New consensus criteria for the genomic staging of high-risk multiple myeloma have been externally validated in a real-world Australian cohort, identifying about a quarter of newly-diagnosed patients have a poor prognosis.

The International Myeloma Society/International Myeloma Working Group Consensus Genomic Staging (IMS/IMWG CGS) was proposed last year to standardise risk stratification in the era of novel therapies, informed by the latest clinical, biological, and molecular/genomic evidence and risk tools.

Under the criteria, high-risk disease is defined by at least one of the following abnormalities:

1. del(17p), with a cut-­off of >20% clonal fraction, and/or TP53 mutation
2. an immunoglobulin heavy chain (IgH) translocation including t(4;14), t(14;16) or t(14;20) along with 1q21+ and/or del(1p32)
3. monoallelic del(1p32) along with 1q21+ or biallelic del(1p32)
4. or beta-­ 2 microglobulin ≥5.5 mg/L with normal creatinine (<1.2 mg/dL)

Australian haematologists assessed a modified version of the criteria (mod-­IMS/IMWG CGS-­HR) using 832 patients from the Australia and New Zealand Myeloma and Related Diseases Registry, of whom 567 had a determinable risk status (166 high risk and 401 standard risk).

The criteria were slightly altered due to the lack of routine NGS testing for TP53 mutation and biallelic del(1p32), noted the team led by the Australian Centre for Blood Diseases at Monash University and the Alfred Hospital in Melbourne.

Of the 112 high-risk patients with complete data, 21%, 20%, 25% and 35% satisfied only one of criterion 1, 2, 3 or 4, respectively, and 13% met two or more criteria. Patients with high-risk disease had higher rates of stage 3 or 4 disease using the previous prognostic scoring systems (ISS, R-ISS, and R2-ISS).

High-risk patients had worse overall and progression-free survival, and nearly double the hazard of death (HR 1.90; 95% CI 1.41–2.55; p < 0.001).

Patients who satisfied more than one high-risk criterion fared even worse (median OS 37.0 months (11.0-­ NR) and PFS 15.6 months (95% CI 5.5-­ NR)).

Subgroup analyses showed high-risk status predicted significantly inferior survival in patients who were transplant-eligible, non-­frail, and with normal renal function, but did not produce statistically significant results for the transplant-­ineligible, frail or renally impaired subgroups.

“These findings suggest that the mod-­IMS/IMWG CGS-­HR criteria may have reduced discriminatory value in populations where competing clinical risk factors dominate prognosis,” the researchers wrote in a research letter published in the British Journal of Haematology [link here].

“Given that frailty and renal impairment remain common and understudied risk modifiers, this observation is particularly relevant when considering risk-­adapted treatment strategies that incorporate IMS/IMWG CGS-­ HR for treatment intensification or stratification.”

High-risk status predicted significantly worse survival in:

• Transplant-eligible patients (HR 2.73, 95% CI 1.62–4.58; p<0.001)
• Non-frail patients (HR 3.22, 95% CI 1.98–5.24; p<0.001)
• Patients with normal kidney function, creatinine under 1.2 mg/dL (HR 2.33, 95% CI 1.59–3.43; p<0.001)

It did not reach statistical significance in:

• Transplant-ineligible patients (HR 1.32, 95% CI 0.88–1.97; p=0.18)
• Frail patients (HR 1.36, 95% CI 0.93–1.98; p=0.11)
• Patients with renal impairment, creatinine 1.2 mg/dL or higher (HR 1.50, 95% CI 0.93–2.41; p=0.09)

They also stressed that while the criteria captured biological high-risk disease, a substantial proportion of patients with functional high-­risk disease were unrecognised at diagnosis, reinforcing the need for early treatment response metrics during front-­line therapy alongside genomic risk models.

One major limitation of the study was the absence of quadruplet regimens in the dataset, limiting its applicability to contemporary treatment settings.