Venetoclax plus bortezomib and dexamethasone in heavily pretreated end‐stage myeloma patients without t(11;14): A real‐world cohort

Abstract

Multiple myeloma (MM) is the second most common blood cancer caused by the uncontrolled proliferation of clonal plasma cells. Despite recent advances in treatment, a majority of patients eventually relapse and die because of progressive disease (PD). Thus, the development of modern molecules with novel mechanisms of action is needed. The overexpression of antiapoptotic proteins (ie, Bcl-2, Bcl-X L , Mcl-1) represents one of the hallmarks of cancer that favors tumor cell survival. It has been demonstrated that a subset of MM is Bcl-2 dependent. These are especially those harboring the t(11;14)molecular subgroup which is associated with a high expression of Bcl-2 and a low expression of Bcl-X L and Mcl-1. 1,2 The presence of translocation t(11;14) is present in 15%-20% of newly diagnosed MM 3 and even up in 50% of primary plasma cell leukemia. 4 Venetoclax (ABT-199, Venclexta), a selective orally bioavailable Bcl-2 inhibitor, is one of the real game changers in cancer therapy. Venetoclax has demonstrated unprecedented efficacy across a major

DLBCL Cells with Acquired Resistance to Venetoclax Are Not Sensitized to BIRD-2 But Can Be Resensitized to Venetoclax through Bcl-XL Inhibition

“…Ever since its launch in the clinic, venetoclax has been a precision medicine with great potential and success [ 11 ]. While initially it was approved as a therapy for CLL, current research focuses on its use in other types of cancer such as DLBCL, follicular lymphoma, myeloma and acute myeloid leukemia [ 11 , 14 , 15 ].…”

Paving the way to precision medicine in multiple myeloma

“…This was noticeably contrasted by poorer outcomes in the low BCL2 and non-t(11;14) group which had lower overall survival rates compared with placebo (n = 130, HR = 3.13, 95% CI = 1.2-8.13, p = 0.019) [16]. The distinct benefit/risk profiles observed in the BELLINI trial and real-world experience with venetoclax [17] provide compelling rationale for a biomarker-driven approach to patient selection that reflects disease biology and critical evaluation of the optimal combination regimen. Venetoclax has also been combined with carfilzomib in the M15-538 phase 2 study, with an ORR of 78% (n = 49) and no new safety signals present compared to prior phase 1 trials [18].…”

Novel Approaches Outside the Setting of Immunotherapy for the Treatment of Multiple Myeloma: The Case of Melflufen, Venetoclax, and Selinexor

“…Venetoclax (800 mg/day), in combination with a standard dose of bortezomib and dexamethasone, was administered until PD or unacceptable toxicity in a real-life experience recently reported ( 46 ). Eleven patients with RRMM and highly pretreated with a median of 7 (range: 4–10) previous lines of therapy were included; all patients were negative for t(11;14).…”

“…In the randomized, double-blind, multicenter phase 3 trial BELLINI (NCT02755597), 291 patients with RRMM who had received one to three previous therapies were enrolled to receive venetoclax (194 patients) or placebo (97 patients) with Venetoclax (800 mg/day), in combination with a standard dose of bortezomib and dexamethasone, was administered until PD or unacceptable toxicity in a real-life experience recently reported (46). Eleven patients with RRMM and highly pretreated with a median of 7 (range: 4-10) previous lines of therapy were included; all patients were negative for t (11;14).…”