Targeted gene sequencing of bone marrow plasma cells in multiple myeloma, light-chain amyloidosis, POEMS syndrome and monoclonal gammopathy of undetermined significance

Plasma cell dyscrasias (PCDs), including multiple myeloma (MM), light-chain amyloidosis (AL), and POEMS syndrome, are malignancies of plasma cells with diverse clinical features. Although they have the same precursor stage, monoclonal gammopathy of undetermined significance (MGUS) and some mutation signatures in common, their shared mutational pathogenesis remain understudied. To comparatively analyze the mutations in PCDs, we subjected bone marrow plasma cells from patients with MM (n=163), AL (n=121), POEMS (n=67), and MGUS (n=13), using targeted gene sequencing including 370 genes. Principal component analysis revealed two major subgroups among patients with PCDs: one with heavily mutated chromatin modifying genes (namely CMGmut) and the other with a subtly higher burden of classical MM driver mutations (namely non-CMGmut). High mutational burden of RUNX1 and KMT2D was potential biomarkers to distinguish CMGmut subgroup from non-CMGmut subgroup. Patients with MM, early-stage AL, and POEMS in CMGmut subgroup were more likely to have prolonged progression-free survival than those in non-CMGmut subgroup, although those with MM and AL showed inferior responses to first-line CyBorD therapy. These results provided mechanistic insights into a patient subgroup of PCDs characterized by a high mutational burden of chromatin-modifying genes and relatively indolent clinical features, and likely to benefit from epigenetic therapy.