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Bortezomib (BTZ) is a proteasome inhibitor (PI) used for the treatment of several hematologic malignancies, including multiple myeloma (MM), and various lymphomas including mantle cell lymphoma (MCL). It acts via disruption of the ubiquitin-proteasome pathway which plays a major role in regulating cell cycle and inhibiting synthesis of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-KB). The ubiquitin-proteasome pathway is also important in maintaining the integral signaling in cardiac myocytes. By inhibiting this system, BTZ induces cellular apoptosis in cancer cells, and possibly the cardiomyocytes. BTZ-induced cardiotoxicity in monotherapy and combination treatments is not well described in the literature. We observed a series of three patients who developed cardiotoxicity after treatment with BTZ. All patients had echocardiograms every 3 months until recovery to assess ejection fraction (EF) and global longitudinal strain (GLS). Two of the patients had a cardiac MRI (CMR) conducted during follow-up to assess for late gadolinium enhancement (LGE).  The median age of our patients was 55 years (range 37-74). Two of them had MM, while one patient had MCL. Table 1 demonstrates patient demographics, past medical histories, and the cumulative dose and duration of BTZ therapy. Of the three patients, only one had a heart failure exacerbation at diagnosis. The other two patients were diagnosed with asymptomatic left ventricular systolic dysfunction on routine pre-transplant echocardiograms. Most importantly, all three patients had improvement or normalization of cardiac function with discontinuation of BTZ and initiation of guideline-directed medical therapy (GDMT) for heart failure. The median duration to recovery was 5 months (range 3-13). One patient had underlying non-compaction cardiomyopathy, and although EF did not normalize, it recovered to his previous baseline. All 3 patients had improvement in GLS. Two patients underwent CMRI at the time of cardiomyopathy diagnosis and neither of them had any late gadolinium enhancement. Since there was no routine pre-treatment echocardiogram, using the GLS trend to detect subclinical cardiac dysfunction was not possible. This case series demonstrates that BTZ-induced cardiomyopathy is potentially reversible with discontinuation of the drug and early initiation of GDMT. Further studies are needed to determine the ideal surveillance strategy for BTZ-induced cardiomyopathy., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Sundaravel et al.)