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Protein electrophoresis and mass spectrometry of serum and cerebrospinal fluid. (A) Serum protein electrophoresis with an M-protein of 2.3 g/ L, shown in green. Immunofixation electrophoresis (insert) confirms an IgG-lambda M-protein. (B) Cerebrospinal fluid (CSF) protein electrophoresis with an Mprotein of 1.1 g/L, shown in green. Immunofixation electrophoresis (insert) confirms an IgG-lambda M-protein. The electrophoretic methods were not sensitive enough to identify the IgG-kappa monoclonal antibody daratumumab in either serum or CSF. (C) M-protein concentration in CSF and serum, measured using mass spectrometry. (D) Daratumumab concentration in CSF and serum, measured using mass spectrometry. Mass spectrometry (C-D) was performed on 3 paired serum and CSF samples obtained 12, 15, and 19 days after the last daratumumab infusion.
Contexts in source publication
Context 1
... total protein level (6.4 g/L). Microscopic analysis of the CSF showed the presence of PCs and immunophenotypic analysis confirmed the presence of lambda-positive, CD19 -CD56 -PCs in the CSF (85% of all nucleated cells). Serum electrophoresis combined with immunofixation electrophoresis showed the recurrence of the IgG-lambda M-protein (2.3 g/L; Fig. 1A). The M-protein concentration in the CSF was 1.1 g/L (Fig. 1B). The electrophoretic methods were not sensitive enough to detect daratumumab in either serum or CSF. 10,11 Additional staging with FDG-PET scan and BM aspiration showed no signs of systemic MM ...
Context 2
... CSF showed the presence of PCs and immunophenotypic analysis confirmed the presence of lambda-positive, CD19 -CD56 -PCs in the CSF (85% of all nucleated cells). Serum electrophoresis combined with immunofixation electrophoresis showed the recurrence of the IgG-lambda M-protein (2.3 g/L; Fig. 1A). The M-protein concentration in the CSF was 1.1 g/L (Fig. 1B). The electrophoretic methods were not sensitive enough to detect daratumumab in either serum or CSF. 10,11 Additional staging with FDG-PET scan and BM aspiration showed no signs of systemic MM ...
Context 3
... were detected in patient's serum and CSF samples, while all 9 control samples were negative. The M-protein concentration, calculated as an average of heavy (IgG) and light (lambda) chain M-protein concentrations, was 2.3, 2.0 and 1.7 g/L in serum samples obtained at day 12, 15 and 19, respectively; and 1.1, 0.6, and 0.6 g/L in CSF samples (Fig. 1C). The daratumumab concentration was 277, 221, and 213 mg/L in these serum samples at day 12, 15, and 19, respectively; and 4, 3, and 3 mg/L in the CSF samples (Fig. 1D). Taken into account daratumumab pharmacokinetics, higher daratumumab-concentrations would have been measured if samples were obtained during more intense weekly ...
Context 4
... and light (lambda) chain M-protein concentrations, was 2.3, 2.0 and 1.7 g/L in serum samples obtained at day 12, 15 and 19, respectively; and 1.1, 0.6, and 0.6 g/L in CSF samples (Fig. 1C). The daratumumab concentration was 277, 221, and 213 mg/L in these serum samples at day 12, 15, and 19, respectively; and 4, 3, and 3 mg/L in the CSF samples (Fig. 1D). Taken into account daratumumab pharmacokinetics, higher daratumumab-concentrations would have been measured if samples were obtained during more intense weekly daratumumab-infusions. 12 The Mprotein index was calculated using the formula: (CSF M-protein  serum albumin) / (CSF albumin  serum M-protein). Based on these MS data, the ...
