Cancer Research

Myeloma Cells Can Permanently Lose CD38 to Escape Daratumumab Therapy

A new genomic study in Blood analyzed 50 multiple myeloma patients who relapsed after CD38-targeted antibody therapy (daratumumab or isatuximab). Researchers found that 20% (10/50) had lost CD38 expression due to genomic alterations, with 6% (3/50) showing full biallelic loss of both gene copies, representing permanent resistance. Remarkably, some patients showed convergent evolution, where independent tumor subclones each developed separate CD38-inactivating mutations. Functional testing identified specific missense mutations (L153H, C275Y, R140G) that reduce antibody binding and tumor killing. One mutation, R140G, selectively blocked daratumumab while preserving isatuximab sensitivity — suggesting genomic testing could guide which CD38 antibody to use on retreatment. No biallelic events were seen in 701 newly diagnosed or 67 antibody-naïve relapsed patients.