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This prospective case series investigated corneal epithelial and subbasal nerve plexus changes associated with belantamab mafodotin (Belamaf) therapy in patients with refractory/relapsed multiple myeloma using a multimodal imaging approach.
Methods
We included eight patients (mean age 66 ± 10) scheduled for Belamaf who were monitored for at least three treatment cycles. Standard clinical eye exams with Snellen best corrected visual acuity (BCVA) measurements were complemented by epithelial thickness mapping, slit lamp photography, corneal sensitivity testing, and corneal confocal microscopy.
Results
The mean drop in BCVA was limited to 1 line (20/25 to 20/32) with mean loss in sensitivity from 5.2 ± 0.4 to 8.7 ± 3.4 mg/S. Corneal epithelial thickness increased (from a mean of 62 ± 4.7 to 74 ± 6.2 μm) presenting an irregular pattern from the apex to the mid-periphery. All patients developed microcystic epithelial changes and ocular surface disease. Confocal microscopy revealed a decrease in mean nerve fiber length and density from 12.46 ± 4.94 mm/mm2 and 21.87 ± 10.27/mm2 at baseline to 3.27 ± 3.9 mm/mm2 and 1.78 ± 3.22/mm2 at last follow-up, respectively, with preserved limbal architecture.
Conclusion
This prospective study confirms and further characterizes the pathognomonic epithelial changes caused by Belamaf, which are accompanied by severe impairment in subbasal nerve fiber architecture, indicating a neurotoxic effect of the medication that requires further investigation.
As a result of the rising number of patients who are treated with antibody drug conjugates such as belantamab mafodotin, its associated corneal adverse events need to be investigated.
Belantamab mafodotin induces changes in the corneal epithelium and the subbasal corneal nerve plexus. Our aim was to further analyze these changes in a prospective clinical setting.
We were able to show a significant reduction in corneal nerve fiber parameters in patients treated with belantamab mafodotin.
By comparing our results to common corneal diseases, we showed that these corneal changes are specific for antibody drug conjugate treatment. Interdisciplinary management with the treating hemato-oncologist is necessary to minimize these adverse events as much as possible while maintaining the effect of the systemic treatment.
Introduction
Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of plasma cells within the bone marrow, which remains incurable until today [1, 2]. Despite rapid advancements in treatment modalities, some patients develop resistance to available therapies, leading to refractory disease. This subgroup of patients is defined as “triple-class refractory” or “refractory/relapsed multiple myeloma” (RRMM). As per the definition, they are refractory to agents of all three major drug classes, namely proteasome inhibitors, monoclonal antibodies, and immunomodulatory drugs, and have a median overall survival of 9.3 months [3, 4].
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Released in 2020, belantamab mafodotin (Belamaf; Blenrep, GlaxoSmithKline) showed promising results in preclinical and clinical studies in patients with RRMM [5‐7]. Belamaf comprises a humanized IgG1 monoclonal antibody targeting B cell maturation antigen (BCMA) and a tubulin polymerization inhibitor agent (monomethyl auristatin F [MMAF]), serving as the active cytotoxic payload within the antibody–drug conjugate (ADC) [5].
Although systemic adverse events including anemia and thrombocytopenia were registered in the approval studies DREAMM-1–3 [5, 8] introduction of Belamaf therapy in patients with RRMM is associated with a manageable systemic safety profile. However, these studies report the occurrence of significant ocular adverse events that require further attention and monitoring.
In the phase 2 trial (DREAMM-2), 73% of all patients developed a pathognomonic superficial keratopathy that was deemed to be associated with Belamaf therapy [5]. The typical clinical presentation is the accumulation of microcystic changes in the epithelium, termed microcystic epithelial changes (MEC), that can lead to blurred vision, “dry eye” symptoms, and a decrease in visual acuity.
With the use of corneal confocal microscopy (CCM), an expedient imaging technology that enables the visualization of individual corneal layers in the “en face” mode with near-histologic detail and a horizontal resolution of 1 μm, it was shown that these MEC formations constitute hyperreflective material rather than true microcystic changes [9]. These epithelial changes also present some similarity to other already reported complications of ADCs [10, 11].
