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Belantamab Mafodotin: Overview
Belantamab mafodotin is a BCMA‑directed ADC.3 This ADC includes an anti-BCMA IgG1-specific monoclonal antibody that binds to BCMA-expressing myeloma cells with a protease‑resistant linker that joins the monoclonal antibody to MMAF, a microtubule-disrupting cytotoxic agent (the payload). This protease-resistant linker allows the payload to be released in the target cell only and leads to apoptosis of BCMA‑expressing myeloma cells without causing excessive bystander cellular toxicity.
Belantamab mafodotin binds to BCMA that is expressed on normal and malignant plasma cells, is internalized by these cells, and MMAF is released after the proteolytic cleavage from the monoclonal antibody. Next, MMAF disrupts the microtubule network intracellularly, causing cell-cycle arrest and apoptosis, as well as inducing tumor-cell lysis via antibody-dependent cellular cytotoxicity and phagocytosis. All these processes eventually result in MM cell death.
Belantamab mafodotin was received FDA approval for the treatment of patients with R/R MM who have received ≥4 previous therapies, including a CD38 monoclonal antibody, a PI, and an IMiD, based on results from the phase II DREAMM‑2 trial.
The DREAMM-2 trial was an open-label study in which 293 patients with R/R MM were enrolled.4 Participants were heavily pretreated, all having progressed after ≥3 prior lines of therapy, excluding anti-BCMA therapy but including a PI, an IMiD, and an anti-CD38 antibody, and were required to have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 at most. Patients were randomized to 1 of 2 doses of belantamab mafodotin; either 2.5 mg/kg or 3.4 mg/kg, each given intravenously every 3 weeks, and treated until progressive disease (PD) or unacceptable toxicity. The primary endpoint in this trial was overall response rate (ORR), and key secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety (including keratopathy).
In this trial, the median patient age was 65 years. Forty‑two percent of patients enrolled in this trial had high‑risk cytogenetics and 23% had extramedullary disease. The median number of prior lines of therapy was 7, and 84% of patients had received more than 4 prior therapy lines. Many of these patients had received all of the standard MM therapies, including bortezomib, carfilzomib, lenalidomide, pomalidomide, and all had received anti-CD38 antibody therapy.
Thirteen-month follow-up data from DREAMM-2 trial were reported in late 2021.5 In this analysis, the ORR with the FDA-approved dose of 2.5 mg/kg was 32% (95% CI: 21.7-43.6). Of interest, the median DoR among responders was 11 months (95% CI: 4.2 to not reached [NR]), suggesting that it is worth trying to keep the patient on therapy once they have responded.
Median OS in the entire intention-to-treat (ITT) population was 13.7 months (95% CI: 9.9-NR).5 Survival was extended among patients who achieved a partial response (PR) or better (median OS not reached) compared with those patients who had progressive disease (median OS 8.7 months; 95% CI: 1.9-13.1) or stable disease (median OS 7.7 months; 95% CI: 4.7-13.4). These data suggest that, for patients who do achieve a response with belantamab mafodotin, the response can potentially be maintained long term even after multiple lines of treatment.
Use of belantamab mafodotin has been associated with corneal toxicity, which is unique to this class of therapy. Keratopathy was reported in 71% of patients, including 44% at grade 3 or 4.6 Keratopathy associated with belantamab mafodotin is not necessarily symptomatic, although decreased visual acuity was reported in 53% of patients and blurred vision in 22%. Because this toxicity can initially manifest as a physical finding on ocular examination before progressing to cause symptoms, belantamab mafodotin is provided through a Risk Evaluation and Mitigation Strategy (REMS) program, and patients receiving this agent must be managed in conjunction with an eyecare specialist for regular monitoring with eye examinations.
Monitoring by eye care professionals and partnership with a multidisciplinary team are required to manage the corneal events associated with use of belantamab mafodotin. In the DREAMM‑2 study, 72% of patients experienced keratopathy, although 44% were asymptomatic.5 Three of 95 (3%) patients with corneal events discontinued treatment with belantamab mafodotin. Visual acuity changes were generally time‑limited, and dose modifications or dose delays can allow for continuation of belantamab mafodotin therapy. Of patients with a grade 3 or 4 keratopathy finding, 84% had recovered at the time of the 13-month analysis, suggesting that this is not a permanent outcome.
To reiterate, patients should receive an ophthalmic examination before starting belantamab mafodotin and again before each dose or in the event of worsening symptoms.
Based on the severity of the ocular toxicity, belantamab mafodotin can be held to help mitigate symptoms.5,7 For patients with mild or superficial examination findings (grade 1 on the Keratopathy Visual Acuity scale), belantamab mafodotin can be continued with close monitoring. For patients with moderate, superficial, or patchy microcyst-like epithelial changes (grade 2), belantamab mafodotin can be held until improvement to grade 1 and then resumed at a reduced dose of 1.9 mg/kg or restarted at the current dose. For patients with severe, superficial keratopathy with diffuse microcyst-like epithelial changes (grade 3), belantamab mafodotin can be held until improvement to grade 1 and then resumed at a reduced dose of 1.9 mg/kg. For patients with any corneal epithelial defects, belantamab mafodotin should be discontinued.
Sixteen patients who had a prolonged delay in belantamab mafodotin were assessed in a post hoc analysis.5 Despite delayed dosing, 88% of these patients maintained clinical benefit, with some deepening their response (38%) or maintaining their response category (38%), although 13% progressed.
These data suggest that most patients will maintain their response, even if it is necessary to delay dosing of belantamab mafodotin due to ocular events or some other toxicity.
Whereas the approval of belantamab mafodotin represented a breakthrough in a novel treatment paradigm for patients with MM, the ORR is only 32%. To try to improve the response rate, combination treatment with belantamab mafodotin for MM is under investigation.
