(OA-33) High-Risk Genomic Consensus Model Validation in a Large Cohort of Newly Diagnosed Multiple Myeloma Patients Using Next Generation Sequencing

The prognostic heterogeneity of multiple myeloma is mainly driven by genomic features of myeloma cells. The International Myeloma Society (IMS) / International Myeloma Working Group (IMWG) recently proposed a revised high-risk (HR) genomic model in order to have a consensus definition of genomic risk. Patients are classified HR if they present (i) del(17p), or (ii) a TP53 mutation, or (iii) a bi-allelic del(1p32), or (iv) a combination of t(4;14) or t(14;16) or t(14;20)/ and either a gain of 1q or a monoallelic del(1p32), or (v) a combination of 1q gain and mono-allelic del(1p32).

Methods: In order to validate this new definition, we performed NGS panel in 6735 new diagnosed myeloma patients (NDMM) and 1588 patients at first relapse, between 2019 and 2024. Only patients with a minimal 18-month follow-up were kept for PFS analyses, thus 2703 patients.

Results:

We observed that 23.9% of patients at diagnosis and 36.7% at first relapse were HR according to the IMS/IMWG genomic consensus. The IMS/IMWG consensus added a non-genomic factor to the HR definition: a high beta2 microglobulin level (≥ 5.5mg/L) in the context of normal renal function (creatinine < 1.2mg/dL). In our NDMM dataset, beta2-microglobulin and serum creatinine levels were available for 3565/6735 patients. We observed that 257 non-HR patients (7.2% of the global cohort) met these criteria. Overall, according to the IMS/IMWG consensus, almost a third (31.4%) of NDMM patients should be considered as high risk.

After a median follow-up of 35 months, the median PFS was 29 months for HR NDMM patients, versus 51 months for non-HR cases (p< 0.0001). When restricted to transplanted patients, the median PFS was 62 months for non-HR patients, versus 47 months for HR cases (p< 0.0001, median follow-up of 38 months). HR cytogenetic criteria from the Revised-ISS score (del(17p), t(4;14) and t(14;16)) were not able to discriminate patients in HR nor SR IMS/IMWG genomic subgroups. Looking at each criteria independently, we found that the presence of del(17p), TP53 mutation, biallelic del(1p32), or the combination of intermediate risk cytogenetics (gain 1q, del(1p32), and translocations) significantly reduces the PFS compared with standard-risk patients. Moreover, patients cumulating several criteria had an even worse prognosis (one criteria vs 2 or more criteria, median PFS respectively 33 and 10 months). Among standard-risk patients according to the genomic definition with normal creatinine, median PFS of those with high beta2-microglobulin was not significantly different from patients with normal beta2-microglobulin level.

Conclusions: This study validates the IMS/IMWG genomic definition of high-risk myeloma in a large cohort of patients diagnosed from 2019.