Study Shows Genetic Factors in Multiple Myeloma Treatment Resistance

Francesco Maura, MD

A litany of genomic determinants of response to combination carfilzomib, lenalidomide, and dexamethasone with daratumumab (DKRd) among patients with newly diagnosed multiple myeloma (MM) have been uncovered in a new whole genome sequencing trial.

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

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

“Targeted immunotherapy combinations including anti-CD38 monoclonal antibody daratumumab have significantly increased the 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 conducted sequencing on BM malignant plasma cells isolated from 58 patients with newly diagnosed MM treated with DKRd (n = 44) or with carfilzomib, lenalidomide, and dexamethasone without daratumumab (KRd; n = 14). They defined sustained minimal residual disease negativity by 2 such results ≥10 months apart.

All but 2 patients from the DKRd arm received 8 cycles; 11 patients who received KRd received ≥12 cycles. At a median 3.7-year follow-up, 38 (66%) patients achieved sustained minimal residual disease negativity; 27 (47%) were sustained and 16 (28%) were progressed. Investigators observed no difference in outcome nor rate of residual disease negativity between either treatment arm.

Via whole genomic sequencing, investigators were able to accurately study 68 recurrent structural variants (SV), complex SC, 152 recurrent aneuploidies, mutational signatures, ad mutations in 80 driver genes. Median mutational burden among patients 6028. Variable did not affect the clinical outcome nor proportion of sustained minimal residual disease negativity. High APOBEC single-base substation 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 = .04, P = .03, P = .009, respectively), in line with what observed in our WGS data,” investigators wrote. “XBP1 loss was particularly interesting because of its inverse correlation with CD38 expression that could explain resistance to daratumumab.”

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

“We identified 2 novel gain of function SV hotspots associated with poor outcome after DKRd,” investigators noted. “Furthermore, we identified 4 novel regions of large chromosomal gain associated with early progression: 18q, 4q, 8q and 17q.”

“In this study, we have defined a comprehensive catalogue of genomic determinants of response to DKRd in NDMM identifying a number of new genomic alterations that explain resistance to the agents currently used in quadruplet combinations,” they concluded.

The study, “Genomic Determinants of Resistance in Newly Diagnosed Multiple Myeloma Treated with Targeted-Immunotherapy,” was presented at ASH 2022.