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Proteasome inhibitor-induced coronary vasospasm in multiple myeloma: a case report.

ABSTRACT:

Background

Coronary vasospasm is an increasingly recognized cause of myocardial infarction or myocardial ischaemia in patients without obstructive coronary artery disease. A thorough medication review may identify drugs or toxins that could trigger coronary vasospasm. This case provides mechanistic insight into the off-target effect of proteasome inhibition leading to coronary vasospasm in a patient referred with chest pain consistent with typical angina.

Case summary

A 72-year-old lady presented with anginal chest pain at rest with electrocardiogram evidence of myocardial ischaemia who was referred for invasive coronary angiography. This demonstrated minor coronary disease without an obstructive lesion. Vasoreactivity testing revealed diffuse coronary vasospasm of the left anterior descending artery. Carfilzomib was identified as the trigger for coronary vasospasm. Symptoms resolved without recurrence after appropriate treatment including cessation of the triggering agent.

Conclusion

Coronary spasm is a rare but important adverse reaction to proteasome inhibitors. This case supports the clinical utility of invasive coronary vasoreactivity testing in patients with ischaemia with no obstructive coronary artery disease.

SUBMITTER: Mikhail P

PROVIDER: S-EPMC8323061 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundMultiple myeloma (MM) remains an incurable malignancy, despite the advent of therapies such as proteosome inhibitors (PIs) that disrupt protein homeostasis and induce ER stress. We have pursued inhibition of geranylgeranyl diphosphate synthase (GGDPS) as a novel mechanism by which to target protein homeostasis in MM cells. GGDPS inhibitors (GGSI) disrupt Rab geranylgeranylation, which in turn results in perturbation of Rab-mediated protein trafficking, leading to accumulation of intracellular monoclonal protein, induction of ER stress and apoptosis. Our lead GGSI, RAM2061, has demonstrated favorable pharmacokinetic properties and in vivo efficacy. Here we sought to evaluate if combination therapy with GGSI and PI would result in enhanced disruption of the unfolded protein response (UPR) and increase anti-MM efficacy.MethodsMTT assays were conducted to evaluate the cytotoxic effects of combining RAM2061 with bortezomib in human MM cells. The effects of RAM2061 and/or PI (bortezomib or carfilzomib) on markers of UPR and apoptosis were evaluated by a combination of immunoblot (ATF4, IRE1, p-eIF2a, cleaved caspases and PARP), RT-PCR (ATF4, ATF6, CHOP, PERK, IRE1) and flow cytometry (Annexin-V). Induction of immunogenic cell death (ICD) was assessed by immunoblot (HMGB1 release) and flow cytometry (calreticulin translocation). Cell assays were performed using both concurrent and sequential incubation with PIs. To evaluate the in vivo activity of GGSI/PI, a flank xenograft using MM.1S cells was performed.ResultsIsobologram analysis of cytotoxicity data revealed that sequential treatment of bortezomib with RAM2061 has a synergistic effect in MM cells, while concurrent treatment was primarily additive or mildly antagonistic. The effect of PIs on augmenting RAM2061-induced upregulation of UPR and apoptotic markers was dependent on timing of the PI exposure. Combination treatment with RAM2061 and bortezomib enhanced activation of ICD pathway markers. Lastly, combination treatment slowed MM tumor growth and lengthened survival in a MM xenograft model without evidence of off-target toxicity.ConclusionWe demonstrate that GGSI/PI treatment can potentiate activation of the UPR and apoptotic pathway, as well as induce upregulation of markers associated with the ICD pathway. Collectively, these findings lay the groundwork for future clinical studies evaluating combination GGSI and PI therapy in patients with MM.