BCL-2 Inhibition in Plasma Cell Disorders: The Work Continues

The BLC-2 inhibitor lisaftoclax showed improvement in progression-free survival with a favorable safety profile in patients with relapsed AL amyloidosis and relapsed/refractory multiple myeloma. In this phase 1b/2 multi-center study, the therapy showed efficacy across patient populations — including those whose disease did not harbor t(11;14).

Initial results were presented at the 2025 SOHO Annual Meeting.

Background

“Currently, there is an unmet need for treating relapsed AL amyloidosis. The only FDA approval

has been in the first-line setting,” says study co-author Jack Khouri, MD, a hematologist/oncologist with Cleveland Clinic Cancer Institute. Patients with multiple myeloma who have highly refractory disease also need additional options especially if they relapse after receiving cell therapy.

Inhibiting BCL-2 is an important principle in treating multiple myeloma and AL amyloidosis. There is currently much research activity underway to study potential BLC-2 inhibitor

therapies in plasma cell disorders. Previous studies found patients with translocation (11;14) or high BLC-2 derived benefit from the BCL-2 inhibitor venetoclax. However, the medication has not received FDA approval for multiple reasons, including safety profile and a study that did not meet its endpoint.

Study design

Previous studies involved only patients who had t(11;14) but this study enrolled all patients regardless of their myeloma cytogenetic profile. In this study, researchers evaluated the efficacy and safety of lisaftoclax at different doses and in different combinations, with three cohorts:

• Cohort 1: Heavily pretreated patients with multiple myeloma, including those who received CAR T-cell therapy or other T-cell engagers, were treated with lisaftoclax with pomalidomide and dexamethasone.
• Cohort 2: Patients with relapsed/refractory multiple myeloma received lisaftoclax with daratumumab, lenalidomide and dexamethasone.
• Cohort 3: Patients with relapsed/refractory AL amyloidosis received llisaftoclax with pomalidomide and dexamethasone.

Study outcomes

Initial outcomes were encouraging for the two cohorts that have reported out so far. Of the 36 patients in cohort one, 64% experienced a response, with a median response time of 9.7 months. Of the ten patients in the AL amyloidosis cohort, 89% experienced a hematologic response.

“This study is very different in that we're enrolling patients regardless of their disease’s t(11;14) status,” says Dr. Khouri. “The responses to date indicate the drug may have broad applicability.”

In terms of adverse events, most were limited to low-grade hematologic abnormalities and GI intolerance, which were manageable.

What's next

The phase 1b/2 study remains active. There are plans to move forward with a phase three study once the researchers finalize the appropriate dose. In addition, correlative studies are also underway to understand the biology behind this medication.

The hope is that lisaftoclax will work in a larger subset of patients and provide a better safety profile than what's been experienced with BCL-2 inhibitors in the past.