{"doi":"10.1002/ajh.27219","title":"Belantamab mafodotin, lenalidomide, and dexamethasone in transplant‐ineligible patients with newly diagnosed multiple myeloma: Analysis of belantamab mafodotin‐associated ocular adverse events and their impact on daily functioning from the part 1 of a phase 1/2 study","abstract":null,"journal":"American Journal of Hematology","year":2024,"id":615781,"datarank":0.32958368660043297,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"self_citation_contribution":0.32958368660043297,"citation_network_contribution":0.0,"self_endowment_contribution":0.32958368660043297,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":336807,"name":"Ioannis Ntanasis‐Stathopoulos","orcid":"0000-0002-6328-9783","position":1,"is_corresponding":false},{"id":1067898,"name":"Panagiotis Malandrakis","orcid":"0000-0002-4673-171X","position":2,"is_corresponding":false},{"id":1022467,"name":"Despina Fotiou","orcid":"0000-0002-0618-8900","position":3,"is_corresponding":false},{"id":1587379,"name":"Magdalini Migkou","orcid":null,"position":4,"is_corresponding":false},{"id":1022466,"name":"Foteini Theodorakakou","orcid":"0000-0001-6926-0351","position":5,"is_corresponding":false},{"id":1587380,"name":"Vasiliki Spiliopoulou","orcid":null,"position":6,"is_corresponding":false},{"id":1023398,"name":"Nikolaos Kanellias","orcid":null,"position":7,"is_corresponding":false},{"id":1587381,"name":"Evangelos Eleutherakis‐Papaiakovou","orcid":null,"position":8,"is_corresponding":false},{"id":1587382,"name":"Maria Roussou","orcid":null,"position":9,"is_corresponding":false},{"id":1587383,"name":"Giorgos Psarros","orcid":null,"position":10,"is_corresponding":false},{"id":296306,"name":"Efstathios Kastritis","orcid":"0000-0001-8191-5832","position":11,"is_corresponding":false},{"id":228859,"name":"Meletios Α. Dimopoulos","orcid":"0000-0001-8990-3254","position":12,"is_corresponding":false},{"id":336801,"name":"Evangelos Terpos","orcid":"0000-0001-5133-1422","position":13,"is_corresponding":false},{"id":881054,"name":"Maria Gavriatopoulou","orcid":"0000-0002-6244-1229","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Belantamab mafodotin, lenalidomide, and dexamethasone in transplant‐ineligible patients with newly diagnosed multiple myeloma: Analysis of belantamab mafodotin‐associated ocular adverse events and their impact on daily functioning from the part 1 of a phase 1/2 study","abstract":"The current study investigated three belantamab mafodotin (belamaf) doses (2.5, 1.9, 1.4 mg/kg) in combination with lenalidomide and dexamethasone in the upfront treatment of transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). We evaluated an increased belamaf dosing interval, once every eight or twelve weeks (Q8W or Q12W), to provide sufficient time for the cornea to recover from belamaf-related keratopathy and thus to limit the occurrence of ocular adverse events (OAEs), defined as best-corrected visual acuity (BCVA) decrease from baseline and/or corneal findings (keratopathy). The assessment of OAEs in this patient population is important because the cytotoxic agent monomethyl auristatin-F of belamaf may result in keratopathy,1 whereas, second, it seems that a substantial (40%) proportion of patients with NDMM already have ocular comorbidities at diagnosis.2 The study is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, following approval by the hospital's ethics committee and institutional review board. All the patients provided written informed consent. Totally 36 patients were enrolled in Part 1 of the study with a median follow-up of 22.9 months (Table S1). At baseline, almost all the patients had ocular comorbidities (Table S2). Overall, 31 (86.1%) patients had cataract, including six (19.4%) and one (3.2%) patients with grade(Gr)3 and Gr4 cataract, respectively. Abnormal