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MRD Status in MM
MRD Status: A New Era of Individualized Medicine in Multiple Myeloma Care

Released: November 22, 2019

Expiration: November 20, 2020

Jesús F. San-Miguel
Jesús F. San-Miguel, MD, PhD
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With new tools to detect premalignant status and minimal residual disease (MRD), we have more information than ever to guide treatment decisions in MM. How and when should these tools be used? Here are my thoughts.

Early Intervention for Smoldering MM
Cancer survival has improved so much in the last decade, and I think this has been due mainly to 2 reasons. The first is the development of new active drugs, and the second is early detection followed by early intervention. This is particularly true for some solid tumors, such as prostate and breast cancer, but the situation is different in hematological malignancies. Why? Although there are circumstances in which you have a patient with premalignant status, until recently, there was no evidence about the subsequent risk of progression to overt malignant hematological disease.

Now, we have the capacity to predict a 50% risk of progression at 2 years in patients with asymptomatic smoldering MM, deemed high-risk smoldering MM. With the ability to identify these patients, the question is: Should these patients be treated? Furthermore, if we do intervene early, should the goal of treatment be to delay progression or cure the disease? I think the best way to cure cancer is by early intervention because progression is often accompanied by more genetic abnormalities that become more difficult to treat. Therefore, if you have a patient with a 70% risk of progressing to overt disease in 2 years, I think this would favor early intervention. Now, we have tools to identify patients with asymptomatic smoldering MM with 50% risk of progression at 2 years.

MRD Status
Our goal in cancer treatment is to eradicate all tumor cells—or, in other words, to achieve MRD negativity and maintain the best possible response as a surrogate for cure. To evaluate the eradication of the tumor cells, you need appropriately sensitive tools. Unfortunately, the term “complete response” is suboptimal because it is based on low-sensitivity methods, such as a negative immunofixation that relies on subjectivity and the number of plasma cells by morphology without discriminating between normal and malignant plasma cells. Moreover, “complete response” is confusing for patients because they think that they have eradicated the disease, and this is not true. MRD techniques allow you to discriminate between normal and malignant cells, either through immunophenotyping of the antigens expressed on malignant cells or by assessing clonality of plasma cells via sequencing of rearranged immunoglobulin genes. These 2 approaches are like fingerprints of the tumor cells.

These techniques have evolved in recent years, and we now have next-generation flow cytometry and next-generation sequencing that allow detection of 1 malignant cell among approximately 1 million healthy cells. These techniques have demonstrated specificity and sensitivity to better predict PFS and OS compared with CR status. This applies not only to patients with MM who are eligible for transplantation, but also to patients with high-risk cytogenetics, patients with advanced disease, and patients who are not transplant eligible. Recent findings suggest that the value of eradicating the tumor cell in these high-risk patients is particularly relevant. In fact, in patients with high-risk cytogenetics, if you reduce the number of tumor cells to less than 1 per 1 million cells (1 x 10-6), the outcome of these patients is similar to that of standard-risk patients. By contrast, if high-risk patients with stage III MM remain MRD positive, the median PFS is only approximately 1 year. The benefits of achieving MRD negativity have been shown not only for patients with newly diagnosed myeloma, but also in the relapse setting. Of importance, after achieving MRD negativity, it is particularly relevant to sustain MRD negativity at 6 and 12 months for optimal treatment outcomes.

Using MRD Status in Clinical Practice
MRD assessment should be used in conjunction with traditional methods for assessing response and with PET/CT imaging, which is necessary to evaluate disease outside of the bone marrow. PET/CT is a valuable tool for evaluating the extent of disease, particularly for patients with extramedullary disease, and to assess response to therapy (PET-MRD). In my practice, we have seen patients who are MRD negative in bone marrow but then present with relapse outside of the bone marrow. Most of these patients had extramedullary disease at diagnosis, and highlights the relevance of evaluating PET-response.

With my patients, I emphasize that MRD positivity is the enemy; if you remain MRD positive, you generally have a higher risk of relapse, with the exception of a small population of patients that remains MRD positive and stable without progression for a long time. However, these patients are a minority that either have reversed to a monoclonal gammopathy of undetermined significance (MGUS) type disease or have a very potent immune system. For the vast majority of patients who remain MRD positive, the outcome is significantly worse compared with MRD-negative patients. In addition, although MRD negativity is a very good prognostic marker, false-negative results do occur. In some patients, for example, the bone marrow sample can be hemo-diluted and not representative of the overall bone marrow composition, resulting in a false-negative result. This is an important caveat to be aware of, and why I always emphasize to my patients that an MRD negative result can potentially be a false negative result, while an MRD positive result is clearly associated with poorer prognosis.

We now must ask, if MRD is more sensitive than traditional methods to confirm a deep response, why not use it to make treatment decisions? This is what we are doing at our practice—we are using MRD to guide many treatment decisions, particularly in those patients with active MM who are high risk. MRD assessment can be very valuable for evaluation of treatment efficacy, particularly for patients who have achieved CR before transplantation, so you can determine if the tumor load has been further reduced with additional treatment intervention. Currently, there are ongoing clinical trials adapting or intensifying treatment in patients who remain MRD positive after initial treatment. In our clinical practice, if a patient remains MRD positive after transplant, we offer consolidation with a different treatment regimen to try to eradicate the remaining tumor cells, particularly for patients with high-risk MM. In the near future, we plan to also adapt individualized maintenance therapy according to a patient’s MRD status.

Determining the best approach to individualize treatment according to the patient’s needs is an important avenue of ongoing research. I expect that as more clinical trials assess this approach, using MRD status to guide treatment decisions will become best practice.

To hear more about how to incorporate the latest prognostic tools into care for patients with MM, please join me and my colleagues for the annual CCO/IMF CME-certified symposium at ASH 2019, “Approaches to Achieve the Best Possible Outcomes in Myeloma.” Brian G.M. Durie, MD; Shaji Kumar, MD; Thomas G. Martin, MD; Philippe Moreau, MD; S. Vincent Rajkumar, MD, and I will discuss patient case studies and key clinical trial data on recent advances in the treatment of MM. Click here to register!

Your Thoughts
Do you currently use MRD to guide treatment decisions in your clinical practice? Please share your thoughts in the comments box below.

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