Study shows genetic factors in multiple myeloma treatment resistance

Study shows genetic factors in multiple myeloma treatment resistance

A litany of genomic determinants of response to the combination of carfilzomib, lenalidomide, and dexamethasone with daratumumab (DKRd) in newly diagnosed patients multiple myeloma (MM) were discovered in a new whole genome sequencing assay.

The results could help interpret resistance to each of the agents used in the quadruple combination regimens to treat the rare form of cancer.

In new data presented at the 2022 Annual Meeting of the American Society of Hematology (ASH) in New Orleans this week, a team of researchers observed molecular variants linked to the DKRd treatment combination for newly diagnosed MM. Led by Francesco Maura, MD, of the Myeloma Division of the Sylvester Comprehensive Cancer Center at the University of Miami, a team of researchers sought to interpret the interplay of genomic factors associated with the promising agent daratumumab, with respect to quadruple treatment regimens.

“Targeted immunotherapy combinations, including the anti-CD38 monoclonal antibody daratumumab, significantly increased depth of response and clinical outcome in newly diagnosed MM,” they wrote. “Despite this improvement, 30-40% of patients still progress and fail to achieve sustained minimal residual disease negativity through largely unknown resistance mechanisms.”

Maura and colleagues performed sequencing on BM malignant plasma cells isolated from 58 newly diagnosed MM patients treated with DKRd (n=44) or carfilzomib, lenalidomide, and dexamethasone without daratumumab (KRd; n=14). They defined minimal sustained residual disease negativity as 2 such findings ≥10 months apart.

All but 2 patients in the DKRd arm received 8 cycles; 11 patients who received KRd received ≥12 cycles. At a median follow-up of 3.7 years, 38 (66%) patients achieved sustained minimal residual disease negativity; 27 (47%) were maintained and 16 (28%) progressed. The investigators observed no difference in outcome or in the rate of residual disease negativity between the two treatment arms.

Using whole genome sequencing, researchers were able to accurately study 68 recurrent structural variants (SVs), complex SCs, 152 recurrent aneuploidies, mutational signatures, and ad mutations in 80 driver genes. Median mutational load in 6028 patients. The variable did not affect clinical outcome or the proportion of sustained minimum residual disease negativity. Elevated APOBEC single-base post signatures were linked to significantly shorter progression-free survival (P = .002).

“Interestingly, we noted a significant correlation between non-responders and low expression of XBP1, FAM46c, and CYLD (P = 0.04, P = 0.03, P = 0.009, respectively), consistent with what was observed in our WGS data,” the investigators wrote. “XBP1 the loss was of particular interest because of its inverse correlation with CD38 expression which could explain daratumumab resistance.

Only 13 (1.7%) of newly diagnosed MM cases had a focal IKZF3 loss; 61% had early progression (P = .01).

“We identified 2 new SV gain-of-function hotspots associated with poor outcomes after DKRd,” the researchers noted. “Furthermore, we identified 4 novel regions of high chromosome gain associated with early progression: 18q, 4q, 8q, and 17q.”

“In this study, we defined a comprehensive catalog of genomic determinants of DKRd response in NDMM identifying a number of novel genomic alterations that explain resistance to currently used agents in quadruplicate combinations,” they concluded.

The study, “Genomic determinants of resistance in newly diagnosed multiple myeloma treated with targeted immunotherapywas presented at ASH 2022.

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