Real-World Use of Belantamab Mafodotin in Relapsed/Refractory Multiple Myeloma: A Systematic Review

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I N T R O D U C T I O N
The prognosis of multiple myeloma (MM) has continued to improve over the years; however, a significant proportion of patients develop relapsed/refractory (R/R) disease and require further treatment options for disease control [1,2]. R/R MM is defined as a disease state that is either unresponsive or progressive to current therapy or therapy within the past 60 days in previously responsive patients [2]. The prognosis of R/R MM continues to be suboptimal [1,3]. In so-called "triple-refractory" disease, which is refractory to an anti-CD38 antibody, a proteosome inhibitor, and an immunomodulatory drug, prognosis is poor and thus, new treatment options are needed [4][5][6].
Belantamab mafodotin, a monoclonal antibody targeting B-cell maturation antigen (BCMA), is a member of the antibody-drug conjugates (ADCs) that has been shown to have a single drug activity with an overall response of 31-34% at various dosing levels [7]. This resulted in an accelerated approval by the Food and Drug Administration (FDA) in August 2020 to use in adult patients with R/R MM who have received at least 4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory drug. In November 2022, belantamab mafodotin was withdrawn from the US market after failure of DREAMM-3 (NCT04162210), a required confirmatory trial comparing belantamab mafodotin vs pomalidomide and dexamethasone. In our systematic review, we aimed to provide a comprehensive review on the use of belantamab mafodotin in real-world setting with focus on efficacy and safety.

M E T H O D S
We performed a literature review within PubMed/ Medline, as well as major oncology societies including the American Society of Hematology, American Society of Clinical Oncology, and HemaSphere to include all reported real-world use of belantamab mafodotin. The identification and reporting of the analyzed studies in this study were done in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist [8].
We included all full-text manuscripts and/or abstracts that have the keywords "belantamab mafodotin," "belamaf," "blenrep," "belantamab mafodotin-blmf," and/or "GSK2857916" (subsequently named as belantamab mafodotin) between January 2006 and December 2022. All search records were screened. We excluded all the following: reports not in the English language; reports not pertaining to treatment e ff i c a c y, o u t c o m e , a n d / o r a d v e r s e e ff e c t s ; duplicate records (e.g., abstracts that were later published as full-text manuscripts); and manuscripts that did not describe "real-world" multiple patient experiences, thus excluding review articles, clinical trials, and case reports/series (Fig. 1). The records that met the criteria were then reviewed for their patient demographics, response rates, survival outcomes, and reported adverse events. Minimum endpoints included the report of overall response rates, median progression-free survival and overall survival, and a report of the incidence of adverse effects in the analyzed sample.

Reports excluded (n=198)
Not in the English Language (n=6) Review articles, clinical trials or case reports/series (n=156) Manuscripts not detailing treatment efficacy,outcomes, and adverse events (n=34) Duplicate records (n=2)

Abstracts (n=6)
Full-text manuscripts (n=5) When combined, a total of 851 patients were analyzed across all the reviewed studies. The median age at which belantamab mafodotin was initiated for each study ranged from 63 to 70 years [10,19]. The median number of prior therapies before belantamab mafodotin initiation for each study ranged from 5 to 8 prior lines of therapy [11,14]. The most frequent dosing reported was 2.5 mg/kg, and the most common dosing frequency, or cycle, was every 21 days, unless delayed due to adverse effects. The median number of cycles administered for each study varied, ranging from 2 to 4 cycles [15,18].
Regarding outcomes, all studies reported data on median progression-free survival (median PFS), median overall survival (median OS), and response rates. When reported, the duration of follow up after belantamab mafodotin therapy ranged from 6 to 13 months [11,14], and the duration of response ranged from 5 to 11 months [14,18]. The response rates in all studies were done in accordance with the International Uniform Response Criteria for Multiple Myeloma [20]. The overall response rate ranged from 21.9% to 45.5% [9,17]. Some studies reported the response rates strictly as part of the response criteria, while others categorized the response as greater or equal than a very good partial response (≥VPGR). When all studies are combined, a ≥VGPR has ranged from 3% in Becnel et al's study [15] to 33% in Hultcrantz et al's study [18]. Stable disease was reported in 5 of 11 studies and ranged from 14% to 28% across the studies [10,12,14,18,19]. When progressive disease was reported in 4 studies, it ranged from 27% to 36% [12, 14, 18, 19]. Regarding survival analysis, all the studies reported data on median PFS, with the reported values ranging from 1.8 months (no confidence interval reported; n = 39 patients) [15] to 6 months (no confidence interval reported; n = 82 patients) [18 ]. Median OS ranged from 6.5 months to 14.5 months [9,14], with 1 study not reaching a median OS [18].

