Venetoclax Highly Effective With Bortezomib/Dexamethasone for Multiple Myeloma

Philippe Moreau, MD

Adding venetoclax (Venclexta) to bortezomib (Velcade) and dexamethasone showed very promising efficacy and acceptable safety for patients with relapsed/refractory multiple myeloma, according to findings presented at the 2016 ASH Annual Meeting.

The triplet was especially effective in bortezomib non-refractory patients pretreated with 1 to 3 prior lines of therapy (n = 30), in whom the overall response rate (ORR) was 97%, according to data from the phase Ib study. The stringent complete response (sCR) in this group was 10%, the CR rate was 23%, and the very good partial response (VGPR) was 41%. Across the full study, which included refractory patients (N = 66), the ORR was 67%.

“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,” said lead investigator Philippe Moreau, MD.

Venetoclax is an orally available small molecule inhibitor of BCL-2 that also enhances the activity of bortezomib, an indirect inhibitor of MCL-1, in vitro and in vivo. In the study, patients with high BCL-2 gene expression had higher response rates than those with low expression, said Moreau, from the Department of Hematology, Nantes University Hospital, Nantes, France..

“There is strong rationale to combine venetoclax with bortezomib in order to induce apoptosis,” he said. “Anti-myeloma activity observed with this new treatment combination both BCL-2 and MCL-1 supports the ongoing phase III clinical trial that is currently enrolling patients, very fast, comparing bortezomib/dexamethasone versus bortezomib/dexamethasone plus venetoclax.”

The open-label phase Ib dose-escalation study enrolled a total of 66 patients with previously treated multiple myeloma. Patient shad an ECOG performance status was 0 or 1, adequate organ function as indicated by creatinine clearance ≥30 mL/min, and normal bone marrow measures.

Fifty-four patients received bortezomib and dexamethasone with daily venetoclax, starting at 50 mg and increased to 1,200 mg. Twelve patients in an expansion cohort received a dose of 800 mg of venetoclax. Of the 66 patients enrolled, 39% were refractory to prior bortezomib, 53% were refractory to prior lenalidomide, and 61% were refractory to their last line of treatment.

Median time to progression (TTP) among bortezomib non-refractory patients was 11.3 months. Among bortezomib refractory patients, the TTP was a median of 1.8 months. The median duration of response was also higher in patients not refractory to bortezomib, at 18 months, compared with a median of 4 months in bortezomib-refractory patients. Median TTP was 11.6 months for patients treated with 1 to 3 prior lines of therapy compared with 4.3 months for patients treated with more than 3 lines of prior treatment. The duration of response was 11 versus 5 months, respectively, in these 2 groups.

Among patients treated with 1 to 3 prior lines of treatment (n = 37), the ORR was 89%. The VGPR or better was 65%. In those sensitive to bortezomib (n = 27), the ORR was 89% and the VGPR or better was 56%. In treatment-naïve patients (n = 12), the ORR was 92%, including 84% with at least a VGPR.

The ORR was higher in patients with high BCL-2 gene expression versus low expression (94% vs 59%), and the TTP was also higher among patients with high BCL-2 gene expression.

As a monotherapy, venetoclax showed an ORR of 40% for patients with t(11:14) heavily pretreated myeloma. The VGPR or better rate was 27%. In those with non-t(11;14) myeloma, the ORR with single-agent venetoclax was 6%.

“We have now some data indicating that maybe we can find some biomarkers that could help in the definition of a subgroup of patients that will benefit most from this combination,” said Moreau, referring to data for venetoclax monotherapy in patients with t(11;14). “In the current phase III study, we are looking at a number of biomarkers to try to identify this subgroup of patients that could benefit from venetoclax in combination with a proteasome inhibitor.”

Any grade toxicity and grade 3/4 adverse events were mostly related to bortezomib and dexamethasone. At the maximum venetoclax dose of 1,200 mg, the maximum tolerated dose was not reached, with the decision to use 800 mg in the expansion phase made based on pharmacokinetic data.

“The addition of venetoclax to bortezomib and dexamethasone did not appear to add any toxicity…no tumor lysis syndrome was observed; it was overall very well-tolerated,” said Moreau.

The phase III study is examining venetoclax plus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma who are considered sensitive or naïve to proteasome inhibitors and received 1 to 3 prior lines of therapy for multiple myeloma. The primary endpoint of the study is progression-free survival, and the study continues to enroll participants (NCT02755597).

Moreau P, Chanan-Khan AA, Roberts AW, et al. Venetoclax combined with bortezomib and dexamethasone for patients with relapsed/refractory multiple myeloma. Presented at: American Society of Hematology 58^th Annual Meeting; December 3-6, 2016; San Diego, CA. Abstract 975.

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Thirty percent of the patients were still receiving the combination at data cut-off of August 19, 2016. Seventy percent of patients discontinued the combination, primarily due to disease progression (56%) and adverse events (6%). Five patients died; 4 due to disease progression and 1 due to viral infection.

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