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Furthermore, in a recent retrospective series, our group found that toxicity of Belamaf is not restricted to the epithelium but can also affect the underlying subbasal nerve plexus (SNP). Specifically, with the use of confocal microscopy, we found a complete loss of the SNP in the course of treatment [12]. We also investigated the structures of the corneal limbus by applying CCM, as it has been suggested that Belamaf uptake into the cornea occurs at the site of the limbal stem cells, as one proposed pathomechanism [13]. In this cohort of patients studied retrospectively, those limbal structures did not seem to be affected by pathological changes [12].
Since the possible occurrence of ocular toxicity during the treatment with Belamaf requires close monitoring by the ophthalmologist as well as an adequate modification of the treatment dosage and interval by the hemato-oncologist, a better understanding of the nature of these corneal changes and the associated symptom profile of the patient should lead to a more personalized treatment regimen [14].
In our previous series we observed a possible neurotoxic effect of Belamaf in the cornea, but it was limited by the retrospective study design. Therefore, the purpose of this study was to investigate and classify the potential neurotoxic effect of Belamaf treatment in patients with RRMM in a prospective clinical setting. We also aimed to further characterize those epithelial changes and any potential alterations in the corneal limbal structures, to define their specificity by comparing them to other corneal diseases by using CCM (in a substudy setting), and to relate these changes to other signs of anterior segment disease and symptoms of the patient.
Methods
This prospective single-center study included adult patients with a confirmed diagnosis of RRMM who were scheduled for treatment with Belamaf, recruited at the Division of Hematology, Department of Internal Medicine I, Medical University of Vienna. Exclusion criteria were any signs of corneal disease prior to study entry, uncontrolled glaucoma, a medical history of polyneuropathy, inability to comply with follow-up consultations, and a known immediate or delayed hypersensitivity reaction to Belamaf or other drugs chemically related to Belamaf. All study investigations complied with the tenets of the Declaration of Helsinki. At the first consultation all patients gave written and oral consent to take part in the study. The study was approved by the Ethics Committee of the Medical University of Vienna (EK 1690/2022).
All patients were examined at baseline, before the introduction of Belamaf therapy, and were monitored at the Department of Ophthalmology, Medical University of Vienna, 3 weeks following every treatment cycle. Dosage was 1.9 mg/kg for all patients at every cycle. Dosage and treatment interval modifications were entirely at the discretion of the caring hemato-oncologist and based on the occurrence of adverse events reported by the study investigators of the eye clinic.
Clinical Evaluation and Symptom Assessment
Clinical Assessment included Snellen best corrected visual acuity (BCVA) testing at 6 m, a slit lamp examination of the anterior segment, non-contact intraocular pressure measurement (iCare IC100, Finland), and a biomicroscopical examination of the posterior segment of the eye (dilated at baseline, but only if clinically indicated thereafter) (mydriaticum 0.5%, Agepha Pharma, Senec, Slovakia). Anterior segment evaluation included fluorescein staining to evaluate the tear film breakup time (BUT), as well as signs of superficial punctate epitheliopathy following the Oxford grading scheme to describe corneal epithelial damage.
Furthermore, Belamaf-associated superficial keratopathy (including MEC, (sub)epithelial/stromal haze, ulceration) was graded using the proposed Keratopathy and Visual Acuity (KVA) Scale [5, 14]. Slit lamp photography was performed with a Canon EOS 90D camera mounted on a slit lamp (HAAG Streit AG, Köniz, Schweiz).
Limbal stem cell deficiency (LSCD) was evaluated at the slit lamp by assessing the number of clock hours of LSCD (fluorescein late staining and inability to differentiate physiological limbal structures). Corneal sensitivity was evaluated and graded using the Cochet–Bonnet esthesiometer [15]. All patients were interviewed on the basis of the Ocular Surface Disease Index (OSDI) score to grade symptoms of blurred vision, dry eye, and photophobia [16].
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Epithelial Thickness Mapping
The MS-39 anterior segment optical coherence tomograph (OCT) with an axial resolution of 3.6 µm was used for a precise quantification of the epithelial thickness represented by an epithelial thickness map. In this sense, irregularities with areas of epithelial thickening and/or thinning were detected and correlated to Belamaf-specific epitheliopathy.
