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Aims: To characterize the genomic and transcriptomic profiles associated with t(11;14) status in NDMM and RRMM. Methods: The global, non-interventional MEDICI study (NCT04721002) enrolled pts aged ≥18 years who provided informed consent and had BM aspirates collected at diagnosis and/or relapse. In this analysis (data cutoff October 31, 2023), BM aspirates were subjected to plasma cell enrichment and next-generation RNA sequencing (RNAseq) followed by differential gene expression analysis. P values were corrected by the Benjamini and Hochberg method. Results: A total of 525 pts were included. Among 110 pts with t(11;14)-positive (NDMM, n = 56; RRMM, n = 54), the median age was 64.5 years (range, 38.0–89.0), 60.0% of pts were male, and 74.5% of pts were White. Among 376 pts with t(11;14)-negative (NDMM, n = 235; RRMM, n = 141), the median age was 67.0 years (range, 37.0–90.0), 54.0% of pts were male, and 75.8% of pts were White. ECOG performance status for pts with t(11;14)-positive vs t(11;14)-negative status was 0–1 in 72.7% vs 69.7%. ISS stages I, II, and III disease were present in 34.5%, 21.8%, and 23.6% of pts with t(11;14)-positive and 30.9%, 24.7%, and 25.0% of pts with t(11;14)-negative status, respectively. Of the 525 pts, 369 had samples subjected to RNAseq for whole transcriptome sequencing (WTS). Differential gene expression analysis showed overexpression of CCND1 (encodes cyclin D1) in pts with t(11;14)-positive vs t(11;14)-negative status in both NDMM and RRMM, as expected. Evaluation of BCL-2 family genes revealed increased expression of the pro-apoptotic BH3 sensitizer PMAIP1 (encodes NOXA) in pts with t(11;14)-positive vs t(11;14)-negative status with NDMM and RRMM. Comparison of differentially expressed genes among pts with t(11;14)-positive NDMM vs RRMM, showed that while BCL2 (encodes BCL-2) expression was similar in both disease settings, MCL1 (encodes MCL-1) and BCL2A1 (encodes BFL-1) expression were significantly increased in RRMM. Overexpression of MCL1 and BCL2A1 have been shown to drive Ven resistance in hematologic malignancies. Whole-exome sequencing analysis will be presented at the meeting. Discussion: The selective, potent, oral BCL-2 inhibitor venetoclax (Ven) has demonstrated efficacy in patients (pts) with t(11;14)-positive relapsed/refractory MM (RRMM) and is currently being evaluated as biomarker-directed therapy in this population. Clinical trials estimate 15%–20% of pts with MM carry t(11;14); however, t(11;14)-positive MM prevalence has yet to be established in a real-world setting. Using BM aspirates from MEDICI, WTS and differential expression analysis of key apoptotic pathway genes showed significantly higher PMAIP1 expression in t(11;14)-positive NDMM and RRMM. Comparison among pts with t(11;14)-positive showed increased MCL1 and BCL2A1 expression in RRMM; further evaluation may offer insights into acquired genomic heterogeneity in RRMM and guide optimal combinations with Ven. Conclusion: The pro-apoptotic BH3 sensitizer PMAIP1 (NOXA) was overexpressed in t(11;14)-positive vs t(11;14)-negative disease in both NDMM and RRMM. Although BCL2 (BCL-2) expression levels were similar, MCL1 (MCL-1) and BCL2A1 (BFL-1) expression levels were higher in t(11;14)-positive in RRMM vs NDMM, and overexpression of these genes has been shown to drive BCL-2 inhibitor resistance in hematologic malignancies. |
