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Potential Genomic Mechanisms of Resistance to Targeted Immunotherapy for Myeloma

By: Vanessa A. Carter, BS
Posted: Tuesday, February 14, 2023

Francesco Maura, MD, of the University of Miami, Sylvester Comprehensive Cancer Center, and colleagues aimed to investigate whether certain molecular events may be associated with resistance to a targeted immunotherapy quadruplet for newly diagnosed multiple myeloma. Presented during the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition (Abstract 470), the results of this study outlined a comprehensive catalog of genomic determinants that offer reasoning behind resistance to this treatment regimen.

Whole-genome sequencing was performed on bone marrow–malignant plasma cells from 58 patients with newly diagnosed multiple myeloma who were treated with carfilzomib, lenalidomide, and dexamethasone with (n = 44) or without daratumumab (n = 14). Whole-genome sequencing enabled the investigators to study 152 recurrent aneuploidies, 68 structural variants, mutations in 80 driver genes, and mutational signatures.

According to mutational signatures analysis, high APOBEC single base substitution signatures appeared to correlate with significantly shorter progression-free survival (P = .002). Other known features associated with poor prognosis included deletions in 1p22 (RPL5), 1p12 (FAM46c), 16q12 (CYLD), and 22q12 (XBP1), as well as a gain1q. Among patients treated with daratumumab, there was a significant correlation between low expression of XBP1 (P = .04), FAM46c (P = .03), and CYLD (P = .009) and lack of response; XBP1 loss and its inverse correlation with CD38 expression may explain resistance to daratumumab.

Two novel gain-of-function structural variant hotspots—KLF2 overexpression (19p13.11; P = .03) and MYC (NSMCE2 and PVT1; P = .017)—were associated with poor outcomes. Additionally, four novel regions of large chromosomal gain—18q, 4q, 8q, and 17q—correlated with early disease progression. Pathway-based analyses demonstrated that nonresponders and those with gain8q appeared to be significantly enriched for E2F and G2M pathway deregulation, with significant downregulation of IFN pathway genes. Furthermore, the MYC targets pathway was enriched in both nonresponders and in all four chromosomal gain regions.

Disclosure: For full disclosures of the study authors, visit

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