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Neuropsychiatric Adverse Events with Monoclonal Antibodies Approved for Multiple Myeloma: An Analysis from the FDA Adverse Event Reporting System

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Abstract
Background/Objectives: Monoclonal antibodies (mAbs) have revolutionized multiple myeloma (MM) treatment. However, post-marketing data on their neuropsychiatric safety is limited. This study aimed to evaluate neuropsychiatric adverse events (AEs) related to mAbs used for MM through a retrospective pharmacovigilance analysis using the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS) database. Methods: Individual case safety reports (ICSRs) from 2015 to 2023 with at least one neuropsy-chiatric AE and one of the MM-approved mAbs as the suspect drug (i.e., daratumumab, elo-tuzumab, isatuximab, belantamab mafodotin, teclistamab, elranatamab, and talquentamab) were analyzed using descriptive and disproportionality approaches. Results: Unknown signals of disproportionate reporting (SDR) included cerebral infarction for daratumumab (n = 45; reporting odds ratio (ROR) = 2.39, 95% confidence interval (CI) = 1.79-3.21; information component (IC) = 1.54, IC025-IC075 = 1.05-1.9), elotuzumab (25; 7.61, 5.13-11.28; 3.03, 2.37-3.51), and isatuximab (10; 2.56, 1.38-4.76; 1.67, 0.59-2.4); mental status changes for daratumumab (40; 2.66, 1.95-3.63; 1.67, 1.14-2.04) and belantamab mafodotin (10; 4.23, 2.28-7.88; 2.3, 1.22-3.03); altered state of consciousness for daratumumab (32; 1.97, 1.39-2.78; 1.32, 0.73-1.74) and belantamab mafodotin (6; 2.35, 1.05-5.23; 1.6, 0.19-2.52); Guil-lain-Barre syndrome (GBS) for daratumumab (23; 6.42, 4.26-9.69; 2.81, 2.11-3.3), isatuximab (8; 10.72, 5.35-21.48; 3.57, 2.35-4.37), and elotuzumab (3; 4.74, 1.53-14.7; 2.59, 0.52-3.8); and orthos-tatic intolerance for daratumumab (10; 12.54, 6.71-23.43; 3.75, 2.67-4.48) and elontuzumab (4; 28.31, 10.58-75.73; 5 , 3.24-6.08). Conclusions: Our analysis highlighted several previously unacknowledged SDRs for MM-approved mAbs. Given the complex and not entirely understood etiology of some neuropsy-chiatric AEs, including GBS, further investigations are necessary.
Keywords: 
Subject: Medicine and Pharmacology  -   Pharmacology and Toxicology

1. Introduction

Multiple myeloma (MM) is characterized by the abnormal growth of plasma cells, which produce monoclonal immunoglobulins. This proliferation of cells within the bone marrow frequently leads to bone lesions, kidney damage, anemia, and elevated calcium levels [1]. Monoclonal antibodies (mAbs) have transformed MM treatment, offering significant effectiveness in both newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM) cases, improving survival rates and treatment compliance while reducing toxicity [2,3]. Five-year overall survival (OS) rates for MM have now surpassed 50% [4]. Daratumumab combined with lenalidomide, and dexamethasone extends median OS to 67.6 months compared to 51.8 months with lenalidomide and dexamethasone alone [5]. Elotuzumab improves median progression-free survival (PFS) to 19.4 months [6], while teclistamab shows a median PFS of 11.3 months [7]. By targeting plasma cell antigens, mAbs induce apoptosis through mechanisms such as antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity, inhibition of mitochondrial transfer, and antibody-dependent cellular phagocytosis [8]. MAbs approved by the Food and Drug Administration (FDA) for MM include daratumumab, isatuximab, elotuzumab, belantamab mafodotin (withdrawn from the market), teclistamab, elranatamab, and talquetamab [9,10,11,12,13,14,15].
Although generally well-tolerated, mAbs can cause several adverse events (AEs) [9,10,11,12,13,14,15], including neuropsychiatric ones. While known neuropsychiatric AEs such as neuropathy for daratumumab, elotuzumab, teclistamab, elranatamab, and talquetamab and immune effector cell-associated neurotoxicity syndrome (ICANS) for teclistamab, elranatamab, and talquetamab are documented in the FDA Prescribing Information for these drugs, the literature suggests other undetected potential neuropsychiatric AEs for mAbs. For example, there have been case series reporting leukoencephalopathy and encephalitis with daratumumab [16,17,18], as well as other neurotoxicities, including movement and/or neurocognitive disorders not reported in FDA labels [15,19,20]. However, a comprehensive post-marketing study investigating the neuropsychiatric profile of the new MM therapies is lacking. The present study aims to evaluate and characterize neuropsychiatric AEs related to all mAbs used for MM by analyzing the US FDA Adverse Event Reporting System (FAERS) database to detect new potential neuropsychiatric safety signals.