D I S C U S S I O N
I n 2 0 1 6 , a p r e c l i n i c a l s t u d y r e v e a l e d t h a t GSK2857916, subsequently named as belantamab mafodotin, had demonstrated promising abilities to cause cytotoxicity in cells containing BCMA, which is expressed on normal and malignant plasma cells [21]. The first human trial, DREAMM-1, which was published in 2018, demonstrated that GSK2857916 was a potentially helpful treatment modality in patients with heavily pretreated R/R MM [22]. Subsequently, a phase II, randomized, open-label study [7] revealed promising response rates in cohorts that received either the 2.5 mg/kg or the 3.4 mg/ kg doses with subsequent drug development at the 2.5 mg/kg dose every 3 weeks. AEs included keratopathy, which was ≥grade 3 in 29% of the 2.5 mg/kg cohort, anemia (≥grade 3 in 21%), and thrombocytopenia (≥grade 3 in 19%) [23]. In phase III of the DREAMM-3 trial, belantamab mafodotin was compared to pomalidomide and dexamethasone [24]. Most recently, on November 7, 2022, GlaxoSmithKline (GSK) had officially released an update on phase III trial, revealing that the targeted endpoint of PFS was not met for belantamab mafodotin in comparison to pomalidomide and dexamethasone. Shortly after, on November 22, 2022, GSK announced they will be withdrawing the use of belantamab mafodotin as per the request of the US FDA, based on the DREAMM phase III results.
In the DREAMM-2 trial, belantamab mafodotin was studied as a single agent on a total of 196 patients who were assessed in an intention-totreat analysis, with 97 patients receiving the 2.5 mg/kg dose and 99 receiving the 3.4 mg/kg dose [7]. In the trial, an overall response rate was achieved in 31% of the 2.5 mg/kg cohort and 34% of the 3.4 mg/kg cohort. A ≥VPGR rate was achieved in 19% of the 2.5 mg/kg cohort and 20% of the 3.4 mg/kg cohort. In our review, only 3 of the reviewed studies reported the use of belantamab mafodotin as a single agent [10,11,16], and only 5 of the 11 reviewed studies achieved a VPGR rate as good as the one reported in the trial [11,12,16,18,19], while the remaining studies had lower response rates. In the DREAMM-2 trial, 97% of the 2.5 mg/kg cohort and 100% of the 3.4 mg/kg cohort had experienced at least one adverse event, with the most common being keratopathy, followed by thrombocytopenia and anemia [7]. While these findings are echoed in the real-life experiences of patients outside of clinical trials, the incidence of the findings have differed. For instance, the majority of the patients in the DREAMM-2 trial with keratopathy had grade 1-2 keratopathy, while the most prevalent keratopathy for patients in the nonclinical trial in our review was ≥grade 3 (Table 2). This discrepancy is important to point out because while both grade 2 and grade 3 keratopathy indicate a need to withhold treatment until ocular improvement, grade 3 keratopathy requires a dose reduction upon clinical improvement [25]. A possible explanation of the discrepancy of keratopathy gradings in the DREAMM-2 and the patients outside of the trial could be explained by the exclusion of patients with corneal epithelial disease, excluding mild punctate keratopathy, in the DREAMM-2 trial. This is further evidenced as a recent study analyzing patients with newly diagnosed multiple myeloma revealed that 39% of patients had ocular comorbidities detected at baseline [26].
Furthermore, while keratopathy led to discontinuation of treatment in only 1% of the patients in the DREAMM-2 trial, our review shows higher numbers of treatment discontinuation due to adverse effects, ranging from 3.8% to 33.8% [9,17]. In the DREAMM-2 trial, adverse events led to dose delays in 54% and dose reductions in 29% of the 2.5 mg/kg cohort. In contrast, dose delays ranged from 11.4% to 35.4% in the reviewed studies [18,19], and dose reductions ranged from 19.6% to 43.9% [18,19]. In both the DREAMM-2 trial as well as the reviewed studies, ocular toxicity was the most common AE leading to treatment interruption. Nonetheless, Mohan et al's real-life experience demonstrated that resuming belantamab mafodotin after resolution of keratopathy was associated with a better outcome when compared to permanent treatment discontinuation [16]. Nonetheless, the contrast in AE incidence, grading, and effect on treatment discontinuation between the DREAMM-2 trial and the reviewed studies is noteworthy for assessment of the risk of AEs during belantamab mafodotin therapy.
Ultimately, according to the most recent results of the DREAMM-3 trial, belantamab mafodotin did not reach its expected PFS and OS target, thus leading to cessation of its use as monotherapy for R/R MM at the time of writing this manuscript. However, its potential to be used in combination for R/R MM, as well as its utility in the management of light-chain amyloidosis and transplant-ineligible MM remains topics of ongoing research [27][28][29][30][31][32][33][34].

C O N C L U S I O N S
Belantamab mafodotin was associated with modest efficacy in reported real-world data with higher incidence of AEs when compared to the original clinical trial that resulted in its accelerated approval.