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000309925 1001_ $$aRiedhammer, C.$$b0
000309925 245__ $$aThe evolution to hepta-refractory myeloma involves sequential loss of CD38, BCMA and GPRC5D.
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000309925 520__ $$aMultiple 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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000309925 7001_ $$aTruger, M.$$b1
000309925 7001_ $$aLee, H.$$b2
000309925 7001_ $$00000-0002-9248-588X$$aLeypoldt, L. B.$$b3
000309925 7001_ $$00000-0002-9038-3265$$aMeggendorfer, M.$$b4
000309925 7001_ $$aHutter, S.$$b5
000309925 7001_ $$aMüller, H.$$b6
000309925 7001_ $$aMersi, J.$$b7
000309925 7001_ $$00009-0003-8871-5261$$aKadel, S. K.$$b8
000309925 7001_ $$aBuchwald, T.$$b9
000309925 7001_ $$aKosch, R.$$b10
000309925 7001_ $$00000-0002-9561-1669$$aHelal, M.$$b11
000309925 7001_ $$aAfrin, N.$$b12
000309925 7001_ $$aRosenwald, A.$$b13
000309925 7001_ $$aGerhard-Hartmann, E.$$b14
000309925 7001_ $$00000-0002-4072-7592$$aBrioli, A.$$b15
000309925 7001_ $$00000-0002-4649-0506$$aKrönke, J.$$b16
000309925 7001_ $$00000-0003-0196-2837$$aHaferlach, T.$$b17
000309925 7001_ $$00000-0002-6333-5049$$aHaferlach, C.$$b18
000309925 7001_ $$00000-0001-9422-6614$$aWeisel, K. C.$$b19
000309925 7001_ $$aNeri, P.$$b20
000309925 7001_ $$00000-0002-7680-0819$$aEinsele, H.$$b21
000309925 7001_ $$00000-0002-7011-0286$$aKortüm, K. M.$$b22
000309925 7001_ $$00000-0001-5340-1818$$aWaldschmidt, J. M.$$b23
000309925 7001_ $$00000-0001-7353-7034$$aBahlis, N.$$b24
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000309925 7001_ $$00000-0002-9536-9649$$aRasche, L.$$b26
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