2. Results

2.1. Selection Process and Descriptive Analysis

After applying the preliminary exclusion criteria and performing the final cleaning of the database, a total of 13,496,241 individual case safety reports (ICSRs) were identified. Among those, 4061 ICSRs met the previously specified inclusion criteria and were classified as cases because they were related to neuropsychiatric AEs and had one of the mAbs approved for MM as suspect drug. Most of these cases (n = 2862; 70.5%) were related to daratumumab, followed by isatuximab (n = 345; 8.5%) and elotuzumab (n = 321; 7.9%) (Figure 1).
Nearly half of the ICSRs were reported for elderly patients (n = 1947; 47.9%). This percentage was significantly higher than that observed in the non-cases (n = 2,895,017; 21.5%). A higher frequency of male patients was also observed in cases compared to non-cases (n = 1849; 45.5% vs. n = 4,670,150; 34.6%) (Table 1). A variation in age frequency was noted when stratifying neuropsychiatric ICSRs by each mAb. Specifically, lower frequencies of elderly patients were shown for teclistamab (n = 86; 39.8%), belantamab mafodotin (n = 69; 28.6%), and talquetamab (n = 13; 27.7%) (Table S1). Neuropsychiatric ICSRs were mainly issued by physicians (n = 2114; 52.1%) and from Europe (n = 1668; 41.1%). In terms of codified outcomes, neuropsychiatric ICSRs were mainly deemed to be linked to AEs of medical importance (n = 1801; 44.4%), followed by AEs leading to or prolonging hospitalization (n = 1397; 34.4%). Additionally, 351 ICSRs (8.6%) reported death as an outcome (Table 1). Considering neuropsychiatric AEs by each mAb, belantamab mafodotin and teclistamab-related ICSRs presented higher frequencies of death (n = 52; 21.6% and n = 42; 19.4%, respectively) (Table S1).
The shortest median (Q1-Q3) time to onset (TTO) for neuropsychiatric AEs was observed with teclistamab at 8 (3-11) days, while the highest median (Q1-Q3) TTO was observed with elranatamab at 72 (18-98) days (Figure 2).

2.2. Disproportionality Analysis

New and previously undetected signals of disproportionate reporting (SDRs) using neuropsychiatric AEs were detected by calculating the Reporting Odds Ratios (ROR) and their 95% confidence intervals (CI). The Bayesian information component (IC) was also computed to gauge the association strength between mAbs and AEs. Unexpected AEs were considered as such if not listed in the FDA Prescribing Information. Further details are provided in the materials and methods section.
Several already acknowledged AEs related to mAbs approved for the treatment of MM emerged as SDRs from our analysis. These included syncope for daratumumab, ICANS for both talquetamab and teclistamab, as well as peripheral neuropathy for both elotuzumab and elranatamab. The entire disproportionality analysis is available in the Table S2. Moreover, some SDRs were linked to other similar known neuropsychiatric AEs. Daratumumab was associated with polyneuropathies, which could include peripheral sensory neuropathy, and encephalopathies possibly linked to the known posterior reversible encephalopathy syndrome. Elranatamab related-ICSRs reported syncope, with a depressed level of consciousness being a known AE. Furthermore, postherpetic neuralgia, possibly tied to herpes zoster infection, was reported for elotuzumab. However, some unknown AEs also emerged as SDRs (Table 2).
Daratumumab had several SDRs which included some unknown nervous system-related AEs as follows: cerebral infarction (n = 45; ROR = 2.39, 95% CI = 1.79-3.21), depressed level of consciousness (42; 1.65, 1.22-2.24), ischaemic stroke (33; 2.24, 1.59-3.15; 1.47, 0.89-1.88), altered state of consciousness (32; 1.97, 1.39-2.78), partial seizures (27; 6.77, 4.63-9.89), spinal cord compression (23; 6.48, 4.29-9.77), Guillain-Barre syndrome (GBS) (23; 6.42, 4.26-9.69), ICANS (18; 5.36, 3.37-8.53), neurotoxicity (17; 1.69, 1.05-2.72), and incoherent (12; 2.61, 1.48-4.61). Considering psychiatric disorders, the AEs not reported in the FDA Prescribing Information for daratumumab were delirium (n = 54; ROR = 2.29, 95% CI = 1.75-2.99), mental status changes (40; 2.66, 1.95-3.63), and body dysmorphic disorder (15; 58.08, 34.3-98.33).
Focusing on belantamab mafodotin, unknown SDRs related to nervous system disorders were neuropathy peripheral (n = 38; ROR = 2.62, 95% CI = 1.90-3.61), altered state of consciousness (6; 2.35, 1.05-5.23), muscle tone disorder (4; 59.56, 22.19-159.81), Bell's palsy (3; 12.77, 4.11-39.68), and neurological decompensation (3; 12.49, 4.02-38.8). Moreover, regarding psychiatric disorders, the only unknown SDR was mental status changes (10; 4.23, 2.28-7.88).
Undocumented nervous system disorders for isatuximab that emerged as SDRs in our analysis included polyneuropathy (n = 21; ROR = 9.26, 95% CI = 6.03-14.22), transient ischaemic attack (17; 3.37, 2.09-5.42), ischaemic stroke (14; 4.59, 2.71-7.75), peripheral sensory neuropathy (11; 12.23, 6.76-22.13), cerebral infarction (10; 2.56, 1.38-4.76), cerebral ischaemia (9; 12.64, 6.56-24.34), GBS (8; 10.72, 5.35-21.48), haemorrhage intracranial (7; 2.76, 1.31-5.79), basal ganglia infarction (6; 132.39, 58.54-299.42), peripheral motor neuropathy (6; 29.61, 13.25-66.18), and subarachnoid haemorrhage (5; 2.95, 1.23-7.09). The only unknown SDR for psychiatric disorders was acute psychosis (3; 8.8, 2.83-27.34).
Spinal cord compression was the only unknown neuropsychiatric AE for teclistamab (n = 4; ROR = 15.87, 95% CI = 5.94-42.38).
Focusing on elotuzumab, unknown nervous system disorders with SDR included syncope (n = 27; ROR = 1.75; 95% CI = 1.2-2.56), cerebral infarction (25; 7.61, 5.13-11.28), cerebral hemorrhage (12; 2.27, 1.29-4; 1.52, 0.54-2.18), cerebrovascular disorder (4; 16.68, 6.24-44.56), orthostatic intolerance (4; 28.31, 10.58-75.73), VIth nerve paralysis (4; 36.99, 13.81-99.05), GBS (3; 4.74, 1.53-14.7), intention tremor (3; 49.87, 15.97-155.8), monoplegia (3; 4.55, 1.46-14.11), and spinal cord compression (3; 4.78, 1.54-14.83). Considering psychiatric disorders, the only unknown SDR was listlessness (3; 5.28, 1.7-16.38). An association between the drug and all unknown AEs was confirmed by the 95% credibility interval limit being greater than 0 for the IC. Further details are available in Table 2.

