Proteolysis-targeting chimeras (PROTAC) leverage the ubiquitin-proteasome system to selectively degrade oncogenic proteins, including those previously seen as undruggable. Recent preclinical studies indicate that PROTACs may represent a novel therapeutic strategy in lymphoma and myeloma. Indeed, preclinically, PROTACs have shown high efficacy and remarkable selectivity, a favorable safety profile, and lower toxicity compared with conventional therapies. Their catalytic, reusable mechanism enables drug dosing and offers the perspective of long-term low-dose treatment. PROTACs have demonstrated their ability to overcome drug resistance by targeting and degrading overexpressed or mutant proteins that are responsible for refractory disease. This review aims to offer a comprehensive evaluation of the currently existing PROTACs that have been tested in lymphoma and myeloma to highlight the need for drug optimization and further translational research that could translate PROTACs to clinical trials.
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