A New Genomic Definition of High-Risk Myeloma, Validated in Thousands of Patients

A large French analysis presented at the 2026 COMy (Controversies in Multiple Myeloma) Conference has confirmed that a new international consensus for identifying high-risk multiple myeloma works as intended, and that around 30% of newly diagnosed patients fall into the high-risk category at diagnosis.

Treatments for multiple myeloma (a cancer of plasma cells in the bone marrow) have improved enormously over the past two decades. Projected progression-free survival (the time before the disease worsens) now reaches 17 years for transplant-eligible patients and 8 years for senior non-transplant patients. Even so, some patients still relapse early, and identifying them at diagnosis would allow doctors to match treatment intensity to risk.

To address this gap, the IMS/IMWG Consensus Genomic Staging (CGS) for high-risk myeloma was developed at a workshop in Barcelona in 2023. Dr. Jill Corre presented her group's validation of this consensus in thousands of French patients.

The consensus is not just one researcher's idea. It was agreed on by an international group of myeloma experts and published in the Journal of Clinical Oncology in 2025, with Dr. Corre among its authors. That paper laid out the exact genetic features that define high risk, and it is the framework her French study was designed to test. You can read the full consensus paper here.

How does the new consensus define high-risk myeloma?

Under the CGS, patients are considered high risk if their myeloma cells carry any of the following:

• Deletion 17p (loss of part of chromosome 17) in more than 20% of sorted plasma cells

• A TP53 mutation (a change in a key tumor-suppressor gene), whether clonal or subclonal

• Biallelic deletion 1p32 (loss of a specific region on both copies of chromosome 1)

• Any two of these intermediate abnormalities: translocations t(4;14), t(14;16), or t(14;20) (where parts of two chromosomes swap places), gain or amplification of 1q (extra copies of part of chromosome 1), or monoallelic deletion 1p32 (loss of the 1p32 region on one chromosome)

Patients with a high level of beta-2 microglobulin (a blood protein that reflects disease burden) in the context of normal kidney function are also considered high risk, even without these genetic markers.

How many patients are high risk?

Dr. Corre and her colleagues applied the consensus to 6,528 French patients newly diagnosed with myeloma. Using only the genetic criteria, 22.4% met the definition of high risk. When beta-2 microglobulin was added, the total rose to roughly 30%. At first relapse, the proportion was higher still, at 36.7%, reflecting how high-risk genetic features become more common as the disease progresses.

Among the genetic high-risk group:

• 40% had deletion 17p, with or without a TP53 mutation

• 12% had a TP53 mutation alone

• 6% had biallelic deletion 1p32

• 13% had 1q gain combined with monoallelic deletion 1p32

• Almost 30% had a translocation combined with a chromosome 1 abnormality

What do the survival numbers show?

For survival analysis, the researchers followed 2,695 patients diagnosed between 2019 and 2024 with 35 months of follow-up. About 41% received intensive treatment, and roughly half received daratumumab (a monoclonal antibody, which is a lab-made protein that targets myeloma cells). The CGS clearly separated outcomes:

• Median progression-free survival of 30 months for high-risk patients versus 51 months for standard-risk patients

• Among transplanted patients: 47 months for high-risk versus 62 months for standard-risk

• The classification also worked well in patients older than 75 years

Looking deeper, the team found that high-risk patients are not a uniform group. About 65% of them, mostly those with isolated TP53 abnormalities or combinations involving 1q gain, had a median progression-free survival of around 30 months. The remaining 35% had a much shorter median of about 16 months, including patients with double TP53 abnormalities or biallelic 1p32 deletion. Patients who accumulated three high-risk criteria had a median progression-free survival of just 7 months.

What about patients who don't fit the genetic criteria?

The study also identified a group the researchers called "functional high risk": 13% of patients who were classified as standard risk by genetics but still relapsed within 18 months. As Dr. Corre put it, "this is an important signal that we have to continue to improve our high-risk definition."

Other findings reinforced the importance of accurate risk identification. Even in patients who achieved undetectable minimal residual disease (MRD; meaning no cancer cells could be found using highly sensitive testing) the new classification still predicted differences in both progression-free survival and overall survival. A separate validation in more than 500 patients treated with daratumumab-based four-drug combinations produced similar results and also confirmed that kidney impairment, which is not part of the CGS, remains a poor prognostic factor.

Which tests can identify these genetic features?

Dr. Corre also discussed how laboratories can apply the new consensus. FISH (fluorescence in situ hybridization), a technique that uses fluorescent probes to detect specific chromosome changes, can identify several of the key abnormalities, and if two of four standard tests come back positive, a patient can be confidently called high risk. However, FISH has real blind spots when it comes to the new criteria. It cannot detect TP53 mutations, and it misses all cases of deletion 1p32, both the biallelic form (which on its own defines high risk) and the monoallelic form (which counts as an intermediate factor). Some very small, or "focal," deletions, such as certain forms of deletion 17p, can also be too tiny for FISH to pick up.

Next-generation sequencing (NGS), a technology that reads large amounts of DNA at once, can capture more of the relevant information in a single test. Whole genome sequencing may eventually become the preferred approach, as it can also identify newer prognostic features such as the APOBEC hypermutation signature, MYC events, and genomic scar scores that other techniques cannot detect.

Why does this matter for patients?

Closing her talk, Dr. Corre stressed why early identification of high-risk patients matters. The first line of treatment is probably the best opportunity to make a difference, and even patients with undetectable disease are not currently taken off therapy. Accurately identifying high-risk patients also makes it possible to recognize the truly standard-risk patients, who may benefit from treatment de-escalation.

She called for the new consensus to be used in all clinical trials going forward, noting that with 30% of patients meeting high-risk criteria, "it is enough to make a clinical trial." Her hope, she said, is that "the true progress will consist of eradicating high-risk myeloma with a good drug."

Key takeaway

If there's one thing worth taking away from this research, it's that doctors now share a common way of spotting which myeloma patients may be more likely to relapse early, and a large French study suggests it really does help tell these patients apart.

About 30% of people newly diagnosed with myeloma fall into this higher-risk group, either because of certain genetic features in their myeloma cells (like deletion 17p, a TP53 mutation, or biallelic deletion 1p32) or because they have high beta-2 microglobulin levels along with normal kidney function.

These patients tend to have shorter periods of disease control, even with today's stronger four-drug combinations. That's why knowing your risk status early matters: the first treatment is often the best chance to get ahead of the disease. If you've been diagnosed with myeloma, it can be worth asking your care team about the genetic tests that look at these features, whether that's FISH or next-generation sequencing.