fundoscopic findings, increased intraocular pressure (>21 mm Hg), and abnormal corneal epithelium were observed in 34 (94.4%), 4 (11.1%), and 1 (2.8%) patients, respectively. Lastly, 5 (13.9%) patients had dry eye symptoms at baseline, including four (11.1%) patients with Gr1 and one (2.8%) patient with Gr2 symptoms. The majority of the patients (32/36, 88.9%) were switched from the Q8W to the Q12W schedule due to OAEs. A total of 750 ophthalmological assessments were performed, comprising 247, 275, and 228 examinations in the 2.5, 1.9, and 1.4 mg/kg belamaf dose cohorts, respectively. Approximately half (48.7%, 365/750) of all assessments had only Gr0–1 OAEs. At the cohort level, higher proportions of ophthalmological examinations with Gr0–1 findings were observed in the 1.9 and 1.4 mg/kg cohorts (52.7% [145/275] and 53.9% [123/228], respectively) than in the 2.5 mg/kg cohort (39.3% [97/247]; Figure 1A). Conversely, the proportions of ophthalmological assessments with Gr2 or Gr3–4 findings were higher in the 2.5 mg/kg (40.1% [99/247] and 20.7% [51/247], respectively) than in the 1.9 mg/kg (33.8% [93/275] and 13.5% [37/275], respectively) and 1.4 mg/kg (34.6% [79/228] and 11.4% [26/228], respectively) cohorts. In addition, the median times to a ≥Gr2 OAE were 3.9, 4.5 and 5.9 months, for cohorts 2.5, 1.9 and 1.4 mg/kg, respectively. Similarly, approximately half (51.2%, 384/750) of all ophthalmological assessments had only Gr0–1 BCVA changes from baseline. At the cohort level, the proportions of ophthalmological assessments with Gr0–1 findings accounted for 40.9% (101/247), 56.4% (155/275), and 56.1% (128/228) in the 2.5, 1.9, and 1.4 mg/kg cohorts, respectively (Figure 1B); the respective proportions of assessments with Gr2 BCVA changes from baseline were 42.1% (104/247), 30.5% (84/275), and 32.9% (75/228), and those with Gr3 BCVA changes from baseline were 17.0% (42/247), 13.1% (36/275), and 11.0% (25/228). No assessments with Gr4 BCVA changes from baseline were recorded across cohorts. The proportions of ophthalmological assessments with a meaningful BCVA decline and ≥3 lines drop in better-seeing eye were 12.1% (30/247), 9.8% (27/275), and 7.7% (17/222) in the 2.5, 1.9, and 1.4 mg/kg belamaf dose cohorts, respectively (Table S3). The respective median (range) times to resolution were 1.2 (1.0–4.5), 1.3 (0.8–2.4), and 1.2 (0.9–5.5) months. The proportions of ophthalmological assessments with BCVA Snellen score worse than 20/200 and ≥3 lines drop in the better-seeing eye were 0.8% (2/247), 1.1% (3/275), and 3.5% (8/228), in the 2.5, 1.9, and 1.4 mg/kg belamaf dose cohorts, respectively. Most (86.0% [646/751]) ophthalmological examinations had only Gr0–1 keratopathy findings. At the cohort level, similar proportions of ophthalmological examinations with Gr0–1 (82.6% [204/247], 87.3% [240/276], and 88.6% [202/228]) or Gr2 (12.1% [30/247], 12.7% [35/276], and 11.0% [25/228]) keratopathy findings were recorded in the 2.5, 1.9, and 1.4 mg/kg cohorts, respectively (Figure 1C). No ophthalmological examinations had Gr3 keratopathy findings, regardless of the cohort, while Gr4 keratopathy was more common in the 2.5-mg/kg cohort than the 1.9 and 1.4 mg/kg cohorts (5.3% [13/247], 0.4% [1/276], and 0.4% [1/228], respectively).The median (range) time to resolution of the keratopathy events was 1.1 (0.5–12.2), 1.4 (0.9–3.4), and 1.0 (0.9–3.7) months for the 2.5, 1.9, and 1.4 mg/kg cohorts, respectively. Of note, the proportion of ophthalmological examinations with ≥Gr2 keratopathy findings without a concurrent ≥Gr2 BCVA change from baseline was low across cohorts (2.5 mg/kg: 1.6%; 1.9 mg/kg: 3.6%; and 1.4 mg/kg: 2.2%). The cataract severity worsened for 23 (74.2%) of these patients. Of note, of 24 patients with cataract of Gr1-2 at baseline, 20 patients (83.3%) experienced a worsening in cataract