3. Discussion

To the best of our knowledge, this is the first study based on mAb-related neuropsychiatric AEs for the treatment of MM using a large-scale spontaneous reporting system database. Focusing on demographic characteristics, we observed a higher frequency of neuropsychiatric ICSRs involving male patients. The different incidence of MM between male and females might be a key factor in interpreting this result. Male sex is a well-recognized risk factor for the onset of MM. Indeed, a population-based study in the US revealed that, from 2000 to 2019, the age-standardized incidence rates of MM per 100,000 people were 8.49 (95% CI 8.43–8.54) for men and 5.58 (95% CI 5.55–5.62) for women [21]. Literature sources have hypothesized that this increased risk might be related genetic factors [22]. Additionally, possible lifestyle-dependent risk factors, more frequent in male patients (such as smoking or obesity), have also been hypothesized to contribute to the onset of monoclonal gammopathy of undetermined significance, a premalignant precursor to MM [23,24,25]. However, no conclusive evidence in MM exists regarding this in MM at present. Elderly patients were the age category with the highest frequency of neuropsychiatric ICSRs. Over 60% of MM diagnoses in the US are made in patients aged 65 years and older [26]. This might be due to early nonspecific symptoms of MM, such as back pain, fatigue, and anemia, which can often be mistaken for age-related issues, leading to delays in MM diagnosis and treatment [27]. Furthermore, elderly patients are known to be more susceptible to the onset of AEs in general [28,29], and age is also considered a risk factor for the development of neuropsychiatric AEs, such as peripheral neuropathy and polyneuropathy, in MM patients [30].
Serious outcomes, including hospitalization and important medical events, were mainly observed in neuropsychiatric ICSRs compared to the non-case group. The line-therapy of mAbs in MM treatment should be considered in this context. Indeed, daratumumab is the only mAb currently approved for NDMM. Thus, a relevant portion of the ICSRs could pertain to patients with RRMM. These patients are typically older, have undergone several lines of previous therapies, and may have disease-related comorbidities [31].
Considering the TTO, elranatamab-related ICSRs exhibited the highest median TTO among all mAbs for neuropsychiatric AEs. Elranatamab-related neuropsychiatric AEs with a longer TTO were mainly associated with alterations in consciousness, such as syncope, depressed level of consciousness, and altered state of consciousness. These manifestations have previously been observed as part of cytokine release syndromes [32]. However, these AEs are mostly reported during the step-up phases of treatment, with randomized controlled trial data highlighting a median (Q1-Q3) TTO 2 (1–9) days [33]. Thus, the observed prolonged TTO might be due to other factors, such as dose delays or interruptions, which could be implemented as mitigation strategies following the onset of previous AEs such as infections or hematologic AEs [33].
The disproportionality analysis highlighted SDRs in vascular disorders involving the central nervous system (CNS). Both cerebral infarction and ischaemic stroke were previously unknown for daratumumab, isatuximab, and elotuzumab. Literature data regarding specific CNS vascular complications in MM patients treated with mAbs is currently lacking. However, pre-marketing safety data for both daratumumab and isatuximab highlighted non relevant effects on the frequency of vascular thromboembolic events (VTE) in general [34,35]. Other factors might play a key role in the onset of these AEs. Indeed, MM patients are frequently characterized by hypercoagulability states, which could facilitate the onset of VTEs [36,37]. Furthermore, the co-administration of mAbs with immunomodulatory drugs, such as lenalidomide and pomalidomide, represents a well-recognized risk factor for VTEs [38]. Additionally, several disproportional haemorrhage-related AEs were observed, such as cerebellar haemorrhage for daratumumab and intracranial haemorrhage for isatuximab. In these cases, disease progression in MM might play a key role in the onset of these AEs. Indeed, MM patients exhibit the highest incidence of thrombocytopenia among those with haematological cancers, which is a significant risk factor for bleeding [39]. Moreover, dysfibrinogenemia, often observed in MM patients due to interactions between MM paraproteins and coagulation proteins, can also lead to bleeding complications [40,41,42].
AEs associated with alterations in the state of consciousness were also identified as unknown SDRs. Specifically, depressed or altered level of consciousness, incoherent state, stupor, and worsening of senile dementia had higher RORs for daratumumab. Alterations in consciousness and mental status were also SDRs for belantamab mafodotin, along with neurological decompensation. Delirium was identified as an SDR for elotuzumab, together with listless. Finally, acute psychotic episodes were unknown SDRs for isatuximab. Altered mental status (AMS) in MM patients is often due to metabolic disturbances such as uremia, hypercalcemia, and hyperviscosity. Elevated levels of serum ammonia have also been reported as a rare but clinically impactful cause of AMS in these patients [43]. Furthermore, a population-based study showed a strong correlation between peripheral neuropathies (PNs) and degradation of cognitive performance, which could lead to AMS in elderly patients [44]. AMS conditions might also result from the co-administration with immunomodulators, which could themselves be related to neurotoxicity [45]. Moreover, AMS might be part of more complex clinical pictures, such as encephalopathies [46], which were disproportionally reported for daratumumab and elotuzumab. The posterior reversible encephalopathy syndrome is an already documented AE for daratumumab. This condition is characterized by reversible vasogenic cerebral edema that manifests acutely with neurological symptoms such as seizures, headaches, and visual disturbances, in addition to AMS [47].
Neuropathies were also identified as SDRs in several mAbs. The onset of PNs was not mentioned in the FDA Prescribing Information for isatuximab and belantamab mafodotin. The neuronal damage that could lead to PNs might theoretically be caused by isatuximab and belantamab mafodotin through mechanisms such as ADCC [48,49] and CDC [50]. However, PNs can also emerge as consequences of worsening MM [30,51] due to deposits of the M-protein produced by myeloma cells on neurons [52]. Furthermore, isatuximab is currently approved only as a third-line treatment, while belantamab mafodotin was approved as a fifth-line therapy before its withdrawn. Thus, compromised patient conditions should be considered as a possible influencing factor [53,54]. Moreover, the concomitant use of pomalidomide and carfilzomib with daratumumab or isatuximab could also be associated with the onset of PNs in MM patients [55,56]. Neuropathies can be associated with both sensory (e.g., numbness, tingling, pain) and motor symptoms (e.g., muscle weakness). In some cases, PNs can also be associated with paralysis [30]. Our data were in line with this, as unknown VIth nerve paralyses were SDRs for daratumumab, belantamab mafodotin, and elotuzumab. Moreover, a rare severe form of PN, characterized by rapidly advancing, symmetrical limb weakness [51,52] and known as GBS, was also disproportionally reported for daratumumab, isatuximab, and elotuzumab [49,50]. The mechanisms underlying the onset of GBS remain unclear; however, the presence of a previous infection is considered an important factor [57]. Although immunodeficiency is a common feature of MM [58,59], both daratumumab and isatuximab-based therapies have been linked to an increased risk of infections [60]. Indeed, the results of a recent meta-analysis showed that among anti-CD38-treated patients, the relative risk for any grade of infection compared with control was 1.27 (95% CI, 1.17–1.37) [61]. This increased susceptibility to infections could potentially trigger the onset of GBS in predisposed individuals.

