(PA-403) Predictors of High-Risk and Ultra High-Risk Multiple Myeloma from the Australia & New Zealand Myeloma and Related Diseases Registry (MRDR).

Introduction:  A significant proportion of newly diagnosed myeloma patients(NDMM) have high-risk multiple myeloma(HRMM): overall survival (OS) < 5y, and ultra high-risk MM(UHRMM), variably defined as OS < 2-3y. This study aims to define the predictors of HRMM and UHRMM based on overall survival, in NDMM in MRDR, a prospective registry involving 60 sites across Australia and New Zealand, from 2012 to 2020.

Methods:   NDMM patients with >5 years follow up were included, and classified into UHRMM, HRMM and SRMM (standard risk MM) according to OS < 3y, 3-5y and >5y respectively. Baseline demographics and clinical characteristics were compared using Pearson’s chi square test; survival analyses with Kaplan Meier method; univariate and multivariate logistic regressions used to identify predictors of HR disease.

Results:   In 2649 patients analysed, median OS and PFS were 80m (IQR 37m – NR) and 33m (IQR 16m – 67m), respectively. 24% had UHRMM, 13% HRMM and 63% SRMM. Most patients received frontline VCd (71%) with only 7% treated with Rd and 2% with VRd. 17% were primary refractory (PR) to frontline therapy and 20% had early relapse (ER) within 12m of diagnosis. PR patients were older with no difference in performance status (PS), ISS or presence of high risk cytogenetics abnormalities (HRCA); 70% had no HRCA, consistent with well-defined functional high risk (FHR) disease. ER patients were older, had worse PS, higher ISS, more end organ damage and t(14;16). When analysing patients based on OS, those with UHRMM and HRMM were older with poorer PS, higher ISS, more end organ damage, high risk cytogenetic abnormalities (HRCA) and co-morbidities than patients with SRMM. When comparing the two high risk groups, patients with UHRMM were older than those with HRMM with worse PS, more hypercalcaemia, renal insufficiency and cardiac disease. With regards to treatment and response, UHRMM patients were less likely to receive frontline ASCT consistent with the age difference and there was a higher proportion of PR and ER compared to the HRMM group. Multivariate regression (MVR) identified age >70 years, ECOG PS, ISS, presence of 1 HRCA as predictors of UHRMM and HRMM when compared to the SRMM group. Within the UHRMM group, presence of 2 or more HRCA was identified on MVR as predictive of UHRMM when compared to HRMM and SRMM groups. ASCT did not abrogate the increased risk associated with poor PS, high ISS stage and HRCA in the UHRMM group when compared to HRMM and SRMM groups.

Conclusions:   This large real-world cohort treated prior to the availability of VRd therapy, highlights the inferior survival in over 1/3 of patients with NDMM. Whilst age, PS, ISS and HRCA remain important predictors of high-risk disease, patients with FHR, who remain difficult to accurately define at diagnosis, account for a significant proportion of the high risk cohort, a major barrier to pursuing frontline risk adapted therapy.