Lisaftoclax, an investigational BCL2 inhibitor, in combination with pomalidomide/dexamethasone (Pd) or daratumumab/lenalidomide/dexamethasone (DRd) led to improved outcomes for patients with relapsed or refractory multiple myeloma and for patients with AL amyloidosis, according to findings from a phase Ib/II trial presented at the 2025 SOHO Annual Meeting (Abstract MM-718). Additionally, lisaftoclax was found to have a favorable safety profile, with no drug–drug interactions found in the study.
“Currently, there is an unmet need for treating relapsed AL amyloidosis. The only FDA approval has been in the first-line setting,” stated study coauthor Jack Khouri, MD, a hematologist/oncologist with Cleveland Clinic Cancer Institute. “The responses to date indicate the drug may have broad applicability.”
Rationale and Study Methods
Previous research has shown that patients with plasma cell disorders who carry translocation (11;14) or high BLC2 expression benefited from treatment with venetoclax, but studies of the agent in this setting have not led to approval by the U.S. Food and Drug Administration (FDA) because of safety concerns.
The phase Ib/II multicenter trial enrolled patients with relapsed or refractory multiple myeloma (n = 42) or AL amyloidosis (n = 10) who had an Eastern Cooperative Oncology Group performance status of 0 to 2 and had received at least one prior line of therapy. The study consisted of three cohorts: the first included patients with multiple myeloma who were heavily pretreated and had also received a chimeric antigen receptor T-cell therapy or other T-cell engager, and these patients received lisaftoclax with Pd; the second included patients with multiple myeloma who received lisaftoclax with DRd; and the third consisted of the patients with AL amyloidosis who received lisaftoclax with Pd. Patients were enrolled regardless of their t(11;14) status.
Key Study Findings
The response rate in the first cohort was 64%, with a median time to response of 9.7 months. All evaluable patients in the second cohort achieved some response, and in the third cohort, the hematologic response rate was 89%.
Among 49 patients included in the safety population, any-grade treatment-related adverse events from lisaftoclax were reported in 69.4%; the most common events were neutropenia in 20.4%, nausea in 16.3%, diarrhea in 12.2%, leukopenia in 10.2%, abdominal distension in 10.2%, constipation in 8.2%, and thrombocytopenia in 6.1%. Eleven patients had grade 3 or higher treatment-related adverse events of neutropenia (14.3%) and febrile neutropenia (2%). Serious adverse events, including febrile neutropenia, acute kidney injury, diarrhea, and electrolyte imbalance, were observed in three patients. Of note, one patient in the second cohort had a QT interval prolongation.
Although the study is ongoing, a phase III trial is planned once the optimal dose is set.
Disclosure: The study was supported by Ascentage Pharma Group Corp Ltd. For full disclosures of the study authors, visit elsevierdigitaledition.com.