Citations
... This may be an issue potentially impacting on drug efficacy in AD, given that the relevance of the contribution of the adaptive immune system to AD is at present not known and could be far less important than the action of the innate immune cells (for a review see Heppner et al., 2015). Indeed, although in the literature the drug is always referred to as brain-permeable, measurements of daratumumab in CSF are scanty, and only two papers addressing this issue are retrievable online, one of which reports, in the CSF of a patient with Leptomeningeal Multiple Myeloma, a concentration of daratumumab 71 times lower compared to serum levels (Zajec et al., 2020). A phase II open-label pilot study is currently testing the potential clinical effect of daratumumab in AD. ...
Despite extensive research, no disease-modifying therapeutic option, able to prevent, cure or halt the progression of Alzheimer’s disease [AD], is currently available. AD, a devastating neurodegenerative pathology leading to dementia and death, is characterized by two pathological hallmarks, the extracellular deposits of amyloid beta (Aβ) and the intraneuronal deposits of neurofibrillary tangles (NFTs) consisting of altered hyperphosphorylated tau protein. Both have been widely studied and pharmacologically targeted for many years, without significant therapeutic results. In 2022, positive data on two monoclonal antibodies targeting Aβ, donanemab and lecanemab, followed by the 2023 FDA accelerated approval of lecanemab and the publication of the final results of the phase III Clarity AD study, have strengthened the hypothesis of a causal role of Aβ in the pathogenesis of AD. However, the magnitude of the clinical effect elicited by the two drugs is limited, suggesting that additional pathological mechanisms may contribute to the disease. Cumulative studies have shown inflammation as one of the main contributors to the pathogenesis of AD, leading to the recognition of a specific role of neuroinflammation synergic with the Aβ and NFTs cascades. The present review provides an overview of the investigational drugs targeting neuroinflammation that are currently in clinical trials. Moreover, their mechanisms of action, their positioning in the pathological cascade of events that occur in the brain throughout AD disease and their potential benefit/limitation in the therapeutic strategy in AD are discussed and highlighted as well. In addition, the latest patent requests for inflammation-targeting therapeutics to be developed in AD will also be discussed.
... 39% [37]. Zajec et al. performed a study to evaluate the ability of daratumumab to cross the BBB [38]. The concentration of daratumumab in the CSF was approximately 71 times lower than that in serum. ...
Multiple myeloma (MM) is a disease caused by the uncontrolled proliferation of clonal plasma cells in bone marrow. Extramedullary plasma cell infiltrations may occur at the time of diagnosis but usually arise during systemic disease progression. Central nervous system (CNS) plasmacytomas are extremely rare (less than 1% of patients with MM) and usually occur as a result of systemic disease progression. The frequency of extramedullary progression to CNS without simultaneous systemic progression is not known. Here, we present a challenging case in which local disease progression to CNS occurred without any signs of systemic progression. The extramedullary plasmacytoma originated from the dura mater of the brain mimicking a brain tumor. We review and discuss further treatment options that are available in such rare clinical scenarios in relation to the treatment already undertaken.
... Although the penetration of systemic daratumumab (anti-CD38 monoclonal antibody) into the CNS was limited, it produced durable responses in some case reports. It is possible that the BBB becomes more permeable in certain disease states, such as when there is disruption of the meninges (28,42). ...
Patients with multiple myeloma (MM) rarely present with central nervous system (CNS) involvement as a manifestation of extramedullary disease (EMD), a condition that is associated with poor prognosis. CNS relapse without evidence of systemic involvement is even rarer, and there is no standardized treatment because there are only few case reports. We present a 47-year-old female who was diagnosed with nonsecretory multiple myeloma (NSMM) 9 years previously. She had a complete remission after receiving aggressive therapies, including high-dose chemotherapy and autologous stem cell transplantation (ASCT). However, after 7 years of progression-free survival, she had CNS relapse without evidence of systemic involvement. We switched to a salvage regimen consisting of high-dose methotrexate with lenalidomide. She achieved rapid clinical improvement, with a reduction in cerebrospinal fluid plasmacytosis of more than 80%, and no notable side effects. Our description of this unique case of a patient with MM and isolated CNS relapse after ASCT provides a reference for physicians to provide more appropriate management of these patients. We also reviewed previously reported cases and summarized the outcomes of isolated CNS relapse after ASCT, and discuss the pathogenesis and possible treatment strategies for MM with isolated CNS relapse.
