Residual disease in multiple myeloma (MM) is currently defined by three different modalities: (1) low sensitivity peripheral blood testing for the monoclonal protein product through serum protein electrophoresis/immunofixation (SPEP/IFIX) and the serum free light chain assay, (2) imaging such as positron emission tomography (PET) to evaluate for extramedullary disease or other occult focal lesions, and (3) bone marrow biopsy and aspiration with high sensitivity evaluation for malignant plasma cells by multiparametric flow cytometry (MFC) or next generation sequencing (NGS). Though patients who are found to be multimodal minimal (measurable) residual disease (MRD)-negative have superior outcomes compared to those who have detectable disease, some of these patients will still experience relapse.
Bone marrow testing may lead to false-negative results due to patchy bone marrow involvement, extramedullary disease, or suboptimal sample collection which often plagues bone marrow aspiration. Both imaging and standard measures of the circulating protein product will often fail to detect residual disease due to relatively high limits of detection. A liquid biopsy to assess for MRD in the peripheral blood remains the ‘holy grail’ in MM (as in many other malignancies), as the appropriate test could overcome many of the issues with current methods. Mass spectrometry (MS) represents a promising modality for evaluating for the monoclonal protein product in the peripheral blood, with two prevailing techniques: matrix‐assisted laser desorption ionization time‐of‐flight MS (MALDI-TOF) and liquid chromatography quadrupole time-of-flight MS (LC-MS). MALDI-TOF has a limit of detection (LoD) of 0.05 g/dL while LC-MS has an LoD of 0.005 g/dL.
To determine if MS may represent a suitable peripheral blood-based method for detection of MRD and prognostication in MM, we assessed the concordance of MS status with existing modalities using peripheral blood (SPEP/IFIX, free light chain assays), bone marrow (MFC and NGS), and imaging (PET). Samples were taken prospectively from patients with newly diagnosed MM who were uniformly treated on a phase 2 study involving carfilzomib, lenalidomide, and dexamethasone (KRd) before and after autologous stem cell transplant (NCT01816971) followed by lenalidomide maintenance. Thirty-six patients had paired peripheral blood and bone marrow samples at baseline and at the end of protocol treatment (cycle 18 KRd); of these patients, twenty-four also had paired peripheral blood and bone marrow samples available at the end of one year of lenalidomide maintenance.
Our main findings were as follows:
- MALDI-TOF-MS in the peripheral blood was at least as sensitive as MRD by NGS with LoD <10-5 in the bone marrow, while LC-MS was at least as sensitive as MRD by NGS with LoD <10-6.
- LC-MS status in particular was a superior predictor of PFS compared to NGS or MALDI-TOF-MS status. In fact, none of the 9 patients who were LC-MS-negative at the end of therapy (cycle 18) experienced progression or death.
- In some cases, LC-MS positivity predated conversion to NGS-positivity, suggesting it may be able to predict progression sooner than state-of-the-art bone marrow based assays.
These exciting preliminary findings need further validation but do suggest that peripheral blood testing for MRD in myeloma using MS is feasible and deeply sensitive. Paired with bone marrow based and functional imaging assessments, MS represents a powerful new modality to comprehensively evaluate for MRD in a multimodal fashion.
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