Phase III Study With Venetoclax Combo Identifies New Biomarker for Relapsed/Refractory Myeloma

Simon Harrison, MBBS, MRCP, FRCPath, FRACP, PhD

Simon Harrison, MBBS, MRCP, FRCPath, FRACP, PhD

The phase III BELLINI trial (NCT02755597) demonstrated translocation(t)(11;14) and high BCL2gene expression are predictive of response to treatment with the addition of venetoclax (Venclexta) to bortezomib (Velcade) plus dexamethasone in patients with relapsed/refractory multiple myeloma, according to the findings presented at the 2019 American Society of Hematology (ASH) Annual Meeting.

Moreover, the triplet regimen led to promising response rates in patients with relapsed/refractory myeloma. The objective response rate (ORR) in the overall population of patients with the addition of venetoclax was 84% versus 70% with placebo. In the venetoclax arm, 61% of patients achieved a very good partial response (VGPR) or better, 29% achieved a complete response (CR) or better, and 13% of patients achieved minimal residual disease (MRD)-negativity versus 40%, 7%, and 1% in the placebo arm, respectively.

In the t(11;14) subgroup, venetoclax induced a 95% ORR, including a ≥VGPR of 75% of patients, a ≥CR of 55%, and MRD-negativity in 25% versus 47%, 27%, 7%, and 0% with placebo, respectively. The ORR in patients with highBCL2was 88% with venetoclax, including a ≥VGPR of 76%, a ≥CR of 41%, and MRD-negativity in 18% versus 75%, 31%, 0%, and 0% in the placebo arm, respectively.

In terms of progression-free survival (PFS), the greatest improvements were seen in patients with t(11;14) (HR=0.10; 95% CI: 0.02-0.46,P= .003) and high&nbsp;BCL2gene expression by quantitative PCR (qPCR). (HR=0.26; 95% CI: 0.13-0.51,&nbsp;P< .001). In a combined subgroup analysis of these 2 groups of patients, the median PFS was not reached in the venetoclax arm compared with 9.9 months with placebo (HR=0.26, 95% CI: 0.14-0.48,&nbsp;P< .001).

Median overall survival (OS) had not yet been reached in either arm, but OS was similar between treatment arms for the combined group of patients with t(11;14) and highBCL2(HR=0.92, 95% CI: 0.36-2.16,&nbsp;P= .85). However, in patients who were t(11;14)-negative and low&nbsp;BLC2, OS favored placebo over venetoclax (HR=3.12, 95% CI: 1.2-8.13,P= .019). The ORR in the combined subgroup of patients was 88% with venetoclax versus 70% with&nbsp;placebo[MOU1].

&ldquo;Adding venetoclax to [bortezomib plus dexamethasone] demonstrates significant efficacy in pts with RRMM harboring either t(11;14) or tumor cells expressing high levels of BCL2,&rdquo; study authors, led by Simon Harrison, MBBS, MRCP, FRCPath, FRACP, PhD, director of the Centre of Excellence in Cellular Immunotherapy at Peter MacCallum Cancer Centre, wrote. &ldquo;The benefit-risk profile appears to be favorable in these subsets of pts and additional studies to gain further safety and efficacy information are warranted.&rdquo;

The randomized double-blind, multicenter phase III BELLINI trial evaluated the efficacy of adding venetoclax to bortezomib plus dexamethasone compared with placebo and bortezomib plus dexamethasone in patients who received 1 to 3 prior lines of therapy and were either sensitive or na&iuml;ve to proteasome inhibitors (PIs). Patients were randomized to receive either venetoclax at 800 mg/day or placebo in addition to standard bortezomib anddexamethasone[MOU2]. The primary end point was PFS.

Biomarker analyses were conducted by cytogenetics by interphase fluorescence in situ hybridization (FISH) and BCL-2 protein expression by immunohistochemistry (IHC) analysis of bone marrow core biopsies. Two particular subgroups noted in the BELLINI trial included t(11;14) and highBCL2gene expression by qPCR. There was an additional subgroup analysis on overlapping patients between these 2 populations, in which 20% of patients with high&nbsp;BCL2were also t(11;14) and 54% of t(11;14) were high&nbsp;BCL2.

To be included in the trial, patients had to have an Eastern Cooperative Oncology Group (ECOG) performance score of 2 or lower and have documented relapse or progressive multiple myeloma on or after any regimen or be refractory to the most recent line of therapy. Patients also had to have received 1 to 3 prior lines of therapy, which could include prior bortezomib or another PI. However, patents were not included if they became refractory to a prior PI, received a PI treatment within 60 days of the first dose of the study drug. They also could not have received a prior allogenic stem cell transplant, among other criteria.

As of the data cut-off of March 18, 2019, 291 patients were randomized to either the venetoclax arm (n = 194) or placebo (n = 97). Overall, 177 patients were evaluable by IHC, 257 by qPCR, and 262 by FISH.

According to Harrison, who&nbsp;presented the phase III Bellini&nbsp;study results during ASH, cell survival is promoted by overexpression of BCL-2 protein in multiple myeloma. Venetoclax is a highly selective and potent oral BCL-2 inhibitor, which can induce apoptosis and has synergistic activity with bortezomib plus dexamethasone. Previous phase I data demonstrated encouraging clinical efficacy with the triplet regimen in patients with t(11;14) multiple myeloma, as well as in a broader population of patients with myeloma.

Reference:

Harrison S, Cavo M, De La Rubia J, et al. 142 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. Presented at: 2019 American Society of Hematology Annual Meeting & Exposition; December 7-10, 2019; Orlando, FL.