Lisaftoclax Shows Promise in Relapsed Multiple Myeloma and AL Amyloidosis Across Cytogenetic Profiles
Key Insights
Lisaftoclax, an investigational BCL-2 (search) inhibitor, demonstrated encouraging efficacy in a phase 1b/2 trial with 64% response rate in heavily pretreated multiple myeloma (search) patients and 89% hematologic response rate in AL amyloidosis (search) patients.
The study enrolled patients regardless of t(11;14) translocation status, showing broad applicability beyond previous BCL-2 (search) inhibitor research that focused on specific cytogenetic profiles.
Safety profile was favorable with manageable low-grade hematologic abnormalities and gastrointestinal intolerance, with most treatment-related adverse events being grade 1-2.
A novel BCL-2 (search) inhibitor called lisaftoclax has shown promising efficacy and safety results in patients with relapsed or refractory multiple myeloma (search) and AL amyloidosis (search), according to initial findings from a phase 1b/2 multicenter trial presented at the 2025 SOHO Annual Meeting. The study represents a significant departure from previous BCL-2 inhibitor research by enrolling patients regardless of their cytogenetic profile.
Addressing Critical Unmet Medical Needs
"Currently, there is an unmet need for treating relapsed AL amyloidosis (search). The only FDA approval has been in the first-line setting," stated study co-author Jack Khouri, MD, a hematologist/oncologist with Cleveland Clinic Cancer Institute (search). The research also targets patients with multiple myeloma (search) who have highly refractory disease, particularly those who relapse after receiving cell therapy.
Previous studies with the BCL-2 (search) inhibitor venetoclax focused primarily on patients with translocation (11;14) or high BCL-2 expression, but the agent has not received FDA approval due to safety concerns and studies that did not meet their endpoints.
Study Design and Patient Populations
The phase 1b/2 multicenter trial enrolled 52 patients across three distinct cohorts, evaluating lisaftoclax at different doses and in various combinations:
Cohort 1 included 36 heavily pretreated multiple myeloma (search) patients, including those who had received CAR T-cell therapy or other T-cell engagers, treated with lisaftoclax combined with pomalidomide and dexamethasone.
Cohort 2 consisted of patients with relapsed/refractory multiple myeloma (search) who received lisaftoclax with daratumumab, lenalidomide, and dexamethasone.
Cohort 3 enrolled 10 patients with relapsed/refractory AL amyloidosis (search) who received lisaftoclax with pomalidomide and dexamethasone.
A key differentiator of this study was the enrollment of patients regardless of their t(11;14) translocation status, expanding the potential patient population beyond previous BCL-2 (search) inhibitor research.
Encouraging Efficacy Results
Initial outcomes demonstrated promising activity across patient populations. In Cohort 1, 64% of the 36 heavily pretreated multiple myeloma (search) patients experienced a response, with a median time to response of 9.7 months. All evaluable patients in Cohort 2 achieved some level of response, though specific numbers were not detailed in the initial presentation.
The AL amyloidosis (search) cohort showed particularly strong results, with 89% of the 10 patients achieving a hematologic response, addressing a critical gap in treatment options for this rare but serious condition.
"This study is very different in that we're enrolling patients regardless of their disease's t(11;14) status," noted Dr. Khouri. "The responses to date indicate the drug may have broad applicability."
Favorable Safety Profile
Among the 49 patients included in the safety population, treatment-related adverse events from lisaftoclax were reported in 69.4% of patients. The most common events were neutropenia (20.4%), nausea (16.3%), diarrhea (12.2%), leukopenia (10.2%), abdominal distension (10.2%), constipation (8.2%), and thrombocytopenia (6.1%).
Most adverse events were limited to low-grade hematologic abnormalities and gastrointestinal intolerance, which were manageable. Eleven patients experienced grade 3 or higher treatment-related adverse events, primarily 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. One patient in Cohort 2 experienced QT interval prolongation.
Importantly, no drug-drug interactions were identified in the study, contributing to the favorable safety profile compared to previous BCL-2 (search) inhibitor experiences.
Future Development Plans
The phase 1b/2 study remains active as researchers work to finalize the appropriate dosing regimen. Plans are underway to advance to a phase 3 trial once the optimal dose is established. Additionally, correlative studies are being conducted to better understand the biological mechanisms behind lisaftoclax's activity.
The hope is that lisaftoclax will demonstrate efficacy in a larger subset of patients while providing an improved safety profile compared to previous BCL-2 (search) inhibitors, potentially addressing significant treatment gaps in both multiple myeloma (search) and AL amyloidosis (search) patient populations.