KEY TAKEAWAYS
- The phase II trial aimed to identify genomic predictors of progression in HR SMM patients undergoing upfront treatment to inform treatment strategies and improve outcomes.
- NGS and FISH analyses were conducted on bone marrow for genetic markers linked to disease progression in HR SMM.
- Findings suggest t(4;14) with FGFR3 or NRAS mutations predict treatment resistance and hasten progression.
While the risk of progression from smoldering multiple myeloma (SMM) to multiple myeloma (MM) varies, existing risk models are primarily based on clinical factors. Genomic predictors of SMM progression have been identified, but their role in predicting treatment outcomes in high-risk SMM (HR SMM) remains unclear.
For this study, researchers aimed to identify genomic predictors of progression in HR SMM patients undergoing upfront treatment to inform treatment strategies and improve outcomes. They conducted Next-Generation Sequencing (NGS) and Fluorescence In Situ Hybridization (FISH) analyses on 57 HR SMM patients enrolled in the GEM-CESAR trial.
The CD138+ plasma cells were isolated from bone marrow, and after DNA extraction, a customized NGS panel targeted 145 Kb across 666 regions in 38 genes linked to MM. This facilitated the detection of single nucleotide variations (SNVs) and insertions/deletions (indels). FISH studies included probes for identifying specific alterations such as t(4;14), t(14;16), del17p, t(11;14), +1q, del1p, and structural aberrations in the MYC locus.
About 44 patients met the current criteria for HR SMM (HR SMM) at diagnosis, while the remaining 13 cases, initially classified as ultra-high risk (UHR), exhibited active disease at baseline under the updated criteria. The median number of SNV and indels per patient was 1 (range: 0–9), with 19.3% of patients (11/57) harboring no alterations in the studied genes.
The mutational profile predominantly featured well-known drivers in MM, such as (KRAS, NRAS, DIS3, and FAM46C). Mutations in the MAPK pathway genes were most prevalent (52.6%), followed by those involved in RNA and protein processing (22.8%). About 7 patients exhibited multihit mutations within the same gene. Concerning cytogenetics, frequencies were comparable to symptomatic MM, with certain aberrations enriched in HR SMM compared to the general SMM population (specifically t(4;14) and +1q).
Conversely, 1p deletions were infrequent (3.8%), and double-hit TP53 alterations were absent. FGFR3 mutations often coexisted with t(4;14): 7 out of 8 cases with FGFR3 mutations also had the translocation. Previously identified risk factors for progression in SMM(mutations in the MAPK pathway, structural alterations affecting MYC, and aberrations in the DNA repair pathway).
NRAS mutations (HR: 5.45, 95% CI: 1.57–18.93, P=0.008) and the co-occurrence of t(4;14) with FGFR3 mutations (HR: 6.75, 95% CI: 1.87–24.34, P=0.004) were associated with a higher risk of biological progression.
The result demonstrated that the presence of t(4;14) plus FGFR3 mutations or NRAS mutations in HR SMM patients may predict resistance to treatment and shorter time to disease progression.
Source: https://imsannual2023.eventscribe.net/fsPopup.asp?PresentationID=1302335&mode=presInfo
Clinical Trial: https://clinicaltrials.gov/study/NCT02415413
Medina-Herrera A, PhD. Postdoctoral Researcher, Departamento de Hematología, Hospital Universitario de Salamanca, (HUSA/IBSAL), Centro de Investigación del Cáncer-IBMCC (CSIC/USAL), CIBERONC, Salamanca, Castilla y Leon, Spain. Genomic profiling of high-risk smoldering myeloma patients treated with a curative strategy: a biological study of the phase II GEM CESAR clinical trial.
