Mechanisms of D-KRd treatment failure in MM identified

Genome-based mechanisms and bone marrow microenvironmental factors that drive treatment resistance in patients with multiple myeloma (MM) treated with daratumumab plus carfilzomib, lenalidomide, and dexamethasone (KRd) have been identified. These findings improve the understanding of treatment failure in this population, potentially adding to the development of improved therapies in the future [1].

Although treatment regimens including anti-CD38 antibodies have resulted in improved health outcomes for patients with MM, treatment resistance remains a substantial issue. The investigation of treatment failure in patients with MM can be done via single-cell microenvironmental analysis and genome-wide tumour genetics analysis.

Dr Eileen Boyle (NYU Langone Health, NY, USA) and her research team collected malignant plasma cells from bone marrow in patients with newly diagnosed MM treated with daratumumab plus KRd (n=46) or KRd alone (n=14) to perform whole-genome sequencing and single-cell RNA sequencing. MRD negativity, sustained MRD negativity, and progression of MRD negativity were the clinical endpoints.

After a median follow-up of 29 months, it was demonstrated that deletion of 13q, biallelic loss of CYLD, deletion of XBP1, deletion of 20q13.12, and 8q gains were linked to MRD positivity. Moreover, deletion of RPL5, IKFZ3 structural variants, and multiple chromothripsis events were associated with disease progression. Furthermore, trisomy 21 was related to improved disease outcomes. These findings reveal novel genomic drivers associated with daratumumab plus KRd treatment failure in patients with MM.

The authors also reported that deletions of XBP1 and 20q13.12 were associated with the loss of memory B cells, naïve B cells, and dendritic cells in the bone marrow microenvironment. In addition, low levels of plasmacytoid dendritic cells at baseline were linked to worse disease outcomes. Also, gains in 6p24 were related to a decreased number of CD8 effectors 1 and 2. These results indicate that specific genomic lesions lead to particular changes in the bone marrow microenvironment.

Finally, a significant difference between MRD-positive and MRD-negative patients was observed regarding the depletion of natural killer cells, and naïve and memory B cells throughout the therapy. Moreover, MRD-negative patients had more CD14-positive monocytes at baseline and after induction therapy. These findings indicate that inflammatory response genes, such as IL-1B, are upregulated in MRD-positive patients and that IL-2, IL-6, and IFNα responses and adipocyte differentiation are linked to (sustained) MRD negativity.

1. Boyle E, et al. Genomic and Immune Signatures Predict Sustained MRD Negativity in Newly Diagnosed Multiple Myeloma Patients Treated with Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone (D-KRd). Abstract 325, ASH 2021 Annual Meeting, 11–14 December.

 

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Posted on 4 February, 2022