The BCL-2 inhibitor venetoclax is the first such inhibitor to target a particular translocation. In early studies, it was tested in myeloma patients with a variety of myeloma genetics and was found to have the greatest impact for those patients with the 11;14 translocation.
An early Phase I clinical trial has now shown the safety of a 1200 mg/day dose of venetoclax for relapsed/refractory patients, according to a recent article in Blood
. Responses occurred predominently in t(11;14) patients and those with a favorable genetic profile.
Time to progression was also evaluated. Those with no t(11;14) had a median time to progression of 1.9 months while the t(11;14) patients had a median time to progression of 6.6 months. Both groups had a median duration of response of 9.7 months.
“The oral BCL-2 inhibitor venetoclax at a daily dose up to 1,200 mg demonstrated single-agent anti-myeloma activity in patients with relapsed/refractory multiple myeloma positive for t(11;14), for whom multiple prior lines of therapy have failed,” wrote Shaji Kumar, MD, of the Mayo Clinic in Rochester, Minnesota, and colleagues. “Venetoclax has a unique mechanism of action and may offer a novel biologic-driven approach in multiple myeloma.”
The study involved 30 patients who received venetoclax monotherapy at either 300-, 600-, 900-, or 1,200-mg doses. All patients had a 2-week lead-in with weekly dose escalation. Thirty patients participated in the dose-escalation cohorts, and 36 participated in the 1,200-mg safety expansion cohort. The median age of patients was 63 years.
Patients had received approximalty five prior lines of therapy. The overall response rate for all patients was 21% while the t(11;14) was an overall response rate of 40%.
Prior number of therapies didn't seem to affect the response to venetoclax for t(11;14) patients. The overall response rate was 22% in patients with one to three prior therapies compared with 48% in patients who had four or more.
Researchers noted that overall, the venetoclax treatment was well tolerated.
Most common adverse events included mild gastrointestinal symptoms (nausea [47%], diarrhea [36%], vomiting [21%]). Cytopenias were the most common grade 3/4 events, with thrombocytopenia (32%), neutropenia (27%), anemia (23%), and leukopenia (23%) reported.
The power of venetoclax for t(11;14) patients is expected to increase as it is added to other standard myeloma therapies in future clinical trials.