Efficacy and a manageable safety profile have been demonstrated previously for belantamab mafodotin-blmf (belamaf), an immunoconjugate targeting B-cell maturation antigen with a unique mechanism of action, in patients with relapsed/refractory multiple myeloma (RRMM). The addition of pomalidomide (POM), an immunomodulatory drug, to belamaf is postulated to enhance immune responses through augmentation of T-cell and natural killer cell–mediated immunity. The current multicenter phase 1 dose-escalation and expansion study assessed the maximum tolerated dose, the recommended dose for phase 2 study, safety, tolerability, and efficacy of belamaf + POM + dexamethasone (DEX) in patients with RRMM.
Enrollment criteria included having received ≥1 lines of prior treatment, exposure to lenalidomide and a proteasome inhibitor, and being refractory to the last line of therapy. POM 4 mg was given on days 1 to 21, DEX 40 mg (or 20 mg if aged >75 years) was given weekly, and belamaf intravenous SINGLE regimen (1.95 or 2.5 mg/kg on day 1) or SPLIT regimen (2.5 or 3.4 mg/kg, split equally on days 1 and 8) was given once every 4 weeks. Alternative dosing schedules were also permitted at the 2.5-mg/kg dose, including a 2.5-mg/kg LOADING dose followed by 1.92 mg/kg once every 4 weeks from Cycle 2 on, and 2.5 mg/kg once every 8 weeks or once every 12 weeks. A standard 3+3 dose-escalation design was used.
Thirty-seven patients completed the 28-day dose-limiting toxicity observation period. Dose levels and schedules were as follows: 1.92 mg/kg SINGLE (n = 12), 2.5 mg/kg SINGLE (n = 7), 2.5 mg/kg LOADING (n = 5), 2.5 mg/kg SPLIT (n = 8), and 3.4 mg/kg SPLIT (n = 5). The median age was 64 years, and patients had received a median of 3 prior regimens; 64.9% received prior autologous stem-cell transplant, 100% received prior proteasome inhibitors (PIs; 81.1% refractory), 100% received prior lenalidomide (89.2% refractory), and 43.2% received prior daratumumab (100% refractory). A total of 73% of patients were double-refractory (lenalidomide and a PI), and 35.1% were triple-refractory (lenalidomide, PI, and daratumumab). Nine patients had high-risk cytogenetics.
The most frequent treatment-emergent adverse events (TEAEs) of any grade across all cohorts were keratopathy/microcyst-like epithelial changes (MECs) among 75.7% of patients, fatigue among 40.5%, neutropenia among 56.8%, thrombocytopenia among 48.6%, and fever among 35.1%. The most common grade 3/4 TEAEs were keratopathy/MECs (51.4%), neutropenia (40.5%), thrombocytopenia (32.4%), decreased visual acuity (16.3%), and lung infection (5.4%). Sixteen patients (43.2%) experienced serious adverse events. Three dose-limiting toxicities resulting from ocular events occurred (2.5-mg/kg SINGLE, n = 1; 3.4-mg/kg SPLIT, n = 2). The maximum tolerated dose was therefore determined to be 2.5-mg/kg SINGLE and 2.5-mg/kg SPLIT + POM/DEX doses.
Among 34 patients evaluable for response across all cohorts, the overall response rate was 88%, with 68% achieving very good partial response or better. Progression-free survival for the total population was not reached; however, it was 14.1 months for those receiving 1.92 mg/kg every 4 weeks. Patients received a median of 6 cycles. At data cutoff, 8 patients discontinued treatment (progressive disease, n = 5; patient withdrawal, n = 2; grade 4 decreased visual acuity, n = 1), and 27 continue.
Results from Part 1 of this phase 1 study show promising efficacy for belamaf + POM + DEX, with a safety profile consistent with that previously reported for these agents. However, concern over the high rate of dose holds at the 2.5-mg/kg dose was deemed to warrant examination of alternative dosing schedules. Dose selection for the phase 2 study will be conducted when complete data from the current cohorts become available.
Reference
Abstract 725. ASH 2020. December 7, 2020. Part 1 Results of a Dose Finding Study of Belantamab Mafodotin (GSK2857916) in Combination with Pomalidomide (POM) and Dexamethasone (DEX) for the Treatment of Relapsed/Refractory Multiple Myeloma (RRMM).