Double-Hit: a subgroup of high-risk newly diagnosed multiple myeloma patients

Newly diagnosed multiple myeloma (NDMM) patients (pts) with high-risk disease have a median overall survival (OS) of less than three years. This compares poorly to the median OS of patients with low-risk disease, which is around 10 years and calls for effective new treatments. Currently, high-risk patients are identified on the basis of multiple clinical, cytogenetic or gene expression features. However, each of these approaches includes certain caveats. Taking into account molecular features into MM risk stratification can provide a better means for identifying high-risk NDMM pts, offering them in a timely manner innovative treatments directed to their unmet medical needs.

In a study published in Leukemia, Brian A. Walker from the Myeloma Institute, University of Arkansas, Little Rock, US, Konstantinos Mavrommatis from the Celgene Corporation, San Francisco, US and Christopher P. Wardell from the Myeloma Institute, University of Arkansas, Little Rock, US, and colleagues,  identified “Double-Hit myeloma”, a new high-risk group of NDMM pts with very poor survival outcomes, despite treatment with novel therapies. Using data from 784 pts from the Myeloma Genome Project, the authors integrated genomic and clinical data into a Cox statistical model and used recursive partitioning, a statistical decision tree method, to identify this new myeloma subgroup. For this, they used either a) bi-allelic TP53 inactivation or b) amplification (≥4 copies) of CKS1B (1q21).

Key Data:

• Number of pts = 784; 27% of pts International Staging System (ISS) Stage III
• Age = <75 years; 45% 65­–74 years
• Number of Double-Hit pts = 48 of which 27 pts (56.3%) ISS III; 24 pts (50%) ≥ 65 years; 30 pts (62.5%) bi-allelic inactivation of TP53; 21 pts (43.8%) amplification of CKS1B
• Median PFS and OS of Double-Hit pts = 15.4 months and 20.7 months, respectively
• Double-Hit pts with available treatment = 34 of which 29 pts (85%) received a ≥ three-drug induction regimen with 15/34 pts (44%) being a triplet
• Outcomes for double-hit pts were similar whether they were IMWG high-risk or IMWG low/standard risk
• Bi-allelic alteration of TP53 is present in 3.7% of NDMM and is associated with very poor outcome
• TP53 mutations = missense mutations in the DNA binding domain
• Amplification of 1q (amp1q) ≥ 4 copies associated with significantly poorer outcomes, especially on a background of ISS III

This study highlights the need for a more precise definition of NDMM pts with high-risk disease. Given that the Double-Hit subgroup has an even worse prognosis than the previously defined high-risk group, it may be worth including analysis of these two features to identify better high-risk patients in order to provide them with optimal treatment/clinical trial options as early as possible.