Hepta-refractory multiple myeloma, a newly defined end-stage entity, is marked by profound genomic complexity and antigen loss. This condition describes patients resistant to multiple drug classes, including CD38 antibodies, immunomodulatory drugs, proteasome inhibitors, and targeted immunotherapies like BCMA and GPRC5D treatments.
In a study of 37 patients, outcomes were poor. Median overall survival was only 12.8 months, with progression-free survival across salvage therapies ranging from 2.7 to 3.7 months. This highlights the limited effectiveness of current options for this highly resistant patient group.
Whole genome sequencing identified frequent biallelic tumor suppressor gene events, particularly involving TP53, contributing to a resistant phenotype. Genomic alterations linked to resistance against various therapies were common, with nearly a third of patients showing concurrent loss of BCMA and GPRC5D. Sequential sequencing revealed evolving resistance mechanisms within individual patients.
Loss of BCMA expression, driven by genomic events, was confirmed. BCMA status proved predictive of clinical benefit for BCMA re-treatment. Overall, hepta-refractory multiple myeloma showcases significant genomic instability and immune target loss, underscoring a critical need for novel treatment strategies and integrated genomic assessment.