Kumar Discusses Path Forward for Venetoclax in Myeloma

Shaji Kumar, MD, a consultant hematologist at the Mayo Clinic

Shaji Kumar, MD

The addition of venetoclax (Venclexta) to the combination of bortezomib (Velcade) plus dexamethasone significantly improved clinical outcomes in patients with relapsed/refractory multiple myeloma in the phase III BELLINI trial, but a venetoclax regimen may be most suited for patients with t(11;14) abnormality or high BCL-2 expression, according to lead investigator Shaji K. Kumar, MD.¹

Although the venetoclax combination met its primary endpoint of improved progression-free survival (PFS), it was associated with an increased risk of death. In March, the FDA suspended enrollment in BELLINI and other multiple myeloma studies in which patients were receiving venetoclax.² The agency lifted a partial clinical hold on the phase III CANOVA study (NCT03539744) evaluating venetoclax plus dexamethasone in patients with the t(11;14) translocation in June.³

The BELLINI findings point to a potential role for venetoclax in subsets of patients with multiple myeloma and illustrate the importance of developing therapies targeted to different types of the malignancy, Kumar said in a presentation during the 17th International Myeloma Workshop (IMW). IMW was held September 12 to 15 in Boston, Massachusetts.

“The results of the BELLINI trial provide us with a blueprint of how we move this drug toward approval for patients who can benefit from it,” Kumar, a hematologist at the Mayo Clinic in Rochester, Minnesota, said in an interview with OncLive. “… Venetoclax is part of an important class of drugs that targets an important pathway in myeloma.”

Venetoclax selectively inhibits BCL-2. During his presentation, Kumar noted that BCL-2, along with MCL-1 and BCL-XL, promotes the survival of multiple myeloma cells.

The BELLINI trial randomized 291 patients who had undergone 1 to 3 prior lines of therapy and who were refractory to a proteasome inhibitor in a 2:1 ratio to receive venetoclax, bortezomib, and dexamethasone or placebo, bortezomib, and dexamethasone.

In the intention-to-treat population, venetoclax demonstrated superior median PFS of 22.4 months versus 11.5 months with placebo (HR, 0.630; 95% CI, 0.443-0.897; P = .010).

Across the board, clinical responses for overall response rate (ORR), very good partial response (VGPR), complete response (CR), and minimal residual disease (MRD) negativity rates were positive for patients receiving venetoclax. ORR was 82% with venetoclax versus 68% with placebo (P = .008). The VGPR was 59% versus 36% (P <.001) in favor of venetoclax and CR was reported as 26% for venetoclax versus 5% for placebo (P <.001). MRD negativity was 13% for patients in the venetoclax arm versus 1% in the placebo arm (P <.001).

However, at the overall survival (OS) interim analysis in November 2018, a higher risk of death was observed in the venetoclax arm compared with placebo for all patients. In an updated analysis in March 2019, 70 deaths were reported: 51 in the venetoclax arm and 19 in the placebo arm (HR, 1.474; 95% CI, 0.870- 2.498; P = .147). In addition, 8 deaths were attributed to infection in the venetoclax arm compared with 0 deaths in the placebo arm.

Subgroup analysis for patients with t(11;14) abnormality showed that median PFS was not reached in the venetoclax group compared with 9.5 months in the placebo group (HR, 0.110; 95% CI, 0.022-0.560; P = .002). Median OS in this subgroup was not reached in either treatment arm (HR, 0.343; 95% CI, 0.031-3.842; P = .363).

For patients identified as BCL-2 high, median PFS was 22.4 months in the venetoclax arm and 10.2 months in the placebo arm (HR, 0.341; 95% CI, 0.146-0.560; P = .011). For both the venetoclax and placebo arms, OS was not reached (HR, 1.114; 95% CI, 0.240-5.179; P = .890) (Table¹).

OncLive: Could you explain your findings from the BELLINI trial?

Kumar: We found a significant increase in the overall response rate, particularly when you look at the complete response rate. There was a significant improvement with the addition of venetoclax to bortezomib and dexamethasone.

We also examined the minimal disease negativity, which was significantly higher, about 13% versus 1%, in patients who received venetoclax versus bortezomib and dexamethasone. This also translated to a better PFS, with significant improvement. Median PFS for patients in the venetoclax arm was 22.4 months compared with 11.5 months in patients who received bortezomib and dexamethasone.

However, we also observed an excess number of deaths in the venetoclax arm, with a total of 51 deaths reported at the last data cut-off. We observed 40 deaths in the venetoclax arm and 11 deaths in the bortezomib and dexamethasone arm. Because of the 2:1 randomization, that translates to twice as often the number of deaths in the venetoclax arm compared with the bortezomib and dexamethasone arm.

