A Single-Center Experience on the Safety and Efficacy of Venetoclax-Based Regimens in Patients with Relapsed/Refractory Multiple Myeloma
Authors: Zolotov Eli , Patel Vanisha , Weiss Yedidyah , Biran Noa , Phull Pooja , Vesole David H. , Siegel David S. , Parmar Harsh 
Published: December 2024

Introduction: Venetoclax, a first-in-class oral BCL-2 inhibitor, has demonstrated remarkable efficacy in several hematologic malignancies. Multiple myeloma cells rely on BCL-2 for survival, and its inhibition has been shown to induce apoptosis. Therefore, several clinical trials have evaluated the safety and efficacy of venetoclax in relapsed/refractory multiple myeloma (RRMM). One prior small retrospective study evaluated the efficacy of venetoclax based combinations in pts with RRMM. We report our single-center experience with the off label use of venetoclax in a larger cohort of patients with RRMM.
Methods: We conducted a single-center retrospective study which included MM patients treated with venetoclax from November 2017 to March 2023 under an IRB-approved protocol. Patient data included demographics, disease characteristics, treatment regimens, and outcomes. Eligibility criteria required patients to be aged 21 and older and to have received at least one cycle of venetoclax. Venetoclax was administered in 28-day cycles, often starting at 400 mg and increasing to the maximum tolerated dose of 800 mg. Progression-free survival (PFS) was the primary outcome, defined as time from initiation of venetoclax-based therapy until progression or death whichever occurred first. Survival curves were estimated using the Kaplan-Meier method. IMW criteria were utilized to determine response depths and progression. Univariable and multivariable analyses were conducted to identify significant survival predictors.
Results: Seventy-nine patients (median age 61, 58.2% female), who received venetoclax in various combinations were included. Patients had received a median of 5 lines of therapy (LOT). The overall response rate was 46.8% for the entire cohort. For patients with t(11;14), the ORR was 64% compared with 36% for those who were negative (p=0.04). The median PFS (mPFS) for the entire cohort was 3.4 months; further, 7.8 months for pts with t(11;14) compared with 2.4 months for pts without (p=0.01). Among the patients, 29 (36.7%) exhibited high BCL-2 expression, which was associated with a longer mPFS of 7 months versus 3.4 months in patients with low BCL-2 expression. Patients achieving very good partial response (VGPR) or better had a median PFS of 7.1 months.The median overall survival (mOS) for the entire cohort was 17.4 months; (for pts with t(11;14) was found to be 37.2 months vs. 16.7 months for those negative). Fifty-one patients (63.2%) received venetoclax in combination with a proteasome inhibitor, 12 (15.1%) patients received venetoclax with an anti-CD38 monoclonal antibody, and 8 patients (10.1%) received venetoclax with a steroid alone. The most common adverse events were fatigue (34%), gastrointestinal symptoms (26.58%), and respiratory infections (30.37%). Eighteen patients (22.8%) experienced grade 3 adverse events, necessitating hospitalization, including pneumonia (13.9%) and sepsis (3.8%); there were no treatment-related deaths. Four patients (5.1%) discontinued venetoclax due to intolerable adverse effects such as severe fatigue and diarrhea. Regarding infection prophylaxis, 98.7% of patients received some anti-viral often in combination with trimethoprim-sulfamethoxazole or fluoroquinolones. Only one patient (3.8%) did not receive prophylaxis during venetoclax treatment.
Conclusions: Our data suggest moderate efficacy with the use of venetoclax in patients with relapsed/refractory multiple myeloma in a setting outside of clinical trials. Efficacy was higher in the group of patients with t(11;14). Our cohort included heavily pre-treated patients (median of 5 prior LOT) with MM, as a result of which the outcomes were inferior to those reported in the clinical trials (median of 2-3 prior LOT). Overall, venetoclax was well tolerated and risk of infections was relatively low since most patients received antimicrobial prophylaxis. Further multicenter research is crucial to better define the role of venetoclax in RRMM.