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Residual Disease and Immune Dysfunction

Ravi Vij, MD, Associate Professor, Washington University School of Medicine in St. Louis and Board Certified Hematologist/Oncologist, describes how immune dysfunction and residual disease contribute to the progression of multiple myeloma.

Tip Sheet about this topic

Advanced sensitive molecular techniques can allow for the detection of minimal residual disease (or MRD), which may help predict outcomes in patients with multiple myeloma.

Hello. My name is Dr. Ravi Vij, I am an associate professor at Washington University School of Medicine in St. Louis, Missouri, and board certified hematologist/oncologist.

Today, I will be speaking with you about immune dysfunction and residual disease—and the risk that these 2 mechanisms pose as they come together to support the progression of multiple myeloma.

In recent years, our understanding of the biology of multiple myeloma management has helped us make great strides in our fight against this devastating disease. This progress has been demonstrated by the SEER analysis for multiple myeloma, which shows that relative 5-year survival has significantly increased over time. While we’ve made extraordinary progress—there’s still room for improvement.

Despite improvement in 5-year survival, patients still experience multiple periods of relapse and remission. Patients will often relapse within 1 to 3 years, which is important because relapse ultimately affects overall survival.

For example, the survival time of a newly diagnosed patient is anticipated to be 20 to 50 months. But once a patient relapses, those expectations are reduced to 14 to 16 months. And with a second relapse, survival time is expected to decrease to 6 to 10 months.

Generally, there’s also a decrease in response duration after each consecutive therapy.

This chart illustrates data from a study that included 578 patients with multiple myeloma.

In this study, researchers noted that relapse from successive treatment regimens resulted in progressively shorter response durations.

We know multiple myeloma is a complex disease. And there are certain elements—that when together—may result in a ‘perfect storm’ that enables disease progression.

Two of these elements are immune dysfunction and residual disease, and both should be taken into consideration when thinking about a long-term strategy for multiple myeloma. Elucidating the complexity of multiple myeloma includes an understanding of immune dysfunction and residual disease.

The majority of patients with multiple myeloma in remission have persistent levels of residual disease. Some of these patients may have minimal residual malignant cells, which are below the sensitivity of conventional methods of detection.

Residual disease may go undetected—even in patients who have achieved a complete response (as defined by current criteria in the International Myeloma Working Group). Persistent levels of residual disease play a role in the recurrence and relapse of multiple myeloma.

Advanced sensitive molecular techniques can allow for the detection of minimal residual disease (or MRD), which may help predict outcomes in patients with multiple myeloma.

As of today, we have many clinical tools to measure multiple myeloma. These include familiar tools such as conventional laboratory assessments for diagnosis, response, and disease burden.

There are also emerging assessments for detection of minimal residual disease such as multi-parameter flow cytometry (or MFC), deep sequencing, and allele-specific oligonucleotide polymerase chain reaction (or ASO-PCR). In multiple myeloma, there is not yet a standardized method for measuring residual disease.

The definitions of complete response, or CR, are also evolving to more accurately describe a patient’s response in the context of residual disease.

The International Myeloma Working Group currently provides several grades of CR, as seen in this table.

In addition to the traditional definition of CR, there are now more specific categories, including:

The definitions of these, however, vary by laboratory and by testing methodologies.

Achievement of a CR does not mean that all myeloma clones have been eliminated.

As you can see, a patient with multiple myeloma may present with 1 times 10 to the twelfth myeloma cells at diagnosis. That equals 1 trillion myeloma cells in the bone marrow!

If that same patient achieves a complete response, approximately 100 million myeloma cells may remain. These patients are referred to as MRD positive. This is when millions of tumor cells are present in the bone marrow, but cannot be detected by conventional laboratory assessments.

Patients who are MRD negative do not have a detectable amount of tumor cells when assessed by more sensitive measurements. But these patients are likely to have an undetectable level of residual disease.

Residual disease may be important for understanding why and when patients relapse.

For example, a retrospective analysis of 133 patients demonstrated that patients who achieved a complete response (n=62) and were MRD negative (n=26) showed a significantly longer time to tumor progression than patients who were MRD positive (n=36).

Those patients who were MRD negative showed a median TTP of 131 months compared to 35 months for patients who were MRD positive.

Residual disease may have prognostic value in patients with multiple myeloma who relapsed after receiving an autologous stem cell transplant. In a randomized study of 297 patients, MRD was assessed by multi-parameter flow cytometry after a re-induction regimen.

For patients who achieved CR, those who were MRD negative had a median time to tumor progression of 25 months compared with 10 months for patients who were MRD positive.

Note that in some cases there were patients who did not achieve CR, but were MRD negative. Recent studies suggest that this may be due to the long half-life of serum M protein, so a conventional CR may not be apparent until several months after a patient becomes MRD negative.

When talking about residual disease in myeloma, another important consideration is clonal evolution. Recent findings suggest that tumors can follow a number of evolutionary paths over a patient’s disease course.

As you can see here, primary and secondary genetic events may lead to the evolution of myeloma clones. The initial light blue circle represents the premalignant clone. After the development of a transforming genetic event—that results in active myeloma—a dominant clone emerges and is likely to produce at least one minor subclone, seen as a dark blue circle.

During this process, dominant and minor clones continue to evolve into more aggressive clones, shown by the yellow and orange circles. These clones put the patient at an increased risk for relapse.

As you have seen, even in patients who achieve a CR (by current International Myeloma Working Group criteria), residual disease may persist.

Therefore, continuous suppression of residual disease is an important part of a long-term strategy.

The cycle of disease mechanisms in multiple myeloma can be characterized by the interaction between malignant plasma cells and immune cells in the bone marrow microenvironment.

One part of this cycle is the production of cytokines and growth factors, which lead to compromised immune function.

For example, cytokines that decrease the activity of T, B, and natural killer cells can lead to a decrease in immune surveillance—the immune system’s ability to identify and eliminate residual myeloma cells.

As multiple myeloma progresses, the proliferation of malignant plasma cells is further enhanced by:

MDSCs help promote the proliferation of myeloma cells, while secreting cytokines that further suppress the immune system. This is another mechanism that can contribute to failure of immune surveillance.

Beyond this cycle, several studies have suggested that patients with multiple myeloma have significant abnormalities of the immune system.

For example, total lymphocyte counts are decreased in patients with multiple myeloma. This includes decreased mature B-cells in peripheral blood and precursor B-cells, and functional defects in natural killer T-cells.

It is also possible that enhanced T-cell suppression of B-cells may play a role in promoting hypogammaglobulinemia. Several disease mechanisms may contribute to immunoparesis.

A decrease in the complement factor C3b is also seen in patients, along with an increase in MDSCs. Each of these factors may play an important role in suppressing the immune system.

While many patients have significant immune abnormalities, some patients have a unique immunological profile that is associated with long-term disease control.

This study showed that elevated levels of immune cells were found in patients who had been in remission for at least 10 years. This suggests that patients with long-term disease control exhibit unique immune changes that suggest improved immune surveillance.

Understanding more about residual disease and immune dysfunction can help us provide optimal care to our patients.

When we know about a risk, we can better plan our strategy.

Now, we are more aware that the complexity of multiple myeloma includes abnormal immune function and residual disease.

We’ve learned how myeloma relapse is characterized by the evolution and proliferation of residual tumor cells and decreased immune function.

We’ve seen how residual disease is present even in patients who are in remission.

And finally, we see how continuous suppression of myeloma cell proliferation and support of immune function is an important long-term strategy when facing this combined risk.

Thank you for joining the discussion about residual disease and immune dysfunction in multiple myeloma.



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