What does this increased morbidity suggest?

This clearly demonstrates some kind of deleterious effect from the treatment combination so additional analysis was conducted to better understand what the nature of these deaths were. What we found was the majority of these deaths in the venetoclax arm was related to progression, especially progression in the context of disease progression.

When we conducted a preplanned subgroup analysis, we found that if we looked at patients with only the t(11;14) abnormality, which was 35 patients in total, 20 in the venetoclax arm and 15 in the bortezomib and dexamethasone arm, there was no excess deaths in patients receiving venetoclax observed in that subgroup of patients. More importantly, there was a significant improvement in PFS which was not reached versus approximately 9 months for patients who received bortezomib and dexamethasone. This translated to a hazard ratio of 0.11.

Similarly, we also looked at the patients with a high BCL2 expression. The BCL2 expression was defined using a quantitate PCR methodology. When we looked at the 62 patients with high BCL2 expression, 43 received venetoclax, there was significant improvement in the PFS, 22.4 months versus 10 months. Again, we did not observe an increase or excess mortality in patients receiving venetoclax when looking at patients in this subgroup.

Our conclusion is that venetoclax certainly has activity and efficacy in patients with t(11;14) in combination with bortezomib and dexamethasone without a significant effect on survival or increased mortality. We found a similar benefit in patients with a high BCL2 expression, determined by quantitative BCR, in patients who received the combination of venetoclax plus bortezomib and dexamethasone, however, this is not something we can translate to the clinic today because there is no validated assay to determine BCL2 expression or to identify appropriate cut points. That biomarker is currently being developed for ongoing and future trials.

Is there ongoing research to explore this subpopulation?

Clearly, there seems to be a subgroup of patients who don’t benefit and may be harmed by the use of venetoclax particularly in combination with bortezomib and dexamethasone. Those appear to be the patients with low BCL2 expression or high-risk cytogenetics.

The CANOVA trial [NCT03539744] is looking at randomizing patients with the t(11;14) abnormality with relapsed myeloma to either venetoclax and dexamethasone or pomalidomide [Pomalyst] and dexamethasone. That will hopefully provide us with the information that we need to get a drug approval in the setting of t(11;14)-positive myeloma.

Does venetoclax improve PFS for patients with myeloma?

The answer is yes in patients with a t(11;14)-positive mutation and patients with high BCL2 expression, which represents roughly 50% of patients with myeloma. There is a potential role for this drug. So the ongoing trials are trying to identify exactly which subgroup of patients benefit, what combination delivers a benefit, and how much benefit does it convey. But at the same time, these trials give us the opportunity to understand the biology of the disease and find out why a subgroup of patients did not benefit.

What is the contribution of your results to our understanding of multiple myeloma?

The results contribute greatly to our understanding of the disease biology for two reasons. One, we need new treatments. The results of the BELLINI trial provides us with a blueprint of how we move this drug forward towards approval for patients who can benefit from it. The second reason is that venetoclax is part of an important class of drugs that targets an important pathway in myeloma.

The trial gives us a starting point for additional work to understand how inhibition of this BCL2 family of proteins, whether it’s venetoclax for BCL2 or some of the newer drugs against MCL1. How will it affect the different types of myeloma? We have been explaining, for the longest time, that myeloma is not 1 disease. We have multiple diseases based on the makeup of the genetic abnormality.

Table. Key Findings in the Bellini Trial

So it’s quite likely that this is a drug for a subgroup of patients with myeloma. The results help move the paradigm of thinking about multiple myeloma as different diseases with different treatments.

References

1. Kumar SK, Harrison SJ, Cavo M, et al. A phase 3 study of venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma. Presented at: International Myeloma Workshop Scientific Program; September 12-16, 2019; Boston, MA. Abstract OAB-045.
2. FDA warns about the risks associated with the investigational use of Venclexta in multiple myeloma. FDA website. www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-risks-associated-investigational-use-venclexta-multiple-myeloma. Published March 21, 2019. Accessed September 16, 2019.
3. AbbVie announces US FDA lifts partial clinical hold on phase 3 study of venetoclax in patients with multiple myeloma positive for the t(11;14) genetic abnormality. North Chicago, IL: AbbVie; June 24, 2019. news.abbvie.com/news/press-releases/abbvie-announces-us-fda-lifts-partial-clinical-hold-on-phase-3-study-venetoclax-in-patients-with-multiple-myeloma-positive-for-t1114-genetic-abnormality.htm. Accessed September 16, 2019.