Multiple Myeloma Staging in Real World Clinical Practice Is Suboptimal: Absence of Beta-2-Microglobulin and Serum Lactase Dehydrogenase Testing Are Limiting Factors
Multiple Myeloma Staging in Real World Clinical Practice Is Suboptimal: Absence of Beta-2-Microglobulin and Serum Lactase Dehydrogenase Testing Are Limiting Factors
复制标题
现实世界临床实践中的多发性骨髓瘤分期并不理想：缺乏 Beta-2-微球蛋白和血清乳糖酶脱氢酶测试是限制因素
DOI：
10.1182/blood-2018-99-119559
复制
发表时间：
2018
期刊：
影响因子：
20.3
通讯作者：
S. Goldberg
中科院分区：
文献类型：
--
作者：
N. Biran;Sukhmani Gill;A. Norden;D. Vesole;Wallace G Stephen;Kenneth Nahum;D. Siegel;S. Goldberg
背景：骨髓瘤的分期系统已经发展，有助于确定预后并影响治疗决策。 Durie-Salmon 系统 (DS) 主要基于感知的骨髓瘤细胞肿瘤负荷。 2005 年，引入了国际分期系统 (ISS)，并纳入了 β-2-微球蛋白水平（肿瘤负荷标志物）和血清白蛋白（炎症细胞因子标志物）。 2015 年，ISS 进行了修订 (R-ISS)，纳入高风险细胞遗传学 [17p-、t(4;14)、t(14;16)} 和血清乳糖酶脱氢酶 (LDH)（与肿瘤侵袭性、髓外疾病和增殖率相关）。尽管 ISS 和 R-ISS 相对简单，但它们需要诊断活检材料和常规化学小组之外的额外实验室研究。尽管 R-IPSS 基础研究 (Palumbo JCO 2015) 中只有 69% 的患者 (pts) 具备可用于完整分期的所有要素，但在现实环境中使用这些较新系统进行分期的充分性尚未报告。
方法：使用 COTA Inc. 数据库识别病例，该数据库根据业务伙伴协议从所有临床站点的电子健康记录中提取和组织相关的人口统计、诊断、治疗和质量数据。经过培训的 COTA Inc. 摘录人员审查并确认了源自医疗记录的数据。出于本研究的目的，任何提及测试的实验室或病理报告都被视为“已测试”，无论方法、供应商或测试完整性如何。然后使用盲法标识符将数据与研究人群合并以进行后续分析。此审查的一个限制是未能在电子图表或医生笔记中记录测试结果（或提及测试性能），因此已执行但未记录的测试可能不会被计算在内。
结果：2013 年 1 月 1 日至 2016 年 12 月 31 日期间，从美国东北部 12 个中心（1 个学术中心和 11 个社区中心）确定了 857 名被诊断为 MM 的患者，由 81 名血液肿瘤学家治疗。在 MM 就诊时，831 名患者 (97%) 拥有免疫球蛋白水平、血红蛋白、钙浓度、肾功能和骨病变数量的 EHR 文件，以便进行 Durie-Salmon 分期。国际空间站需要 B2M 和白蛋白；在最初演示时，696 点 (81%) 可以由 ISS 进行分类，但 161 点 (19%) 没有 B2M 级别的文件，因此无法进行演示。学术中心更有可能获得 B2M 以允许完成 ISS（学术中心获得 84%，社区获得 72%；p<0.001）。 R-ISS 包含细胞遗传学异常和 LDH。在初次报告时，除了没有 B2M 的患者外，353 名患者 (41%) 没有 LDH 测试记录，122 名患者 (14%) 没有 t(14;16) 测试记录，112 名患者 (13%) 没有 t(4;14) 测试记录，91 名患者 (11%) 没有 del17 测试记录。学术中心和社区中心均未能平等地收集 LDH（学术中心获得的 LDH 为 53%，社区中心为 56%；p=0.37；但值得注意的是，18% 的学术患者在社区初步分期后被转诊进行移植，并且 Cota 中心可能没有源文件）。因此，只有 350 点 (41%) 可以通过 R-ISS 进行分类。 2015 年底 R-ISS 发布之前 (40%) 和之后 (44%) 获取 R-ISS 要素的充分性没有差异 (p=0.22)。数据库中的大多数患者在就诊时均为 DS III。然而 DS 与 ISS 或 R-ISS 不相关，因此表明需要执行完整的诊断/分期评估 [表 1]。
结论：在现实世界（非研究）环境中，使用 ISS 和 R-ISS 对多发性骨髓瘤进行分期，需要实验室超出基于诊断骨髓的材料（包括细胞遗传学），但仍然不够理想，可能反映出 R-ISS (2015) 延迟纳入临床使用。主要缺陷是在初次就诊时未能获得 B2M 和 LDH 水平。
表 1 按 ISS 和 R-ISS 对 DS 分期患者的重新分类
Biran：Amgen：咨询、演讲局；武田：咨询、演讲局； Celgene：咨询、酬金、演讲局； BMS：研究经费；默克：研究经费。 Norden：Cota Inc：就业。西格尔：Celgene：咨询、酬金、研究经费、演讲局；安进：咨询、酬金、演讲局； Karyopharm：咨询、酬金；诺华：酬金，演讲局；武田：顾问、酬金、演讲局；杨森：咨询、酬金、演讲局；默克：咨询、酬金、演讲局； BMS：咨询、酬金、演讲局。戈德堡：COTA Inc.：就业、股权。
Background: Staging systems, which help define prognosis and influence treatment decisions, for myeloma have evolved. The Durie-Salmon system (DS) was based largely on perceived myeloma cell tumor burden. In 2005, the International Staging System (ISS) was introduced and incorporated beta-2-microglobulin levels (a marker of tumor burden) and serum albumin (a marker of inflammatory cytokines). In 2015 the ISS was revised (R-ISS) to include high risk cytogenetics [17p-, t(4;14), t(14;16)} and serum lactase dehydrogenase (LDH) (correlating with tumor aggressiveness, extramedullary disease and proliferation rate). Although the ISS and R-ISS are relatively simple, they require additional laboratory studies outside of the diagnostic biopsy material and routine chemistry panel. The adequacy of staging using these newer systems in real world settings has not been reported, although only 69% of patients (pts) in the R-IPSS foundational study (Palumbo JCO 2015) had all of the elements available for complete staging.
