Alterations in the apoptotic pathway play a major role in the disease biology of plasma cell neoplasms, including multiple myeloma. Preclinical work has demonstrated that inhibition of anti-apoptotic Bcl-2 family members using a variety of different mechanisms can result in myeloma cell death.
Venetoclax is a highly specific, small molecule inhibitor of Bcl-2 protein, which has demonstrated efficacy in other hematologic malignancies, such as chronic lymphocytic leukaemia, where it is currently approved for clinical use. Laboratory evaluation had previously shown that venetoclax can induce cytotoxicity in myeloma cell lines and in primary myeloma cells; also, it can synergize with dexamethasone as well as proteasome inhibitors, such as bortezomib. Based on these data, initial phase 1 and 2 clinical trials were performed with venetoclax alone and in combination with bortezomib.
Based on the promising results, a phase 3 trial, Bellini, was designed to evaluate the efficacy and toxicity of adding venetoclax to a combination of bortezomib and dexamethasone. The clinical trial accrued 291 patients with relapsed or refractory multiple myeloma who had previously received 1–3 lines of therapy and were not refractory to bortezomib.
At the first interim analysis, the addition of venetoclax significantly improved the progression-free survival compared to using bortezomib and dexamethasone alone, with a near doubling of progression-free survival from 11.5 months to 22.4 months. With the addition of venetoclax, there was a higher overall response rate as well as deeper responses, which were demonstrated by higher rates of complete response and minimal residual disease negativity.
Specifically looking at the subgroups of patients, it was clear that patients with translocation t(11;14) had the maximum benefit, while patients with high-risk disease – as indicated by the presence of high-risk genetic abnormalities or ISS stage III – did not derive as much benefit. In addition, Bcl-2 expression was evaluated in a subset of the patients using immunohistochemistry, which demonstrated a reduced efficacy in patients who had lower levels of Bcl-2 expression. However, there was an unexpected increase in the numbers of deaths noted in the venetoclax arm leading to an inferior overall survival for the experimental arm. However, the overall rates of toxicity were similar between the two clinical trial arms. On further assessment of the data, it was clear that the increased deaths observed in the experimental arm were mostly related to infection – many of which occurred in the context of disease progression with or without subsequent therapy. Most of these excess deaths seen in the experimental arm occurred during the first 6 months of the clinical trial.
From the analysis, it appears that patients with high-risk myeloma and those with a low expression of Bcl-2 – who are the patients least likely to derive benefit in terms of disease control with the addition of venetoclax – are at the highest risk of dying. In contrast, patients with t(11;14) appear to derive the maximum benefit with significant improvement in progression-free survival with no deleterious effect on overall survival.
Patients on the clinical trial continue to be followed up, and updated survival analysis will be available in the future. Meanwhile, the ongoing clinical trials will focus on better delineating the role of venetoclax in patients with t(11;14) and the identification of appropriate partner drugs for combinations in patients outside of this subgroup.