BELLINI trial of venetoclax paves the way for precision therapy in multiple myeloma
Venetoclax in combination with bortezomib and dexamethasone significantly improved progression-free survival (PFS) and response rates in the BELLINI trial in patients with relapsed/refractory (R/R) multiple myeloma (MM), with even greater benefits seen in patients with t(11;14) translocation or high BCL2 gene expression.
The randomized, double-blind, multicentre phase III trial included 291 patients (median age, 66 years) with R/R MM who had received 1–3 previous therapies. The patients were randomized (2:1) to receive venetoclax (800 mg/day orally) or placebo in combination with bortezomib (1.3 mg/m2 subcutaneously or intravenously) and dexamethasone (20 mg orally), given in 21-day cycles for the first eight cycles and 35-day cycles from the ninth cycle onwards. [Lancet Oncol 2020, doi: 10.1016/S1470-2045(20)30525-8]
After a median follow-up of 18.7 months, the primary endpoint of independent review committee–assessed PFS in the intention-to-treat (ITT) population was 22.4 months in the venetoclax group vs 11.5 months in the placebo group (hazard ratio [HR], 0.63; 95 percent confidence interval [CI], 0.44 to 0.90; p=0.010).
In the ITT population, the overall response rate (ORR) was 82 percent vs 68 percent (p=0.0081) for venetoclax vs placebo, with very good partial response or better (≥VGPR) achieved in 59 percent vs 36 percent (p=0.00029), complete response or better (≥CR) achieved in 26 percent vs 5 percent, and minimal residual disease (MRD) negativity (10-5) achieved in 13 percent vs 1 percent (p=0.00066) of patients.
While median overall survival (OS) was not reached in either group, an unexpected increase mortality was observed with venetoclax vs placebo (21 percent vs 11 percent; HR, 2.03; 95 percent CI, 1.04 to 3.95; p=0.034).
However, a prespecified subgroup analysis demonstrated improved responses and PFS, without increased mortality, in patients with t(11;14) translocation or high BCL2 gene expression treated with the venetoclax-based regimen.
Among 35 patients with t(11;14) translocation (20 in the venetoclax group, 15 in the placebo group), median PFS was not reached with venetoclax vs 9.5 months with placebo (HR, 0.11; 95 percent CI, 0.02 to 0.56; p=0.004). ORR was 90 percent vs 47 percent (p=0.0038), while rates of ≥VGPR and ≥CR were 70 percent vs 27 percent (p=0.016) and 45 percent vs 7 percent, respectively. MRD negativity (10-5) was achieved in 25 percent vs none of the patients (p=0.056).
In 98 patients with high BCL2 gene expression (66 in the venetoclax group, 32 in the placebo group), median PFS was 22.4 months vs 9.9 months (HR, 0.24; 95 percent CI, 0.12 to 0.48; p<0.0001). ORR and rates of ≥VGPR and ≥CR were 85 percent vs 75 percent (p=0.367), 71 percent vs 28 percent (p=0.00013), and 36 percent vs 0 percent (p=0.00024), respectively. MRD negativity (10-5) was achieved in 18 percent vs none of the patients (p=0.025).
The most common grade ≥3 treatment-emergent adverse events (TRAEs) were neutropenia (18 percent for venetoclax vs 7 percent for placebo), pneumonia (16 percent vs 9 percent), thrombocytopenia (15 percent vs 30 percent), anaemia (15 percent vs 15 percent), and diarrhoea (15 percent vs 11 percent). Serious TRAEs occurred in 48 percent vs 50 percent of patients, with treatment-emergent fatal infections reported in 4 percent vs none of the patients in the venetoclax vs placebo group.
According to the investigators, these results highlight the importance of appropriate selection of patients for venetoclax-based treatment.
“The BELLINI study is is paving the way for a new era of precision therapy in MM,” wrote Dr Irene Ghobrial of the Harvard Medical School, Boston, Massachusetts, US, in an editorial. “For venetoclax to truly change the history of MM treatment, the benefit to patients selected by t(11;14) or BCL2 expression needs to be shown in a prospective trial, combined with a companion diagnostic functional study such as BH3 profiling to help identify those who would benefit.” [Lancet Oncol 2020, doi: 10.1016/S1470-2045(20)30587-8]