Sensitive multiple myeloma disease monitoring by mass spectrometry

High-Resolution Mass Spectrometry (HRMS) is a sensitive and specific approach for quantification of M-protein in multiple myeloma.

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Multiple myeloma (MM) is hematologic cancer characterized by clonal expansion of malignant plasma cells. These cells produce monoclonal immunoglobulin frequently referred to as M-protein. Measurement of M-protein plays a central role in myeloma disease diagnosis and monitoring. However, clinical laboratories quantitate M-protein using protein electrophoresis-based tests, which are many decades old. These tests have severe limitations including low sensitivity, inconsistency of assay results, and therapeutic antibody interference that can impact the clinical response assessment. Furthermore, current tests are unable to monitor most patients in complete response, therefore flow cytometry and next generation sequencing (NGS) based assays are used for further follow-up of patients with deep responses1. Flow and NGS-based approaches use a bone marrow biopsy, which is highly invasive, painful for patients, and not well-suited for serial sampling.

There is a need to establish more sensitive and precise response and progression monitoring methodologies to better guide therapeutic decisions in MM. In 2014, the researchers from Mayo Clinic elegantly showed that accurate molecular mass of the monoclonal light chain could be used to detect and quantify M-protein2. Since then, several studies have demonstrated that Mass Spectrometry (MS)-based methods can deliver better sensitivity and eliminate false positives3-7. We evaluated these studies and the power of MS in our quest to find a solution for resolving interference from elotuzumab, a monoclonal antibody drug developed by our company. Our choice was to focus on high-resolution mass spectrometry (HRMS). Here, we applied the HRMS assay8 to serum samples from the ELOQUENT-3 trial9. In our study, we used patients’ samples from a full clinical trial and compared the performance of traditional electrophoresis tests to a method based on middle-down HRMS detection of light chains. The analysis of elotuzumab-treated patients’ samples using the selected approach showed the value of HRMS in disease monitoring. Analysis of 1052 study samples from 112 subjects demonstrated efficient removal of antibody interference, tracking of monoclonal light chain across treatment cycles with increased sensitivity over standard methods, and allowed earlier detection of sustained increases in M-protein upon disease progression. Our results are in line with data published by Mayo clinic2,4,5, independently validating their observations. A limitation of current studies is their retrospective nature, so additional work is required for the prospective validation of HRMS methodology.

Mass spectrometry-based technologies are disruptive and challenging standard methods deeply embedded in clinical practice is a demanding task. As demonstrated by our work and previous studies by Mayo clinic, this challenge is absolutely worth it. HRMS-based methodology offers not only superior precision, sensitivity, specificity for M-protein analysis, but also has a great potential for allowing non-invasive monitoring of myeloma patients in complete response in order to complement minimal residual disease and detect disease relapse earlier than current M-protein tests. Here at Bristol Myers Squibb, we work for patients by developing better therapies and bringing in innovative solutions that contribute to patients’ well-being.

DISCLAIMER
Views expressed in this blog are those of the authors and do not necessarily represent an official Bristol Myers Squibb position.

 References

1            Kumar, S. et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol 17, e328-e346, doi:10.1016/S1470-2045(16)30206-6 (2016).

2            Barnidge, D. R. et al. Using mass spectrometry to monitor monoclonal immunoglobulins in patients with a monoclonal gammopathy. J Proteome Res 13, 1419-1427, doi:10.1021/pr400985k (2014).

3            Milani, P. et al. The utility of MASS-FIX to detect and monitor monoclonal proteins in the clinic. Am J Hematol 92, 772-779, doi:10.1002/ajh.24772 (2017).

4            Mills, J. R., Barnidge, D. R., Dispenzieri, A. & Murray, D. L. High sensitivity blood-based M-protein detection in sCR patients with multiple myeloma. Blood Cancer J 7, e590, doi:10.1038/bcj.2017.75 (2017).

5            Mills, J. R. et al. A universal solution for eliminating false positives in myeloma due to therapeutic monoclonal antibody interference. Blood 132, 670-672, doi:10.1182/blood-2018-05-848986 (2018).

6            Moore, L. M., Cho, S. & Thoren, K. L. MALDI-TOF mass spectrometry distinguishes daratumumab from M-proteins. Clin Chim Acta 492, 91-94, doi:10.1016/j.cca.2019.02.017 (2019).

7            Kohlhagen, M. C. et al. Clearing drug interferences in myeloma treatment using mass spectrometry. Clin Biochem, doi:10.1016/j.clinbiochem.2021.02.011 (2021).

8            Santockyte, R. et al. High-Throughput Therapeutic Antibody Interference-Free High-Resolution Mass Spectrometry Assay for Monitoring M-Proteins in Multiple Myeloma. Analytical Chemistry 93, 834-842, doi:10.1021/acs.analchem.0c03357 (2021).

9            Dimopoulos, M. A. et al. Elotuzumab plus Pomalidomide and Dexamethasone for Multiple Myeloma. N Engl J Med 379, 1811-1822, doi:10.1056/NEJMoa1805762 (2018).

Rasa Santockyte

Principal Scientist, Bristol Myers Squibb