Belantamab Mafodotin in Combination with Vrd for the Treatment of Newly Diagnosed Transplant Eligible Multiple Myeloma Patients: Results from the Phase II, Open Label, Multicenter, GEM-BELA-Vrd Trial

Introduction: The use of bortezomib, lenalidomide and dexamethasone (VRd) as induction triplet has resulted in deep and durable responses in newly diagnosed transplant-eligible multiple myeloma (NDTE MM) patients, as shown by the Spanish group in the GEM2012 trial. The addition of anti-CD38 monoclonal antibodies to VRd deepen responses without impairing safety. The BCMA antibody-drug conjugated belantamab mafodotin (belamaf) is approved for relapsed and refractory MM, but its role in the frontline setting is not established.

Patients and methods: 50 patients (pts) were planned to be recruited in this phase II, open label, multicenter, non-randomized single arm clinical trial (GEM-BELA-VRd). Treatment consisted of six induction cycles with VRd every 4 wks and belamaf 2.5 mg/kg iv every 8 wks (on day 1 of cycles 1, 3 and 5), followed by high dose melphalan (200mg/m2) and autologous stem cell transplant. Patients also receive two consolidation cycles with VRd (Q4W) and belamaf (Q8W), and maintenance with R until progression/toxicity and belamaf (Q8W) for 2 yrs.

Primary endpoint was safety, evaluated in terms of incidence of adverse events (AEs) [according to CTCAE v. 4.0], of ocular events (OEs) [according to Visual Acuity - KVA scale] and of deaths. Main key secondary endpoints were overall response rate (ORR), complete response rate (CR), and progression-free survival (PFS). Cut-off date: July 7^th 2022. Here, we report the initial safety and efficacy results of patients included after 4 cycles of induction with Belamaf-VRd.

Results: Forty pts had already completed the four induction cycles and were included in this analysis. Half of them were women and the median age at diagnosis was 58 years old (27-74).

Ocular toxicity was the most frequent AE. Thirty-eight pts (95%) presented any eye symptom, the most frequent one was blurred vision (77.5%; G3-4: 27.5%); followed by eye irritation (57.5%; G3-4: 10%) and dry eye (50%; G3-4: 10%). Four wks from first belamaf dose (C2 of VRD), 24 pts (60%) had any grade of keratopathy related to belamaf (mild: 50.0%; moderate: 45.8%, and severe: 4.2%); that persisted 4 wks later (C3), as 21 pts (52.5%) still had keratopathy (mild: 47.6%; moderate: 47.6%, and severe: 4.8%). Seven pts (17.5%) did not receive the second planned belamaf dose, 9 (22.5%) received reduced dose (1.9 mg/kg) and the remaining 24 pts received the full planned dose. At C4D1, four wks after the second planned belamaf dose, 32 pts (80%) had keratopathy (mild: 37.5%; moderate: 53.1%, and severe: 9.4%) and, after 8 wks, 27 pts (67.5%) (mild: 48.1%; moderate: 37.0%, and severe: 14.8%).

In addition, hematological toxicity was reported in 24 pts (60%). Neutropenia and thrombocytopenia were the most frequent hematological AEs (both 20%; G3-4 in 12.5 and 7.5%, respectively).

Twenty-two patients (55%) had any infection during this induction period, with respiratory infection as the most frequent one, in 20 pts (50%; G3-4: 22.5%). Pneumonia was registered in 8 patients (20%), in 7 of them was considered as a serious adverse event, 3 were caused by SARS-CoV-2 and 2 pts died. Skin toxicity, like maculo-papular rash, was reported in 35% of pts, G3-4 was present in 6 pts (15%). Peripheral neuropathy (PN) occurred in 27.5% of pts, none of them had G3-4 PN.

With a median follow-up of 6 mo (3-12), 2 pts died, both due to COVID pneumonia and 1 progressed resulting in 6-mo PFS of 89.3%. After 4 cycles, ORR was 82.1%; VGPR or better was achieved in 69.2% of pts, and CR in 5 patients (12.8%), all of them with MRD negativity (except one that was not evaluable).

Conclusions: The results of adding belamaf to VRD seem encouraging, although ocular toxicity is a concern. The study is ongoing with belamaf as part of the maintenance and longer follow-up will confirm whether the combination improves outcomes in NDTE MM patients.

"Funding and product for this study was provided by GSK [NCT04802356]. GSK was provided the opportunity to review a preliminary version of this manuscript for factual accuracy, but the authors are solely responsible for final content and interpretation".

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