Genetic Evolution in Multiple Myeloma: From MGUS to Active Disease

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• Early Genetic Changes in MGUS and SMM
• Two Distinct Myeloma Genetic Subtypes
• Hyperdiploid Myeloma Chromosomal Changes
• Secondary Mutations Drive Disease Progression
• Clinical Implications and Future Research
• Full Transcript

Early Genetic Changes in MGUS and SMM

Multiple myeloma development follows a predictable pathological progression. Dr. Nikhil Munshi, MD, explains that the disease is typically preceded by monoclonal gammopathy of unknown significance (MGUS). MGUS then advances to smoldering multiple myeloma (SMM) before becoming active multiple myeloma. Importantly, only about 1% of MGUS patients progress to multiple myeloma each year.

Dr. Munshi's research reveals that key genetic changes occur remarkably early in this process. Chromosomal abnormalities and translocations are already present at the MGUS stage. These initial genetic alterations provide the signals that trigger abnormal plasma cell growth. This early genetic foundation sets the stage for potential disease progression.

Two Distinct Myeloma Genetic Subtypes

Multiple myeloma presents with two primary genetic patterns according to Dr. Nikhil Munshi, MD. Approximately half of cases demonstrate hyperdiploid myeloma, characterized by extra copies of certain chromosomes. The other half show translocations involving chromosome 14. Despite these different genetic pathways, both mechanisms ultimately lead to the same clinical disease.

Dr. Nikhil Munshi, MD, emphasizes that both genetic subtypes emerge early in the disease spectrum. These fundamental chromosomal changes are established during the MGUS phase. The research conducted by Dr. Munshi's lab focused on deciphering the evolution of these copy number changes in myeloma development.

Hyperdiploid Myeloma Chromosomal Changes

Hyperdiploid myeloma involves specific chromosomal gains that serve as disease hallmarks. Dr. Nikhil Munshi, MD, identifies six to seven chromosomes that typically show trisomy in this subtype. These include chromosomes 3, 5, 7, 9, 11, 15, and 19. The research reveals critical patterns in how these chromosomal changes accumulate.

Dr. Munshi's team discovered that certain chromosome gains consistently appear together. The presence of any two of these trisomies occurs in nearly 100% of hyperdiploid cases. This pattern indicates these are early, foundational genetic changes that initiate the disease process. Subsequent chromosomal losses then contribute to disease advancement toward active myeloma.

Secondary Mutations Drive Disease Progression

The transition from smoldering to symptomatic multiple myeloma requires additional genetic events. Dr. Nikhil Munshi, MD, explains that secondary changes involving gene mutations trigger this progression. These mutations occur alongside more subtle alterations in non-coding DNA regions. Transcriptomic changes further contribute to disease activation.

Dr. Nikhil Munshi, MD, emphasizes that while early chromosomal changes establish MGUS and SMM, different mechanisms drive the shift to symptomatic disease. Researchers have identified numerous genes that acquire mutations during this transition phase. Understanding these secondary genetic events is crucial for developing interventions that might prevent progression to active multiple myeloma.

Clinical Implications and Future Research

Deciphering the genetic evolution of multiple myeloma has significant clinical applications. Dr. Nikhil Munshi, MD, highlights how this knowledge informs therapeutic development. Understanding the sequence of genetic changes enables researchers to target specific pathways at different disease stages. This approach could lead to more effective treatment strategies.

The research also opens possibilities for prevention strategies. By identifying patients with high-risk genetic profiles early, clinicians might intervene before progression occurs. Dr. Munshi's work represents important progress in unraveling the complete genetic spectrum of multiple myeloma development. This comprehensive understanding ultimately benefits patient care and outcomes.

Full Transcript

Dr. Anton Titov, MD: Multiple myeloma is usually preceded by a premalignant pathological process called MGUS, monoclonal gammopathy of unknown significance. MGUS then becomes smoldering myeloma, SMM, and only then does multiple myeloma develop. But only 1% of people who have monoclonal gammopathy of unknown significance develop multiple myeloma every year.

You are a world-renowned expert on the genetic changes in multiple myeloma. So what are the key genetic changes in the development of multiple myeloma along the pathological process? We have great interest—and a lot of people have great interest in that—because once we understand that, we may be able to prevent the progression. We may be able to prevent even the development of smoldering myeloma or MGUS.

Dr. Nikhil Munshi, MD: So actually, our own lab a few years ago took up this task of understanding or deciphering the evolution of copy number changes in myeloma. In myeloma, we see two things: about half of myelomas have certain chromosomes increased in number—what we call trisomy or hyperdiploid myeloma. The other half, almost literally half, are where we see predominantly translocations involving chromosome 14. Both myelomas have very different genetic changes but lead to the same outcome.

What we attempted to do was identify what changes first and what changes next, eventually leading to the development of myeloma. And what we found, surprisingly, is that these copy number changes and translocations happen very early. They happen when MGUS develops; they happen when smoldering myeloma is there.

So some of these chromosomal changes are important for causing or inducing the initial signals that lead to the growth of plasma cells, developing MGUS and smoldering myeloma. I think that’s important.

Within these various chromosomes, we also began to identify which ones are the real drivers. To give an idea, there are six to seven chromosomes that become trisomic—that’s a hallmark of hyperdiploid myeloma: chromosomes 3, 5, 7, 9, 15, 19, and 11. What we identified was that chromosomes 3 and 5 are always present almost 100% of the time. That tells us that’s an early change.

That change leads to the beginning of developing the disease as we know it. Subsequently, the other chromosomal changes happen. Eventually, we have identified loss of certain chromosomes that play a role and lead to myeloma.

However, these changes are observed early. So we hypothesize that these changes are required for the development of MGUS and smoldering myeloma. But something else is required to change from smoldering disease to symptomatic myeloma, where we need to do treatment.

What we believe are the secondary changes—they are related to mutations. We and others have identified a number of genes with mutations. It will again be associated with more subtle changes in what we call non-coding DNA regions and various other transcriptomic changes.

So we are beginning to decipher the early change and the late change, which relates to the development of myeloma. I think putting this whole spectrum together is beginning to unravel what’s happening that causes the disease.

This is a very important development because it’s going to help us with therapeutic strategies. It’s going to help us with preventative strategies for this disease.