The evolution to hepta-refractory myeloma involves sequential loss of CD38, BCMA and GPRC5D - PubMed
5 days ago
- #hepta-refractory
- #multiple myeloma
- #genomic alterations
- Hepta-refractory myeloma is defined by resistance to CD38 antibodies, two immunomodulatory drugs (IMiDs), two proteasome inhibitors (PIs), and both BCMA- and GPRC5D-directed immunotherapies.
- Median overall survival for hepta-refractory myeloma patients is 12.8 months, with progression-free survival across salvage therapy lines ranging from 2.7 to 3.7 months.
- Whole genome sequencing (WGS) shows frequent biallelic tumor suppressor gene events, particularly TP53, indicating proliferative, apoptosis-resistant disease.
- Genomic alterations linked to IMiD, BCMA, GPRC5D, and CD38 resistance occur in 71%, 41%, 35%, and 12% of patients, respectively.
- Almost one-third of patients exhibit concurrent loss of BCMA (TNFRSF17) and GPRC5D.
- Sequential WGS reveals branching evolutionary trajectories with multiple distinct TNFRSF17 and GPRC5D variants within individual patients, suggesting persistent clones with ongoing mutational processes.
- Immunohistochemistry (IHC) confirms BCMA expression loss due to biallelic TNFRSF17 genomic events and other mechanisms.
- BCMA status predicts benefit from BCMA re-treatment.
- Hepta-refractory myeloma is characterized by profound genomic complexity, antigen loss, and poor outcomes, necessitating novel therapies and broader diagnostics like integrated genomic and IHC testing.