Venetoclax has demonstrated promising efficacy and a tolerable safety profile as monotherapy and in combinations for patients with relapsed/refractory multiple myeloma
Cyrille Touzeau, MD
Venetoclax (ABT-199) has demonstrated promising efficacy and a tolerable safety profile as monotherapy and in combinations for patients with relapsed/refractory multiple myeloma, according to findings from two studies presented at the 2015 ASCO Annual Meeting.
In a phase Ib study, the combination of the BCL-2 inhibitor venetoclax, bortezomib (Velcade), and dexamethasone demonstrated an objective response rate (ORR) of 83% in bortezomib-naive patients with relapsed/refractory multiple myeloma (n = 6). In patients with bortezomib-sensitive multiple myeloma (n = 16), the ORR was 63%. However, in patients refractory to prior bortezomib (n = 10), a response was not seen with the triplet therapy.
In a phase I study, monotherapy with venetoclax demonstrated an ORR of 29% in evaluable t(11;14)-positive patients with relapsed/refractory multiple myeloma (n = 7). This response rate included 1 complete response (CR) and 1 partial response (PR). In this same population, the median time on study of 5.1 months compared with 1.9 months for t(11;14)-negative patients.
"Multiple myeloma remains a high area of unmet medical need and additional research to identify new therapies is important," Cyrille Touzeau, MD, Department of Hematology, University of Nantes, France, said in a statement when the data were presented. "The response rates shown in these studies suggest potential of venetoclax in this patient population and warrant further evaluation."
A total of 32 patients were enrolled in the study. The mean age of patients was 65 years and 63% were male. Patients had received a median of five prior lines of therapy and 63% had undergone autologous stem cell transplant.
The phase Ib study enrolled 38 patients. The mean age of patients was 65 years and 63% were male. Patients had received a median of five prior lines of therapy and 63% had undergone autologous stem cell transplant. Of the 82% of patients previously treated with bortezomib, 26% were refractory, and of the 84% of patients receiving prior lenalidomide, just over half (55%) were refractory. Overall, 68% of patients had received both drugs and 21% of these were refractory to both. All patients also received prophylaxis against tumor lysis syndrome.
Overall, 19% of patients achieved very good partial response (VGPR) or better; two patients (6%) showed stringent complete response, one patient (3%) achieved a complete response, four (11%) achieved VGPR, and 10 (28%) achieved PR following treatment.
Stable disease was seen in 6 patients (17%) and 9 patients (25%) experienced progressive disease. The overall median duration of response was 6.0 months months.
Nearly all patients (98%) experienced an adverse event (AE) of any grade; constipation was reported by 37% of patients, diarrhea and insomnia were each reported in 32%, and thrombocytopenia occurred in 29% of patients. Dyspnea, asthenia, and peripheral neuropathy were each reported by 26% of patients, peripheral edema in 24%, and anemia in 21%.
Grade 3/4 AEs included thrombocytopenia in 21% of patients, anemia in 13%, and dyspnea in 11%. Serious AEs occurred in 47% of patients: cardiac failure, embolism, pneumonia, pyrexia, respiratory failure, and sepsis each occurred in 5% of patients. One dose-limiting toxicity occurred that was linked to dexamethasone.
In the monotherapy study, the most common AEs included diarrhea (32%), nausea (32%), neutropenia (21%) and fatigue (21%). The most frequently seen grade ¾ AEs were thrombocytopenia (18%), anemia (14%) and neutropenia (14%).
"We are extremely encouraged by these results and will continue evaluating this compound in a variety of tumor types, including additional studies in patients with multiple myeloma," Gary Gordon, MD, vice president, oncology clinical development, AbbVie.
In addition to multiple myeloma, phase III clinical trials continued to assess venetoclax as a treatment for patients with relapsed/refractory chronic lymphocytic leukemia (CLL). In May 2015, the FDA granted a Breakthrough Therapy Designation to venetoclax for the treatment of patients with relapsed/refractory CLL with a 17p deletion.