EHA 2019: Late-breaking abstracts at EHA
Article written by Maria Dalby. Interview by Hannah Chatfield.
Oral selective BCL-2 inhibitor venetoclax has demonstrated encouraging clinical efficacy against MM. As monotherapy, venetoclax has shown to be especially effective in MM patients with t(11;14), whereas combination with bortezomib and dexamethasone has proven effective in a broader MM patient population with acceptable tolerability in phase 1 studies. On the basis of these findings, the clinical development of venetoclax for the treatment of MM has progressed to phase 3.
Dr Shaji Kumar (Mayo Clinic, Rochester, MN, USA) presented the results of the phase 3 BELLINI study which aimed to document the efficacy and safety of combination therapy with venetoclax, bortezomib and dexamethasone (VenBd) versus placebo, bortezomib and dexamethasone alone (PboBd) in patients with relapsed/refractory MM who had received up to three prior lines of therapy. A total of 291 patients were randomised 2:1 to receive either VenBd (n=194) or PboBd (n=97). Bortezomib was given at a dose of 1.3 mg/m2 in 21-day cycles for the first eight cycles and thereafter in 35-day cycles.
The primary endpoint was PFS as assessed by an independent review committee. Key secondary endpoints included overall and deep response rates, OS, and patient-reported outcomes including quality of life. At the clinical data cut-off on 26 November 2018, the primary endpoint analysis showed that the study had met its primary endpoint – median PFS in the VenBd arm was almost twice as long as in the PboBd arm (22.4 months versus 11.9 months; HR=0.63; 95% CI 0.443, 0.897; p=0.010) at a median follow-up time of 18.7 months. Patients treated with VenBd had significantly higher ORR and deep response rates (ORR 82% versus 68%, p=0.008; ≥VGPR 59% versus 36%, p<0.001; ≥CR, 26% versus 5%, p<0.001), and a significantly higher proportion of patients in the VenBd arm achieved MRD negativity at detection levels down to 10-6.
Median OS had not been reached in either treatment arm, but a significant survival benefit could be seen in favour of PboBd. A total of 41 patients (21%) had died in the VenBd arm, compared with 11 patients (11%) in the PboBd arm (HR=2.027; 95% CI 1.042, 3.945; p=0.034). The BELLINI investigators attributed this difference to a higher rate of infectious adverse events and progressive disease in the VenBd arm – out of a total of 14 treatment-emergent deaths (13 in the VenBd arm and one in the PboBd arm), eight deaths were due to infection and three (of which one was the death in the PboBd arm) were due to progressive disease.
However, a planned subgroup analysis showed that in patients with t(11;14), treatment with VenBd achieved the same PFS and response benefit as in the overall study population, but with a trend towards favourable OS as well – among patients with t(11;14), median PFS had not been reached in the VenBd arm compared with 9.5 months in the PbdBd arm (HR=0.110; 95% CI 0.022, 0.560; p=0.002). Median OS had not been reached in either arm – one patient (5%) had died in the VenBd arm versus two (13%) in the PboBd arm, suggesting that VenBd may have a more favourable risk-benefit profile in this MM subset.
Other subgroup analyses indicated that patients with ISS stage III disease, high-risk cytogenetics or low BCL-2 expression had inferior clinical outcomes. Following these results, recruitment for all clinical studies with venetoclax in MM have been put on hold. Future development of venetoclax for MM will focus on the t(11;14) subset of MM patients and use of venetoclax as part of a biomarker-driven approach.