Multiple Myeloma Staging in Real World Clinical Practice Is Suboptimal: Absence of Beta-2-Microglobulin and Serum Lactase Dehydrogenase Testing Are Limiting Factors
Authors: Biran Noa , Gill Sukhmani , Norden Andrew D , Vesole David H. , Stephen Wallace G , Nahum Kenneth D , Siegel David S , Goldberg Stuart L. 
Published: October 2019

Abstract
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

Disclosures
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.