Monitoring MRD in Multiple Myeloma in Serum by Mass Spectrometry

Multiple myeloma (MM) is a severe plasma cell cancer caused by proliferation and accumulation of malignant plasma cells in the bone marrow. Novel therapies have improved responses and survival considerably. Recently, it was shown that achieved and sustained minimal residual disease (MRD) negativity is the best predictor for long-term disease-free and overall survival. Achieving and maintaining MRD negativity will therefore be the new treatment goal for patients with MM. Two methods are established for MRD analysis; next-generation flowcytometry (NGF), e.g., the Euro-MRD flow assay, and next-generation sequencing (NGS), e.g., the ClonoSeq assay. Both methods are highly sensitive, with 10\^-5 as the standard goal, and currently reaching for 10\^-6. Both methods are based on bone marrow sampling, which is inconvenient and painful for the patients, particularly for serial analyses.

Blood-based MRD analyses of high sensitivity would allow more frequent sampling and monitoring. Methods based on circulating free tumor DNA are found to have rather low sensitivity. Mass spectrometry (MS) based analysis of patient-specific M-protein is another potential candidate for sensitive and specific monitoring of patients in deep remission. This method is under development, e.g., at the Mayo Clinic, USA, but is not fully standardized. No commercial assays have been approved.

The investigators will assess and validate the sensitivity of MS-based MRD analyses in monitoring patients with MM in remission. Reproducibility and quality controls will be performed in collaboration with an international partner. The investigators will compare the sensitivity of MS-based analysis with Euro-flow MRD assay and NGS LymphoTrack assay, both performed on bone marrow aspirates. Prospectively, the investigators will monitor a cohort of 40 patients in stringent, complete remission. Imaging by FDG-PET/CT (fluoro-deoxyglucose (FDG) positron-emission tomography (PET) combined with computerized tomography (CT)) is part of MRD assessment according to the International Myeloma Working Group (IMWG) and will be included in our studies.

Establishing a blood based MRD analysis will potentially not only be more convenient, it may, in some patients, be more sensitive. The blood reflects disease status in the whole body, whereas bone marrow sampling only allows examining what is present at this particular site. MRD in MM may be patchily located in the skeleton, highlighting the relevance of including FDG PET/CT in the assessment.