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Addition of Bcl-2 Inhibitor to MM Regimen Produces Promising Responses in Relapsed/Refractory MM

CyrilleTouzeau98pxVenetoclax, an investigational oral selective small molecule Bcl-2 inhibitor, added to bortezomib and dexamethasone resulted in impressive response rates in a phase 1b trial of patients with heavily pretreated relapsed/refractory (RR) multiple myeloma (MM).

In the trial, the objective response rate (ORR) was higher among patients whose myeloma cells produced higher levels of the Bcl-2 protein compared with those whose cells produced low levels of the protein, said Cyrille Touzeau, MD.

Synergy between bortezomib, which inhibits Mcl-1, and venetoclax had previously been demonstrated in xenograft models of MM, providing 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 RRMM,” said Dr Touzeau, from CHU de Nantes, Hospital Dieu, Nantes, France.

In April 2016, venetoclax was approved by the FDA for the treatment of chronic lymphocytic leukemia with 17p deletion.

The phase 1b study included 54 patients with RRMM who had received a median of 3 prior lines of therapy, ranging from 1 to 15. Thirty-seven percent had developed resistance to bortezomib at the time of enrollment. Patients were treated with daily venetoclax, 50 to 1200 mg/day per designated dose escalation, combined with bortezomib 1.3 mg/m2 subcutaneously and dexamethasone 20 mg/day orally for 11 cycles. For cycle 12 and beyond, patients received venetoclax monotherapy until disease progression.

Almost one-third of the patients had high-risk cytogenetics, including 26% of patients with 17p deletion.

At the time of data analysis, with approximately 5 months of follow-up, 19 patients were still on treatment. Thirty-five (65%) discontinued treatment, 34 because of disease progression. Five patients died, 4 because of disease progression.

The ORR for the entire cohort was 58%, with 24% achieving a partial response as best 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,” said Dr Touzeau. Patients with bortezomib-refractory disease at the time of enrollment had an ORR of 16%, compared with an ORR of 84% in those who were not refractory to bortezomib. Patients not refractory to bortezomib had a median time to progression of about 11 months.

The number of prior lines of therapy was found to influence the outcome. The ORR was highest (91%) in the 23 patients not refractory to bortezomib who received 1 to 3 prior lines of therapy. Median duration of response (16 months) and median time to progression (11 months) were both superior in patients who received 1 to 3 prior lines of therapy compared with more heavily pretreated patients.

Bcl-2 expression was provided in 26 patients at baseline. The ORR in 17 patients with a high level of Bcl-2 expression was 71% compared with 22% in 9 patients with low Bcl-2 expression and therefore “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: constipation (37%), diarrhea (37%), nausea (33%), and thrombocytopenia (32%). The vast majority of the gastrointestinal side effects were grade 1 or 2. Grade 3/4 thrombocytopenia was reported in 22%. Two of the 54 patients discontinued treatment because of side effects.

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