3.1. Strengths and Limitations

Spontaneous reporting system database-based analyses are among the most widely used methodologies for generating hypotheses about drug safety in pharmacovigilance [62,63]. The large-scale nature of the FAERS database enables the detection of AEs not previously identified in controlled environment studies [64]. However, some limitations inherent to the chosen methodology are present. The absence of a proper denominator prevents us from determining the incidence of the observed AEs [65]. Additionally, pharmacovigilance databases are mainly based on spontaneous reporting, which can lead to underreporting or overreporting of events due to various external factors [66,67]. Another limitation is the potential presence of duplicate ICSRs. To mitigate this issue, we implemented a multi-step control process based on key information fields, as detailed in the materials and methods section. Several additional measures were also implemented to improve data quality, such as eliminating undescriptive AEs and using validated data extraction and processing tools, as well as a standardized drug naming dictionary [68]. Most of the mAbs considered are prescribed as a second or subsequent lines of treatment for patients with RRMM. Therefore, the influence of disease progression on the reporting of neuropsychiatric AEs cannot be excluded. The observed disproportionalities may also have been influenced by the presence of other co-administered drugs, which complicates establishing a causal relationship between the observed AEs and mAbs. Furthermore, the lack of complete patient clinical histories, which are not available in the open FAERS data, limits our ability to conduct a more comprehensive evaluation. Despite these limitations, we believe our study provides valuable insights for oncologists, aiding in the understanding of the neuropsychiatric safety profile of mAbs and assisting in the management of MM patients.

4. Materials and Methods

4.1. Study Design

A retrospective pharmacovigilance study was conducted to identify neuropsychiatric AEs associated with mAbs approved for MM using the FAERS database. The FAERS database, a widely utilized public resource, has consistently demonstrated its reliability as a platform for drug safety evaluation studies [69,70,71,72]. This database aggregates over 20 million ICSRs from patients, healthcare providers, and pharmaceutical companies across the US, Europe, and Asia. Each ICSR includes a primary ID, data related to the individual (e.g., gender, age, and weight), reporting details such as the reporting country and the qualification of primary sources, information on suspected and concomitant drugs – including their indications and administration dates – and suspected AEs classified by the Medical Dictionary for Regulatory Activities (MedDRA®) Preferred Term (PT) [73], along with details on the date of onset and the outcome.

4.2. Selection of Cases

From the zipped ASCII FAERS quarterly data extract files accessible at https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html (accessed on the 29th of January 2024) we downloaded data from the quarter 1 (Q1) of 2015 to the fourth quarter (Q4) of 2023, covering the period since the approval of the first mAbs for MM.
In detail, we retrieved data from each DEMO, DRUG, INDI, OUTC, REAC, and THER files. These files were merged based on the primary ID and the case ID. Information from INDI and THER files was combined with DRUG data to create a comprehensive file named DRUG_ALL. Similarly, OUTC data was merged with DEMO data to generate a file renamed DEMO_ALL. Additionally, the REAC_ALL file contained data exclusively from the REAC file.
Each of these three files —DRUG_ALL, DEMO_ALL, and REAC_ALL— was cleaned by removing all duplicated ICSRs based on primary ID and case ID, as well as key fields including type of AEs, date of onset, gender, age, reporting country, and suspected drug. This process followed FDA recommendations, wherein, in cases with multiple ICSRs sharing the same primary ID, only the most recent case ID version was retained [74].
From the DEMO_ALL file, premarketing ICSRs with supporting literature were excluded. Additionally, for the DRUG_ALL file, we utilized the DiAna dictionary – a dynamic, open-source tool known for its dynamic nature, transparency and adaptability. This dictionary was used to map all drug names in active substances within each ICSR according to the Anatomical Therapeutic Chemical (ATC) classifications [68]. We also excluded ICSRs that contained at least one investigational product, investigational biosimilar, or blinded product. Similarly, from the REAC_ALL file, all cases with the PT “no adverse event” were excluded.
For defining our cases, we selected all ICSRs where one of the following drugs was listed as the primary or secondary suspect: daratumumab, elotuzumab, isatuximab, belantamab mafodotin, teclistamab, elranatamab, and talquentamab. To avoid therapeutic biases, ICSRs with indications other than MM were excluded. Moreover, to analyze neuropsychiatric AEs, we considered all ICSRs containing at least one AE classified under the SOC “nervous system disorders” or “psychiatric disorders”.

