Resistance to proteasome inhibitors and other targeted therapies in myeloma
Craig T Wallington-Beddoe1,2,3, Magdalena Sobieraj-Teague2,4, Bryone J Kuss2,4
1Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia.
Abstract:
The number of novel therapies for the treatment of myeloma is rapidly increasing, as are the clinical trials evaluating them in combination with other novel and established therapies. Proteasome inhibitors, immunomodulatory agents and monoclonal antibodies are the most well known and studied classes of novel agents targeting myeloma, with histone deacetylase inhibitors, nuclear export inhibitors and several other approaches also being actively investigated. However, in parallel with the development and clinical use of these novel myeloma therapies is the emergence of novel mechanisms of resistance, many of which remain elusive, particularly for more recently developed agents. Whilst resistance mechanisms have been best studied for proteasome inhibitors, particularly bortezomib, class effects do not universally apply to all class members, and within-class differences in efficacy, toxicity and resistance mechanisms have been observed. Although immunomodulatory agents share the common cellular target cereblon and thus resistance patterns relate to cereblon expression, the unique cell surface antigens to which monoclonal antibodies are directed means these agents frequently exhibit unique within-class differences in clinical efficacy and resistance patterns. This review describes the major classes of novel therapies for myeloma, highlights the major clinical trials within each class and discusses known resistance mechanisms.
Insights
Novel myeloma therapies are advancing, but new resistance mechanisms are emerging. Understanding these resistance patterns is crucial for effective treatment strategies in multiple myeloma.
Area of Science:
- Hematology
- Oncology
- Pharmacology
Background:
- The landscape of multiple myeloma treatment is rapidly evolving with numerous novel therapeutic agents.
- Key classes of novel agents include proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies, with ongoing research into others like HDAC inhibitors.
Purpose of the Study:
- To review the major classes of novel myeloma therapies.
- To highlight significant clinical trials for each therapy class.
- To discuss the known mechanisms of therapeutic resistance in myeloma.
Main Methods:
- Literature review of novel myeloma therapies and clinical trials.
- Analysis of established and emerging resistance mechanisms for different drug classes.
- Synthesis of information on drug targets and resistance pathways.
Main Results:
- Novel agents like proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies show promise in myeloma treatment.
- Emergence of novel resistance mechanisms parallels the development of new therapies, with varying impact across drug classes.
- Resistance mechanisms are best understood for proteasome inhibitors but differ within the class; immunomodulatory drugs relate to cereblon expression, and monoclonal antibodies have unique resistance patterns.
Conclusions:
- Understanding diverse resistance mechanisms is critical for optimizing novel myeloma therapies.
- Tailoring treatment strategies based on specific resistance profiles may improve patient outcomes.
- Further research is needed to elucidate elusive resistance mechanisms for newer agents.
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