Corneal Confocal Microscopy
Each patient underwent in vivo imaging using the Heidelberg HRT III Retina Tomograph (HRT III; Heidelberg Engineering, Heidelberg, Germany). The HRT III uses a 670-nm-wavelength diode laser source for confocal laser scanning to allow a detailed en face visualization of each layer of the cornea separately within a 400 × 400 μm field of view.
Both eyes were topically anesthetized using a drop of oxybuprocaine 1% (Pharmacy General Hospital Vienna). Afterwards a soft bandage contact lens was placed in each eye to minimize corneal irritation.
Correct alignment and contact of the microscope relative to the cornea was ensured with a camera positioned perpendicular to the eye. The distance between the cornea and microscope was kept stable using a disposable sterile, single-use polymethylmethacrylate cap (TomoCap, Heidelberg Engineering) coupled optically to the lens with the aid of a viscous gel (Siccaforte, Agepha). The section mode was used to acquire more than 100 images of the individual (superficial, wing, basal) epithelial cell layers as well as the SNP. Considering quality, depth, focus position, and contrast, three images of the central SNP were chosen for further analysis. A good-quality image was defined as an image with the largest number of well-defined subbasal nerves, with high contrast and no distortion. The following nerve parameters were analyzed using ACCMetrics v3 [17‐21]: CNFD (number of major nerve fibers per square millimeter) and CNFL (total length of nerves in millimeters per square millimeter).
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Corneal Confocal Microscopy Substudy
In the cross-sectional substudy, we included patients with a confirmed diagnosis of epithelial basement membrane dystrophy (EBMD) (also known as map-dot-fingerprint dystrophy), LSCD, or severe keratoconjunctivitis sicca recruited at the outpatient clinic for corneal diseases at the Department of Ophthalmology, Medical University of Vienna. Exclusion criteria were other associated corneal pathologies or systemic conditions that may affect the cornea. All patients underwent standard slit lamp examination of the anterior segment of the eye and CCM examination as described above.
Results
We included a total of 11 patients in this prospective study. Eight patients met the defined criteria of a complete follow-up interval at 3 weeks following the third cycle of Belamaf infusion therapy. The median treatment infusion interval was 4 weeks in the study cohort. For the remaining three patients, the therapy had to be stopped and changed because of either the severe subjective ocular impairment, affecting daily activity (n = 2), or because of a lack of therapeutic success and underlying disease progression (n = 1). In these three cases, therapy was stopped after two cycles, and patients were still regularly examined until the resolution of the corneal adverse event was complete.
The mean age of the patients with complete follow-up was 66 ± 10 years; there were four female and four male patients. In three patients, Snellen BCVA at the initial presentation was worse than 20/20. These patients either presented visually relevant cataract with significant nuclear sclerosis (n = 2) or dry age-related macular degeneration (n = 1). The median Snellen BCVA was 20/25 (20/32–20/20). No other visually relevant anterior or posterior changes were documented. Over the course of the treatment, Snellen BCVA in the worse of both eyes declined to a mean of 20/32 (20/40–20/20).
At baseline, corneal sensitivity in seven patients was full, measured at 5 mg/S (milligrams/surface unit). In two patients it was slightly reduced. All results were symmetrical between both eyes. The mean overall sensitivity was 5.2 ± 0.4 mg/S at baseline. At the end of the follow-up period the sensitivity had decreased to 8.7 ± 3.4 mg/S.
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Over the course of treatment, every patient developed some degree of ocular adverse event and superficial keratopathy with intraepithelial cysts (see Figs. 1 and 2 for examples). Four out of eight patients progressed to KVA grade 2, which led to an extension of the infusion interval in accordance with the decision of the hemato-oncologist. We did not diagnose any KVA grade 3 or 4 or any sign of corneal ulceration during follow-up. BCVA never dropped below 20/32 in any of the patients. Table 1 shows an overview of the adverse events in all patients during Belamaf treatment.