The phase II DREAMM‑6 trial is evaluating belantamab mafodotin in combination with various MM therapies, including bortezomib/dexamethasone (Vd) for patients with R/R MM.8 The ORR among 18 patients in this trial who received belantamab mafodotin + Vd was 78%, even among 16 patients with prior bortezomib exposure the ORR was 75% or 67% for those who had previously been exposed to daratumumab. Most patients (67%) achieved a very good partial response (VGPR) or better. All patients experienced keratopathy, with 61% at grade 3.
The phase I ALGONQUIN study was designed to test varying doses of belantamab mafodotin with pomalidomide/dexamethasone (Pd) in patients with R/R MM.9 Patients received various doses/administration schedules of belantamab mafodotin, including 1.92 mg/kg or 2.5 mg/kg every 4 weeks, or 2.5 mg/kg every 8 weeks or every 12 weeks. ORRs ranged from 82% to 95% across dosing arms. Again, most patients experienced keratopathy, including 70% at grade 3.
These preliminary findings suggest that combining belantamab mafodotin with other known effective myeloma therapies boosts response rate compared with giving this agent alone and is consistent with the known adverse event (AE) profile.
In ALGONQUIN, median PFS was not yet reached in patients who received belantamab mafodotin dosed 2.5 mg/kg every 8 weeks or every 12 weeks.9 For those who received 2.5 mg/kg every 4 weeks, the median PFS was 25.3 months, and 16.2 months for patients who received 1.92 mg/kg every 4 weeks. By way of comparison, in the phase III APOLLO trial, the addition of daratumumab to Pd significantly improved PFS versus Pd in R/R MM (median, 12.4 months with the addition of daratumumab vs 6.9 months with Pd; HR: 0.63; 95% CI: 0.47-0.85; P = .0018).10 So, the data from ALGONQUIN was similar to other trials with Pd combinations.
By previous treatment exposure, median PFS was 17 months for all patients in ALGONQUIN, compared with 25.3 months for those patients refractory to lenalidomide and PI refractory, and 16.2 months for those who were also refractory to daratumumab (triple refractory). So, although patients who were more heavily pretreated responded less well, overall, these findings show that combining belantamab mafodotin with other effective therapies can produce encouraging results in patients with R/R MM.
In addition to exploring combination approaches with belantamab mafodotin in heavily pretreated patients, the DREAMM‑9 trial is a phase I study of belantamab mafodotin as a part of induction therapy for patients with newly diagnosed MM.11 Participants in this study were ineligible for autologous stem cell transplant due to frailty or comorbidity, and were randomized to 1 of 8 doses of belantamab mafodotin with a backbone of bortezomib/lenalidomide/dexamethasone (VRd) in various dosing cohorts. Data have been presented for the first 5 of these cohorts, with doses ranging from 1.0 mg/kg every 3 to 4 weeks up to 1.9 mg every 3 to 4 weeks or every 6 to 8 weeks.
ORR of 83% to 100% were reported in these various dosing arms, with 50% of patients in the highest dosing group achieving a stringent complete response (sCR). The frequency of corneal events ranged from 50% with less frequent dosing up to 100% in the highest dose cohort, including 33% to 80% at grade 3 or higher, although most events did not require dose reduction. I think that if we can figure out a way to manage these corneal events better, it does seem that belantamab mafodotin is an effective regimen and can be considered as an addition to our already very effective therapy for newly diagnosed MM.
DREAMM‑5 is a platform, or basket, trial assessing combinations of belantamab mafodotin with several investigational immunotherapy agents to try to understand optimal synergistic combinations for belantamab mafodotin. This trial design allows for the expansion of cohorts with combinations showing the most promising efficacy and safety data. Data from the cohort treated with belantamab mafodotin and the inducible T‑cell costimulator (ICOS) agonist, feladilimab, were presented at the 2021 ASH Annual Meeting.12
As mentioned, one cohort of the DREAMM‑5 study assessed belantamab mafodotin in combination with an ICOS agonist for patients with R/R MM.
The rationale for this approach is that combining the immunomodulatory effects of belantamab mafodotin with an immune-response–enhancing agent could enhance antitumor activity. Belantamab mafodotin has multiple mechanisms of action to cause myeloma cell death. One is the traditional approach for ADCs delivering a cytotoxic payload directly to the tumor cell, but belantamab mafodotin also induces tumor cell lysis via antibody-dependent cellular toxicity (ADCC) and phagocytosis (ADCP) by bringing immune effector cells in proximity with myeloma cells through Fc receptor binding while on the cell surface before being internalized. The myeloma cell death caused by belantamab mafodotin can potentially further activate the immune response through activation of antigen presenting cells and subsequent T-cell priming
The ICOS agonist, feladilimab, was designed to enhance T-cell function and improve antitumor immune responses. Combining the immune enhancing properties of both belantamab mafodotin and feladilimab could resulted in enhanced anti-myeloma immune response.
The preliminary ORR for the total population of 25 patients was 52% with the combination of belantamab mafodotin plus feladilimab.12 However, the ORR varied across the different dosing cohorts, from 44% with belantamab mafodotin 1.9 mg/kg dose plus feladilimab 8 mg to 67% with belantamab mafodotin 2.5 mg/kg plus feladilimab 24 mg
Overall, 60% of participants experienced corneal events with belantamab mafodotin plus feladilimab, and 44% experienced keratopathy.12 However, the rate of ocular events was reduced in the lowest dosing cohort, with 33% any grade corneal events and 33% with any grade keratopathy. I think we need to see more data, but it is interesting to think that combining these 2 modalities may provide a reasonable response rate in heavily pretreated patients and potential for minimizing keratopathy with optimal dosing of belantamab mafodotin.
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