4.3. Data Analyses

The demographic and clinical characteristics of FAERS ICSRs were analyzed using a descriptive statistical approach with a case-non-cases comparison. Continuous variables are presented as median with quartiles (Q1–Q3), while categorical variables are shown as absolute values with corresponding percentages. Key variables analyzed include gender, age, the primary source of information, year of reporting, reporting country, and detailed descriptions of AEs, including their outcome and TTO. TTO was calculated as the interval between drug administration (start date) and AE manifestation (event date) and presented as a median (Q1–Q3) for clarity.
A disproportionality analysis was conducted to detect new and previously undetected SDRs for neuropsychiatric PTs, by calculating the ROR and its 95% CI. Statistical significance was determined if the lower limit of the 95% CI for the ROR was greater than one, with a minimum of three ICSRs for each drug-event combination [70].
To reduce the risk of identifying spurious associations and assess the strength of the association between mAbs and AEs, the Bayesian IC was computed. An association between the drug and the AE was indicated by a 95% credibility interval limit greater than 0 (IC025 > 0). AEs not listed in the FDA Full Prescribing Information for each mAb at the time of the study were considered unexpected [9,10,11,12,13,14,15].
The significance level for statistical analyses was set at a p value <0.05. All data processing and statistical analyses were conducted using R (version 4.3.1) with the RStudio (version 2024.04.2+764) [75,76].

5. Conclusions

This study underscores the crucial role of large-scale spontaneous reporting system databases in evaluating AEs. Our findings are consistent with the limited existing literature on neuropsychiatric AEs associated with mAbs used in the treatment of MM. We identified several previously unrecognized neuropsychiatric AEs related to mAbs, including VTE, AMS, and GBS. Further research is needed to better understand and contextualize these tolerability issues. Additionally, our study highlights the importance of ongoing monitoring of MM patients for neuropsychiatric AEs. Timely management of these AEs can enhance patient quality of life and, in some cases, such as alterations in consciousness, may help reduce the impact of associated complications.

Author Contributions

Conceptualization, G.R. and M.A.B.; methodology, G.R. and M.A.B.; software, M.A.B.; validation, M.A.B. and E.S.; formal analysis, G.C., G.R., and M.A.B.; investigation, G.C. and M.A.B; data curation, G.R.; writing—original draft preparation, G.C. and G.R.; writing—review and editing, M.A.B., T.F., M.S., E.S.; visualization, G.C., G.R., V.S., T.F., N.S., M.S., E.S., and M.A.B.; supervision, E.S. and M.A.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

The study used publicly available safety ICSR data that were provided in an anonymous form and were already compliant with ethical standards. Therefore, no further ethical evaluation was necessary.

Data Availability Statement

This study was entirely based on publicly anonymized data made available by the Food and Drug Administration. The raw data can be downloaded at the following link https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html.

Conflicts of Interest

The authors declare no conflicts of interest.

Appendix – List of Abbreviations

ADCC: antibody-dependent cellular cytotoxicity
AE: adverse event
AMS: altered mental status
ATC: Anatomical Therapeutic Chemical
CI: confidence interval
FAERS: Food and Drug Administration Adverse Events Reporting System
FDA: Food and Drug Administration
GBS: Guillain-Barre syndrome
IC: information component
ICANS: immune effector cell-associated neurotoxicity syndrome
ICSR: Individual Case Safety Report
mAbs: monoclonal antibodies
MedDRA: Medical Dictionary for Regulatory Activities
MM: multiple myeloma
NDMM: newly diagnosed multiple myeloma
PN: peripheral neuropathy
PT: Preferred Term
ROR: Reporting Odds Ratio
RRMM: relapsed/refractory multiple myeloma
SDR: signal of disproportionate reporting
TTO: time to onset
VTE: vascular thromboembolic events