Fig. 1
Corneal changes in patient number 3: a, b slit lamp photography; c, d MS-39 epithelial thickness mapping; e–l confocal microscopy of the different layers of the cornea. a Translucent, clear cornea; b slit lamp photograph of microcystic changes of the epithelium; c regular, homogenous epithelial thickness map; d irregular changes of the epithelial thickness measured with the MS-39 device. Red area highlights a thickening, especially centrally at the corneal apex, diminishing towards the periphery; e, g physiologic superficial and basal epithelial layers; f, h microcystic keratopathy in individual layers of the epithelium depicted by CCM: hyperreflective cyst-like structures in the superficial epithelium (f) and wing cell layer (h); i, j healthy limbal structures with healthy palisades of Vogt at baseline and follow-up showing no sign of toxicity caused by therapy; k physiologic corneal subbasal nerve structures; l complete loss of subbasal nerve structures compared to baseline (k)
Corneal changes BL (top row) compared to F/U (bottom row) in patient number 7: a, b slit lamp photography; c, d MS-39 epithelial thickness mapping; e–l confocal microscopy of the different layers of the cornea. a Translucent, clear cornea; b slit lamp photograph of microcystic changes of the epithelium; c regular, homogenous epithelial thickness map; d irregular changes of the epithelial thickness measured with the MS-39 device. Red area highlights a thickening, especially centrally at the corneal apex, diminishing towards the periphery; e, g physiologic superficial and basal epithelial layers; f, h microcystic keratopathy in individual layers of the epithelium depicted by CCM: hyperreflective cyst-like structures in the superficial epithelium (f) and grape-like small hyperreflective structures in the basal epithelium (h); i, j healthy limbal structures with healthy palisades of Vogt at baseline and follow-up showing no sign of toxicity caused by therapy; k physiologic corneal subbasal nerve structures; l complete loss of subbasal nerve structures compared to baseline (k)
Summary of ocular changes during the observation period
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Patient 6
Patient 7
Patient 8
BL
F/U
BL
F/U
BL
F/U
BL
F/U
BL
F/U
BL
F/U
BL
F/U
BL
F/U
Treatment intervala
4/5
4/8
4/5
5/5
3/3
3/8
4/4
5/3
BCVA (Snellen)
20/25
20/32
20/20
20/20
20/20
20/20
20/20
20/20
20/32
20/32
20/20
20/25
20/20
20/20
20/20
20/32
Corneal sensitivity (mg/S)
5
9.5
5.5
5.5
5
9.5
5
5
5
6
6
9.5
5
8
5
15.5
OSDI
2.1
14.6
6.8
35
6.8
13.9
0
4.5
0
14.6
2.1
6.8
0
36.4
6.3
37.5
BUT (s)
11
5
8
6
9
4
11
10
9
3
9
2
7
2
7
2
Intraepithelial cysts
0
1
0
1
0
1
0
1
0
1
0
1
0
1
0
1
(0 = no; 1 = yes)
KVA grade
0
2
0
1
0
1
0
1
0
1
0
1
0
2
0
2
Confocal microscopy
CNFD (n/mm2)
12.46
6.24
25
6.24
31.25
0
ND
ND
25
0
6.24
ND
31.24
0
31.25
0
CNFL (mm/mm2)
11.37
8.84
12.96
6.85
18.51
3.93
ND
ND
9.54
0
5.17
ND
17.21
0
12.13
0
Basal epithelial hyper-reflectivities
0
1
0
1
0
1
0
1
0
1
0
1
0
1
0
1
(0 = no; 1 = yes)
Superficial epithelial cysts
0
1
0
1
0
1
0
1
0
1
0
1
0
1
0
1
(0 = no; 1 = yes)
BCVA best corrected visual acuity, BL baseline, F/U follow-up examination 3 weeks after third treatment cycle, OSDI Ocular Surface Disease Index, BUT breakup time, KVA Keratopathy and Visual Acuity Score, CNFD corneal nerve fiber density, CNFL corneal nerve fiber length, ND non detectable (i.e., ACCMetrics software fails to detect nerve fibers correctly because of high accumulation of dendritic/inflammatory cells and severe nerve fiber fragmentation; see Supplementary Fig. 1)
aInterval between first and second/second and third infusion; patients were monitored 3 weeks after every infusion at the eye clinic (more regularly with occurring adverse events)
Epithelial Thickness Mapping
Mean epithelial thickness at baseline was 62 ± 4.7 μm and increased to 74 ± 6.2 μm over the course of the treatment cycles. Figures 1 and 2 show the epithelial changes in two exemplary patients (c = baseline, d = follow-up): specifically, irregular thickening of the epithelium concentrated at the apex area of the cornea (bottom row, warmer colors depict thicker epithelium) compared with the initial examination in the treatment-naïve eyes (top row). Peripheral parts of the corneal also show some signs of irregular epithelial thickening, but the changes decrease towards the limbus in all eyes (cooler colors including green and blue highlight thinner epithelium).
