Whole-genome analysis identifies novel drivers and high-risk double-hit events in relapsed/refractory myeloma

Abstract

Large-scale analyses of genomic data from newly-diagnosed multiple myeloma patients (ndMM) have been undertaken, however, large-scale analysis of relapsed/refractory multiple myeloma (rrMM) has not been performed. We hypothesize that somatic variants chronicle the therapeutic exposures and clonal structure of myeloma from ndMM to rrMM stages. We generated whole genome sequencing (WGS) data from 418 tumors (386 patients) derived from six rrMM clinical trials and compared them with WGS from 198 unrelated ndMM patients in a population-based case-control fashion. We identified significantly enriched events at the rrMM stage, including drivers (DUOX2, EZH2, TP53), biallelic inactivation (TP53), non-coding mutations in bona fide drivers (TP53BP1, BLM), copy number aberrations (CNA; 1qGain, 17pLOH) and double-hit events (Amp1q-ISS3, 1qGain-17pLOH). Mutational signature analysis identified a subclonal defective mismatch repair signature enriched in rrMM and highly active in high mutation burden tumors, a likely feature of therapy-associated expanding subclones. Further analysis focused on the association of genomic aberrations enriched at different stages of resistance to immunomodulatory agent (IMiDsÒ)-based therapy. This analysis revealed that TP53, DUOX2, 1qGain and 17pLOH increased in prevalence from ndMM to lenalidomide (LEN)- to pomalidomide (POM)-resistant stages while enrichment of MAML3 along with IGL and MYC translocations distinguished POM from the LEN subgroup. Genomic drivers associated with rrMM are those that confer clonal selective advantage under therapeutic pressure. Their role in therapy evasion should be evaluated further in longitudinal patient samples, to confirm these associations with the evolution of clinical resistance and to identify molecular subsets of rrMM for the development of targeted therapies.

Quantitative Analysis of Whole‐Body MRI for Accessing the Degree of Diffuse Infiltration Patterns and Identifying High Risk Cases of Newly Diagnosed Multiple Myeloma

“…3 Multiple prognostic factors affect the survival in multiple myeloma, of which cytogenetic markers represent the most significant prognostic factors. 4 The common prognostic systems for multiple myeloma encompass International Staging System (ISS) and Revised International Staging System (R-ISS). 21 R-ISS staging integrates ISS staging with high-risk cytogenetic abnormalities (HRCA) and LDH, but only encompasses three cytogenetic markers.…”

“…3 Cytogenetic abnormalities (CAs) have been included in myeloma risk stratification system as a major index for the assessment of risk profile in myeloma patients. 4 However, infiltration of bone marrow plasma cells is irregular, which increases the risk of false negatives when relying solely on bone marrow biopsy. 5 Additionally, the clinical and imaging characteristics of MM cases showed significant correlations with tumor burden and had a prognostic value, 6 which may help improve reproducibility and availability in the risk stratification of MM.…”

“…Early detection of disease progression and accurate risk stratification is important in improving HRMM prognosis 3 . Cytogenetic abnormalities (CAs) have been included in myeloma risk stratification system as a major index for the assessment of risk profile in myeloma patients 4 . However, infiltration of bone marrow plasma cells is irregular, which increases the risk of false negatives when relying solely on bone marrow biopsy 5 .…”

The genome of IMiD-refractory myeloma

“…In this issue of Blood, Ansari-Pour et al 1 present findings from their analysis on the largest whole-genome sequencing data set of relapsed and refractory multiple myeloma (rrMM), which comprised 418 tumor samples from 386 patients. The data were retrieved from 6 clinical trials that included patients refractory to lenalidomide and/or pomalidomide, which are 2 immunomodulatory imide drugs (IMiDs) that are commonly used therapeutics for newly diagnosed and relapsed patients with multiple myeloma (MM), respectively.…”

Impact of rare structural variant events in newly diagnosed multiple myeloma

“…Analysis of large datasets of clinically annotated WGS paired with RNA sequencing (RNA-seq) have allowed the interrogation of SVs within the MM genomic landscape. Multiple studies have shown a heavy SV enrichment in MM beyond the canonical SV events, which account for only a minor fraction of the full SV repertoire [11][12][13][14]. Interestingly, the MM SV landscape shows a high prevalence of chromothripsis and chromoplexy, and has one of the highest prevalence of templated insertions described in cancer [12,15].…”