Lisaftoclax (APG-2575) Combined with Novel Therapeutic Regimens in Patients (pts) with Relapsed or Refractory Multiple Myeloma (R/R MM) or Immunoglobulin Light-Chain (AL) Amyloidosis

Introduction

MM is characterized by the proliferation of abnormal clonal plasma cells, causing destructive bone lesions, kidney injury, anemia, and hypercalcemia. Treatment of MM involves immunomodulatory agents, proteasome inhibitors, and anti-CD38 monoclonal antibodies to achieve disease remission. AL amyloidosis comprises disorders of abnormal extracellular deposition of misfolded proteins in various organs with resultant damage, and the key strategy of treatment is to prolong the time to or reverse organ dysfunction. However, many patients will relapse from the standard triplet or quadruplet therapies, necessitating additional treatments with novel mechanisms of action. Lisaftoclax is a novel investigational BCL-2 inhibitor with strong antitumor activity in hematologic malignancies. Here, we report clinical trial data on lisaftoclax combined with novel therapeutic regimens in pts with R/R MM or R/R AL amyloidosis.

Methods

Eligible patients had an ECOG performance status ≤ 2, ≥ 1 prior line of therapy, and adequate organ function. Patients with R/R AL amyloidosis had confirmed symptomatic organ involvement, purpura, and/or carpal tunnel syndrome. Lisaftoclax was administered orally daily at doses assigned in repeated 28-day cycles. Pomalidomide, daratumumab, and lenalidomide were administered per label use. Dexamethasone 40 mg (20 mg, pts > 75 years old) was administered on days 1, 8, 15, and 22 of 28-day cycles. This study evaluated the safety and efficacy of lisaftoclax combined with pomalidomide and dexamethasone (Pd; Arm A) or daratumumab, lenalidomide, and dexamethasone (DRd; Arm B) in R/R MM and lisaftoclax combined with Pd in R/R AL amyloidosis (Arm C). Intensive blood samples were collected for pharmacokinetic (PK) analyses.

Results

As of May 29, 2024, 52 pts were enrolled, including 42 with R/R MM and 10 with AL amyloidosis. In Arm A (n = 35), lisaftoclax was administered orally at dose assigned: 400 mg (n = 3), 600 mg (n = 4), 800 mg (n = 15), 1,000 mg (n = 7), and 1,200 mg (n = 6). In Arm B (n = 7), all pts were treated with lisaftoclax 600 mg. In Arm C (n = 10), lisaftoclax was administered at 400 mg (n = 1), 600 mg (n = 4), 800 mg (n = 3), and 1,000 mg (n = 2). The median (range) age of all patients was 69.5 (24-88) years, of whom 63.5% were male and 63.5% were ≥ 65 years of age. The enrolled patients were heavily treated, with a median (range) number of treatment cycles of 4 (1-26), and a median (range) number of prior therapy lines of 3 (1-19). In Arm A, out of 31 evaluable patients, 3 (9.7%) achieved complete remission (CR), 7 (22.6%) reached very good partial remission (VGPR), and 9 (29.0%) achieved partial response (PR). The overall response rate (ORR) was 19 (61.3%), and the ≥ VGPR rate was 10 (32.3%). In Arm B, of 4 evaluable patients, 2 (50%) achieved CR and 2 (50%) ≥ VGPR. In Arm C, of 7 assessed patients, 1 (14.3%) achieved CR, 4 (57.1%) VGPR, 1 (14.3%) PR, and 5 (71.4%) ≥ VGPR, for an ORR of 6 (85.7%); 2 pts had cardiac response.

Among 49 pts in the safety population, 34 (69.4%) reported any-grade lisaftoclax treatment-related AEs (TRAEs; ≥ 5% incidence), including neutropenia (20.4%), thrombocytopenia (6.1%), leukopenia (10.2%), nausea (16.3%), abdominal distension (10.2%), diarrhea (12.2%), and constipation (8.2%). A total of 11 pts experienced grade ≥ 3 TRAEs, including neutropenia (14.3%) and febrile neutropenia (2%), and 3 pts experienced lisaftoclax-related serious AEs (1 each): febrile neutropenia, acute kidney injury, and diarrhea with electrolyte imbalance. In Arm B, 1 pt experienced a dose-limiting toxicity (prolonged QT interval). Pharmacokinetic analyses showed no drug-drug interaction (DDI) in all pts treated with lisaftoclax at all doses in combination with other therapeutic agents used in 3 arms.

Conclusions

Our findings suggest that lisaftoclax improves the depth of response in pts with R/R MM or AL amyloidosis when combined with Pd or DRd. These combination therapies demonstrated a favorable safety profile with no drug-drug interactions, particularly in hematologic side effects. ClinicalTrials.gov registration: NCT04942067; internal study identifier: APG2575MU101.

Ailawadhi:Ascentage: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Xencor: Research Funding; Regeneron: Consultancy; Abbvie: Research Funding; Johnson and Johnson: Consultancy, Research Funding; Cellectar: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Beigene: Consultancy; Takeda: Consultancy; BMS: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Sanofi: Consultancy; Janssen: Consultancy, Research Funding; Pharmacuclics: Consultancy, Research Funding. Chanan-Khan:Starton Therapeutics: Membership on an entity's Board of Directors or advisory committees. Khouri:GPCR Therapeutics: Honoraria; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Legend Biotech: Honoraria; Janssen: Consultancy. Chen:Ascentage Pharma Group International: Current holder of stock options in a privately-held company; Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment. Wang:Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment; Ascentage Pharma Group International: Current holder of stock options in a privately-held company. Guo:Guangzhou Healthquest Pharma Co. Ltd.: Current Employment; Ascentage Pharma Goup International: Current holder of stock options in a privately-held company. Wang:Ascentage Pharma Group International: Current holder of stock options in a privately-held company; Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment. Li:Ascentage Pharma Group International: Current holder of stock options in a privately-held company; Ascentage Pharma Group Inc.: Current Employment. Ahmad:Ascentage Pharma Group International: Current holder of stock options in a privately-held company; Ascentage Pharma Group Inc.: Current Employment. Yang:Ascentage Pharma Group International: Current holder of stock options in a privately-held company, Other: Leadership and fiduciary officer roles; Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Other: Leadership and fiduciary officer roles, Patents & Royalties; Ascentage Pharma Group Inc.: Current Employment, Other: Leadership and fiduciary officer roles, Patents & Royalties. Zhai:Ascentage Pharma Group International: Current holder of stock options in a privately-held company; Guangzhou Healthquest Pharma Co. Ltd.: Current Employment, Other: Leadership role, Patents & Royalties; Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Other: Leadership role, Patents & Royalties; Ascentage Pharma Group Inc.: Current Employment, Other: Leadership role, Patents & Royalties.