Study on the Molecular Genetic Characteristics of Multiple Myeloma Patients in China
Authors: Yang Yang , He Jingsong , Zheng Gaofeng , Han Xiaoyan , Nie Yang , Sun Li , Ma Haoran , Wu Ying , Zhang Jie , Cai Zhen 
Published: December 2024

Background:
Multiple myeloma (MM) is a clonal plasma cell malignancy characterized by significant heterogeneity in genetic abnormalities. To further investigate the genetic mutation characteristics and related clinical significance of MM in the Chinese population, we performed targeted genes sequencing in newly diagnosed MM patients.
Methods
93 MM patients are enrolled from May 2022 to December 2023 at the First Affiliated Hospital of Zhejiang University. Plasma cells were enriched from bone marrow using CD138 magnetic beads, and DNA was extracted for targeted sequencing of 254 genes. The targeted panel covers genes related to MM disease progression, clonal evolution, risk stratification, and targeted therapy.
Results
The basic clinical characteristics were as follows: the median age at diagnosis was 65 years (range 32-87), and 63.4% of the patients were male. The distribution of M protein types was as follows: IgG (63.4%), IgA (19.4%), IgD (3.2%), kappa (6.5%), and lambda (7.5%). Regarding the Revised International Staging System (R-ISS), the distribution of stages was as follows: Stage I (18.2%), Stage II (56.8%), and Stage III (25.0%). 45.5% of the patients exhibited 1q abnormalities, 22.7% had IGH rearrangements, and 9.9% showed other chromosomal aberrations. After 4 cycles of treatment, 79.6% of the 64 evaluable patients achieved Very Good Partial Response (VGPR) or better.
Mutation burden analysis in MM patients revealed a median of 11 gene mutations per patient (range 0-31), with λ type MM showing the highest mutation burden. Patients who did not achieve VGPR had a significantly higher mutation burden compared to those achieving VGPR or better treatment responses (14.6 vs 10.4, P=0.03). This suggests that mutation burden may indicate disease severity and treatment prognosis Signaling pathway analysis highlighted key pathways like RTK-RAS, Hippo, NOTCH etc. RTK-RAS genes dominated (69.89%), with KRAS mutations (32%) activating this pathway. Hippo pathway mutations (43.01%) included FAT1/3/4 alterations inhibiting Hippo signaling.
We conducted correlation screening on the gene mutation spectrum and clinical characteristics. The diversity of mutation types of the ZFHX3 gene ranks first among the top 20 genes. IGLL5 mutations were found in high-risk cytogenetics, notably in R-ISS stages II/III. TRAF3 mutations, common in R-ISS stage III and lambda MM, may signify elevated tumor burden. MSH3 mutations, frequent in stages II/III but absent in IgA MM. Cluster analysis revealed intriguing gene combinations in MM patients: IGLL5 and TRAF3 mutations co-occur, showing a strong genetic correlation (P&lt;0.05). ZFHX3 and MSH3 mutations also co-occur, suggesting a strong genetic correlation (P&lt;0.05).
Conclusions
Molecular genetic characteristics of multiple myeloma patients in China were analyzed through targeted sequencing of 254 genes, revealing diverse gene mutations associated with disease progression and prognosis. This study highlights the clinical relevance of specific gene mutations in MM and emphasizes the predictive value of comprehensive mutational profiling in disease prognosis.