A novel combination of sonrotoclax and dexamethasone is showing promising results in patients with relapsed/refractory multiple myeloma (R/R MM) harboring t(11;14). Data from the phase 1b/2 BGB-11417-105 study, presented at the 21st International Myeloma Society Annual Meeting, indicate deep and durable responses in a heavily pretreated population. The study, led by Abel Costa, MD, suggests a potential new treatment option for this challenging patient group.
The open-label, multicenter dose-escalation study evaluated the safety and efficacy of sonrotoclax in combination with dexamethasone in patients with R/R MM and t(11;14). The study's primary endpoints were safety and overall response rate (ORR), with secondary endpoints including pharmacokinetics, duration of response (DOR), time to response (TTR), progression-free survival, and overall survival.
Efficacy and Response Rates
The efficacy-evaluable population (n = 24) demonstrated an ORR of 75% (95% CI, 53%-90%). A significant proportion of patients, 50% (95% CI, 29-71), achieved very good partial responses (VGPR) or better, and 21% (95% CI, 7%-42%) achieved complete responses (CR) or stringent complete responses (sCR). Furthermore, 13% of patients had a minor response, and 13% achieved stable disease. Among those achieving CR or sCR, two patients attained minimal residual disease negativity based on a threshold of 10-5 using flow cytometry.
The median TTR was rapid, at 0.7 months, and the median DOR was 8 months (95% CI, 4-not evaluable). Ten patients experienced improved responses over time, with the longest DOR reaching 18 months. Two patients remained on treatment for over a year. These results suggest a sustained benefit in a subset of patients.
Safety and Tolerability
Regarding safety, 87.5% of patients (n = 32) experienced treatment-emergent adverse events (TEAEs) of any grade. Grade 3 or higher TEAEs occurred in 31.3% of patients, and serious TEAEs were reported in 18.8%. A TEAE led to death in 3.1% of patients; however, these deaths were not deemed related to the study drug. The most common any-grade TEAEs were fatigue and insomnia (each 28.1%), diarrhea (1.9%), and constipation and nausea (each 15.6%).
Hematologic TEAEs were observed in 12.5% of patients, including decreases in platelet count (6.3%) and neutrophil count (3.1%). Infections were relatively infrequent, occurring in 21.9% of patients, with COVID-19 and upper respiratory tract infections being the most common.
Study Design and Patient Characteristics
The study enrolled patients with R/R MM harboring t(11;14), a genetic abnormality present in approximately 15-20% of MM cases. This translocation leads to high expression of BCL2, making it a therapeutic target. The study included a dose-escalation phase (Part 1a) and an expansion phase (Part 2b). The recommended dose for expansion (RDFE) was determined to be 640 mg of sonrotoclax in combination with 40 mg of dexamethasone.
As of March 25, 2024, 32 patients were treated with the RDFE of sonrotoclax plus dexamethasone, with a median follow-up of 4.6 months (range, 0.1-19). The median age of patients was 69 years (range, 48-80), and the median prior lines of systemic therapy was 3 (range, 1-12). All patients had prior exposure to a proteasome inhibitor (PI) and immunomodulatory drugs (IMiDs), and 71.9% had exposure to an anti-CD38 antibody. A significant proportion of patients were refractory to PIs (56.3%), IMiDs (71.9%), anti-CD38 antibodies (56.3%), or all three treatments (46.9%).
Implications and Future Directions
"These results indicate that sonrotoclax plus dexamethasone is well tolerated in a heavily pretreated population, as the sonrotoclax plus dexamethasone combination provided deep and durable responses in this relapsed/refractory population," said Dr. Costa. The ongoing study continues to investigate other combination treatments with sonrotoclax, offering hope for improved outcomes in patients with R/R MM.
