Venetoclax Active in Heavily Treated Multiple Myeloma

Shaji Kumar, MD

The BCL-2 inhibitor venetoclax (Venclexta) demonstrated activity in one-fifth of patients with heavily pretreated multiple myeloma, according to results of a phase I clinical trial presented at the 2016 ASH Annual Meeting.¹

Overall, 21% of patients achieved objectives responses to single-agent venetoclax. The response rate increased to 40% in the subgroup of patients with t(11;14) chromosomal translocation.

Regarding the safety profile, venetoclax was generally well tolerated and grade 3/4 toxicities were relatively infrequent, particularly nonhematologic toxicity, and no patient developed tumor lysis syndrome.

“Venetoclax monotherapy had an acceptable safety profile in this heavily pretreated multiple myeloma population,” said Shaji Kumar, MD, a myeloma consultant and professor of Medicine at the Mayo Clinic. “A higher response rate and deeper responses were seen in patients with the 11/14 translocation. These results confirm the single-agent antitumor activity of venetoclax in patients who have relapsed/refractory multiple myeloma with 11/14 translocation.”

“The results are encouraging enough that additional studies are planned, especially alternative combinations,” he added. “I think we have a drug that can change the outcome for a lot of patients with myeloma. It may be the first drug that is actually going to be a biomarker-driven drug in this disease.”

The rationale for evaluating venetoclax in multiple myeloma has support from the observation that the antiapoptotic proteins BCL-2 and MCL-1 promote survival of multiple myeloma cells.² Venetoclax induces cell death in myeloma cell lines and tissue samples. The drug has proven especially active in myeloma associated with t(11;14), which correlates with higher ratios of BCL-2:MCL1 and BCL-2:BCL2L1 (BCL-X_L) mRNA.³

Kumar reported findings from a phase I open-label, multicenter trial of venetoclax in patients treated with 1 or more prior myeloma regimens. All patients received venetoclax daily in 21-day cycles. Patients whose disease progressed on venetoclax monotherapy could receive dexamethasone and continue treatment.

Investigators enrolled 66 patients who had a median age of 63. About 60% had International Scoring System (ISS) stage II/III disease. The most common cytogenetic abnormalities were 13q deletion (48%), t(11;14) translocation (46%), and hyperdiploid (41%). The patients had received a median of 5 prior lines of therapy for myeloma. Two-thirds of the patients had disease that was refractory to both bortezomib (Velcade) and lenalidomide (Revlimid).

The objective response rate for the entire study population was 21%, including stringent complete responses (sCR) in 6%, complete responses (CR) in 4%, and very good partial responses (VGPR) in 8%. Among the 30 patients with the t(11;14) abnormality, 13% achieved sCR, 13% had VGPR, and 10% had CR. Venetoclax activity in t(11;14) myeloma was independent of refractory status to prior therapies, said Kumar.

Venetoclax had the greatest activity in a subgroup of patients with t(11;14) translocation associated with a high BCL-2:BCL2L1 ratio. Eight of 9 patients in the subgroup responded to treatment, including 3 sCR, 3 CR, and 1 VGPR. In contrast, 15 patients with a low BCL-2:BCL2L1 ratio had an overall response rate of 20%.

Two patients had dose-limiting toxicity (abdominal pain and nausea) at 600 mg of venetoclax. The most common grade 3/4 hematologic adverse events were thrombocytopenia (26%), neutropenia (21%), anemia (14%), leukopenia (14%), and lymphopenia (15%). The most common grade 3/4 nonhematologic adverse event was back pain (8%). Pneumonia was the most common serious adverse event (8%), followed by sepsis (5%), and pain, pyrexia, cough, and hypotension (3% each).

References

1. Kumar S, Vij R, Kaufman JL, et al. Venetoclax monotherapy for relapsed/refractory multiple myeloma: safety and efficacy results from a phase I study. Presented at: 58th ASH Annual Meeting and Exposition; December 3-6, 2016; San Diego, CA. Abstract 488.
2. Touzeau C, Dousset C, Le Gouill S, et al. The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t(11;14) multiple myeloma. Leukemia. 2014;28:210-212.
3. Punnoose EA, Leverson JD, Peale F. Expression profile of BCL-2, BCL-XL, and MCL-1 predicts pharmacological response to the BCL-2 selective antagonist venetoclax in multiple myeloma models. Mol Cancer Ther. 2016;15:1132-1144.