Tear-Film Stability
The mean tear-film breakup time before any treatment was 8 ± 2 s. The mean OSDI score was 3. Alongside corneal side effects, the mean BUT decreased to 4 ± 2 s at the end of follow-up, and the OSDI score increased to 20.
Corneal Confocal Microscopy
Initial CCM imaging showed healthy, age-related epithelial cell structures in all patients. Follow-up CCM examinations revealed morphological alterations in specific corneal layers in all patients (see exemples in Figs. 1 and 2). The basal epithelial layers exhibited grape-like configured hyperreflective, white spots, which appeared to enlarge towards the more superficial epithelial layers (wing cell layer and superficial epithelium). There was a noticeable associated change in morphology, with the structures then resembling round, polymorphous-structured cysts. These cysts were characterized by a hyperreflective and well-defined wall containing intracystic content of variable reflectivity. These changes were limited to the central and paracentral cornea, with limbal structures (such as the epithelium around the Vogt palisades and focal stromal projections) being spared such pathological features.
With the exception of two patients (patients 4 and 6), in whom nerve fiber counts were already reduced at baseline, SNP configurations were within normal limits at the initial confocal examination [22]. The mean CNFD was 21.87 ± 10.27/mm2 and the mean CNFL was 12.46 ± 4.94 mm/mm2. At follow-up, the subbasal nerve plexus showed signs of significant impairment in all measured parameters (Fig. 3). CCM revealed a clear reduction in CNFD and CNFL with severe nerve fiber fragmentation, which even led to failure of automated nerve fiber analysis (and therefore quantitative analysis) in two patients (patients 4 and 6). The mean CNFD at follow-up was reduced to 1.78 ± 3.22/mm2 and the mean CNFL was 3.27 ± 3.9 mm/mm2. Table 1 shows the overall results of all measurements with CCM. Figure 4 highlights example CCM results in the substudy population.
Fig. 3
Changes of the subbasal nerval plexus (SNP) over the course of three Belantamab cycles (a baseline examination, b after first infusion, c after second infusion, d after third infusion). Top row depicts the SNP layer imaged with confocal microscopy; bottom row shows the analysis with automated ACCMetrics software: detected nerve fibers presented in green; b severe nerve fiber thinning and fragmentation; c, d “false” detection of nerves; only residual inflammatory cells are visible
Exemplary images of corneal confocal microscopy in the substudy population. a–e Patient with epithelial basement membrane dystrophy: a small cysts within the epithelium; b basal epithelial cells are highly distorted and show changes in the cytoplasm and reflective nuclei; c, d abnormal basement membrane extending into the epithelium shown by highly reflective tissue within the intermediate and basal epithelial layer [23‐25], e normal configuration of the subbasal nerves. f‐j Patient with limbus stem cell deficiency (LSCD), f single, distorted, hyperreflective epithelial cells with bright nuclei; g healthy stroma with keratocytes and stromal nerves [26]; h, i reduced cellular reflectivity in the transitional zone of limbus and cornea, j subbasal-nerve plexus detectable. k–o Patient with severe dry eye disease: k, l highly distorted epithelium and scarring into the deeper layers and stroma (m) after multiple erosions and ulcera, there was no detection of nerve fibers; n, o conjunctivalized limbal area
In this prospective case series, we confirm our previous retrospective results [12] suggesting that corneal pathology related to Belamaf treatment in patients with relapsed/refractory multiple myeloma is not restricted to the corneal epithelium. Our previous retrospective report suggested a complete loss of the architecture of the corneal subbasal nerve plexus in all studied patients. We here provide further evidence for severe destruction of these delicate corneal sensory nerves as part of the trigeminal nerve with a decrease in CNFD and CNFL in all patients. However, in contrast to our recent findings, we did not detect a complete loss in every patient until the end of the defined follow-up. This may be attributed to the very carefully chosen reduced treatment dose (1.9 mg/kg) and adjusted treatment intervals chosen by the caring hemato-oncologist in close cooperation with the study investigators at the eye clinic with the ultimate goal of prolonging Belamaf treatment whilst minimizing ocular adverse events in a personalized approach. The median time between infusion cycles in this study was 4 weeks. Two patients (patients 1 and 2, see Table 1) showed some residual nerves at the end of follow-up. One of these patients had an accountable delay of their third infusion (8-week interval) because of an active COVID infection. One may hypothesize that an extension of the treatment intervals may decelerate nerve fiber fragmentation, but our study sample is too small to draw reliable conclusions.
