Myeloma Genomics and Microenvironment and immune profiling

Single nucleotide variants in PTPRD, NOTCH4, SH3RF3, DCC, and CSMD genes as potential prognostic biomarkers of newly-diagnosed multiple myeloma.

P-212: Single nucleotide variants in PTPRD, NOTCH4, SH3RF3, DCC, and CSMD genes as potential prognostic biomarkers of newly-diagnosed multiple myeloma.

Friday, September 27, 2024

David Garrido, MD

Hematology fellowship
Hospital de Clínicas Dr. Manuel Quintela
Montevideo, Montevideo, Uruguay

Introduction: Monoclonal gammopathy of uncertain significance (MGUS) is a premalignant condition that may progress to diverse neoplasms or monoclonal gammopathies, with active multiple myeloma (MM) being the most frequent

Aims: To analyze the differences of single nucleotide variants (SNVs) frequencies between MGUS and MM patients by microarray genomic analysis, and its discriminatory capability.

Methods: This retrospective study included 56 newly-diagnosed MM (NDMM) patients
(median age: 57.5 years, ISS-3: 30.4%), with 57.2% undergoing frontline autologous stem
cell transplantation (ASCT). PIR were distributed as follow: complete response (CR) 25%,
very good partial response (VGPR) 33.9%, partial response (PR) 26.8%, and stable
disease/refractory (<PR) 14.3%. Early relapse (ER; within 24 months) occurred in 48.2%
cases. Genomic DNA was purified from peripheral blood or bone marrow cells by
conventional methods. SNVs were analyzed using the Illumina Infinium GSA on the Illumina
iScan Platform which contains 654,027 markers. Binary Discriminant Analysis (BDA),
Principal Components Analysis (PCA), and k-means clustering were employed. The PIR was
assessed per IMWG recommendations.

Results: The analysis of the entire cohort showed 692 SNVs that were able to differentiate
between the various PIR groups (Dim1 11.2%, Dim2 6.8%) (t.score > 3). Among the 42 most
significant SNVs (t.score > 4), five are for PR, and 33 are for (<PR). Of these, 60% and 12%,
respectively, have been associated with tumoral activity. On the other hand, in patients who
received ASCT (n=32), 151 SNVs effectively discriminated between ER and non-early
relapsed (NER) (Dim1 34.7%, Dim2 6.5%) (t.score > 3). Among them, we found 12
overlapping SNVs between ER and ≤PR. Patients hetero- or homozygous for the alternative
allele (Group A; n=9) carrying PTPRD (rs12343415, rs77411943, rs10978084), NOTCH4
(rs8192588), SH3RF3 (rs76256617), DCC (rs72920200), and CSMD1 (rs11781684) variants
had a higher ≤PR rate (88.9%) compared to cases homozygous for the reference allele
(Group B, n=47) (34%) (p=0.005). Group A also had a higher ER rate (88.9%) versus 40.4% of
Group B (p=0.021). Additionally, in a multivariate analysis including first-line ASCT and ISS,
Group A had worse overall survival (p=0.008) and progression-free survival (p=0.017).

Conclusions: Our analysis showed that a significant number of SNVs detected by a wide
genotyping through microarray technology can classify patients with different PIR groups. In
addition, even with a limited number of patients, our results suggest that the presence of
alternative alleles in specific SNVs may be associated with inferior induction response, PFS,
and OS in NDMM. These findings suggest the potential predictive role of our genomic
analysis and the clinical relevance of SNVs in MM. However, more studies are required to
corroborate our results.

Financing.: IMS and The Paula and Rodger Riney Foundation.