Cytogenetic testing in newly diagnosed multiple myeloma (NDMM): Real world evidence of adverse outcomes for high risk groups.

Abstract Aim: To compare baseline characteristics, treatments and outcomes in newly diagnosed multiple myeloma (NDMM) patients based on the number of high-risk cytogenetic abnormalities (HRCA) present. Method: We analyzed Australian and New Zealand Myeloma and Related Diseases Registry (MRDR) patients from 2012 to 2025 with NDMM and fluorescent in situ hybridization (FISH) cytogenetic data available. Patients were grouped based on the number of HRCA present (HRA0, HRA1 and HRA2+), including t[4;14], t[14;16], del[17p] and gain[1q]. Results: Of 5927 NDMM patients identified on the MRDR, 3397 (57%) patients had available myeloma FISH results which were categorised into HRA0 (2406, 70.8%), HRA1 (808, 23.8%) and HRA2+ (183, 5.4%). Patients with multiple HRCA were more likely to be female, have higher lactate dehydrogenase (LDH) and β2-microglobulin levels at diagnosis. Patients with 2 or more HRCA were more likely to present with anaemia (haemoglobin <100 g/L), thrombocytopenia and greater bone marrow plasma cell burden at diagnosis (p<0.001). Paraprotein subclass also differed across the groups; patients with increasing HRCA were more likely to produce IgA paraprotein (17.1% HRA0 vs 33.3% HRA2+) and less likely to produce IgG paraprotein (59.7% HRA0 vs 44.8% HRA2+) [p<0.01]. There was no statistically significant difference between the groups in the incidence of bone disease, white cell count or renal function (median serum creatinine) at diagnosis. The cumulative presence of HRCA at diagnosis was associated with shorter progression-free survival (PFS) [median 35.6 months for HRA0, 25.7 for HRA1 and 20.2 for HRA2+ (p<0.001)]. Similarly, increasing numbers of HRCA correlated with poorer overall survival (OS) [median OS was 86.1, 56.6 and 37.5 months respectively (p<0.001)]. Overall survival was significantly worse for those with del(17p) as the only HRCA compared to other single HRCA. However, the addition of other HRCA with del(17p) did not affect OS compared to del(17p) alone. Patients with gain(1q) were more likely to have concurrent del(17p) than those without gain(1q) (12.7% vs 6.3%, p<0.001). Most patients in each HRCA group received bortezomib-based first-line therapy in combination with cyclophosphamide or lenalidomide. Despite similar overall response rate across the HRCA groups (84% HRA0, 87% HRA1, 88% HRA2+), the duration of treatment response was significantly shorter with increasing HRCA burden [median duration: 30.9 months (HRA0), 19.1 months (HRA1), 16.8 months (HRA2+)(p<0.001)] Conclusion: This real-world data confirms that increasing HRCA burden in NDMM is associated with distinct disease characteristics and poorer clinical outcomes, including shorter PFS and OS despite similar overall response rates between the three groups. However, the addition of other HRCA with del(17p) did not affect OS compared to del(17p) alone which remained to greatest risk single HRCA.