B-cell maturation antigen (BCMA) plays a pathobiologic role in myeloma and is a validated target with five BCMA-specific therapeutics having been approved for relapsed/refractory disease. However, these drugs are not curative, and responses are inferior in patients with molecularly-defined high-risk disease, including those with deletion 17p (del17p) involving the tumor suppressor TP53 , supporting the need for further drug development. Del17p has been associated with reduced copy number and gene expression of RNA polymerase II subunit alpha ( POLR2A ) in other tumor types. We therefore studied the possibility that HDP-101, an anti-BCMA antibody drug conjugate (ADC) with the POLR2A poison α-amanitin could be an attractive agent in myeloma, especially with del17p. HDP-101 reduced viability in myeloma cell lines representing different molecular disease subtypes, and overcame adhesion-mediated and both conventional and novel drug resistance. After confirming that del17p is associated with reduced POLR2A levels in publicly available myeloma patient databases, we engineered TP53 wild-type cells with a TP53 knockout (KO), POLR2A knockdown (KD), or both, the latter to mimic del17p. HDP-101 showed potent anti-myeloma activity against all tested cell lines, and exerted enhanced efficacy against POLR2A KD and dual TP53 KO/POLR2A KD cells. Mechanistic studies showed HDP-101 up-regulated the unfolded protein response, activated apoptosis, and induced immunogenic cell death. Notably, HDP-101 impacted CD138-positive but not-negative primary cells, showed potent efficacy against aldehyde dehydrogenase-positive clonogenic cells, and eradicated myeloma in an in vivo cell line-derived xenograft (CDX). Interestingly, in the CDX model, prior treatment with HDP-101 precluded subsequent engraftment on tumor cell line rechallenge in a manner that appeared to be dependent in part on natural killer cells and macrophages. Finally, HDP-101 was superior to the BCMA-targeted ADC belantamab mafodotin against cell lines and primary myeloma cells in vitro , and in an in vivo CDX. Together, the data support the rationale for translation of HDP-101 to the clinic, where it is now undergoing Phase I trials, and suggest that it could emerge as a more potent ADC for myeloma with especially interesting activity against the high-risk del17p myeloma subtype., Competing Interests: Disclosure of Conflicts of Interest H.C.L. has provided consultancy services to Amgen, Inc., Celgene, a wholly owned subsidiary of Bristol-Myers Squibb, GlaxoSmithKline, Janssen Pharmaceutical, Sanofi-Aventis, and Takeda Pharmaceutical, and has received research funding from Amgen, Inc., Celgene, a wholly owned subsidiary of Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Janssen Pharmaceutical, and Takeda Pharmaceuticals. K.K.P. declares research support from Celgene, a wholly owned subsidiary of Bristol-Myers Squibb. A.P. is an employee of Heidelberg Pharma AG, which is developing HDP-101. R.Z.O. declares research funding from Heidelberg Pharma AG related to this work, and unrelated funding from Asylia Therapeutics and BioTheryX. Also, R.Z.O. has served on advisory boards for Amgen, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Sanofi-Aventis, Servier, and Takeda Pharmaceuticals North America, Inc., and is a Founder of Asylia Therapeutics, Inc., with an equity interest. The remaining authors have no conflicts of interest to declare.