A Multicenter Phase 2 Study Evaluating the Optimized Schedule of Belantamab Mafodotin 1.9 Mg/Kg Q8W Plus Bortezomib and Dexamethasone in Relapsed Refractory Multiple Myeloma

Background: Belantamab mafodotin monotherapy was recently removed from the markets in the US and EU. However, results of two phase 3 studies for patients (pts) with relapsed refractory multiple myeloma (RRMM) have been released recently– DREAMM-7 and DREAMM-8. Belantamab in combination with bortezomib and dexamethasone (Vd) and belantamab in combination with pomalidomide and dexamethasone (Pd) confirmed significant benefit in PFS over daratumumab Vd and bortezomib Pd, respectively (V Hungria, NEJM 2024; MA Dimopoulos, NEJM 2024). However, ocular findings are still considerable adverse events (AE), therefore, the schedule needs to be adjusted to further optimize the use of belantamab.

Methods: The single-arm phase 2 study CMG012022 (EudraCT 2022-002515-34) is designed to assess whether a lower dose of belantamab (1.9 mg/kg) given less frequently (Q8W) in combination with weekly Vd in RRMM pts can achieve at least similar efficacy (63% ORR) while improving the toxicity profile (14% incidence rate of Grade ≥3 ocular AE) than intensive dosage regimen used in the DREAMM-6 trial (2.5 mg/kg Q3W) (R Popat, ASH 2020). Therefore, RRMM pts after ≥1 line of therapy were intended for enrollment. The inclusion/exclusion criteria matched those of the DREAMM-7 study, however, belantamab dose and frequency were reduced. The patients receive eight 28-day cycles of bortezomib: 1.3 mg/m² SC days 1, 8, 15, 22 and dexamethasone: 20mg PO days 1, 2, 8, 9, 15, 16, 22, 23 plus belantamab: 1.9 mg/kg IV every 8 weeks until progression or unacceptable toxicity. The primary endpoints consist of the overall response rate (ORR) and the incidence rate of Grade (gr.) ≥3 ocular AE according to the keratopathy visual acuity (KVA) scale, which combines grading of corneal events and changes in the best corrected visual acuity. The data cut-off for this review was June 30, 2024. Informed consents were obtained.

Results: At the data cut-off, 45 pts after a median of 3 (range 1-7) prior lines of therapy had started the treatment at seven Czech university hematooncology centers. The median age at the screening was 71 (range 44-89) years with male/female ratio of 1.04. High-risk cytogenetics [t(4;14), t(14;16), del(17p)] was found in 35% (15/43) of pts, 9% (4/45) and 31% (14/45) of pts were double and triple-class refractory, respectively. After a median follow-up of 145 days (IQR 68; 258) and a median of 4 (range 1-11) cycles of belantamab Vd, the response is evaluable in 39 patients. Despite a significantly reduced belantamab intensity, ORR has reached 64% (25/39) so far with CR in 10% (4/39), VGPR in 28% (11/39) and PR in 25% (10/39) of pts. Out of 10 pts evaluated for minimal residual disease (MRD), four were MRD negative representing 10% (4/39) of the whole cohort. Two pts progressed and one withdrew the informed consent shortly after an initiation of the therapy. Six pts in total died; none of the death causes (progression, infection, surgical complication, heart failure) were related to the treatment. Any treatment-related AE was observed in 64% (29/45) of patients, of whom 34% (10/29) had gr. 3/4 AE. Ocular AE developed in 34% (11/32) of pts who were evaluated for ocular findings - maximum gr. 3 in one patient (3%; 1/32), gr. 2 in eight pts (25%; 8/32) and gr. 1 in two pts (6%; 2/32). Four pts had dose reduction of belantamab (12.5%; 4/32) and 11 pts experienced dose delays to manage ocular findings (34%; 11/32). One patient terminated the treatment after the first dose of study drugs due to hepatopathy gr. 3 (related to bortezomib, possibly related to belantamab) and one patient decided to discontinue belantamab because of vision changes. The study fulfilled patient recruitment.

Conclusion: The ocular findings seem to be limited due to the significantly de-escalated belantamab dosing and still the ORR reaches 64% (25/39) with MRD negativity rate of 10% (4/39). The clinical trial is ongoing, these results will have to be confirmed by the final analysis.