Imagine a rare blood cancer that can hide in your bones before you notice a symptom. A cancer that, after treatment that successfully quells signs of the disease, returns to make you sick again. A cancer that typically cycles between relapse and remission with treatment and where each subsequent remission gets shorter, and you become overwhelmed by this insidious disease and its attendant bone pain, fatigue, and increased susceptibility to infections. Meet multiple myeloma, which has long challenged scientists and clinicians alike.
But now an investigational scientific approach called targeted protein degradation is garnering significant interest in biomedical research. Whereas many cancer drugs bind to and inhibit proteins that cause disease, targeted protein degraders initiate their physical destruction and removal. They harness the cell's natural protein removal systems to help eliminate disease-related proteins rather than impeding their function. Researchers at Bristol Myers Squibb are at the forefront of exploring various modalities that leverage this principle, each designed to tackle complex biological challenges in unique ways.
One of the most exciting treatment developments in fighting blood cancer over the past 20 years has been the introduction of immunomodulatory drugs, now a standard of care in certain blood cancers, including multiple myeloma. Delving into the fundamental science behind these medicines, Bristol Myers Squibb researchers built a deep mechanistic understanding. Says Neil Bence, senior vice president and head of the Protein Homeostasis Thematic Research Center at Bristol Myers Squibb, “Our scientists, along with members in the academic community, were involved in really understanding how immunomodulatory drugs worked. We knew this approach was benefitting patients before we knew exactly how it worked at a molecular level."
Scientists discovered that immunomodulatory drugs work through a mechanism of protein degradation by binding to a protein called cereblon, part of a larger group of enzymes that helps tag proteins the cell, no longer needs so they can be cleared away. When engaged, cereblon can help guide proteins, like those linked to the growth and survival of cancer cells, towards this natural cleanup process. These advancements created the field of CELMoD (cereblon E3 ligase modulator) research, which aims to apply this approach to other cancers and diseases. Shaped by decades of scientific research, this field opens new possibilities for targeting proteins that have been difficult to address and expands researchers’ ability to exploit biology insights to invent novel medicines.
A Novel Approach in Multiple Myeloma
This innovative research approach holds particular significance for complex diseases like multiple myeloma, which is still considered incurable, leading to recurring disease and relapse. Patients frequently experience shorter periods of remission with each subsequent relapse, underscoring a critical unmet medical need. The American Cancer Society estimates that about 36,000 new cases of multiple myeloma will be diagnosed in the U.S. in 2026 and that 10,850 Americans will die from the disease this year.
Arising in the bone marrow, multiple myeloma results from an overproduction of cancerous white blood cells, called myeloma cells, that both multiply rapidly and continue to live beyond the point when healthy cells naturally die. As a result, myeloma cells crowd out healthy blood cells, undermining bone marrow function and interfering with the production of infection - fighting cells. And while myeloma cells, like healthy plasma cells, make antibodies, they generate large amounts of a single, nonfunctional antibody that the body cannot use. These monoclonal proteins can accumulate over time and damage the kidneys and other organs.
It was through the study of immunomodulatory drugs that researchers discovered that their clinical benefit in multiple myeloma stemmed from the cereblon - based targeting of the transcription factors Ikaros and Aiolos, key proteins involved in myeloma growth. Building on this insight, investments in CELMoD research enabled the team at Bristol Myers Squibb to explore how to optimally engage cereblon to target Ikaros and Aiolos to fully maximize the therapeutic potential of this mechanism.
Accelerating Discovery with AI and Machine Learning
To further accelerate insights into multiple myeloma and other cancers, Bristol Myers Squibb leverages cross - disciplinary teams of chemists, biologists, and computational scientists, significantly aided by advanced artificial intelligence and machine learning. Researchers are now exploring how these AI-enabled approaches may help accelerate the discovery of novel molecular glues, building on the foundational science behind CELMoD research established long before the emergence of modern AI technologies.
AI helps researchers analyze vast quantities of patient biopsy data, revealing molecular details and subtle patterns in multiple myeloma that might otherwise be missed. This computational power is crucial for identifying potential new therapeutic targets.
Says Neil Bence, “We're leveraging advanced AI approaches that are helping us to accelerate the complex drug discovery process - to find that one Goldilocks molecule that has all the right properties.” Bristol Myers Squibb’s “Predict First” approach integrates AI into the design phase, allowing scientists to predict how novel molecules will interact with specific proteins in myeloma cells - optimizing for efficacy, selectivity, and safety even before physical synthesis.
Multiple myeloma is just one of the malignancies whose secrets scientists are uncovering. “Cancer is many different diseases, and it is a disease state that is constantly trying to trick you and evade you,” Bence says. “What makes [this research] really exciting is we're operating at an intersection of the deepest understanding of disease with the greatest number of tools that we’ve ever had to design new medicines.”
A Vision for the Future
Thanks to continuous advances in precision medicine, data - driven research, and a deeper understanding of human biology, the landscape of care for multiple myeloma is evolving rapidly. Cutting - edge science, supported by advanced computational methods and data analysis, is exploring how to detect and manage the disease - investigations that could offer even more hope to patients in the future.
“Connecting the dots - to be able to see what the best target is, to have clarity around the causal human biology, and to be able to design a molecule with this knowledge that may lead to a novel medicine - is like opening a treasure chest of new opportunities and is every scientist's dream,” Bence says.
This upwelling of opportunity signals a future in which scientific understanding and therapeutic innovation continue to grow for patients facing challenging diseases like multiple myeloma.