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Figure 1. Database Cleaning and Cases Selection Flowchart. AE = adverse event; ICSR = individual case safety report; MM = multiple myeloma; PT = Preferred Term.
Figure 1. Database Cleaning and Cases Selection Flowchart. AE = adverse event; ICSR = individual case safety report; MM = multiple myeloma; PT = Preferred Term.
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Figure 2. Time to onset of neuropsychiatric AEs. The data are sorted in descending order of frequency and presented as a box plot, with the box extending from the first quartile (Q1) to the third quartile (Q3), and a horizontal line in the middle representing the median time to onset (TTO).
Figure 2. Time to onset of neuropsychiatric AEs. The data are sorted in descending order of frequency and presented as a box plot, with the box extending from the first quartile (Q1) to the third quartile (Q3), and a horizontal line in the middle representing the median time to onset (TTO).
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Table 1. Characteristic of cases related to neuropsychiatric adverse events of monoclonal antibodies approved for multiple myeloma compared to non-cases.
Table 1. Characteristic of cases related to neuropsychiatric adverse events of monoclonal antibodies approved for multiple myeloma compared to non-cases.
Characteristic Neuropsychiatric cases
(n= 4061)		 Non-cases
(n= 13,492,180)		 Total
(n=13,496,241)
Age group, n (%)
Neonate 3 (<0.1%) 39,379 (0.3%) 39,382 (0.3%)
Infants 15,400 (0.1%) 15,400 (0.1%)
Child 7 (0.2%) 150,436 (1.1%) 150,443 (1.1%)
Adolescent 10 (0.3%) 196,410 (1.5%) 196,420 (1.5%)
Adult 1006 (24.8%) 4,157,969 (30.8%) 4,158,975 (30.8%)
Elderly 1947 (47.9%) 2,895,017 (21.5%) 2,896,964 (21.5%)
Not available 1088 (26.8%) 6,037,569 (44.8%) 6,038,657 (44.7%)
Sex, n (%)
Female 1588 (39.1%) 7,145,404 (53.0%) 7,146,992 (53.0%)
Male 1849 (45.5%) 4,670,150 (34.6%) 4,671,999 (34.6%)
Not available 624 (15.4%) 1,676,626 (12.4%) 1,677,250 (12.4%)
Primary source qualification, n (%)
Consumers 580 (14.3%) 6,659,308 (49.4%) 6,659,888 (49.4%)
Health professional 685 (16.9%) 1,185,741 (8.8%) 1,186,426 (8.8%)
Physician 2114 (52.1%) 2,801,856 (20.8%) 2,803,970 (20.8%)
Other health-professional 352 (8.7%) 1,140,098 (8.5%) 1,140,450 (8.5%)
Pharmacist 312 (7.7%) 884,427 (6.6%) 884,739 (6.6%)
Lawyer 502,463 (3.7%) 502,463 (3.7%)
Not available 18 (0.4%) 318,287 (2.4%) 318,305 (2.4%)
Outcome codification, n (%)
Death 351 (8.6%) 780,158 (5.8%) 780,509 (5.8%)
Disability 69 (1.7%) 147,322 (1.1%) 147,391 (1.1%)
Hospitalization - Initial or prolonged 1397 (34.4%) 2,090,657 (15.5%) 2,092,054 (15.5%)
Life-threatening 112 (2.8%) 143,135 (1.1%) 143,247 (1.1%)
Other serious (Important Medical Event) 1801 (44.4%) 4,233,022 (31.4%) 4,234,823 (31.4%)
Required intervention to prevent permanent impairment/damage 5 (0.1%) 12,674 (0.1%) 12,679 (0.1%)
Congenital anomaly 21,535 (0.2%) 21,535 (0.2%)
Not available 326 (8.0%) 6,063,677 (44.9%) 6,064,003 (44.9%)
Reporter Country, n (%)
Africa 19 (0.5%) 37,622 (0.3%) 37,641 (0.3%)
Asia 635 (15.6%) 667,858 (5.0%) 668,493 (5.0%)
Central America 18 (0.4%) 28,633 (0.2%) 28,651 (0.2%)
Europe 1668 (41.1%) 1,749,620 (13.0%) 1,751,288 (13.0%)
North America 1414 (34.8%) 10,100,868 (74.9%) 10,102,282 (74.9%)
Oceania 77 (1.9%) 95,927 (0.7%) 96,004 (0.7%)
South America 172 (4.2%) 227,114 (1.7%) 227,286 (1.7%)
Not available 58 (1.4%) 584,538 (4.3%) 584,596 (4.3%)
Year of reporting, n (%)
2015 17 (0.4%) 1,239,483 (9.2%) 1,239,500 (9.2%)
2016 251 (6.2%) 1,300,142 (9.6%) 1,300,393 (9.6%)
2017 250 (6.2%) 1,356,259 (10.1%) 1,356,509 (10.1%)
2018 414 (10.2%) 1,616,069 (12.0%) 1,616,483 (12.0%)
2019 471 (11.6%) 1,628,852 (12.1%) 1,629,323 (12.1%)
2020 469 (11.6%) 1,681,724 (12.5%) 1,682,193 (12.5%)
2021 535 (13.2%) 1,706,194 (12.7%) 1,706,729 (12.7%)
2022 748 (18.4%) 1,628,953 (12.1%) 1,629,701 (12.1%)
2023 906 (22.3%) 1,334,504 (9.9%) 1,335,410 (9.9%)
Median age (Q1–Q3), years 69 (61 - 75) 60 (44 - 71) 60 (44 - 71)
Median weights (Q1–Q3), Kgs 70 (60 - 85) 73 (60 - 88) 73 (60 - 88)
