(PA-463) Poor Outcomes in Extramedullary Multiple Myeloma Persist Despite Novel Therapies

Extramedullary disease (EMD) arises in 10-30% of multiple myeloma (MM) patients, and is associated with poor survival. EMD arising via haematogenous spread is particularly aggressive yet remains poorly characterised due to limited cohort sizes. We conducted a retrospective cohort study to define clinical presentation, treatments and outcomes.


Methods:

85 patients with EMD arising by haematogenous spread were included, diagnosed between June 2009 and September 2024. Clinical features, treatment exposures and survival outcomes were obtained.


Results:

Twelve patients (14%) had primary EMD. The median age of the cohort was 58 years, and 61% were male. Notably, 48.2% (n=41) demonstrated lambda light chain restriction, increased relative to BM-restricted MM. The most frequent anatomical sites at diagnosis were muscle (30.6%), liver, pleura and lymph nodes (all 26%), with a median of 2 anatomical sites (range 1-8).

Secondary EMD occurred a median of 36 months (range 1-159) after MM diagnosis, following a median of 3 prior lines of therapy (range 1-11). 80% were proteasome inhibitor exposed, 83% immunomodulatory agent exposed and 70% had undergone autologous transplantation. Median overall survival (mOS) from EMD diagnosis was 11 months and 26 months for secondary and primary EMD, respectively. From initial MM diagnosis, mOS in secondary EMD was 4.5 years. There was no improvement in survival over three eras of therapy (2009-2013, 2014-2018, 2019-2024) despite increasing use of novel and immunotherapies with mOS 16, 11 and 11 months, respectively (p=0.7608).

Interpretation of therapy outcomes is limited by the treatment landscape and drug reimbursement in the Australian setting. The median time to next therapy (TTNT) after first line EMD treatment was 17 weeks; (22 and 16 weeks in primary and secondary EMD respectively). There was no significant shortening of TTNT with second and subsequent lines (p=0.544). The use of anti-CD38 monoclonal antibodies was associated with shorter TTNT (HR 2.83, p=0.035). Regimens including radiotherapy were associated with longer TTNT (HR 0.096, p=0.007); this may reflect bias towards low disease burden. 25% of patients died before second line therapy, and < 25% of patients reached fifth-line therapy. There was no improvement in TTNT with the use of novel therapies including bispecific antibodies and drug antibody conjugates (21 weeks, p=0.416).


Conclusions:

This is one of the largest EMD cohorts reported to date. The high rate of lambda restriction suggests distinct biology and warrants further investigation. Secondary EMD is preceded by rapid progression through therapies, suggesting innate resistance in patients destined for EMD development. Despite major improvements in outcomes in bone marrow restricted MM with newer agents, the outcomes in EMD remain dismal. This underscores the need for better understanding of EMD biology and the development of targeted therapeutic strategies.