Gastrointestinal Toxicities of Proteasome Inhibitor Therapy

Introduction: Proteasome inhibitors (PI) are a class of cancer drugs that cause cell death via the accumulation of tumor suppressors and pro-apoptotic proteins. The development of PI, such as Bortezomib, Carfilzomib, and Ixazomib, has provided a breakthrough in the management of many malignancies. A limiting factor in the use of these drugs is their side effect profile, which includes neuropathy, fatigue, and gastrointestinal (GI) toxicity. Despite this, PI remain an integral component of treatment regimens due to improvement in patient outcomes. In this study, we evaluated PI related GI toxicities and compared the differences in GI toxicities between Bortezomib, Carfilzomib, and Ixazomib. Methods: We conducted a retrospective study among cancer patients at a tertiary care cancer center to investigate the clinical characteristics of PI related GI toxicity. We included patients receiving a PI and excluded patients with GI symptoms from other etiologies. Results: 973 patients who received PI treatment between 2017 and 2022 were reviewed with a PI related GI toxicity incidence of 193 patients (20%). 114 (59%) of the patients received Bortezomib, 55 (29%) received Carfilzomib, and 24 (12%) received Ixazomib. The median time from PI initiation to GI toxicity was 79 days. The most common symptom was diarrhea, present in 169 (88%). The median symptom duration was 12 days. 70 (36%) required hospitalization. 157 (81%) received treatment for their GI toxicity and 99.3% of these patients were treated with supportive care including antimotility agents, antiemetics, and intravenous fluids. 17 patients (8.8%) received colonoscopy at the time of toxicity. 11 (65%) had normal findings and 6 (36%) had evidence of inflammation. 8 patients had calprotectin levels checked and all were within normal range. 145 (92%) patients who received treatment achieved remission. 71 (37%) developed recurrence of GI toxicity. Median time between PI initiation and development of GI toxicity was significantly (P=0.002) higher for Ixazomib (313 days) compared to Bortezomib (58 days) or Carfilzomib (89 days). Ixazomib also had a significantly (P=0.048) lower percentage of GI toxicity presenting as diarrhea (71%) compared to Bortezomib (96%) or Carfilzomib (91%) (Table 1). Conclusion: PI related GI toxicities vary based on different regimens, but overall has a high incidence. However, our review demonstrates that the vast majority of GI toxicities resolved with supportive treatment and had favorable outcome without long term consequence. Table 1. - Patient Characteristic by Type of PI Received Patient clinical characteristics, n=193 Characteristic BortezomibN=114 CarlfilzomibN=55 IxazomibN=24 No. (%) No. (%) No. (%) Time from PI initiation to symptom onset, days, median (IQR) 58.3(17.1-148.4) 89(31-193) 312.5(42.5-835.5) Other irAEs 37 (32.5%) 18 (32.7%) 10(41.7%) Distribution of gastrointestinal toxicity Upper GI 9(7.9%) 7(12.7%) 9(37.5%) Lower GI 109 (95.6%) 50(90.9%) 16(66.7%) Hepatobiliary 1(0.9%) 1(1.8%) 1(4.2%) Pancreatic - - - Presenting symptoms Nausea/vomiting 7(6.1%) 9(16.4%) 9(37.5%) Diarrhea 102(89.5%) 50(90.9%) 17(70.8%) Constipation 8(7.0%) 1(1.8%) 0(0%) Blood in stool 3(2.6%) 2(3.6%) 0(0%) Abdominal pain 3(2.6%) 4(7.3%) 2(8.3%) Peak Diarrhea CTCAE Grade 1 24(45.3%) 19(51.4%) 10(58.8%) 2 21(39.6%) 16(43.2%) 6(35.5%) 3 7(13.2%) 2(5.4%) 1(5.9%) 4 1(1.9%) 0(0%) 0(0%)