... Daratumumab, which takes the place of rituximab, has been used in combination with pomalidomide and dexamethasone, first in systemic relapsed and/or refractory MM treatment [24]. Both drugs have CNS penetration [25][26][27], although daratumumab is likely to have a suboptimal penetration given a case report of leptomeningeal myelomatosis which occurred while on daratumumab maintenance [26]. Daratumumab has been used at a shorter interval, weekly in cycle 1 and 2 of some regimens [24,28]. ...
... Daratumumab, which takes the place of rituximab, has been used in combination with pomalidomide and dexamethasone, first in systemic relapsed and/or refractory MM treatment [24]. Both drugs have CNS penetration [25][26][27], although daratumumab is likely to have a suboptimal penetration given a case report of leptomeningeal myelomatosis which occurred while on daratumumab maintenance [26]. Daratumumab has been used at a shorter interval, weekly in cycle 1 and 2 of some regimens [24,28]. ...
... Other IT agents commonly used in lymphoma were cytarabine and dexamethasone. However, cytarabine is ineffective against myeloma although there was a case report which might support its use [26], while dexamethasone has a doubtful effect as a single agent. IT thiotepa is probably a better choice as a case series reported a median OS of 17 months (n = 13) [30]. ...
Central nervous system (CNS) involvement in multiple myeloma (MM) (MM-CNS) in the form of leptomeningeal myelomatosis or brain parenchyma plasmacytoma is rare, causing challenges in clinical diagnosis and treatment. We would like to report a case of leptomeningeal myelomatosis and illustrated the challeges. A 61-year-old man was diagnosed with MM with left paravertebral plasmacytoma, R-ISS II with high suspicion of double-hit MM, either biallelic aberrancy of TP53 or del(17p) and IGH aberrancy depending on the definition chosen, treated with lenalidomide-bortezomib-dexamethasone and local radiotherapy, later developed systemic relapse and progression to MM-CNS in the form of leptomeningeal myelomatosis. A modified CNS-based treatment not reported before, consisting of daratumumab, pomalidomide, vincristine, procarbazine, and dexamethasone, brought a rapid clinical improvement and warrants a further study. Incorporation of intrathecal thiotepa into the regimen would likely increase the efficacy.
... From shotgun MS performed on a baseline sample, clonotypic peptides are first identified by aligning the M-protein primary sequence to the most homologous germline variable region of the IMGT reference directory (www.imgt.org). For all subsequent samples of that same patient, the M-protein clonotypic peptides and t-mAb specific peptides are measured and quantified using targeted MS [33]. Advantage of this bottom-up MS method is that it allows extremely sensitive mAb measurements down to 1 mg/L. ...
Objectives
The therapeutic monoclonal antibody (t-mAb) daratumumab, used to treat multiple myeloma (MM) patients, interferes with routine, electrophoretic based M-protein diagnostics. Electrophoretic response assessment becomes increasingly difficult when multiple t-mAbs are combined for use in a single patient. This is the first study to address the analytical challenges of M-protein monitoring when multiple t-mAbs are combined.
Methods
In this proof-of-principle study we evaluate two different methods to monitor M-protein responses in three MM patients, who receive both daratumumab and nivolumab. The double hydrashift assay aims to resolve t-mAb interference on immunofixation. The MS-MRD (mass spectrometry minimal residual disease) assay measures clonotypic peptides to quantitate both M-protein and t-mAb concentrations.
