ArticleLeukemia2026
The evolution to hepta-refractory myeloma involves sequential loss of CD38, BCMA and GPRC5D.
Article in Leukemia, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- TNFRSF17 genomic profiling guides retreatment with alternative BCMA-directed immunotherapies in multiple myeloma.Blood advances · 2026Article
- A structural framework for mutation-guided immunotherapy sequencing of GPRC5D-targeted T cell engagers in multiple myeloma.Blood cancer journal · 2026Article
- Melflufen in Multiple Myeloma: Clinical Limitations, Biological Rationale, and Future Perspectives.Cancers · 2026Review
- Integrin alpha8beta1 is Identified as a Potential CAR-T Target for BCMA-Resistant Relapsed Multiple Myeloma.ImmunoTargets and therapy · 2026Article
Corrections and comments
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Authors and funding
27 authors.
Funding
Abstract
Multiple myeloma (MM) resistant to CD38 antibodies, two immunomodulatory drugs (IMiDs), two proteasome inhibitors (PIs), and both BCMA- and GPRC5D-directed immunotherapies defines hepta-refractory MM, a novel end-stage entity. In a multi-center cohort of 37 patients, median overall survival was 12.8 months, with progression-free survival across salvage therapy lines of only 2.7-3.7 months. Whole genome sequencing (WGS) revealed frequent biallelic tumor suppressor gene events, particularly TP53, consistent with proliferative, apoptosis-resistant disease. Genomic alterations linked to IMiD, BCMA, GPRC5D, and CD38 resistance occurred in 71%, 41%, 35%, and 12% of patients, respectively. Almost one-third of patients showed concurrent loss of BCMA (TNFRSF17) and GPRC5D. Sequential WGS demonstrated branching evolutionary trajectories with multiple distinct TNFRSF17 and GPRC5D variants arising within individual patients, pointing to a hidden reservoir of persistent clones with ongoing mutational processes even after deep remissions. Immunohistochemistry (IHC) confirmed loss of BCMA expression caused by biallelic TNFRSF17 genomic events but also revealed loss of expression attributable to other mechanisms. Importantly, BCMA status predicted benefit from BCMA re-treatment. Hepta-refractory MM is marked by profound genomic complexity, antigen loss, and poor outcomes, highlighting the need for novel therapies and broader diagnostics such as integrated genomic and IHC testing for this ultra-refractory population.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.