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-X_L ) 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.

FIGURE 1

(A) Overall response rate by cohorts. ORR indicates a response of PR or better. ORR: Objective Response Rates; CR: Complete response; VGPR: Very good partial response; VenDex: Venetoclax and dexamethasone combination therapy; PR: Partial response. (B) Duration of response. (C) Time to progression. (D) Overall survival of patients in phase two venetoclax plus dexamethasone cohort stratified by patient response status (responders: patients with a partial response or better; non‐responder: patients without a minimum of a partial response). DoR: duration of response; OS: overall survival; TTP: time to progression

FIGURE 2

Baseline BCL2, BCL2L1, and BCL2 : BCL2L1 gene expression levels by response in t(11;14) positive R/R MM patients treated with VenDex. Quantitation of BCL2 and BCL2L1 was performed on CD138‐selected BMMCs collected at baseline using qPCR. Presented are the (A) BCL2, (B) BCL2L1, and (C) BCL2: BCL2L1 gene expression levels by response in t(11;14) positive R/R MM patients treated with VenDex. Horizontal bars represent the median and whiskers extend to the 95% confidence intervals. p values determined by Wilcoxon rank‐sum test. (D) Mutational landscape of t(11;14) positive patients treated with VenDex. Oncoprint representation of the frequency and characteristics of recurrent mutations in MM as determined by whole‐exome sequencing of CD138‐selected BMMCs collected at baseline from t(11;14) positive patients treated with VenDex. Colored squares indicate mutated genes, while gray squares indicate non‐mutated genes. Each color represents a different type of mutation: missense (blue), frameshift (red), stop codon gain (yellow), stop codon lost (green), splice region (pink). The structural variants t(11;14), del(17p), gain(1q), and hyperdiploid (gains in Ch5, Ch9 or Ch15) as determined by FISH are also denoted (dark gray). Percentages in the heatmap represent the mutation rate among all patients presenting at least one mutated gene of the reported gene list. Tumor mutation burden calculated by the number of non‐synonymous somatic mutations (single nucleotide variants and small insertions/deletions) per megabase in coding regions is shown on top of oncoprint. Study phase (Phase one: red; Phase two: blue) and best objective response (CR: orange; VGPR: blue; PR: purple; MR: teal; SD: gray; PD: red; NA: gold) are shown below the oncoprint