Here, we report that S100A8/S100A9 promotes multiple myeloma progression and that blockade of S100A9 with TQ has antimyeloma activity in vivo, as well as our surprising observation that part of the effect of S100A8/S100A9 on multiple myeloma progression is independent of the adaptive immune system and instead mediated by Toll-like receptor 4 (TLR4)- and STAT5-driven expansion of megakaryocytes (MK) and increased angiogenesis. Here, S100A9 is linked to AL amyloidosis.