The combination of belantamab mafodotin with bortezomib, lenalidomide, and dexamethasone (VRd) has demonstrated promising efficacy and manageable toxicity in patients with newly diagnosed, transplant-eligible multiple myeloma. These findings come from the phase 2 GEM-BELA-VRD trial (NCT04802356), which were presented at the 21st Annual International Myeloma Society Meeting and Exposition. The study evaluated the safety and efficacy of this novel combination in improving outcomes for myeloma patients eligible for autologous stem cell transplantation (ASCT).
Efficacy Outcomes
The intent-to-treat (ITT) population showed a 94% objective response rate (ORR) across all treatment phases, including induction, ASCT, consolidation, and one year of maintenance therapy. Complete response (CR) rates significantly improved over the course of the treatment: 36% during induction, 56% post-ASCT, 70% after consolidation, and 82% following the maintenance phase. Flow cytometry analysis revealed that minimal residual disease (MRD)-negative rates also improved, reaching 60.9%, 69.0%, 84.2%, and 91.2% across the respective treatment phases.
Notably, similar response outcomes were observed in patients with both high-risk and standard-risk cytogenetics. All patients with high-risk cytogenetics achieved MRD-negative status after consolidation and maintenance therapy. Other MRD-negative rates in the high-risk group included 64.3% post-induction and 83.3% post-ASCT.
After a median follow-up of 28.5 months, progression-free survival (PFS) events were observed in only four patients. The PFS rates at 12 and 24 months were 90% and 85%, respectively, while the time to progression (TTP) rates were 96% and 95%. Overall survival (OS) data indicated that eight patients died, with causes including COVID-19 pneumonia (n = 4), sepsis (n = 1), inflammatory colitis (n = 1), disease progression (n = 1), and unknown reasons (n = 1). The 12-month and 24-month OS rates were 92% and 85%, respectively.
In the high-risk cytogenetics subgroup, the PFS rates were 91% at both 12 and 24 months, compared to 91% and 82% in the standard-risk cytogenetics group (P >.05). The OS rates at 12 and 18 months were 93% and 93% for high-risk patients and 91% and 82% for standard-risk patients (P >.05).
Investigator Commentary
Verónica González-Calle, MD, MS, PhD, from the Hematology Department at the University Hospital of Salamanca, commented on the findings: “The efficacy of the combination seems to be encouraging. Depth of response improved over the course of treatment, with 82% of patients with CR or better after 1 year of maintenance in the ITT population, and 91% of evaluable patients with negative MRD. Maintenance is ongoing, and further analysis after completing 2 years of maintenance is planned.”
Trial Design and Patient Population
The open-label, multi-center GEM-Bela-VRD trial enrolled patients who received induction therapy with bortezomib (1.3 mg/m2 subcutaneously on days 1, 4, and 11 of each cycle), lenalidomide (25 mg daily on days 1 to 21), dexamethasone (40 mg on days 1 to 4 and 9 to 12), and belantamab mafodotin (2.5 mg/kg intravenously every 8 weeks). Following ASCT, patients underwent consolidation with belantamab mafodotin plus VRd for two cycles. The maintenance phase involved belantamab mafodotin (1.9 mg/kg intravenously every 8 weeks) plus lenalidomide (10 mg per day on days 1 to 28 of each cycle).
The primary endpoint of the trial was safety, focusing on ocular events and other adverse effects (AEs). Key secondary endpoints included ORR, CR rate, MRD after each treatment phase, PFS, and OS.
From June 2015 to June 2017, 50 patients were enrolled. All 50 underwent induction therapy, 45 proceeded to ASCT, 44 received consolidation therapy, and 41 received maintenance therapy. The median patient age was 56 years (range, 27-75), with 48% being male. Most patients had an ECOG performance status of 0 (66%), IgG κ multiple myeloma (64%), κ light chain disease (64%), and stage I disease (65.3%). Approximately 30.4% of patients had high-risk cytogenetics, including 17p deletions (10.9%), t(4;14) (17%), and t(14;16) (4.3%).
Safety and Tolerability
Ocular toxicities were the most frequent adverse events following induction therapy. Common any-grade ocular AEs included blurred vision (89.6%), foreign body sensation (62.5%), dry eyes (58.3%), and eye irritation (37.5%). Grade 3/4 ocular AEs included blurred vision (41.7%), foreign body sensation (18.8%), dry eyes (14.6%), and eye irritation (8.3%). Changes in best-corrected visual activity (BCVA) showed that 40% of evaluable patients experienced blurred vision, with a median onset of 49 days and a median resolution time of 150 days. Dose reductions, delays, or interruptions occurred in 30%, 48%, and 2% of patients, respectively, due to ocular events. No patients experienced impaired vision after induction therapy.
During the induction phase, any grade and grade 3 or higher hematological AEs affected 62% and 40% of patients, respectively. The most common hematological AEs included thrombocytopenia (28%), neutropenia (22%), and anemia (12%). Patients also experienced infections (80%), peripheral neuropathy (42%), and skin toxicity (38%).
During consolidation, any grade ocular AEs included blurred vision (58.3%), dry eye (37.5%), foreign body sensation (31.3%), and photophobia (18.8%). Grade 3/4 events were less frequent. Blurred vision occurred in 19% of patients with a median duration of 73 days. Dose reductions and delays due to ocular AEs occurred in 30% and 2% of patients, respectively, with no discontinuations.
After one year of maintenance, any grade ocular AEs included blurred vision (72.9%), dry eye (56.3%), foreign body sensation (47.9%), and photophobia (43.8%). Grade 3/4 events were also reported. Blurred vision was reported in 26% of patients with a median duration of 110 days. One patient experienced impaired vision that was ongoing at the time of analysis. Dose reductions, delays, and discontinuations due to ocular AEs were required in 54%, 70%, and 4% of patients, respectively.
Any grade and grade 3 or higher hematological AEs affected 56% and 38% of patients, respectively, during the maintenance phase. Other non-hematological AEs included infections (56%), pneumonia (8%), COVID-19 (12%), and skin toxicity (14%).
These results suggest that belantamab mafodotin in combination with VRd is a promising regimen for newly diagnosed, transplant-eligible multiple myeloma patients, offering high response rates and manageable toxicity.