Table 2. Disproportionality analyses and notoriety evaluations based on Food and Drug Administration Prescribing Information for neuropsychiatric adverse events related to monoclonal antibodies approved for multiple myeloma.
Table 2. Disproportionality analyses and notoriety evaluations based on Food and Drug Administration Prescribing Information for neuropsychiatric adverse events related to monoclonal antibodies approved for multiple myeloma.
Daratumumab
SOC PT N ROR (95%CI) IC (IC025-IC075) Expected in FDA Prescribing Information
Nervous system disorders Neuropathy peripheral 533 5.89 (5.4-6.42) 2.64 (2.49-2.74) Uk (peripheral sensory neuropathy)
Polyneuropathy 189 17.74 (15.34-20.5) 4.15 (3.91-4.32) Uk (peripheral sensory neuropathy)
Syncope 145 1.66 (1.41-1.95) 1.11 (0.83-1.31) Yes
Encephalopathy 71 5.07 (4.01-6.41) 2.48 (2.08-2.76) Uk (posterior reversible encephalopathy syndrome)
Peripheral sensory neuropathy 45 10.49 (7.81-14.08) 3.45 (2.96-3.81) Yes
Cerebral infarction 45 2.39 (1.79-3.21) 1.54 (1.05-1.9) No
Depressed level of consciousness 42 1.65 (1.22-2.24) 1.12 (0.6-1.48) No
Ischaemic stroke 33 2.24 (1.59-3.15) 1.47 (0.89-1.88) No
Altered state of consciousness 32 1.97 (1.39-2.78) 1.32 (0.73-1.74) No
Presyncope 32 1.42 (1-2.01) 0.96 (0.37-1.37) Yes
Posterior reversible encephalopathy syndrome 29 6.13 (4.25-8.84) 2.74 (2.12-3.18) Yes
Nervous system disorder 28 1.69 (1.16-2.45) 1.15 (0.52-1.59) Yes
Partial seizures 27 6.77 (4.63-9.89) 2.87 (2.23-3.33) No
Leukoencephalopathy 26 14.8 (10.04-21.84) 3.93 (3.28-4.4) Uk (posterior reversible encephalopathy syndrome)
Spinal cord compression 23 6.48 (4.29-9.77) 2.82 (2.12-3.31) No
Guillain-Barre syndrome 23 6.42 (4.26-9.69) 2.81 (2.11-3.3) No
Brain oedema 20 2.51 (1.62-3.9) 1.62 (0.87-2.14) Uk (peripheral oedema)
Facial paralysis 19 1.6 (1.02-2.52) 1.1 (0.33-1.64) Uk (peripheral sensory neuropathy)
Peripheral sensorimotor neuropathy 18 22.42 (14.02-35.85) 4.51 (3.72-5.07) Uk (peripheral sensory neuropathy)
ICANS 18 5.36 (3.37-8.53) 2.58 (1.79-3.13) No
Neurotoxicity 17 1.69 (1.05-2.72) 1.16 (0.35-1.73) No
Peripheral motor neuropathy 14 14.48 (8.53-24.58) 3.93 (3.02-4.55) Uk (peripheral sensory neuropathy)
Incoherent 12 2.61 (1.48-4.61) 1.68 (0.71-2.35) No
Orthostatic intolerance 10 12.54 (6.71-23.43) 3.75 (2.67-4.48) No
Stupor 8 4.48 (2.23-8.98) 2.39 (1.18-3.19) No
Senile dementia 6 10.24 (4.57-22.93) 3.52 (2.1-4.43) No
Intracranial mass 6 4.61 (2.07-10.3) 2.45 (1.04-3.36) No
Cytotoxic oedema 5 41.17 (16.71-101.45) 5.44 (3.88-6.42) Uk (peripheral oedema)
Allodynia 5 8.64 (3.57-20.86) 3.31 (1.74-4.29) Uk (nerve damage causing tingling, numbness or pain)
Hyperammonaemic encephalopathy 5 7.57 (3.13-18.26) 3.13 (1.57-4.11) Uk (posterior reversible encephalopathy syndrome)
Paraparesis 5 3.69 (1.53-8.89) 2.18 (0.62-3.17) Uk (peripheral sensory neuropathy)
Pleocytosis 4 11.42 (4.25-30.68) 3.72 (1.95-4.8) No
VIth nerve paralysis 4 6.48 (2.42-17.35) 2.95 (1.19-4.03) Uk (nerve damage causing tingling, numbness or pain)
Cerebellar haemorrhage 4 3.04 (1.14-8.11) 1.97 (0.2-3.04) No
Loss of proprioception 3 12.5 (3.99-39.14) 3.89 (1.82-5.1) No
Cerebellar haematoma 3 11.42 (3.65-35.74) 3.77 (1.7-4.98) No
Toxic neuropathy 3 10.67 (3.41-33.38) 3.68 (1.61-4.88) Uk (peripheral sensory neuropathy)
Autonomic neuropathy 3 3.93 (1.26-12.21) 2.34 (0.27-3.55) Uk (peripheral sensory neuropathy)
Psychiatric disorders Delirium 54 2.29 (1.75-2.99) 1.49 (1.04-1.81) No
Mental status changes 40 2.66 (1.95-3.63) 1.67 (1.14-2.04) No
Body dysmorphic disorder 15 58.08 (34.3-98.33) 5.81 (4.94-6.41) No
Anxiety disorder 12 3.6 (2.04-6.35) 2.08 (1.1-2.75) Yes
Belantamab Mafodotin
SOC PT N ROR (95%CI) IC (IC025-IC075) Expected in FDA Prescribing Information
Nervous system disorders Neuropathy peripheral 38 2.62 (1.9-3.61) 1.65 (1.11-2.03) No
Altered state of consciousness 6 2.35 (1.05-5.23) 1.6 (0.19-2.52) No
Muscle tone disorder 4 59.56 (22.19-159.81) 6.06 (4.29-7.14) No
Bell's palsy 3 12.77 (4.11-39.68) 3.94 (1.87-5.15) No
Neurological decompensation 3 12.49 (4.02-38.8) 3.91 (1.84-5.12) No
