{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T22:04:31Z","timestamp":1790633071629,"version":"4.1.0"},"reference-count":39,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,19]],"date-time":"2025-01-19T00:00:00Z","timestamp":1737244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Dutch Cancer Society","award":["14465"],"award-info":[{"award-number":["14465"]}]},{"name":"Dutch Cancer Society","award":["184.034.019"],"award-info":[{"award-number":["184.034.019"]}]},{"name":"Dutch Cancer Society","award":["LSHM21032"],"award-info":[{"award-number":["LSHM21032"]}]},{"name":"Dutch Research Council (NWO)","award":["14465"],"award-info":[{"award-number":["14465"]}]},{"name":"Dutch Research Council (NWO)","award":["184.034.019"],"award-info":[{"award-number":["184.034.019"]}]},{"name":"Dutch Research Council (NWO)","award":["LSHM21032"],"award-info":[{"award-number":["LSHM21032"]}]},{"name":"PPP Allowance made available by Health~Holland, Top Sector Life Sciences &amp; Health","award":["14465"],"award-info":[{"award-number":["14465"]}]},{"name":"PPP Allowance made available by Health~Holland, Top Sector Life Sciences &amp; Health","award":["184.034.019"],"award-info":[{"award-number":["184.034.019"]}]},{"name":"PPP Allowance made available by Health~Holland, Top Sector Life Sciences &amp; Health","award":["LSHM21032"],"award-info":[{"award-number":["LSHM21032"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Multiple Myeloma (MM) is a hematologic malignancy caused by clonally expanded plasma cells that produce a monoclonal immunoglobulin (M-protein), a personalized biomarker. Recently, we developed an ultra-sensitive mass spectrometry method to quantify minimal residual disease (MS-MRD) by targeting unique M-protein peptides. Therapeutic antibodies (t-Abs), key in MM treatment, often lead to deep and long-lasting responses. However, t-Abs can significantly decrease the total polyclonal immunoglobulin (Ig) levels which require supplemental IgG infusion. Here, we demonstrate the simultaneous monitoring of M-proteins, t-Abs, and polyclonal Ig-titers using an untargeted mass spectrometry assay, offering a comprehensive view of therapy response. Methods: Sera collected between 2013 and 2024 from four patients and cerebrospinal fluid (CSF) from one patient who received various t-Abs were analyzed with MS-MRD. M-protein sequences were obtained with a multi-enzyme de novo protein sequencing approach. Unique peptides for M-proteins and t-Abs were selected based on linearity, sensitivity, and slope coefficient in serial dilutions. Ig constant regions were monitored using isotype-specific peptides. Results: The MS-MRD multiplex analysis provided detailed information on drug concentrations and therapy response kinetics. For example, in two patients with refractory disease over five lines of therapy, the MS-MRD analysis showed that the deepest responses were achieved with bispecific t-Ab (teclistamab) treatment. M-protein and t-Ab were also detectable in the CSF of one patient with MS-MRD. Conclusions: This proof-of-concept study shows that the multiplex monitoring of the M-protein, any t-Ab combination, and all Ig-isotypes within one mass spectrometry run is feasible and provides unique insight into therapy response kinetics.<\/jats:p>","DOI":"10.3390\/pharmaceutics17010135","type":"journal-article","created":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T04:04:12Z","timestamp":1737345852000},"page":"135","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Monitoring M-Protein, Therapeutic Antibodies, and Polyclonal Antibodies in a Multiparametric Mass Spectrometry Assay Provides Insight into Therapy Response Kinetics in Patients with Multiple Myeloma"],"prefix":"10.3390","volume":"17","author":[{"given":"Charissa","family":"Wijnands","sequence":"first","affiliation":[{"name":"Laboratory Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3770-8702","authenticated-orcid":false,"given":"Peter G. A.","family":"Karel","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Chemistry, Deventer Ziekenhuis, 7416 SE Deventer, The Netherlands"},{"name":"Department of Clinical Chemistry, Laboratory Medicine, Unilabs Oost, 7500 KA Enschede, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5976-8426","authenticated-orcid":false,"given":"Jolein","family":"Gloerich","sequence":"additional","affiliation":[{"name":"Translational Metabolic Laboratory, Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6503-9673","authenticated-orcid":false,"given":"Gad","family":"Armony","sequence":"additional","affiliation":[{"name":"Translational