In two patients (patients 4 and 6), the baseline parameters of corneal nerve fiber vitality were already decreased compared to a healthy age-matched population. This may be explained by effects of prior treatments such as bortezomib, a proteasome inhibitor with a neurotoxic component, which is often prescribed prior to Belamaf treatment [27]. This baseline impairment of the SNP may have influenced the CCM measurements and ACCMetrics analyses (automated analysis was not possible because of severe nerve fiber fragmentation and inflammatory cell invasion), as well as the rate of nerve fiber decrease caused by Belamaf medication. This highlights the need for a detailed investigation of the effect of commonly used medications in patients with MM on the SNP using CCM.
As highlighted in our previous study, the limbal structures of the cornea were not compromised during Belamaf treatment as studied with CCM. This may suggest an alternative route of Belamaf uptake into corneal epithelial cells (i.e., through the tear film). Another possible explanation for this finding is that we did not assess the patient at the time of Belamaf uptake into the limbal stem cells and epithelial progenitor cells (which we would expect shortly after Belamaf infusion), but rather at a time when the internalized medication in epithelial cells has reached the corneal mid-periphery/apex area (at a mean of 3 weeks after Belamaf infusion). The cycle of renewal of epithelial cells takes around 20 days [28]. These pathomechanistic hypotheses require further investigations.
Our study is the first to describe epithelial changes related to Belamaf treatment using epithelial thickness mapping. Using the MS-39 device, we were able to show an increase in epithelial thickness concentrated at the corneal apex, correlating with the observed MECs and keratopathy by the end of the follow-up period. The pattern of thickening was highly irregular with a decline from the center to the periphery of the cornea (see Figs. 1 and 2).
Moreover, we included a cross-sectional substudy in our approach to be able to better classify and compare the observed changes with other corneal diseases that have already been studied using CCM. We can therefore confirm that the epithelial changes, as studied with CCM, are pathognomonic for Belamaf therapy and include the appearance of grape-like, small hyperreflective material located in the basal epithelium, as well as cyst-like structures in the superficial epithelium. Moreover, the SNP is characterized by a gradual loss of nerve fibers, whilst the limbal structures are preserved.
One can clearly recognize substantial differences between Belamaf-associated keratopathy and the appearance of other corneal diseases using CCM imaging: Epithelial basement membrane dystrophy is characterized by an abnormal basement membrane that extends into the epithelial layers (as seen in Fig. 4). This can lead to an insufficient adherence of the overlying epithelial cells and cause recurrent corneal erosions. The noticeable cysts represent entrapped epithelial cells and are distinct from the grape-like conglomerates and cyst-like structures observed in cells affected by Belamaf-associated keratopathy. A loss of SNP structure has not been reported in this disease, as we can confirm herewith. The limbus does not show any particular changes in EBMD and is therefore comparable to the healthy limbus in our main study population [25]. This stands in contrast to the subgroup of patients with LSCD, where the degeneration of the palisades of Vogt is a hallmark of the disease. CCM can visualize the progressive conjunctivalization of epithelial cells, which appear distorted with bright hyperreflective nuclei. Our representative patient with LSCD (Fig. 4) was diagnosed with a partial form of LSCD of three clockwise notations. In such patients with partial LSCD, the SNP is preserved in most cases, partly showing increased tortuosity. In patients with a complete LSCD, nerve fiber density decreases significantly, with a possible complete SNP loss [26].
Our representative patient with severe dry eye disease (Fig. 4) had an underlying diagnosis of Sjögren syndrome with a history of corneal ulceration. We can visualize highly distorted epithelial cells and diffuse scarring with CCM, which explains the loss of the SNP next to the Sjögren diagnosis.