Methods: Cases were identified using the COTA Inc. database, which abstracts and organizes relevant demographic, diagnostic, treatment, and quality data from the electronic health records at all the clinical sites under business associate agreements. Trained COTA Inc. abstractors reviewed and confirmed the medical record-derived data. For the purposes of the present study, any laboratory or pathology report mentioning testing was counted as "tested," regardless of method, vendor, or test completeness. The data were then merged with the study population using blinded identifiers for subsequent analysis. A limitation of this review is failure to document test results (or mention of test performance) in the electronic chart or physician notes, thus tests performed but not documented may not have been counted.
Results: 857 pts diagnosed with MM between Jan 1, 2013 and Dec 31, 2016 were identified from 12 northeast USA centers (1 academic and 11 community based) treated by 81 hematologist-oncologists. At the time of MM presentation 831 pts (97%) had EHR documentation of immunoglobulin levels, hemoglobin, calcium concentration, renal function and number of bone lesions to permit Durie-Salmon staging. The ISS requires B2M and albumin; at the time of initial presentation 696 pts (81%) could be classified by the ISS but 161 pts (19%) had no documentation of B2M levels and thus could not be staged. The academic center was more likely to obtain B2M to permit complete ISS (84% academic obtained vs 72% community obtained; p<0.001). The R-ISS incorporates cytogenetic abnormalities and LDH. At the time of initial presentation, in addition to the pts without B2M, 353 pts (41%) had no documentation of LDH testing, 122 pts (14%) had no documentation of t(14;16) testing, 112 pts (13%) were without documentation of t(4;14) testing, and 91 pts (11%) were without documentation of del17 testing. The academic and community centers both failed to collect LDH equally (53% academic obtained vs 56% community; p=0.37; however notable that 18% of the academic patients were referred for transplant after initial staging in the community and may not have source documentation at the Cota center). Thus, only 350 pts (41%) could be classified by R-ISS. There was no difference in adequacy of obtaining R-ISS elements before (40%) and after (44%) publication of the R-ISS in late 2015 (p=0.22). The majority of the pts in the database were DS III at presentation. However DS did not correlate with ISS or R-ISS, thus demonstrating the need to perform the complete diagnostic/staging evaluation [Table1].
Conclusions: In real world (non-research) settings staging of multiple myeloma using the ISS and R-ISS that require laboratories beyond diagnostic marrow based material (including cytogenetics) remains suboptimal and may reflect delayed incorporation of R-ISS (2015) into clinical use. Lack of obtaining B2M and LDH levels at initial presentation is the major deficiency.
Table 1 Reclassification of DS staged pts by ISS and R-ISS
Biran: Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; BMS: Research Funding; Merck: Research Funding. Norden:Cota Inc: Employment. Siegel:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Novartis: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Goldberg:COTA Inc.: Employment, Equity Ownership.