As many as one third of newly diagnosed multiple myeloma (MM) cases are classified as high risk, with widely varying rates of progression-free survival (PFS), as shown in a validation of consensus recommendations that were proposed for revised genomic criteria of high-risk MM.

“We found the presence of each of the criteria independently reduces progression-free survival compared with standard-risk patients,” said first author Anais Schavgoulidze, PharmD, PhD, a medical biologist with IUCT Oncopole Toulouse, in Toulouse, France. She presented these findings at International Myeloma Society’s 2025 annual meeting in Toronto in mid-September.

“Furthermore, patients cumulating several criteria had an even worse prognosis,” Schavgoulidze noted.

In routine practice, the current tool for defining high-risk MM is the Revised International Staging System (R-ISS), utilizing serum biomarkers and chromosomal abnormalities, assessed with fluorescence in situ hybridization.

However, some criteria are based on older therapies and fail to address rapidly evolving advances such as novel triplet or quadruplet therapies, new insights on molecular and genomic prognostic factors, and stratification tools that are increasingly improving prognostic capabilities.

In recommendations published in June in the Journal of Clinical Oncology, the International Myeloma Society/International Myeloma Working Group outlined a proposed Consensus Genomic Staging (CGS) definition for high-risk MM that consists of five key criteria:

• Del(17p) and/or a TP53 mutation
• A bi-allelic del(1p32)
• A combination of t(4;14), t(14;16), or t(14;20), and either a gain of 1q or a monoallelic del(1p32)
• A combination of 1q gain and mono-allelic del(1p32)

In addition, the criteria include a nongenomic factor: the presence of a high beta2-microglobulin level (≥ 5.5 mg/L) in the context of normal renal function (creatinine < 1.2 mg/dL).

Validation of Proposed High-Risk Criteria

To validate the model, the groups performed next-generation sequencing on 6528 patients with newly diagnosed MM between 2019 and 2024, which showed that 22.4% had high-risk MM at diagnoses according to the CGS criteria.

Of 1583 analyzed at their first relapse, the rate of high-risk MM was 36.7% with the new criteria.

Among the patients, 2695 were available for an assessment at a median 35-month follow-up. Their median age was 67 years, 57% were men, and 42% received stem cell transplants.

Using the criteria, the median rate of PFS at the follow-up was 30 months in the high-risk group compared with 51 months in the standard-risk group (HR for high-risk vs standard risk, 2.11; P < .0001).

Among patients receiving stem cell transplants, the median PFS was 47 months for high-risk cases vs 62 months for non-high-risk patients (HR, 2.12; P < .0001).

Compared With R-ISS

In further comparison of the prognoses with those that used the R-ISS criteria, Schavgoulidze noted that 18.2% of patients who would have been considered standard-risk using R-ISS became high-risk when applying the CGS criteria.

Conversely, 8% of patients who were considered high-risk with the R-ISS became standard-risk using the CGS, for a total of 10% of the cohort being reclassified as high-risk under the new system.

A significant reduction in PFS was observed with each of the five genomic criteria compared with standard-risk patients.

Patients presenting with multiple criteria had worse prognoses. While those assessed as standard-risk based on CGS criteria had a PFS of 51 months, the PFS of those assessed with one high-risk criteria dropped to 34 months. Those having two criteria were associated with 20-month PFS, and in those having three high-risk criteria, the probable PFS dropped to just 7 months.

Among the 7.3% of patients who were classified as high-risk according to CGS criteriaof having beta2-microglobulin while having normal renal function, no significant differences in PFS were observed between those with high beta2-microglobulin and normal beta2-microglobulin levels.

Overall, with the new classification, “around 23% of high-risk patients [are determined] with genomics only, and 30% are determined including the beta2-microglobulin criterium,” Schavgoulidze said.

She noted that “the high-risk group is very heterogenous, with PFS of subgroups ranging from 12 months to 32 months.” 

New Criteria a ‘Clear Step Forward’

Commenting on the report about the new criteria at the meeting, Jill Corre, MD, also of the University Hospital, IUCT Oncopole, Toulouse Cancer Research Center, noted that “traditional factors no longer capture prognosis accurately in the era of triplets and quadruplets.”

Furthermore, “there is a lack of uniformity in the definition of high-risk myeloma across clinical studies, in nonclinical research, and in routine practice,” she said. The new consensus can therefore represent “a breakthrough in improving the outcomes of high-risk patients.” 

Caveats include that the high-risk definition “is a simplification of a very complex reality, and we still have a lot of work to challenge this definition with many other prognostic aspects of the disease,” Corre noted.

However, “it is a clear step forward because now we have the opportunity to speak the same language when it comes to high risk in myeloma,” she said.

Further commenting on the findings, Jonathan Keats, PhD, an assistant professor in the Cancer Genomics and Therapeutics Division and director of the Bioinformatics and Collaborative Sequencing Center at the Translational Genomics Research Institute, which is part of the City of Hope Center in Phoenix, said that the criteria have important implications.

He told Medscape Medical News that, “for the clinic today, this [criteria] really changes how you leverage genetic results in your patient visits. In addition, it helps to standardize clinical trials on the group of patients with notably poor outcomes,” he said.

“In the past seeing t(4;14) or t(14;16) was considered a high-risk marker, but now it must exist with a 1p32/CDKN2C deletion or 1q21 gain,” he added. “So we need to ensure patients have all of these tests so you can properly council patients and propose appropriate clinical trials.”

One limitation is that most of the studies occurred in the past, “so even though the suggestion is that the median outcome is 5 years for these high-risk patients, that was largely before the availability of CAR T and T-cell engager therapies, and frequently before the availability of CD38 therapies, so patient outcomes even for this subgroup will likely be better than we suggest today,” Keats said.

“I think we were all surprised by how high levels of beta2-microglobulin still identified a subset of patients with poor outcomes who did not have one of the genomic features detected,” Keats added. “I personally suspect a sizeable proportion of those cases do have events in these markers but were undetectable by the legacy methods.”

“Ultimately, this uniform definition will help the field identify optimum therapies and ultimately tailor therapy for these difficult to manage patients,” said Keats, who also serves as scientific director of the Judy and Bernard Briskin Center for Multiple Myeloma Research at City of Hope.

Schavgoulidze disclosed ties with Sanofi, Amgen, and Menarini Stemline. Corre reported relationships with Amgen, Celgene, Janssen, Sanofi, Takeda, Bristol Myers Squibb/Celgene, Pfizer, and AbbVie. Keats reported serving as project lead for the MMRF CoMMpass study that provided significant data to justify development of the new model, which he helped author. He also disclosed ties with Illumina Inc.