In vivo models of multiple myeloma (MM)
Eric Sanchez1, Haiming Chen1, James R Berenson1
1Institute for Myeloma & Bone Cancer Research, West Hollywood, California, USA.
Abstract:
The development of the plasma cell tumor (PCT) model was the first widely accepted in vivo model of multiple myeloma (MM). Potter and colleagues used this chemically induced PCT model to study the pathophysiology of malignant plasma cells and also used it to screen anti-MM agents. Two decades later the C57BL/KaLwRij mouse strain was found to spontaneously develop MM. Testing of pamidronate using this endogenously arising MM model revealed significant reductions in MM-associated bone disease, which was subsequently confirmed in human trials in MM patients. Transgenic models have also been developed in which the MM is localized in the bone marrow causing lytic bone lesions. Experiments in a transgenic model showed that a new oral proteasome inhibitor was effective at reducing MM burden. A clinical trial later confirmed this observation and validated the model. The xenograft model has been used to grow human MM in immunocompromised mice. The xenograft models of MM have been very useful in optimizing drug schedules and doses, which have helped in the treatments given to MM patients. However, in vivo models have been criticized for having a low clinical predictive power of new chemical entities (NCEs). Despite this, the knowledge gained from in vivo models of MM has without a doubt benefited MM patients.
Insights
In vivo models, including plasma cell tumor, spontaneous, transgenic, and xenograft models, have been crucial for understanding multiple myeloma (MM) and screening anti-MM agents, benefiting patient treatment.
Area of Science:
- Oncology
- Hematology
- Translational Medicine
Background:
- The plasma cell tumor (PCT) model was the first in vivo model for multiple myeloma (MM).
- Spontaneous and transgenic mouse models have been developed to study MM pathophysiology and bone disease.
- Xenograft models allow for the study of human MM in immunocompromised mice.
Purpose of the Study:
- To review the historical development and utility of various in vivo models for multiple myeloma research.
- To highlight the contributions of these models in understanding MM and screening therapeutic agents.
- To discuss the clinical relevance and limitations of in vivo models in multiple myeloma drug development.
Main Methods:
- Review of chemically induced plasma cell tumor (PCT) models.
- Analysis of spontaneously developing multiple myeloma models in C57BL/KaLwRij mice.
- Examination of transgenic models with bone marrow-localized MM.
- Evaluation of xenograft models using human MM in immunocompromised mice.
Main Results:
- Early PCT models aided in understanding MM pathophysiology and agent screening.
- Spontaneous MM models demonstrated pamidronate's efficacy in reducing bone disease, confirmed in human trials.
- Transgenic and xenograft models have been instrumental in optimizing drug schedules and doses for MM patients.
- In vivo models have shown success in validating therapeutic strategies, such as oral proteasome inhibitors.
Conclusions:
- In vivo models have significantly advanced the understanding and treatment of multiple myeloma.
- Despite criticisms regarding clinical predictive power for new chemical entities, these models remain invaluable.
- Knowledge gained from in vivo studies has directly benefited multiple myeloma patients.
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