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Despite effective therapies such as proteasome inhibitors, multiple myeloma (MM) patients relapse with refractory disease. Analysis of RNA sequencing data from CD138 + MM patient cells (n = 813) across disease stages identifies an autophagy gene signature. Particularly elevated ULK3 expression is strongly associated with disease progression. Functional studies reveal that ULK3 supports MM cell survival via the ULK-ATG13-FIP200 complex. We generate small-molecule kinase inhibitors (SG3-014/MA9-060) exhibiting nanomolar potency against ULK3, with binding confirmed by co-crystallization. While exhibiting multikinase activity, pharmacologic targeting reduces MM burden in vivo, improves survival, and mitigates MM-associated bone disease. Here, we also show that MA9-060 enhances sensitivity to proteasome inhibitors in resistant MM cells, with effects confirmed ex vivo in primary patient samples, particularly those with high ULK3 expression. These findings implicate ULK3-associated autophagy in MM progression and support further evaluation of ULK3-directed kinase inhibition as a therapeutic strategy in newly diagnosed and refractory MM.