severity to Gr3/4 during follow-up. Moreover, numerically higher proportions of patients with Gr ≥ 2 cataract experienced a concomitant Gr2–3 BCVA change from baseline than patients with Gr < 2 cataract, particularly in the 2.5 and 1.4 mg/kg cohorts. Ocular symptoms were assessed in 246, 276, and 228 ophthalmological examinations in the 2.5, 1.9, and 1.4 mg/kg cohorts, respectively. In the majority of the ophthalmological examinations, only Gr0–1 ocular symptoms were observed. Specifically, Gr0–1 symptoms were observed in 50.0% (123/246), 58.0% (160/276), and 56.1% (128/228) in the 2.5, 1.9, and 1.4 mg/kg cohorts, respectively. Gr2 and Gr3 symptoms were observed in 43.5% (107/246), 38.0% (105/276), 40.4% (92/228), and 6.5% (16/246), 3.6% (10/276), 3.5% (8/228) of ophthalmological assessments in the 2.5, 1.9, and 1.4 mg/kg cohorts, respectively. No Gr4 ocular symptoms were identified across cohorts. The most common ≥Gr2 ocular symptom was dry eye; proportions of ophthalmological assessments with Gr0–1, Gr2, and Gr3 dry eye were 65.3% (490/750), 33.7% (253/750), and 0.8% (6/750), respectively (Table S4). The numbers of patient-reported Ocular Surface Disease Index (OSDI) assessments were 233, 264, and 217 in the belamaf 2.5, 1.9, and 1.4 mg/kg dose cohorts, respectively (Figure S1). The proportions of assessments with “all of the time” and “most of the time” worst responses were 2.6% (6/233), 2.3% (6/264), and 3.7% (8/217) in the ocular symptoms category (questions 1–5), and 2.6% (6/233), 1.5% (4/264), and 1.4% (3/217) in the activities of daily living (ADL) category (questions 6–9), in the 2.5, 1.9, and 1.4 mg/kg belamaf dose cohorts, respectively. The proportions of assessments with “half of the time” worst responses were 47.2% (110/233), 40.5% (107/264), and 40.1% (87/217) in the ocular symptoms category, and 7.7% (18/233), 3.0% (8/264), and 7.4% (16/217) in the ADL category in the belamaf 2.5, 1.9, and 1.4 mg/kg dose cohorts, respectively. Taken together, our findings show that there is substantial patient heterogeneity with regard to the belamaf-related OAEs and their association with the dose level and the dosing schedule of the drug. Thus, it could be suggested that the optimal belamaf dose, and dosing interval should be sought for each patient individually to maximize its treatment effect and mitigate dose holds and delays due to OAEs (Figure S2). Furthermore, the Q12W dosing interval should be considered as, despite the extended interval between doses, the clinical activity of belamaf is not compromised (Table S5). Belamaf could be initiated at 1.9 mg/kg Q8W, and in the presence of OAEs, the dosing could be extended to Q12W. Subsequently, if required, the belamaf dosing could be reduced to 1.4 mg/kg 12 W, as this study showed that the latter schedule resulted in fewer OAEs while achieving the same response rate compared with higher doses (Table S6). Although cross-study comparisons should be made with caution, our findings advocate for a more favorable ocular toxicity profile compared with previous clinical trials and real-world studies with a 3-week administration of belamaf.3-6 Overall, a proactive dose modification approach, stopping treatment at first sign of OAE and restarting therapy at full recovery of OAE (Table S7), may significantly reduce ocular toxicities and improve the management of individual patients. Regarding the OSDI questionnaire, it is important to note that the proportions of assessments with “all of the time” and “most of the time” worst responses were equally low in the OSDI ocular symptoms (questions 1–5: sensitivity to light, gritty eyes, sore or painful eyes, blurred vision, poor vision; range 2.6%–4.1%) and the ADL (questions 6–9: reading, driving at night, working with a computer or ATM machine, watching TV; range 1.5%–3.0%), across the belamaf