Psychiatric disorders Mental status changes 10 4.23 (2.28-7.88) 2.3 (1.22-3.03) No
Elranatamab
SOC PT N ROR (95%CI) IC (IC025-IC075) Expected in FDA Prescribing Information
Nervous system disorders Altered state of consciousness 3 20.7 (6.61-64.83) 4.6 (2.53-5.81) Yes
Syncope 3 3.82 (1.22-11.98) 2.29 (0.22-3.5) Uk (depressed level of consciousness)
Neuropathy peripheral 3 3.6 (1.15-11.28) 2.22 (0.15-3.42) Yes
Isatuximab
SOC PT N ROR (95%CI) IC (IC025-IC075) Expected in FDA Prescribing Information
Nervous system disorders Polyneuropathy 21 9.26 (6.03-14.22) 3.31 (2.58-3.82) No
Transient ischaemic attack 17 3.37 (2.09-5.42) 1.98 (1.17-2.55) No
Ischaemic stroke 14 4.59 (2.71-7.75) 2.39 (1.48-3.01) No
Peripheral sensory neuropathy 11 12.23 (6.76-22.13) 3.72 (2.7-4.42) No
Cerebral infarction 10 2.56 (1.38-4.76) 1.67 (0.59-2.4) No
Cerebral ischaemia 9 12.64 (6.56-24.34) 3.78 (2.64-4.54) No
Guillain-Barre syndrome 8 10.72 (5.35-21.48) 3.57 (2.35-4.37) No
Haemorrhage intracranial 7 2.76 (1.31-5.79) 1.79 (0.48-2.64) No
Basal ganglia infarction 6 132.39 (58.54-299.42) 7.11 (5.7-8.02) No
Peripheral motor neuropathy 6 29.61 (13.25-66.18) 5.01 (3.6-5.92) No
Subarachnoid haemorrhage 5 2.95 (1.23-7.09) 1.9 (0.34-2.89) No
Acute motor-sensory axonal neuropathy 4 93.02 (34.43-251.26) 6.68 (4.91-7.76) No
Meningoradiculitis 3 179.87 (56.31-574.58) 7.64 (5.57-8.85) No
Chronic inflammatory demyelinating polyradiculoneuropathy 3 11.95 (3.84-37.14) 3.85 (1.78-5.05) No
Psychiatric disorders Acute psychosis 3 8.8 (2.83-27.34) 3.42 (1.36-4.63) No
Talquetamab
SOC PT N ROR (95%CI) IC (IC025-IC075) Expected in FDA Prescribing Information
Nervous system disorders Dysgeusia 13 17.71 (10.11-31.02) 4.16 (3.22-4.8) Yes
ICANS 7 185.55 (87.3-394.35) 7.59 (6.29-8.44) Yes
Taste disorder 7 26.81 (12.63-56.93) 4.82 (3.52-5.68) Yes
Ageusia 5 18.81 (7.75-45.66) 4.37 (2.81-5.36) Yes
Neurotoxicity 3 26.11 (8.35-81.62) 4.93 (2.86-6.14) Yes
Teclistamab
SOC PT N ROR (95%CI) IC (IC025-IC075) Expected in FDA Prescribing Information
Nervous system disorders ICANS 96 450.7 (364.76-556.89) 8.66 (8.32-8.9) Yes
Neurotoxicity 22 31.49 (20.65-48.02) 5 (4.29-5.51) Yes
Polyneuropathy 5 6.45 (2.68-15.53) 2.92 (1.36-3.91) Yes
Nervous system disorder 5 4.27 (1.78-10.28) 2.37 (0.81-3.36) Yes
Depressed level of consciousness 5 2.79 (1.16-6.71) 1.83 (0.27-2.82) Yes
Spinal cord compression 4 15.87 (5.94-42.38) 4.19 (2.43-5.27) No
Encephalopathy 4 4.02 (1.51-10.72) 2.32 (0.56-3.4) Yes
Unresponsive to stimuli 4 3.44 (1.29-9.19) 2.13 (0.36-3.21) Uk (depressed level of consciousness)
Psychiatric disorders Mental status changes 5 4.7 (1.95-11.31) 2.5 (0.94-3.48) Yes
Elotuzumab
SOC PT N ROR (95%CI) IC (IC025-IC075) Expected in FDA Prescribing Information
Nervous system disorders Neuropathy peripheral 41 2.52 (1.85-3.43) 1.6 (1.08-1.97) Yes
Syncope 27 1.75 (1.2-2.56) 1.19 (0.55-1.64) No
Cerebral infarction 25 7.61 (5.13-11.28) 3.03 (2.37-3.51) No
Cerebral haemorrhage 12 2.27 (1.29-4) 1.52 (0.54-2.18) No
Cerebrovascular disorder 4 16.68 (6.24-44.56) 4.26 (2.5-5.34) No
Clumsiness 4 7.82 (2.93-20.86) 3.21 (1.45-4.29) Uk (peripheral motor neuropathy)
Orthostatic intolerance 4 28.31 (10.58-75.73) 5 (3.24-6.08) No
VIth nerve paralysis 4 36.99 (13.81-99.05) 5.38 (3.62-6.46) No
Guillain-Barre syndrome 3 4.74 (1.53-14.7) 2.59 (0.52-3.8) No
Intention tremor 3 49.87 (15.97-155.8) 5.86 (3.79-7.06) No
Monoplegia 3 4.55 (1.46-14.11) 2.54 (0.47-3.74) No
Post herpetic neuralgia 3 11.39 (3.67-35.39) 3.78 (1.71-4.99) Uk (herpes zoster)
Spinal cord compression 3 4.78 (1.54-14.83) 2.6 (0.53-3.81) No
Toxic encephalopathy 3 6.51 (2.1-20.22) 3.01 (0.95-4.22) No
Psychiatric disorders Delirium 15 3.63 (2.18-6.02) 2.08 (1.21-2.68) Uk (mood altered)
Listless 3 5.28 (1.7-16.38) 2.73 (0.66-3.94) No
CI = Confidence Interval; FDA = Food and Drug Administration; IC = Information Component; ICANS = Immune effector Cell-Associated Neurotoxicity Syndrome; PT = Preferred Term; ROR = Reporting Odds Ratio; SOC = System Organ Class; Uk= Unknown.
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