Metabolic Laboratory, Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Tzasta","sequence":"additional","affiliation":[{"name":"Laboratory Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corrie M.","family":"de Kat Angelino","sequence":"additional","affiliation":[{"name":"Laboratory Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciano","family":"Di Stefano","sequence":"additional","affiliation":[{"name":"Sebia, 91090 Lisses, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4341-6981","authenticated-orcid":false,"given":"Vincent","family":"Bonifay","sequence":"additional","affiliation":[{"name":"Sebia, 91090 Lisses, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theo M.","family":"Luider","sequence":"additional","affiliation":[{"name":"Department of Neurology, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6654-994X","authenticated-orcid":false,"given":"Martijn M.","family":"VanDuijn","sequence":"additional","affiliation":[{"name":"Department of Neurology, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3101-1194","authenticated-orcid":false,"given":"Sandra J.","family":"Croockewit","sequence":"additional","affiliation":[{"name":"Department of Hematology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0125-9543","authenticated-orcid":false,"given":"Elizabeth A.","family":"de Kort","sequence":"additional","affiliation":[{"name":"Department of Hematology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daan A. R.","family":"Castelijn","sequence":"additional","affiliation":[{"name":"Department of Hematology, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands"},{"name":"Department of Internal Medicine, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7476-0609","authenticated-orcid":false,"given":"Claudia A. M.","family":"Stege","sequence":"additional","affiliation":[{"name":"Department of Hematology, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans J. C. T.","family":"Wessels","sequence":"additional","affiliation":[{"name":"Translational Metabolic Laboratory, Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0010-5286","authenticated-orcid":false,"given":"Alain J.","family":"van Gool","sequence":"additional","affiliation":[{"name":"Translational Metabolic Laboratory, Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7445-2603","authenticated-orcid":false,"given":"Niels W. C. J.","family":"van de Donk","sequence":"additional","affiliation":[{"name":"Department of Hematology, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6208-6386","authenticated-orcid":false,"given":"Joannes F. M.","family":"Jacobs","sequence":"additional","affiliation":[{"name":"Laboratory Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/S0140-6736(21)00135-5","article-title":"Multiple myeloma","volume":"397","author":"Pawlyn","year":"2021","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1182\/blood-2021-149024","article-title":"Daratumumab (DARA) Plus Lenalidomide, Bortezomib, and Dexamethasone (RVd) in Patients (Pts) with Transplant-Eligible Newly Diagnosed Multiple Myeloma (NDMM): Updated Analysis of Griffin after 24 Months of Maintenance","volume":"138","author":"Laubach","year":"2021","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1016\/S1470-2045(21)00428-9","article-title":"Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): An open-label, randomised, phase 3 trial","volume":"22","author":"Moreau","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1182\/blood.2020005288","article-title":"Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: The GRIFFIN trial","volume":"136","author":"Voorhees","year":"2020","journal-title":"Blood"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1056\/NEJMoa2312054","article-title":"Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma","volume":"390","author":"Sonneveld","year":"2024","journal-title":"N. 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Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/s41408-024-01003-z","article-title":"Teclistamab in relapsed refractory multiple myeloma: Multi-institutional real-world study","volume":"14","author":"Mohan","year":"2024","journal-title":"Blood Cancer J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1056\/NEJMoa2203478","article-title":"Teclistamab in Relapsed or Refractory Multiple Myeloma","volume":"387","author":"Moreau","year":"2022","journal-title":"N. Engl. J. 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