HEPTA REFRACTORY multiple myeloma is associated with profound genomic complexity, antigen loss, and a median overall survival of 12.8 months, according to new multi-centre data. This newly defined end stage entity describes patients with multiple myeloma who are resistant to CD38 antibodies, two immunomodulatory drugs, two proteasome inhibitors, and both B cell maturation antigen and G protein coupled receptor class C group 5 member D directed (GPRC5D) immunotherapies.
Clinical Outcomes in Hepta Refractory Multiple Myeloma
In a cohort of 37 patients with hepta refractory multiple myeloma, outcomes were poor across successive salvage therapies. Median overall survival was 12.8 months. Progression free survival across salvage therapy lines ranged from 2.7–3.7 months, underscoring the limited durability of currently available options in this ultra refractory population. These data position hepta refractory multiple myeloma as a distinct clinical state characterised by aggressive disease biology and limited therapeutic benefit with standard approaches.
Genomic Landscape and Resistance Mechanisms
Whole genome sequencing revealed frequent biallelic tumour suppressor gene events, particularly involving TP53, consistent with a proliferative and apoptosis resistant phenotype. Genomic alterations associated with resistance to immunomodulatory drugs, B cell maturation antigen directed therapies, G protein coupled receptor class C group 5 member D directed therapies, and CD38 antibodies occurred in 71%; 41%; 35%; and 12% of patients, respectively. Notably, nearly one third of patients exhibited concurrent loss of B cell maturation antigen (BCMA), encoded by TNFRSF17, and GPRC5D.
Sequential whole genome sequencing demonstrated branching evolutionary trajectories, with multiple distinct TNFRSF17 and GPRC5D variants arising within individual patients. These findings suggest the presence of persistent clonal reservoirs and ongoing mutational processes, even after deep remissions.
Implications For Targeted Re Treatment
Immunohistochemistry confirmed loss of B cell maturation antigen expression driven by biallelic TNFRSF17 genomic events and also identified alternative mechanisms of antigen loss. Importantly, B cell maturation antigen status predicted clinical benefit with regard to B cell maturation antigen re treatment.
Overall, hepta refractory multiple myeloma is defined by marked genomic instability, immune target loss, and dismal outcomes, highlighting an urgent need for novel therapeutic strategies and broader diagnostic integration, including genomic and immunohistochemical assessment.
Reference
Riedhammer C et al. The evolution to hepta-refractory myeloma involves sequential loss of CD38, BCMA and GPRC5D. Leukaemia. 2026; https://doi.org/10.1038/s41375-026-02889-3.
