Venclexta Safe and Effective for Certain Multiple Myeloma Patients, Trial Data Show

Venclexta (venetoclax), approved to treat lymphoma and leukemia, may also be promising for multiple myeloma patients who failed at least one prior treatment, particularly those with a common genetic abnormality called t(11;14) or with high levels of the cell survival protein BCL2, data from two studies suggest.

Findings in these studies will soon be presented at the American Society of Hematology (ASH) 2019 Annual Meeting, being held in Orlando, Florida, Dec. 7-10.

Venclexta is a potent selective inhibitor of the B-cell lymphoma-2 (BCL-2) protein that works by preventing cancer cells from over-producing this protein, priming them for programmed cell death. It is being developed and marketed by Genentech and AbbVie.

The treatment is given people with blood cancers like chronic lymphocytic leukemia, small lymphocytic lymphoma, and acute myeloid leukemia. Its benefits for multiple myeloma have been less clear, with patients in a Phase 3 trial experiencing longer times without disease worsening, but poorer survival rates.

The BELLINI trial (NCT02755597) included 291 multiple myeloma patients who failed to adequately respond to one to three prior lines of therapy, and were either sensitive to proteasome inhibitors like Kyprolis (carfilzomib) and Velcade (bortezomib) or had not been given any such therapies.

It was designed to assess the safety and efficacy of Venclexta plus standard Velcade and dexamethasone compared to Velcade and dexamethasone alone as standard care.

That trial reached its primary goal, with patients on the Venclexta combo living a median of 22.4 months without their disease getting worse, compared to 11.5 months in the placebo group. Additionally, significantly more patients in the Venclexta group had any response (84% vs. 70%) or a complete tumor clearance (29% vs. 7%).

A pre-planned safety analysis, however, revealed that the rate of death was significantly higher in the Venclexta group — 21% vs. 12% — which led the U.S. Food and Drug Administration to stop all clinical trials of Venclexta for multiple myeloma patients.

But researchers found a subgroup of multiple myeloma patients in which Venclexta appears to be both safe and effective, and a new Phase 3 trial is now opening (details below).

Details will be presented in the study, “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.”

To determine if some patients were more responsive to Venclexta than others, researchers examined the amount of BCL2 protein — which is Venclexta’s target — and the presence of certain genetic mutations associated with multiple myeloma development, including some translocations.

Many multiple myeloma patients have a type of genetic alteration, called a translocation. Translocations are instances where chromosome segments and their genes change positions within the same chromosome or into another chromosome. The designation t(11;14) means there is a translocation between chromosome 11 and chromosome 14.

The team found two subgroups of patients who lived significantly longer without disease progression and had a trend toward longer survival, although this last measure was not significant in either group.

These were patients with the t(11;14) translocation, and those with high levels of BCL2, as measured by the protein’s RNA levels. Negativity for minimal residual disease — very low levels of myeloma cells that can cause a relapse — was also elevated in these groups of patients.

Many, but not all, patients with the translocation tended to have the highest BCL2 levels. For this reason, researchers created a group that include patients either with the translocation or with high BCL2 levels.

When given Venclexta, this group had a 74% reduction in their risk of disease progression or death compared to placebo, a trend toward longer survival, higher response rates (88% vs. 70%), higher rates of complete response or better (42% vs. 3%), and higher rates of minimal residual disease negativity (19% vs. 0%).

Overall, the findings support that treatment with Venclexta plus Velcade and dexamethasone is of benefit to people with relapsed or refractory multiple myeloma bearing the t(11;14) translocation or with high levels of BCL2, and suggest these as potential biomarkers of response to the Venclexta combination.

The second presentation, “Phase I/II Study Evaluating the Safety and Efficacy of Venetoclax in Combination with Dexamethasone As Targeted Therapy for Patients with t(11;14) Relapsed/Refractory Multiple Myeloma,” also supports the use of a different Venclexta combination in myeloma patients with the t(11;14) translocation.

It will include results from an ongoing Phase 1/2 trial (NCT01794520) assessing the safety and efficacy of Venclexta plus dexamethasone in patients positive for the t(11;14) translocation. The study was conducted in two parts.

First, it enrolled 20 people, all previously treated with a proteasome inhibitor and an immunomodulatory agent, to determine the combination’s safety and behavior inside the body, and to look for early signs of efficacy.

In this part, 65% of patients responded to the combination, including 30% with very good partial responses or better. Patients lived without disease worsening for a median of 12.4 months. The most common treatment-related adverse events reported were insomnia, low phosphate levels, high blood sugar, diarrhea, and low platelet counts.

Part 2 included 31 patients, previously given at least two prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, the CD38 antibody Darzalex (daratumumab), and glucocorticoids.

Here, 45% of patients responded to the combination, including 26% with very good partial responses or better. At the time of the analysis, more than half of patients remained alive and progression free, and more than half of responders were still responding to treatment.

The most common adverse events were diarrhea, nausea, and low lymphocyte numbers. One patient died due to an adverse event.

Given its promising efficacy and tolerable safety, researchers are running a Phase 3 trial — called CANOVA (NCT03539744) — comparing this Venclexta combination to a combination of Pomalyst (pomalidomide) and dexamethasone in advanced multiple myeloma patients with the t(11;14) translocation.

This trial, sponsored by AbbVie, is currently enrolling eligible patients at sites across the U.S., Europe, Australia and Asia. More information is available here.