Venetoclax may be of benefit to MM patients with t(11;14) translocation
New data from the suspended BELLINI study suggest that venetoclax may be of benefit to a subgroup of patients with relapsed/refractory multiple myeloma (R/R MM) with the t(11;14) translocation.
These results, reported after previous findings of an increased mortality risk with venetoclax in the overall population (n=291) that led to suspension of the trial, suggest that a biomarker-driven approach to the use of venetoclax may be the most appropriate in MM, the BELLINI investigators noted. [Kumar S, et al, EHA 2019, abstract LB2601]
The new data, based on a median follow-up of 18.7 months, showed a median progression-free survival (PFS) of 22.4 months in patients randomized to receive venetoclax in combination with bortezomib and dexamethasone (Bd) (n=194) vs 11.5 months in those receiving placebo plus Bd (n=97) (hazard ratio [HR], 0.63; 95 percent confidence interval [CI], 0.443 to 0.897; p=0.01).
“The overall response rate [ORR] was 82 percent in the venetoclax arm vs 68 percent in the placebo arm,” reported investigator Dr Shaji Kumar of the Mayo Clinic, Rochester, Minnesota, US. “Complete response or better [≥CR] was achieved by 26 percent of patients in the venetoclax arm vs 5 percent of those in the placebo arm. Rates of very good partial response or better [≥VGPR] and minimal residual disease [MRD] negativity were also higher in the venetoclax vs placebo arm, being 59 percent vs 36 percent and 13 percent vs 1 percent, respectively.”
The median duration of response was not reached in the venetoclax arm compared with 12.8 months in the placebo arm.
Although median overall survival (OS) had not been reached in either arm in the overall study population, the data reported at EHA 2019 was in favour of placebo (HR, 2.027; 95 percent CI, 1.042 to 3.945).
Among 51 deaths in the safety population, 40 (21 percent) occurred in the venetoclax arm and 11 (12 percent) were in the placebo arm, with progressive disease (PD) being the most common cause of death (40 percent in the venetoclax arm vs 64 percent in the placebo arm). Of the 14 cases of treatment-emergent death (occurring on treatment or within 30 days from the last dose), 13 occurred in the venetoclax arm (eight due to infection, two due to PD) and one occurred in the placebo arm.
“Patients with the t(11;14) translocation appeared to have the most benefit and lowest risk from venetoclax treatment,” said Kumar.
In the 35 patients with t(11;14) R/R MM, median PFS was not reached in those treated with venetoclax plus Bd compared with 9.5 months in those receiving placebo plus Bd (HR, 0.110; 95 percent CI, 0.022 to 0.560; p=0.002).
“The ORR was 90 percent among t(11;14) patients in the venetoclax arm compared with 47 percent in the placebo arm. Rates of ≥VGPR and MRD negativity were 70 percent vs 27 percent and 25 percent, respectively,” said Kumar.
“Importantly, there was no significant difference in mortality risk between the venetoclax and placebo arms in patients with t(11;14) translocation,” he continued. “The HR for OS in these patients was 0.343 [95 percent CI, 0.031 to 3.842; p=0.36], with one death reported in the venetoclax arm vs two deaths in the placebo arm.”
The phase III BELLINI study was conducted in patients (median age, 66 years) with R/R MM who had received 1–3 prior lines of therapies and were either sensitive or naïve to proteasome inhibitors. The primary endpoint was PFS.
At baseline, 53 percent of patients had International Staging System (ISS) stage II/III disease, 54 percent had received 2–3 prior lines of therapy, and 59 percent had undergone prior stem cell transplantation. In terms of prior drug treatment, 70 percent had received proteasome inhibitor therapy, 68 percent had received immunomodulatory drugs, and 41 percent had received both. Eighteen percent of the patients had high-risk cytogenetics.
The most common grade 3/4 treatment-emergent adverse events (TRAEs) in the safety population were neutropenia (18 percent for venetoclax vs 7 percent for placebo), pneumonia (16 percent vs 9 percent), thrombocytopenia (15 percent vs 30 percent), and anaemia (15 percent vs 15 percent). The rate of treatment discontinuation due to TRAEs was 16 percent vs 8 percent, while rates of serious AEs (48 percent vs 50 percent) and serious infections (28 percent vs 27 percent) were comparable between the treatment arms.