Understanding Minimal Residual Disease (MRD)

MRD results are a more sensitive test than normal blood monoclonal protein tests that try to detect if there is a measurable disease (in this case, myeloma) left within your body after treatment.

Why is this a relatively new topic in the world of myeloma? Simply put, it wasn’t available or needed until very recently. As myeloma treatments have advanced, the majority of myeloma patients’ responses are deeper than what can be detected with standard testing. Because of this, more sensitive tests were needed to determine whether the myeloma was truly gone, or just undetectable through “normal” blood and urine testing protocols.

There are still a lot of open questions in Minimal Residual Disease Testing, and a lot of research is left to be done in the field. Some questions that remain include:

1. What is the best method of minimal residual disease testing? (There is more than one!)
2. How feasible is this type of testing?
3. Can it predict clinically meaningful outcomes?
4. Can it be used as a surrogate endpoint in clinical trials?

Different Types of MRD Testing

There are different types of MRD testing available and the reason it’s important to note this is they all have varying levels of sensitivity. The two Dr. Costa chose to highlight are Next Generation Flow (NGF) and Next Generation Sequencing (NGS). They vary based on availability, and NGS currently is more sensitive than NGF. It’s important to know when you are receiving an MRD test which of the tests/methodologies you are receiving.

Using Minimal Residual Disease as a Prognosticator for Progression-Free Survival

Despite all the caveats that we have when it comes to Minimal Residual Disease (for example, the different methodologies, the different levels of sensitivity, etc.) when you put it all together, MRD negativity can help predict progression-free survival and overall survival.

Of course, the deepest level of sensitivity in your MRD test, the more precise the results are. That applies to both standard and high-risk patients.

Let’s take a look at a couple of clinical trials to better understand how MRD results can be a good prognosticator of progression-free survival.

IMF 2009

In this study, every patient received an induction therapy of VRd (Velcade, Revlimid, and dexamethasone) and then the patients received an early transplant in one arm or delayed transplant in the other arm. Those who received a transplant did better, but more impressive results were found in the MRD testing. After 7 years, the patients that stopped maintenance therapy after one year (due to trial design) that had achieved MRD negativity, remained without progression seven years later. Without any therapy at all, the majority of patients that achieved MRD negativity had not had any progression of their myeloma. Fascinating!

The problem with this trial is not every patient is going to need/respond well to that kind of treatment. Myeloma is not a one treatment fits all disease.

CASSIOPEA

In this study, for the first time, daratumumab was added to the VTd (Velcade, thalidomide, and dexamethasone) induction therapy for patients with newly diagnosed myeloma who were receiving an autologous stem cell transplant.

One of the arms in the trial included daratumumab in the induction therapy while the other arm did not. Then, differing maintenance therapies were randomized for the whole patient subset. Interestingly enough, in this case, the type of maintenance therapy did not matter. Those in the arm with daratumumab included in their induction therapy achieved higher levels of response (MRD negativity) and their durations lasted three years without progression.

MASTER

With the other two trials indicating strong progression-free survival rates in patients that achieved MRD negativity, Dr. Costa and his team wanted to further examine if they could then tailor therapy for those patients that were achieving MRD negative results from NGS (next-generation sequencing, highly sensitive testing).

They began with a Dara-KRd (daratumumab, Kyprolis, Revlimid, dexamethasone) regimen, and administered four cycles.

Patients then went on to have an autologous stem cell transplant, followed by an optional 8-round cycle of Dara-KRd.

Patients were tested for MRD- after each treatment phase (after induction, after transplant, after a consolidation therapy of 4 rounds and another consolidation therapy of 4 rounds). If they achieved 2 consecutive MRD- results at any of these 4 points, they were then allowed treatment-free observation and MRD surveillance.

Patients that were treatment-free were MRD tested 24 and 72 weeks after the completion of therapy. If they never achieved MRD negativity they were placed on Revlimid maintenance.

What about when it comes to risk? While all patients were equally as likely to achieve MRD negativity, patients with 2+ high-risk genetic abnormalities had a shorter duration of MRD negativity and quicker progressions than other myeloma patients.

Patients with 1 or fewer high-risk genetic characteristics experienced a longer duration of response.

What Next for MRD Use in Clinical Trials?

We need trials that identify early which patients are responding well to treatment and achieving MRD negativity so we can tailor treatment accordingly. 

One of the trials accomplishing this type of research is called the French MIDAS trial. This trial is testing whether or not you can opt out of an SCT (stem cell transplant) if you achieve MRD- before the said procedure, and receive the same results as MRD + patients who have an SCT. They are also looking into whether or not MRD+ patients can benefit from a tandem transplant versus just one.

Another trial that is being designed, MASTER 2, is similar to the MASTER trial (Dara-VRd with 6 cycles) and tests whether an SCT is needed for those that achieve MRD negativity (like the MIDAS trial), but what makes this trial different is adding a bispecific called teclistamab after a stem cell transplant to see if this increases the duration of MRD negative responses.

Starting Treatment Again After New MRD+ Result

Many patients wonder "If I am MRD negative for a while, but then receive an MRD positive result, how would I know when to start treatment?" This is for patients who have no physical or even clinical indicators that they are relapsing (still no m-spike in the “regular” myeloma tests and no side effects), but whose sensitive tests show a small resurgence of the disease.

This is a difficult question and one that has not been answered through the research that we currently have. Many myeloma specialists have differing opinions on this (watch and wait vs treat right away). There are pros and cons to either one of these strategies. Look into the issue yourself and decide ahead of time what you feel most comfortable with. Make sure that your doctor is on board.

Should I Continue Maintenance Therapy if I am MRD Negative?

This is another controversial question in the world of myeloma. Unfortunately, we do not have a one size fits all response as it depends on genetic factors, your personal philosophy, and your myeloma specialist’s opinion.

However, in the case of Dr. Costa, he believes that if his patient were to struggle immensely with side effects (for example, chronic diarrhea that doesn’t allow you to leave the house) on maintenance therapy, and you have tested MRD negative for a prolonged period of time with the most sensitive test available, that would be an ideal candidate for stopping maintenance therapy.

For those who tested MRD negative and wish to discontinue therapy for other reasons, Dr. Costa is open to considering it, especially if you test with the most sensitive tests available to make sure that your MRD negative result is truly negative.

Watch the Q&A and learn other details through Dr. Costa’s presentation here: