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967 Transient M-Proteins: Epidemiology, Causes, and the Impact of Mass Spectrometry: The Istopmm Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 652. Multiple Myeloma and Plasma Cell Dyscrasias: Clinical and Epidemiological: Disease Monitoring
Hematology Disease Topics & Pathways:
Plasma Cell Disorders, Diseases, Lymphoid Malignancies
Monday, December 12, 2022: 4:30 PM

Robert Palmason1,2,3*, Oscar Berlanga, PhD4*, Jon Kristinn Sigurdsson1*, Sæmundur Rögnvaldsson, MD5,6*, Sigrun Thorsteinsdottir, MD, PhD1,7, Sara Ekberg, PhD8*, Michael Crowther, PhD8*, Marina Levy1*, Elin Ruth Reed1*, Jon Þórir Oskarsson, MSc9*, Gudrun Asta Sigurdardottir1*, Brynjar Vidarsson, MD6, Pall Torfi Onundarson, MD6, Bjarni Agnar Agnarsson, MD6*, Margret Sigurdardottir, MD6*, Ingunn Thorsteinsdottir, MD, PhD6*, Signy Vala Sveinsdottir, MD PhD6*, Fridbjorn Sigurdsson, MD10*, Isleifur Olafsson, MD, PhD6*, Asdis Rosa Thordardottir1*, Elias Eythorsson, MD, PhD11*, Asbjorn Jonsson, MD10*, Runolfur Palsson, MD6*, Olafur Skuli Indridason, MD, MHS6*, Thor Aspelund, PhD1*, Gauti Gislason1*, Andri Olafsson1*, Ingigerdur Solveig Sverrisdottir, MD, BSc1*, Hlif Steingrimsdottir, MD6*, Thorir Einarsson Long, MD, PhD3,12*, Malin Hultcrantz, MD, PhD13, Ola Landgren, MD14, Stephen Harding, PhD15, Brian G.M. Durie, MD16, Thorvardur Jon Love, MD, PhD1* and Sigurdur Y Kristinsson, MD, PhD1,6

1Faculty of Medicine, University of Iceland, Reykjavik, Iceland
2Landspitali - The National University Hospital of Iceland, LUND, Sweden
3Skåne University Hospital, Lund, Sweden
4The Binding Site Group Ltd, Birmingham, United Kingdom
5Faculty of Medicine, University of Iceland, Reykjavík, Iceland
6Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland
7Department of Hematology, Rigshospitalet, København, Copenhagen, Denmark
8Red Door Analytics AB, Stockholm, Sweden
9Faculty of Medicine, University of Iceland, Reykjavik, Reykjavik, Iceland
10Akureyri Hospital, Akureyri, Iceland
11Landspitali - The National University Hospital of Iceland, Reykjavík, Iceland
12Faculty of Medicine, University of Iceland, Reykjavik, AL, Iceland
13Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
14Myeloma Division, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL
15The Binding Site Inc., Birmingham, United Kingdom
16Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Outpatient Cancer Center, Los Angeles, CA

Background:

Among clinicians, it is well-known that the identification of a monoclonal(M) protein may disappear at a later timepoint (transient M protein) after certain infections, in the setting of some automimmune conditions, or other conditions. However, there is no information from a systematic study investigating patterns of transient M-proteins in a prospectively monitored cohort.The aim of this large, population-based study was to describe the epidemiology and characteristics of individuals with transient M-proteins in the prospective screening manner based on the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study. Furthermore, given the recent introduction of highly sensitive mass spectrometry (MS) based assays for the identification and quantification of M proteins, we were motivated to investigate whether transience is also related to an increased sensitivity of the assay used in a comparison with conventional serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE).

Methods:

The iStopMM study is an ongoing nationwide screening study for multiple myeloma precursors in Iceland. A total of 75,422 Icelanders ≥40 years old (51% of the population) were screened for M protein using SPEP and free light chains. Participants with a detectable M-protein entered a randomized controlled trial with three arms where arms 2 and 3 underwent initial testing and longitudinal follow-up. The transient M-protein cohort was defined as individuals with a positive SPEP who at a later timepoint returned a negative SPEP/IFE sample. Comorbidity data and prescription medicine use was acquired from three high-quality national disease and prescription medicine registries. MS (EXENT®, Binding Site, Birmingham, UK) analyses were performed on the original diagnostic sample and a follow-up sample with a cutoff of 0,02g/L considered as positive. We evaluated comorbidity and medication use comparing individuals with transient M protein to age- and sex-matched subjects with persistent M protein in a 4:1 matched nested case-control study. Differences between the groups were analyzed with chi square tests.

Results:

Overall, the iStopMM MGUS cohort comprises 3,358 individuals. Of those 2,037 underwent annual follow-up testing. A total of 198 (9.8%) individuals were identified as having transient M protein according to SPEP and IFE.

In the transient M protein cohort we observed an increased prevalence of infections, autoimmune disorders, cancer, and obstructive pulmonary conditions (Table 1). We even observed increased usage of corticosteroids (17.7% vs 9.8%; p = 0.01), immunosuppressive medications (5.6% vs 2.2%; p=0.02), azithromycin (9.6% vs 4.9%; p=0.02), and diuretics (20.7% vs 13.3%; p=0.03). These drugs were found to be given between one year prior to one month after the subjects tested negative for M protein with SPEP/IFE.

Among 198 individuals reported to have transient M protein according to SPEP and IFE, baseline MS samples were positive at in 183 (92%). The remaining 15 (8%) did not have an identifiable M protein on MS at baseline. Twelve (80%) of these 15 individuals had an active infection, autoimmune disorder, or active cancer at the initial measurement.

Of the 183 individuals who had M protein identified at baseline by both SPEP/IFE and MS, MS identified the same M protein in 70% (129/183) of the cases at follow-up when SPEP/IFE was negative.

Fifty four individuals were observed to be MS positive at baseline and negative at a follow-up testing indicating a prevalence of transient M-proteins of 2.6% within a cohort of MGUS patients when measured by MS. MS showed good concordance with IFE (Table 1), and, as expected, use of more sensitive MS in baseline samples results in additional increase by 33% in low-concentration M protein spikes, compared to conventional SPEP/IFE.

Conclusion:

In this large prospective study we found that M proteins were transient in almost 10% of cases. Using a more sensitive MS, the proportion of transient M proteins was only 2.6%. Thus, most of individuals with transient M proteins based on SPEP/IFE are falsely negative, when using MS as the benchmark. Our prospective cohort study provides novel insights on longitudinal patterns of abnormal serum proteins, it highlights how the use of MS results in the identification of low M proteins, and it shows that transient M proteins are often only below the limit of detection with conventional SPEP/IFE.

Disclosures: Berlanga: The Binding Site: Current Employment. Onundarson: Pall T. Onundarson MD: Patents & Royalties: patent for a new coagulation test, the Fiix prothrombin time. Hultcrantz: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Curio Science LLC: Consultancy; Intellisphere LLC: Consultancy; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen, Daichii Sankyo, Cosette, GSK: Research Funding. Landgren: Merck: Consultancy, Other: Independent Data Monitoring Committee (IDMC) member for clinical trials; Pfizer: Consultancy; Janssen: Consultancy, Other: Independent Data Monitoring Committee (IDMC) member for clinical trials, Research Funding; Amgen: Research Funding. Harding: The Binding Site: Current Employment, Membership on an entity's Board of Directors or advisory committees. Durie: Amgen: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Kristinsson: Celgene: Research Funding; Amgen: Research Funding.

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