Chromosomal abnormalities are found in most multiple myeloma (MM) patients. While myeloma patients have generally benefited from the advancement of treatment modalities over the years, the treatment outcome for patients having two or more high-risk prognostic events remains poor. In a novel step forward, a research team led by Professor Chng Wee Joo from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS) embarked on a study which aims to address the unmet clinical need in this group of patients.

The deletion of chromosome 17p13 (17p13(del)) and the gain of chromosome 1q21 (1q21(gain)) are long-standing independent high-risk biomarkers. However, the biological significance underlying the poor outcome in MM patients having co-occurrence of both chromosomal abnormalities has never been interrogated.

In the study recently published in Oncogene in February 2022, Prof Chng and his team uncovered that MM cells of patients harbouring concomitant 17p13(del) with 1q21(gain) have loss of functional p53 and NEIL1 respectively, both of which are important DNA repair genes. MM cells of this high-risk patient group demonstrated defective DNA damage response (DDR) associated with high genomic instability signature and persistent activation of Chk1 pathway.

Findings revealed that in the event of NEIL1 and p53 inactivation, cells would be highly dependent on the Chk1 pathway, suggesting a synthetic lethal relationship between p53-NEIL1-Chk1 abnormalities. Interestingly, this proof-of-concept study is one of the first in this high-risk myeloma patient subgroup.

Their findings present the biological and therapeutic relevance of Chk1 inhibition in targeting DDR and genomic instability, both of which are characteristic traits of high-risk patients with co-occurrence of the two chromosomal abnormalities. More importantly, discovering the Achilles' heel of this disease has opened doors for more effective and novel treatment modalities to address an unmet medical need of myeloma.

Moving forward, Prof Chng and his team are hoping to establish Chk1 inhibitors as the standard of care and targeted treatment for 17p13(del)-1q21(gain) high-risk patients. The team plans to further investigate the leverage of this genomic instability on the armamentarium of novel therapies in myeloma, including immune-based and cell therapy products.