Results
After exposure to daratumumab and nivolumab, both t-mAbs become visible on immunofixation electrophoresis (IFE) as two IgG-kappa bands that migrate close to each other at the cathodal end of the γ-region. In case the M-protein co-migrates with these t-mAbs, the observed interference was completely abolished with the double IFE hydrashift assay. In all three patients the MS-MRD assay was also able to distinguish the M-protein from the t-mAbs. Additional advantage of the MS-MRD assay is that this multiplex assay is more sensitive and allows quantitative M-protein-, daratumumab- and nivolumab-monitoring.
Conclusions
Daratumumab and nivolumab interfere with electrophoretic M-protein diagnostics. However, the M-protein can be distinguished from both t-mAbs by use of a double hydrashift assay. The MS-MRD assay provides an alternative method that allows sensitive and simultaneous quantitative monitoring of both the M-protein and t-mAbs.
Multiple myeloma (MM) is characterized by the clonal expansion of plasma cells and the excretion of a monoclonal immunoglobulin (M-protein), or fragments thereof. This biomarker plays a key role in the diagnosis and monitoring of MM. Although there is currently no cure for MM, novel treatment modalities such as bispecific antibodies and CAR T-cell therapies have led to substantial improvement in survival. With the introduction of several classes of effective drugs, an increasing percentage of patients achieve a complete response. This poses new challenges to traditional electrophoretic and immunochemical M-protein diagnostics because these methods lack sensitivity to monitor minimal residual disease (MRD). In 2016, the International Myeloma Working Group (IMWG) expanded their disease response criteria with bone marrow-based MRD assessment using flow cytometry or next-generation sequencing in combination with imaging-based disease monitoring of extramedullary disease. MRD status is an important independent prognostic marker and its potential as a surrogate endpoint for progression-free survival is currently being studied. In addition, numerous clinical trials are investigating the added clinical value of MRD-guided therapy decisions in individual patients. Because of these novel clinical applications, repeated MRD evaluation is becoming common practice in clinical trials as well as in the management of patients outside clinical trials. In response to this, novel mass spectrometric methods that have been developed for blood-based MRD monitoring represent attractive minimally invasive alternatives to bone marrow-based MRD evaluation. This paves the way for dynamic MRD monitoring to allow the detection of early disease relapse, which may prove to be a crucial factor in facilitating future clinical implementation of MRD-guided therapy. This review provides an overview of state-of-the-art of MRD monitoring, describes new developments and applications of blood-based MRD monitoring, and suggests future directions for its successful integration into the clinical management of MM patients.
Leptomeningeal myelomatosis is a rare complication of multiple myeloma (<1% of the patients). There was an increase in the incidence of leptomeningeal myelomatosis during the last decade; the prognosis of leptomeningeal myelomatosis remains poor, (overall median survival from the time of diagnosis of 2 months). We discuss a rare case of a monoclonal gammopathy evolving into multiple myeloma and finally into a rapidly progressing leptomeningeal disease. A 76 year-old woman in hematologic follow-up for advanced stage multiple myeloma in sixth-line treatment had an episode of generalized tonic-clonic seizure with sphincter release followed by altered state of consciousness. The unenhanced head CT scan showed a mild enlargement of the ventricular system without intra-axial or extra-axial hemorrhages nor significant changes in brain parenchyma. The subsequent contrast-enhanced brain MRI revealed a widespread nodular leptomeningeal enhancement characterized by contrast-enhancement of the pia mater extended into the subarachnoid spaces of the sulci and cisterns, involving supra- and sub-tentorial regions and the statoacoustic nerve in the inner ear canal bilaterally. The fluid-attenuated inversion recovery MRI images demonstrated an abnormally elevated signal within the sulci in the parieto-occipital regions. The radiological diagnosis of leptomeningeal myelomatosis was made. The patient died 4 days after the examination. In patients with long-lasting multiple myeloma and onset of neurological signs or symptoms, a contrast-enhanced brain MRI should be performed to assess the actual burden of central nervous system involvement in leptomeningeal myelomatosis; CT may provide a clue to the diagnosis when progressive enlargement of the ventricles over time is noted.
