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
Charissa Wijnands,
Peter G. A. Karel,
Jolein Gloerich,
Gad Armony,
Anastasia Tzasta,
Corrie M. de Kat Angelino,
Luciano Di Stefano,
Vincent Bonifay,
Theo M. Luider,
Martijn M. VanDuijn,
Sandra J. Croockewit,
Elizabeth A. de Kort,
Daan A. R. Castelijn,
Claudia A. M. Stege,
Hans J. C. T. Wessels,
Alain J. van Gool,
Niels W. C. J. van de Donk,
Joannes F. M. Jacobs
Affiliations
Charissa Wijnands
Laboratory Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
Peter G. A. Karel
Laboratory of Clinical Chemistry, Deventer Ziekenhuis, 7416 SE Deventer, The Netherlands
Jolein Gloerich
Translational Metabolic Laboratory, Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
Gad Armony
Translational Metabolic Laboratory, Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
Anastasia Tzasta
Laboratory Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
Corrie M. de Kat Angelino
Laboratory Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
Luciano Di Stefano
Sebia, 91090 Lisses, France
Vincent Bonifay
Sebia, 91090 Lisses, France
Theo M. Luider
Department of Neurology, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
Martijn M. VanDuijn
Department of Neurology, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
Sandra J. Croockewit
Department of Hematology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
Elizabeth A. de Kort
Department of Hematology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
Daan A. R. Castelijn
Department of Hematology, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands
Claudia A. M. Stege
Department of Hematology, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands
Hans J. C. T. Wessels
Translational Metabolic Laboratory, Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
Alain J. van Gool
Translational Metabolic Laboratory, Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
Niels W. C. J. van de Donk
Department of Hematology, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands
Joannes F. M. Jacobs
Laboratory Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
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.
