San Diego, CA—The addition of venetoclax (Venclexta) to bortezomib (Velcade) and dexamethasone yields high response rates in patients with relapsed or refractory multiple myeloma, especially in patients with disease that is not refractory to bortezomib and who received 1 to 3 previous lines of therapy, according to findings presented by Philippe Moreau, MD, Department of Hematology, Nantes University Hospital, France, at the 2016 American Society of Hematology meeting.
In this phase 1b dose-escalation study, the overall response rate (ORR) with the triplet therapy was 97%. Patients with high BCL-2 gene expression had greater response rates than patients with low BCL-2 gene expression, said Dr Moreau.
The rationale to add venetoclax to bortezomib is strong, because venetoclax, a BCL-2 inhibitor, has been shown to enhance the activity of bortezomib, an indirect inhibitor of MCL-1, in vitro and in vivo, Dr Moreau added.
“Anti-myeloma activity observed with this new treatment combination of both BCL-2 and MCL-1 supports the ongoing phase 3 clinical trial that is currently enrolling patients, very fast, comparing bortezomib and dexamethasone versus bortezomib and dexamethasone plus venetoclax,” Dr Moreau said.
Venetoclax plus Bortezomib and Dexamethasone
In this dose-escalation study involving 66 patients with previously treated multiple myeloma and adequate organ function, 54 patients received venetoclax, starting at 50 mg daily and increasing to 1200 mg daily, plus bortezomib and dexamethasone; and 12 patients in an expansion cohort received venetoclax 800 mg daily. Of the 66 patients, 39% had disease refractory to previous bortezomib therapy, 53% had disease refractory to previous lenalidomide therapy, and 61% had disease refractory to their last line of treatment.
Approximately 37% of patients were still receiving the combination therapy at the data cutoff date (August 19, 2016). Of the 70% of patients who discontinued treatment, the primary reason (56%) was attributed to disease progression.
The ORR was 67% for all evaluable patients, but reached 90% in patients with disease that was not refractory to bortezomib, including 36% of patients with at least a very good partial response. In patients who were naïve to bortezomib therapy, the ORR was 92%, including 84% with at least a very good partial response.
“Importantly, 31% of the patients that were bortezomib refractory at the time of study entry were able to respond to the treatment combination, and this is a proof of concept that venetoclax is able to overcome bortezomib resistance,” Dr Moreau said.
In patients with disease that was not refractory to bortezomib at study entry who received 1 to 3 previous treatments, the ORR was 97%, including 74% with at least a very good partial response.
The median time to disease progression in patients with disease not refractory to bortezomib was 11.3 months versus 1.8 months in patients with refractory disease. The median duration of response was also higher, as expected, in patients with disease not refractory to bortezomib than in patients with refractory disease (18 months vs 4 months, respectively).
The median time to disease progression was 11.6 months in patients who received 1 to 3 lines of therapy compared with 4.3 months in patients who received more than 3 lines of therapy; the duration of response was 11 months and 5 months, respectively.
In patients with high BCL-2 expression, the ORR was 94% compared with 59% in patients with low BCL-2 expression.
When considered with other data showing high venetoclax activity as monotherapy in patients with a translocation between chromosome 11 and chromosome 14, “we have now some data indicating that maybe we can find some biomarkers that could help in the definition of a subgroup of patients who will benefit most from this combination,” said Dr Moreau.