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Molecular Variants Associated With Resistance to a Quadruplet Treatment Combination in Newly Diagnosed Multiple Myeloma
At the 64th American Society of Hematology Annual Meeting and Exposition, Francesco Maura, MD, presented “Genomic Determinants of Resistance in Newly Diagnosed Multiple Myeloma Treated with Targeted Immunotherapy,” in which he and his colleagues reviewed a comprehensive catalogue of genomic determinants of response to carfilzomib, lenalidomide, and dexamethasone (DKRd) in patients with newly diagnosed multiple myeloma (NDMM) and identified new genomic alterations that may explain resistance to agents used in quadruplet combinations.
Although targeted immunotherapy combinations have significantly increased depth of response and clinical outcomes in NDMM, less than half of patients with NDMM still fail to achieve sustained minimal residual disease negativity (MRD-neg; defined as two MRD-neg results, the first at the end of induction and the subsequent tested after at least 10 months) through largely unknown resistance mechanisms. Whole genome sequencing (WGS) was performed on bone marrow (BM) malignant plasma cells that were isolated using CD138+ magnetic flow cytometry (CD38, CD138, and CD45) from 58 NDMM patients who were treated with DKRd with (n = 44; MANHATTAN trial) or without daratumumab (KRd, n = 14; NCT01402284).
“Why did we choose whole genome sequencing vs other technology? Well, first, because we like it, and second, it’s very comprehensive,” Dr Maura said.
Forty-two (95%) of 44 patients in the DKRd group received a total of eight cycles; of the 14 patients who received KRd, 11 consisted of 12 cycles or two additional cycles after achieving MRD-neg complete response. Twelve (20.7%) of the total number of patients received autologous stem cell transplantation. After a median 3.7 years of the most updated follow-up, 38 (66%) patients achieved MRD-neg, 27 (47%) were sustained, and 16 (28%) progressed. There were no observed differences in outcome or rate of MRD-neg between KRd or DKRd, or in other key clinical features. The researchers identified 68 recurrent structural variants (SV), complex SV, 152 recurrent aneuploidies defined by GISTIC2.0, mutational signatures, and mutations in 80 driver genes.
The median mutational burden was 6,028 (range 1,268-16,745), and neither the clinical outcome nor the proportion of sustained MRD-neg were affected by this variable.
Significantly shorter progression free survival (P = .002) was associated with high apolipoprotein B mRNA editing enzyme, catalytic polypeptide—or APOBEC—single-base substation signatures (SBS2 and SBS13).
Poor prognosis was associated with del1p22 (RPL5), del1p12 (FAM46c), gain1q, del16q12 (CYLD), and del22q12 (XBP1). A significant correlation was noted between nonresponders and low expression of XBP1, FAM46c, and CYLD (P = .04, P = .03, P = .009, respectively), which was aligned with WGS data. XBP1 loss had an inverse correlation with CD38 expression, possibly explaining the resistance to daratumumab. Focal loss of 17q12 (IKZF3) was seen in four cases, all of which progressed after DKRd. The role of this deletion in resistance to lenalidomide-based treatment was validated using CoMMpass (n = 752), and 13 (1.7%) of the 752 NDMM cases showed focal IKZF3 loss, with 61% having early progression (P = .01).
Two novel gain-of-function SV hotspots associated with poor outcome after DKRd were identified: 19p13.11 (the site of KLF2; P = .00019), where the association between KLF2 overexpression and poor prognosis was also observed in the KyDaR study (P = .03), and MYC (ie, events on NSMCE2 and PVT1; P = .017). Additionally, the researchers identified four novel regions of large chromosomal gain associated with early progression: +18q, +4q, +8q, and +17q.
“The problem of when you have large events like +8q, +17q, +18q, or +4q is that you don’t have one single gene,” Dr Maura said. “You have hundreds of genes. So it’s difficult to say, ‘This is the driver,’ and report that as the mechanism of resistance.”
The researchers validated the prognostic and biological impact of these events in KyDaR and CoMMpass studies, respectively. KyDaR nonresponders and gain 8q patients are significantly enriched for E2F and G2M pathway deregulation with significant down-regulation of interferon pathway genes, as was the MYC targets pathway. These associations were also confirmed by restricting the analysis to the patients who were treated with DKRd (N = 44).
Maura F, Boyle E, Coffey D, et al. Genomic Determinants of Resistance in Newly Diagnosed Multiple Myeloma Treated with Targeted-Immunotherapy. Presented at: 64th ASH Annual Meeting and Exposition; December 10-13, 2022. Abstract 470.