dose cohorts. Additionally, the analysis of the assessments with “half of the time” worst responses did not reveal a linear relationship between ocular symptoms and ADLs. More specifically, “half of the time” worst responses ranged between 38.8%–46.5% for the ocular symptoms category and 3.4%–8.4% for the ADL category across belamaf cohorts. Consequently, it seems that although ocular symptoms continue to manifest as a result of belamaf-related OAEs, they do not affect the patients' daily functioning in a significant way. By extent, this implies that OAEs do not have a major deteriorating effect on health-related QoL, either. We acknowledge that, as with any dose-finding study, the number of patients included in Part 1 and presented in this analysis is low; hence, the findings should be interpreted with caution. Funding and belantamab mafodotin for this study (NCT04808037) was provided by GSK. GSK was given the opportunity to review the preliminary version of this publication for accuracy, but the authors are solely responsible for the final content and interpretation. MG-research funding: Karyopharm, X4 Pharmaceuticals; honoraria: GSK, Karyopharm, Takeda, Janssen, Amgen, Celgene/Genesis, Sanofi; Scientific Advisory Board: Janssen, Amgen, Takeda, Karyopharm, Sanofi, GSK, Teva. GP-current employment: Health Data Specialists. EK-honoraria: Amgen, Janssen, GSK, Pfizer, Sanofi; research support: Janssen, Amgen, GSK, PfizerMAD- honoraria from participation in Advisory Boards: Abbvie, Amgen, Bristol Myers Squibb, Beigene Inc, GSK, Janssen, Menarini, Regeneron, Sanofi and Takeda. ET-honoraria: Amgen, BMS, ASTRA/Zeneca, EUSA Pharma, GSK, Janssen, Menarini/Stemline, Pfizer, Sanofi, Takeda; research funding: Amgen, GSK, Janssen, Sanofi, Takeda; travel expenses: Amgen, AstraZeneca, EUSA Pharma, Sanofi, Takeda. INS – no conflicts of interest; PM– no conflicts of interest; DF– no conflicts of interest; MM– no conflicts of interest; FT– no conflicts of interest; VS- no conflicts of interest; NK- no conflicts of interest; EEP- no conflicts of interest; MR- no conflicts of interest. Primary data are available upon reasonable request from the corresponding author. Data S1.Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.","is_dataset_classified":null,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"38270219","pmcid":null,"openalex_id":"https://openalex.org/W4391223231","authors":[],"funders":[{"funder_name":"belantamab mafodotin for this study","grant_id":"NCT04808037","title":null},{"funder_name":"GlaxoSmithKline","grant_id":"","title":null}],"total_grants":2,"fwci":2.4578,"citation_percentile":0.88854811,"influential_citations":0,"citation_trend":[{"year":2024,"count":1},{"year":2025,"count":7}],"oa_status":"bronze","license":"http://onlinelibrary.wiley.com/termsAndConditions#vor","oa_locations":[{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ajh.27219","host_type":"journal"},{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ajh.27219","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/pdf/10.1002/ajh.27219","host_type":"publisher"},{"url":"https://doi.org/10.1002/ajh.27219","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/38270219","host_type":"repository"}],"fields_of_study":["Multiple Myeloma Research and Treatments","Protein Degradation and Inhibitors","Platelet Disorders and Treatments"],"mesh_terms":["Lenalidomide","Antineoplastic Combined Chemotherapy Protocols","Dexamethasone","Humans","Multiple Myeloma","Antibodies, Monoclonal, Humanized"],"keywords":["Lenalidomide","Dexamethasone","Multiple myeloma","Medicine","Adverse effect","Internal medicine","Oncology","Bortezomib"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Zero hunger"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-02T21:03:39.256795Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}