Selective blockade of NOTCH3 with a neutralizing antibody or pan-Notch inhibition with a bone-targeted inhibitor reduced tumor burden and eliminated coexisting dormant and bortezomib-resistant cells in clinically relevant models of MM disease.<h4>Conclusions</h4>Our findings reveal that NOTCH3-dependent survival programs represent a shared vulnerability in both cells refractory to therapy and dormant cells. Here, NOTCH3 is linked to neoplasm.