Recent research shows that a biomarker-driven approach to treating multiple myeloma patients with venetoclax may be best fit. This work was presented by Dr. Shaji Kumar of the Mayo Clinic in Rochester at the 24th Congress of the European Hematology Association in Amsterdam on June 15.
As the second most common cancer of the blood, multiple myeloma poses a prominent threat to public health. Though there are several treatments available for the condition, no therapies are effective in curing the disease. For this reason, emphasis has been placed upon the identification and targeting of biological pathways that are unique to multiple myeloma.
Changes in apoptotic pathways are commonly found in cancers, with proteins like those of the Bcl2 family playing an important role in regulating apoptosis (programmed cell death). Bcl2 inhibitors like venetoclax function to induce apoptosis in cancer cells that depend on Bcl2 presence to survive. Venetoclax is currently being used to treat chronic lymphocytic leukemia (CLL), however these researchers hypothesized that alongside existing treatments, the drug could potentially treat myeloma as well.
Based on preclinical trials regarding venetoclax’s ability to induce apoptosis in myeloma cells, phase 1 and 2 trials using venetoclax alone or in complex with dexamethasone or bortezomib have been carried out in humans with success. This efficacy was most pronounced in patients with translocation t(11;14) in the myeloma cells.
To expand upon these findings, Kumar and colleagues conducted a phase 3 clinical trial with venetoclax. This study was a randomized, double-blind multicenter trial, that involved 291 pretreated patients with relapsed or refractory multiple myeloma who were also sensitive/naïve to treatment with proteasome inhibitors. They were assigned to either receive venetoclax (800 mg/d) or to a control group. Both groups received treatment with bortezomib/dexamethasone and the primary endpoint was progression-free survival in the patients.
The researchers found that the median progression-free survival was 22.4 months in those treated with venetoclax, compared to 11.5 months in those treated only with bortezomib/dexamethasone (hazard ratio=0.630, P=0.01). Overall response rates for the venetoclax and control groups were 82% and 68%, respectively. In addition, very good partial or better response rate was found to be 59% and 36% in the two groups, and undetectable minimal residual disease rate 13% and 1%.
The median duration of response was 12.8 months in the control group and was not reached yet in the venetoclax group. Median overall survival wasn’t achieved yet in either group but favored the control group upon evaluation. Analyses of subgroups showed low Bcl-2 expression was associated with decreased progression-free survival and overall survival in the treatment group.
The researchers also observed 51 deaths in the participant population, 40 of which in the venetoclax group and only 11 in the control group. Most of these deaths were due to progressive disease. Only 1 treatment-emergent death was recorded in the control group, compared to 14 in the treatment group.
The authors concluded that although the addition of venetoclax to bortezomib/dexamethasone treatment significantly improved progression-free survival, overall response rate, very good partial or better response, and undetectable minimal residual disease rates, the increased chance of death with this treatment presents an unfavorable risk-benefit profile. They note that the addition of venetoclax treatment in t(11;14) patients improved progression-free survival and showed a positive trend in overall survival. These results suggest that a biomarker-driven approach with venetoclax may be the best treatment route for those with multiple myeloma.
— VJHemOnc (@VJHemOnc) June 15, 2019