Can Biomarkers Predict Myeloma Patients’ Response to Venetoclax?

In an analysis of the phase III BELLINI trial, researchers identified 2 biomarkers that predict response to venetoclax in patients with relapsed/refractory multiple myeloma (MM): t(11;14) and high BCL2 expression. These results were presented by Simon Harrison, MBBS, PhD, from the Peter MacCallum Cancer Centre in Melbourne, Australia, at the 2019 ASH Annual Meeting.

The randomized, double-blind, multicenter BELLINI study compared outcomes between patients treated with bortezomib and dexamethasone (Bd) with or without venetoclax (V+Bd). All participants had received 1 to 3 prior therapies and had proteasome inhibitor-sensitive or -naïve disease. Findings showed that treatment with V+Bd improved clinical response rates and progression-free survival (PFS) compared with Bd therapy. Subgroup analyses of the trial also revealed differing efficacy and survival outcomes according to tumor cytogenetics and BCL2 expression.

In this report, Dr. Harrison and investigators analyzed participants’ pretreatment tumor samples for BCL2 protein expression by immunohistochemistry (IHC) analysis of bone marrow biopsies, BCL2 gene expression by quantitative polymerase chain reaction (qPCR), and cytogenetic abnormalities by interphase fluorescence in situ hybridization (FISH) analysis of CD138-enriched bone marrow mononuclear cells.

A total of 291 participants were enrolled in the trial and randomized 2:1 to V+Bd and Bd (194 in the V+Bd arm and 97 in the Bd arm). Of those, 177 patients were evaluable by IHC (61%), 257 by qPCR (88%), and 262 by FISH (90%). Patient characteristics were well balanced between the 2 arms, with similar proportions of patients having high-risk cytogenetics, t(11;14)-positive disease, and high BCL2 expression.

Researchers observed a broad range of BCL2 gene expression, which strongly correlated with BCL2 protein expression. Patients with t(11;14)-positive MM had the highest levels of BCL2 expression among cytogenetic groups. However, high BCL2 expression was not limited to patients with the t(11;14) biomarker, the authors noted. In univariate analyses, for example, higher BCL2 expression was also associated with presence of del13q or gain1q.

Based on these findings, the researchers identified a threshold value for BCL2 expression that could guide selection of patients likely to experience the maximum survival improvement with V+Bd.

As of data cutoff (July 15, 2019), researchers observed “a continuing PFS advantage, with basically a doubling of the median PFS in favor of the venetoclax combination,” Dr. Harrison reported. “Unfortunately, this hasn’t driven an overall survival (OS) benefit because of increased toxicity associated with the venetoclax combination.”

Looking across key biomarker subgroups to determine which patients had the greatest improvement in PFS, the investigators found a significant PFS advantage with the V+Bd combination in patients with the following characteristics (compared with those whose disease was negative for the biomarkers):

  • t(11;14): hazard ratio (HR) = 0.09 (95% CI 0.02-0.44; p=0.003)
  • high BCL2 expression: HR=0.32 (95% CI 0.17-0.59; p<0.001)

This association was also seen in the OS analysis, Dr. Harrison added.

Next, the authors performed a combined subgroup analysis of patients with t(11;14) and high BCL2, compared with those without either biomarker. Again, they found that the presence of these biomarkers led to a PFS advantage with venetoclax treatment, but not with Bd plus placebo (not reached vs. 9.9 months; HR=0.26; 95% CI 0.14-0.48; p<0.001).

Overall, patients receiving V+Bd had a better response to therapy (see TABLE), including a higher rate of measurable residual disease–negativity among those with the t(11;14) or BCL2 biomarkers treated with V+Bd.

The researchers said additional studies are needed to gain further safety and efficacy information on this treatment combination, adding that these data support biomarker-selected trials in patients with either t(11,14) or high BLC2 expression.

Study authors report relationships with AbbVie and Genentech, which sponsored the BELLINI trial.

Reference

Harrison S, Cavo M, De La Rubia J, et al. T(11;14) and high BCL2 expression are predictive biomarkers of response to venetoclax in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma: biomarker analyses from the phase 3 Bellini study. Abstract 142. Presented at the 2019 American Society of Hematology Annual Meeting, December 7, 2019; Orlando, Florida.