In patients with relapsed/refractory multiple myeloma (RRMM), although promising efficacy and acceptable toxicity were reported for belantamab mafodotin plus pomalidomide and dexamethasone, the high dose rate holds at the 2.5-mg/kg dose level were deemed to warrant examination of alternative-dosing schedules.
In patients with RRMM, efficacy and a manageable safety profile have been shown previously for belantamab mafodotin-blmf (belamaf), an immunoconjugate targeting B-cell maturation antigen with a unique mechanism of action. 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 maximum tolerated dose (MTD), recommended dose for phase 2 study, safety, tolerability, and efficacy of belamaf plus POM and dexamethasone (DEX) in patients with RRMM were assessed in the current multicenter, phase 1, dose-escalation and dose-expansion study.
Enrollment criteria included ≥2 lines of prior treatment, exposure to lenalidomide and a proteasome inhibitor (PI) and being refractory to their last line of therapy. POM 4 mg was given on days 1 through 21, DEX 40 mg was dosed weekly (or 20 mg if patients were aged >75 years), and belamaf IV SINGLE (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 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 every 4 weeks from cycle 2 on, and 2.5 mg/kg every 8 weeks or every 12 weeks. A standard 3+3 dose-escalation design was used.
Through July 13, 2020, the 28-day dose-limiting toxicity observation period was completed by 35 patients. 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 = 6), and 3.4 mg/kg SPLIT (N = 5). Median age was 64 years. Patients received a median of 3 prior regimens; 68.6% received prior autologous stem-cell transplantation, 100% prior proteasome inhibitors (80% refractory), 100% prior lenalidomide (88.6% refractory), and 45.7% prior daratumumab (100% refractory). A total of 71.4% of patients were double refractory (lenalidomide and a PI), and 37.1% were triple refractory (lenalidomide, PI, and daratumumab). Eight (42.1%) of 19 patients with available cytogenetics had del17p13, t(4;14), t(14;16) or 1q gain and were, therefore, defined as high risk.
Regarding the most frequent treatment-emergent adverse events (TEAEs), any grade, across all cohorts, 65.7% of patients experienced keratopathy/microcyst-like epithelial changes (MECs), 48.6% fatigue, 48.6% neutropenia, 48.6% thrombocytopenia, and 31.4% fever. The most common grade 3/4 TEAEs were keratopathy/MECs (40.0%), neutropenia (37.1%), thrombocytopenia (34.3%), decreased visual acuity (22.9%), lung infection (11.4%), and dyspnea (11.4%). Serious adverse events were experienced by 16 (45.7%) patients. Dose holds of belamaf due to adverse events occurred more often in the 2.5-mg/kg SINGLE (57.9%) versus the 1.92-mg/kg SINGLE (22.9%) dosing cohorts. Three dose-limiting toxicities due to ocular events occurred (2.5 mg/kg SINGLE: N = 1; 3.4 mg/kg SPLIT: N = 2). Therefore, the MTDs were determined to be 2.5 mg/kg SINGLE and 2.5 mg/kg SPLIT plus POM/DEX doses.
Overall response rate among 29 patients evaluable for response across all cohorts was 86.2% (4 patients with stringent complete response, 15 with very good partial response, and 6 with partial response); median follow-up was 6 months. 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 patients continued treatment.
Part 1 results of this phase 1 study show promising efficacy for treatment with belamaf plus POM and DEX. The safety profile was consistent with that previously reported for these agents. However, there was concern over the high rate of dose holds at the 2.5-mg/kg dose. Therefore, alternative-dosing schedules were examined. For the phase 2 study, dose selection will be selected when complete data from the current cohorts become available.
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).