Multiple Myeloma Risk Stratification and Treatment Selection

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• Evolution of Risk Stratification
• Current Cytogenetic Risk Criteria
• ISS Staging System
• Revised ISS Staging
• Emerging Genomic Technologies
• Treatment Implications of Risk
• Full Transcript

Evolution of Risk Stratification

Multiple myeloma risk stratification has evolved significantly over time. Dr. Nikhil Munshi, MD, explains that the field previously relied on the Durie-Salmon system. The introduction of new chemotherapeutic drugs and transplant procedures changed risk assessment priorities. Chromosome 13 deletion became a critical marker during this period. Modern treatment advances have now identified new genomic features that determine patient risk more accurately.

Current Cytogenetic Risk Criteria

Current multiple myeloma risk stratification focuses on specific chromosomal abnormalities. Dr. Nikhil Munshi, MD, identifies translocations involving chromosome 14 with chromosomes 4, 16, or 20 as high-risk features. Amplification of chromosome 1q has emerged as another prominent high-risk marker. Research continues on other potential risk factors like 1p deletion. These cytogenetic abnormalities help oncologists identify patients with more aggressive disease biology.

ISS Staging System

The International Staging System (ISS) provides a globally accessible risk assessment tool. Dr. Nikhil Munshi, MD, emphasizes that ISS staging requires only two simple blood tests. Serum albumin and serum beta-2 microglobulin levels determine the staging. ISS stage 1 and 2 indicate better prognosis multiple myeloma. ISS stage 3 identifies patients with more aggressive disease requiring intensive treatment strategies.

Revised ISS Staging

The Revised International Staging System (R-ISS) combines cytogenetic and laboratory data. Dr. Nikhil Munshi, MD, describes how R-ISS integrates ISS staging with cytogenetic risk factors. This comprehensive approach creates a more accurate prognostic model. R-ISS stage 3 patients have significantly poorer outcomes despite modern therapies. This staging system represents the current standard for multiple myeloma risk stratification worldwide.

Emerging Genomic Technologies

Advanced genomic technologies are revolutionizing multiple myeloma risk assessment. Dr. Nikhil Munshi, MD, highlights how whole genome sequencing has become faster and more affordable. What once took weeks and thousands of dollars now takes days at reduced cost. Researchers are investigating mutational burden and clonal heterogeneity as prognostic indicators. More heterogeneous disease appears to correlate with worse prognosis in multiple myeloma.

Treatment Implications of Risk Stratification

Risk stratification directly informs multiple myeloma treatment decisions. Dr. Nikhil Munshi, MD, explains that high-risk patients receive more aggressive therapeutic approaches. Treatment intensity and duration are tailored based on individual risk profiles. Novel agents like bortezomib have improved outcomes for certain high-risk groups. Standard-risk patients may receive less intensive regimens to minimize treatment toxicity while maintaining efficacy.

Full Transcript

Dr. Nikhil Munshi, MD: Precision medicine teaches us that each patient with cancer is unique, and multiple myeloma is a heterogeneous disease. Correct risk stratification of each multiple myeloma patient is crucial for selection of the best therapy and for obtaining the best possible prognosis.

Dr. Anton Titov, MD: What are the key risks, stratification criteria, and challenges in multiple myeloma?

Dr. Nikhil Munshi, MD: It's a complex but important question. The risk stratification criteria have existed for a long time; we used to use a system called the Durie-Salmon system. Over time, when we came up with new treatments—in those days, there were new chemotherapeutic drugs—we began to use transplant. Then the Durie-Salmon system was not as critical as, say, chromosome 13 deletion.

With the new drugs, we have new features that are determining the risk stratification in the patient. Currently, for example, the applicable features are patients with myeloma having translocations involving chromosome 14 with chromosome 4, or chromosome 16 or 20. More recently, amplification of chromosome 1q is also important.

There are a few other features that are in our research setting, like 1p deletion and others, that we are continuing to study. What is happening in risk stratification is that as we identify risk factors, we have new drugs that begin to work well in those higher-risk diseases. Those features become less important, but some new features begin to be identified.

For example, t(4;14) myeloma was a very high-risk disease. Now with the use of drugs like bortezomib and others, we are able to partly overcome the risk carried by this translocation. It is still in a high-risk disease group, but those patients do better than they used to.

But 1q is becoming much more prominent. This stratification is done by looking at chromosomal content—that's one method. The second risk stratification being used is the ISS staging system, which can be done all across the world with minimal technology by measuring serum albumin and serum beta-2 microglobulin in blood.

Two very simple laboratory tests tell us whether the patient is ISS stage one or two, which are better stages, or stage three, which is a more aggressive stage. Then we combined both the ISS stage with the cytogenetic stage into what is called the revised ISS. Patients in stage three do not do as well.

This is what is standard today; that is what everybody utilizes. We all meet periodically and revisit to see how we change with new things that are coming. Using newer technology, we have the ability to do whole genome sequencing.

To give an idea: what we used to do in the old days, which is like 10–15 years ago, would take weeks and months to sequence and cost thousands of dollars. We can do whole genome sequencing today in less than a week or sometimes three days; we have the results immediately available and much cheaper than before.

These advances are beginning to trickle down to our practice. It's still research, but we are beginning to use it where the number of mutations matters. Very importantly, the clonal heterogeneity we talked about earlier—we are beginning to think that the more heterogeneous the disease, the worse the prognosis.

We're beginning to define those kinds of genomic parameters to also re-stratify patients. For high-risk patients, we can take higher risks in treatment as well, meaning we use more aggressive treatment and may use longer treatment. On the other hand, we may use what is standard for a standard-risk or low-risk patient.