Mass spectrometry detection of MRD for patients with multiple myeloma

Mass spectrometry (MS) is a sensitive, emerging alternative for M-protein blood-based detection of minimal residual disease (MRD) in multiple myeloma. Dr Joannes F. M. Jacobs (Radboud University Medical Center, the Netherlands) reviewed the recent developments of these methods as well as their potential application in dynamic monitoring of MRD during treatment [1]. 

Bone marrow MRD is currently the best prognostic marker for multiple myeloma and is used as an endpoint in clinical trials (including the primary endpoint). Several ongoing clinical trials are assessing the utility of MRD-guided treatment decisions [1]. On the other hand, blood-based techniques have several advantages: they are less invasive, can be easier performed serially for determining sustained negativity and treatment adaptation, can detect extramedullary disease, and avoid bone marrow sampling bias arising due to the patchy nature of multiple myeloma [1].

Overall, blood-based methods are well established using either next-generation sequencing or next-generation flow cytometry, but right now can only serve as a complementary biomarker to bone marrow methods. Blood-based detection is less sensitive due to a 100-fold lower presence of myeloma cells in blood versus bone marrow and they are also limited by the large volumes of plasma (>50 mL) which are needed for testing [1]

So what techniques are emerging for MRD detection? Intact M-protein mass spectrometry (MS) has been used successfully using the MASS-FIX method which showed improved sensitivity compared with immunofixation electrophoresis. This method can also differentiate between M-proteins and therapeutic monoclonal antibodies and detect immunoglobulin light chain glycosylation, which is a risk factor for monoclonal gammopathy of uncertain significance progression [2].

The MS detection of patient-specific clonotypic M-protein peptides (bottom-up MS-MRD) is another potential technique [3,4]. This method has shown a good agreement with next-generation sequencing methods, has been used for dynamic monitoring of MRD, and can detect therapeutic monoclonal antibodies. MRD negativity detected by this method was also shown to be an independent prognostic factor of progression-free survival and overall survival, either alone or together with cytogenetic risk factors [5].

Currently, many groups are working on a clinical implementation of MS-MRD. Potential future applications of dynamic blood-based MRD monitoring include use as a complementary marker, optimising timing of bone-marrow sampling, detection of extramedullary growth as well as MRD-guided treatment decisions. Dr Jacobs ended the presentation with a future perspective for MS-based techniques: assessment of M-protein pathogenicity by detection M-protein glycosylation [3] and λ-free light chains [6].

1. Jacobs JFM. The future of MRD testing in multiple myeloma. Session III: MRD in clinical trials and application challenges in clinical practice. EMN 2024, 18–20 April, Turin, Italy.
2. Dasari S, et al. Mayo Clin Proc. 2022;97(2):294-307.
3. Wijnands C, et al. Crit Rev Clin Lab Sci. 2023;60(7):518-534.
4. Noori S, et al. Blood Cancer J. 2023;13(1):30.
5. Fan H, et al. Clin Cancer Res. 2024 15;30(6):1131-1142.
6. Jian X, et al. Blood. 2023;142(Supplement 1):536.

Medical writing support was provided by Mihai Surducan, PhD.

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Posted on 22 April 202422 April 2024