We complemented our CCM examinations with corneal esthesiometry using the Cochet–Bonnet device. Six out of eight patients showed reduced corneal sensitivity at the end of follow-up, which is in line with our CCM results of corneal nerve toxicity. However, we have to consider the sources of error in this test including the subjective response of the proband (reflective versus arbitrary lid closure) and touch of eyelashes leading to lid closure.
It is important to acknowledge that only three patients experienced a drop in Snellen BCVA of 1 (n = 2) or 2 (n = 1) lines, which may be associated with the accumulation of MECs at the corneal center/apex at the time of monitoring. Two of these three patients were classified with KVA grade 2.
Table 1 also demonstrates that Belamaf treatment affects the ocular surface and tear film homeostasis, which is represented as a reduction in the tear film BUT (objective) and an increase in the OSDI score (subjective), partly demonstrating severe subjective disability in some patients.
Our study is limited by its small sample size. In December 2023, the European Medicines Agency (EMA) confirmed their initial recommendation to withdraw market authorization of Belamaf because of the lack of significant effectiveness. This recommendation was based on the recent results of the DREAMM-3 study that failed to prove a statistically significant difference in progression-free survival in patients treated with Belamaf compared with those treated with a combination of pomalidomide and low-dose dexamethasone as the primary outcome [8]. This decision led to the premature termination of this study because of the inability to recruit further patients.
However, this prospective series confirms our preliminary retrospective results that Belamaf medication has a negative impact on corneal subbasal nerve fiber vitality. This finding suggests a neurotoxic impact of Belamaf on these delicate sensory nerves, which play a pivotal role in ocular surface homeostasis and corneal epithelial wound healing.
We present a multimodel imaging approach for the monitoring of patients with RRMM on Belamaf therapy including epithelial thickness mapping, slit lamp photography, and CCM to characterize Belamaf-associated keratopathy, and to differentiate its pathognomonic features from other frequent corneal diseases.
Conclusions
Adding to our retrospective results, these prospective findings suggest that a decrease in dosage and a slight extension of the treatment intervals may have a positive impact on the severity of corneal adverse events and the speed of nerve fiber decline and may lead to a prolonged time of treatment tolerance in the individual patient. Since a successful systemic treatment in these patients is necessary for survival and good quality of life, regular examinations of the eyes and specifically the cornea might contribute to a better treatment outcome overall and lead to a more successful therapy for patients with RRMM. This highlights the need for future studies investigating the optimal personalized treatment regime for Belamaf, if market authorization returns, but also in regard to upcoming combination treatments.
Acknowledgements
We want to thank all the participants of the study.
Declarations
Conflict of Interest
We hereby confirm that Jakob Schweighofer, Hermine Agis, Maria Krauth, Ruth Donner, Marion Funk, Jan Lammer, Michael Klimek, Geral Schmidinger, and Julia Aschauer have no conflicts of interest to declare.
Ethical Approval
All study investigations complied with the tenets of the Declaration of Helsinki. All patients gave written oral consent to take part in the study. The study was approved by the Ethics Committee of the Medical University of Vienna (EK 1690/2022).
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In einer Kohortenstudie wurde ein Zusammenhang zwischen oralen Bakterien und Pilzen und dem Auftreten von Pankreaskarzinomen gesehen. Diese Assoziation könnte helfen, Patientinnen und Patienten für gezielte Vorsorgeuntersuchungen ausfindig zu machen.
Ein Team aus Frankreich hat Fälle von plötzlichem Herzstillstand während des Paris-Marathons ausgewertet. In fast 90% waren Männer betroffen, und zwar überwiegend auf dem letzten Kilometer vor dem Ziel.
Patienten mit Adipositas weisen erniedrigte Spiegel des N-terminalen pro-B-Typ-natriuretischen Peptids (NT-ProBNP) auf. Ob sich das auf die NT-proBNP-gestützte Diagnostik von Herzinsuffizienz auswirkt, haben britische Mediziner untersucht.
Auch 2025 gab es wieder neue Studien, deren Ergebnisse zu einer Optimierung der symptomatischen und prognoseverbessernden Therapie bei Patienten mit Herzinsuffizienz in der Praxis beitragen könnten.
