Suzanne Lentzsch, MD, PhD, Professor of Medicine and Director of the Multiple Myeloma and Amyloidosis Service at Columbia University, offered her thoughts on venetoclax-based regimens, such as the one described by Dr. Kaufman.
Suzanne Lentzsch, MD, PhD
“Despite tremendous progress in the treatment of multiple myeloma, the disease still lacks a targeted approach, as all our patients are treated ‘the same.’ With venetoclax, for the first time, we have a targeted treatment for patients with t(11;14), which shows especially synergistic effects in combination with proteasome inhibitors such as bortezomib.1 Therefore, venetoclax, in combination with a proteasome inhibitor, is a promising combination that might be implemented as the first targeted therapy in patients carrying t(11;14),” Dr. Lentzsch said.
She further predicted that venetoclax may play a role in AL amyloidosis, where treatment options are much more limited, as patients do not seem to tolerate immunomodulatory agents or carfilzomib. Since nearly 50% of patients with AL amyloidosis harbor t(11;14),2 venetoclax could be a promising treatment approach and should be evaluated in this setting, Dr. Lentzsch added.
Ensuring Optimal Risk/Benefit Balance
Nevertheless, an interim safety analysis of the ongoing multicenter double-blind BELLINI trial (M14-031; ClinicalTrials.gov identifier NCT02755597)3 triggered the U.S. Food and Drug Administration to initiate a partial clinical hold in mid-2019 on all clinical trials examining venetoclax in multiple myeloma, noted Dr. Lentzsch. The study, which enrolled previously treated patients with relapsed or refractory disease who were sensitive or naive to proteasome inhibitors, randomly assigned patients to bortezomib and dexamethasone (Vd) plus either venetoclax or placebo. There were more patient deaths in the venetoclax arm (41/194 [21.1%]) than the placebo arm (11/97 [11.3%]; hazard ratio [HR] = 2.03, 95% confidence interval [CI] = 1.042–3.945). For venetoclax plus Vd vs Vd alone, the overall response rate was significantly improved (82% vs 68%, respectively), as was the median progression-free survival (22.4 vs 11.4 months); this translated to a 37% reduction in the risk of disease progression or death (HR = 0.63; 95% CI = 0.44–0.90).
“Fortunately, the hold has been lifted since then, but it is still not clear why patients treated with venetoclax, bortezomib, and dexamethasone showed an increased risk of death despite better response rates. Therefore, future clinical trials need to be carefully designed to ensure an optimal risk/benefit balance for patients with myeloma treated with venetoclax,” Dr. Lentzsch offered.
Disclosure: Dr. Lentzsch has consulted for or received honoraria from Janssen, Proclara, Sanofi, Sorrento, and Amgen; has received research funding from Karyopharm and Sanofi; has equity ownership and serves on the board of directors or advisory committee for Caelum Biosciences in the past 12 months.
1. Moreau P, Chanan-Khan A, Roberts AW, et al: Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory multiple myeloma. Blood 130:2392-2400, 2017.
2. Bryce AH, Ketterling RP, Gertz MA, et al: Translocation t(11;14) and survival of patients with light chain (AL) amyloidosis. Haematologica 94:380-386, 2009.
3. Kumar S, Harrison S, Cavo M, et al: A phase III study of venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma. 2019 European Hematology Association Annual Meeting. Abstract LB2601. Presented June 16, 2019.
In a phase I/II study of patients with advanced multiple myeloma and t(11;14) translocations, the combination of venetoclax and dexamethasone showed strong, durable activity, even in patients refractory to daratumumab, study investigators reported at the 2019 American Society of Hematology (ASH)...