The addition of venetoclax, an oral selective small-molecule BCL-2 inhibitor, to bortezomib and dexamethasone resulted in impressive response rates in a phase 1b trial of patients with heavily pretreated relapsed or refractory multiple myeloma, said Cyrille Touzeau, MD, of Centre Hospitalier Universitaire de Nantes, France, who presented the trial’s results at ASCO 2016.
The objective response rate (ORR) in this study was higher in patients whose myeloma cells produced greater levels of the BCL-2 protein than those whose cells produced low levels of the protein, Dr Touzeau said.
In April 2016, venetoclax was approved by the US Food and Drug Administration for the treatment of patients with chronic lymphocytic leukemia and the 17p deletion.
Synergy between bortezomib, which inhibits the MCL-1 protein, and venetoclax had previously been demonstrated in xenograft models of multiple myeloma, which provided the rationale for this study.
“Efficacy results indicate antitumor activity of this novel combination, which targets both BCL-2 and MCL-1, and supports the upcoming phase 3 trial with this regimen in patients with relapsed or refractory multiple myeloma,” said Dr Touzeau.
This study included 54 patients with relapsed or refractory multiple myeloma who had received a median of 3 previous lines of therapy (range, 1-15). At the time of enrollment, 37% of the patients had disease resistant to bortezomib. The patients received 50 mg to 1200 mg of venetoclax daily per designated dose escalation, which was combined with bortezomib 1.3 mg/m2 subcutaneously and dexamethasone 20 mg daily orally, for 11 cycles. For cycles 12 and beyond, patients received venetoclax monotherapy until disease progression.
Almost 33% of the patients had high-risk cytogenetics, including 26% of patients with the 17p deletion.
At the time of data analysis, with approximately 5 months of follow-up, 19 patients were still receiving treatment. A total of 35 (65%) patients discontinued treatment, 34 because of disease progression; 5 patients died (4 as a result of disease progression).
The ORR for the entire cohort was 58%, with 24% of the patients achieving a partial response, 16% a very good partial response, 12% a complete response, and 6% a stringent complete response.
“There was a dramatic difference in response according to bortezomib status,” Dr Touzeau said. Patients with bortezomib-refractory disease at the time of enrollment had an ORR of 16% compared with an ORR of 84% in those whose disease was not refractory to bortezomib. Patients with disease that was not refractory to bortezomib had a median duration of response and a median time to progression of approximately 11 months.
The number of previous lines of therapy influenced the outcome. The ORR was highest (91%) in the 23 patients whose disease was not refractory to bortezomib and who received 1 to 3 previous lines of therapy. The median duration of response (16 months) and the median time to progression (11 months) were superior in patients who received 1 to 3 previous therapies compared with more heavily pretreated patients.
BCL-2 gene expression was known in 26 patients at baseline. The ORR in 17 patients with high BCL-2 gene expression was 71% compared with 22% in 9 patients with low BCL-2 expression; therefore, BCL-2 “would be a good biomarker of response,” said Dr Touzeau.
There were no dose-limiting toxicities. The most common side effects of the combination regimen were those expected with a bortezomib-containing regimen, including constipation (37%), diarrhea (37%), nausea (33%), and thrombocytopenia (32%). The majority of gastrointestinal side effects were grade 1 or 2. Grade 3 or 4 thrombocytopenia was reported in 22% of patients. Of the 54 patients in the study, 2 discontinued treatment because of side effects.