Targeting BCL‐2 with venetoclax and dexamethasone in patients with relapsed/refractory t(11;14) multiple myeloma

Abstract

Venetoclax (Ven) is a selective small‐molecule inhibitor of BCL‐2 that exhibits antitumoral activity against MM cells with t(11;14) translocation. We evaluated the safety and efficacy of Ven and dexamethasone (VenDex) combination in patients with t(11;14) positive relapsed/refractory (R/R) multiple myeloma (MM). This open‐label, multicenter study had two distinct phases (phase one [P1], phase two [P2]). Patients in both phases received VenDex (oral Ven 800 mg/day + oral Dex 40 mg [20 mg for patients ≥75 years] on days 1, 8, and 15, per 21–day cycle). The primary objective of the P1 VenDex cohort was to assess safety and pharmacokinetics. Phase two further evaluated efficacy with objective response rate (ORR) and very good partial response or better. Correlative studies explored baseline BCL2 (BCL‐2) and BCL2L1 (BCL‐XL) gene expression, cytogenetics, and recurrent somatic mutations in MM. Twenty and 31 patients in P1 and P2 with t(11;14) positive translocation received VenDex. P1/P2 patients had received a median of 3/5 lines of prior therapy, and 20%/87% were refractory to daratumumab. Predominant grade 3/4 hematological adverse events (AEs) with ≥10% occurrence included lymphopenia (20%/19%), neutropenia (15%/7%), thrombocytopenia (10%/10%), and anemia (5%/16%). At a median follow‐up of 12.3/9.2 months, ORR was 60%/48%. The duration of response estimate at 12 months was 50%/61%, and the median time to progression was 12.4/10.8 months. In biomarker evaluable patients, response to VenDex was independent of concurrent del(17p) or gain(1q) and mutations in key oncogenic signaling pathways, including MAPK and NF‐kB. VenDex demonstrated efficacy and manageable safety in heavily‐pre‐treated patients with t(11;14) R/R MM.

Multiple Myeloma Relapse Is Associated with Increased NFκB Pathway Activity and Upregulation of the Pro-Survival BCL-2 Protein BFL-1

“…BCL-XL and BCL-2 are known for their contribution to intrinsic apoptosis resistance in MM, and the BCL-2-targeting BH3-mimetic Venetoclax was shown to have clinical efficacy in RR-MM patients harboring a t(11;14) translocation [ 33 ]. A potential role for BFL-1 in MM is less clear, since BFL-1 expression is downregulated by transcriptional repressor Blimp-1, which is required for the differentiation of B cells into antibody-secreting PC [ 19 ].…”

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“…Apoptosis is accompanied by up-regulation of Cas-3 mRNA expression levels and down-regulation of Bcl-2 mRNA expression levels. There were demonstrated earlier that the caspase-3, Bcl-2, and his family members contribute significantly to the regulate apoptosis of human MM cells [47][48][49][50][51][52].…”

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

“…The safety and efficacy of venetoclax was also evaluated in combination with dexamethasone in 51 RRMM patients with t(11;14) in an open-label phase 1/2 study (NCT01794520) ( 34 ). The phase 1/2 patients had respectively received a median of 3/5 lines of prior therapy, and 20/87% were refractory to daratumumab.…”