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Updated: May 12, 2026
Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
Proteasome inhibitor therapy for Waldenström's macroglobulinemia
Meletios A Dimopoulos1, Evangelos Terpos, Efstathios Kastritis
1Department of Clinical Therapeutics, University of Athens, School of Medicine, Athens, Greece. mdimop@med.uoa.gr
Abstract:
Proteasome inhibitors effectively kill tumor cells in myeloma and other plasma cell-related diseases. Preclinical data indicated that lymphoplasmatic cells are also vulnerable to proteasome inhibition and proteasome-targeting therapies have proved their clinical activity in Waldenström's macroglobulinemia (WM). Bortezomib is the first in class proteasome inhibitor (PI), and has been used in several clinical trials either alone or in combination with rituximab. Bortezomib treatment alone might induce major responses in 25%-60% of patients with WM but in combination with rituximab major responses might be as high as 50%-83%. Bortezomib might reduce immunoglobulin M levels rapidly and is not myelotoxic. However, peripheral neuropathy remains a major toxicity of bortezomib therapy; alternative schedules and dosing or route of administration (subcutaneous) might reduce neurotoxicity. Second generation PIs, such as carfilzomib, are also promising but further investigation is needed.
Insights
Proteasome inhibitors show clinical activity in Waldenström
Area of Science:
- Oncology
- Hematology
Background:
- Proteasome inhibitors (PIs) are effective against myeloma and related plasma cell disorders.
- Preclinical data suggest lymphoplasmatic cells are susceptible to proteasome inhibition.
- Proteasome-targeting therapies have demonstrated clinical activity in Waldenström's macroglobulinemia (WM).
Purpose of the Study:
- To evaluate the efficacy and toxicity of bortezomib in Waldenström's macroglobulinemia.
- To assess the impact of combining bortezomib with rituximab in WM patients.
- To explore strategies for mitigating bortezomib-induced neurotoxicity.
Main Methods:
- Review of clinical trial data for bortezomib in WM.
- Analysis of response rates and toxicity profiles.
- Investigation of alternative bortezomib administration schedules and dosing.
Main Results:
- Bortezomib monotherapy achieved major responses in 25%-60% of WM patients.
- Combination therapy with bortezomib and rituximab resulted in major responses in 50%-83% of patients.
- Bortezomib demonstrated rapid reduction in immunoglobulin M levels and was not myelotoxic, but peripheral neuropathy is a significant toxicity.
Conclusions:
- Bortezomib is an active agent in Waldenström's macroglobulinemia, particularly in combination with rituximab.
- Strategies to reduce bortezomib-related neurotoxicity, such as alternative dosing or subcutaneous administration, warrant further investigation.
- Second-generation proteasome inhibitors like carfilzomib show promise and require additional study.
