had no HRCAs, 46 (37%) had one HRCA, and 24 (20%) had two or more HRCAs. For 118 (96%) of 123 participants, MRD was evaluable by next-generation sequencing; the remaining five had an absence of sufficiently unique clonogenic sequences to enable tracking by the assay. Of these 118 participants, 96 (81%, 95% CI 73-88) reached MRD of less than 10 (comprising 39 [78%, 64-88] of 50 participants with no HRCAs, 38 [86%, 73-95] of 44 participants with one HRCA, and 19 [79%, 58-93] of 24 participants with two or more HRCAs) and 84 (71%, 62-79) reached MRD-SURE and treatment cessation. 36-month progression-free survival among all 123 participants was 88% (95% CI 78-95) for participants with no HRCAs, 79% (67-88) for those with one HRCA, and 50% (30-70) for those with two or more HRCAs. For the 84 participants reaching MRD-SURE, the 24-month cumulative incidence of progression from cessation of therapy was 9% (95% CI 1-19) for participants with no HRCAs, 9% (1-18) for those with one HRCA, and 47% (23-72) for those with two or more HRCAs. 61 participants (comprising 52% of 118 MRD-evaluable participants and 73% of 84 participants who reached MRD-SURE) remain free of therapy and MRD-negative as of Feb 7, 2023. The most common grade 3-4 adverse events were neutropenia (43 patients, 35%), lymphopenia (28 patients, 23%), and hypertension (13 patients, 11%). Three treatment-emergent deaths were recorded: two sudden deaths and one due to viral infection, none of which were judged to be treatment-related.
This approach provided positive outcomes and a pathway for treatment cessation in most patients with newly diagnosed multiple myeloma. Outcomes for patients with ultra-high-risk multiple myeloma, defined as those with two or more HRCAs, remain unsatisfactory, and these patients should be prioritised for trials with early introduction of therapies with novel mechanisms of action.
Amgen and Janssen Pharmaceuticals.
对于新诊断的多发性骨髓瘤患者，在治疗后达到微小残留疾病（MRD）阴性与改善预后相关；然而，使用 MRD 来调节治疗仍难以实现。我们报告了达雷妥尤单抗、卡非佐米、来那度胺和地塞米松（Dara-KRd）治疗新诊断的多发性骨髓瘤的 MASTER 试验的最终分析，该试验中使用了 MRD 状态来调节治疗持续时间和停药。
MASTER 是一项在美国五家学术医疗中心进行的多中心、单臂、2 期临床试验。纳入标准为年龄 18 岁或以上，新诊断的多发性骨髓瘤（通过血清或尿液蛋白电泳或血清游离轻链可测量），预期寿命至少 12 个月，Eastern Cooperative Oncology Group 体能状态 0-2，且除了至多一个包含硼替佐米、环磷酰胺和地塞米松的治疗周期外，没有接受过多发性骨髓瘤的其他治疗。该研究富集了具有高风险染色体异常（HRCAs）的患者。在诱导期，患者接受四个 28 天周期的 Dara-KRd 治疗，每个周期包括达雷妥尤单抗（16mg/kg，静脉注射，第 1、8、15 和 22 天）、卡非佐米（56mg/m2，静脉注射，第 1、8 和 15 天）、来那度胺（25mg，口服，第 1-21 天）和地塞米松（40mg，口服或静脉注射，第 1、8、15 和 22 天）；诱导后进行自体造血干细胞移植，并进行两个周期的巩固治疗，使用 Dara-KRd。我们在每个阶段或期间后评估通过下一代测序的 MRD。主要终点是达到 MRD 阴性（<10）。在两个连续阶段后达到 MRD 阴性的患者停止治疗并开始进行 MRD 监测（MRD-SURE）；未达到两个连续 MRD 阴性结果的患者接受维持来那度胺治疗。次要终点包括无进展生存期和进展累积发生率。所有分析均在意向治疗人群中进行。该试验在 ClinicalTrials.gov 注册，NCT03224507，并已完成。
2018 年 3 月 21 日至 2020 年 10 月 23 日，共招募了 123 名患者参加该研究，其中 70 名（57%）为男性，53 名（43%）为女性，94 名（76%）为非西班牙裔白人，25 名（20%）为非西班牙裔黑人，4 名（3%）为其他种族或族裔。患者的中位年龄为 61 岁（IQR 55-68），24 名（20%）年龄在 70 岁或以上。中位随访时间为 42.2 个月（IQR 34.5-46.0）。在 123 名患者中，53 名（43%）无 HRCAs，46 名（37%）有一个 HRCA，24 名（20%）有两个或更多 HRCAs。118 名（96%）患者的 MRD 可通过下一代测序进行评估；其余 5 名患者的克隆序列缺乏足够的独特性，无法通过该检测进行跟踪。在这 118 名患者中，96 名（81%，95%CI 73-88）达到了低于 10 的 MRD（包括 50 名无 HRCAs 的患者中有 39 名（78%，64-88），44 名有一个 HRCA 的患者中有 38 名（86%，73-95），24 名有两个或更多 HRCAs 的患者中有 19 名（79%，58-93）），84 名（71%，62-79）达到了 MRD-SURE 和治疗停止。在所有 123 名患者中，无 HRCAs 的患者 36 个月无进展生存率为 88%（95%CI 78-95），有一个 HRCA 的患者为 79%（67-88），有两个或更多 HRCAs 的患者为 50%（30-70）。对于达到 MRD-SURE 的 84 名患者，从停止治疗开始的 24 个月进展累积发生率为无 HRCAs 的患者为 9%（95%CI 1-19），有一个 HRCA 的患者为 9%（1-18），有两个或更多 HRCAs 的患者为 47%（23-72）。截至 2023 年 2 月 7 日，61 名患者（占 118 名可评估 MRD 患者的 52%和 84 名达到 MRD-SURE 的患者的 73%）仍无治疗且 MRD 阴性。最常见的 3-4 级不良事件是中性粒细胞减少症（43 例，35%）、淋巴细胞减少症（28 例，23%）和高血压（13 例，11%）。记录了 3 例治疗相关死亡：2 例猝死和 1 例病毒感染，均未被认为与治疗有关。
这种方法为大多数新诊断的多发性骨髓瘤患者提供了积极的结果和治疗停止的途径。超高危多发性骨髓瘤患者（定义为有两个或更多 HRCAs 的患者）的预后仍然不理想，这些患者应优先考虑早期引入具有新型作用机制的治疗方法。
安进公司和杨森制药公司。
