Role of MRD Still Evolving Across Hematologic Cancers

Imad Tabbara, MD

Novel therapeutic advances in multiple myeloma, acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML) have led to a rapid evolution of disease management, which has increased the focus on the appropriate role of minimal residual disease (MRD) as a prognosis predictor, said Imad Tabbara, MD.

“MRD—that is the topic in every hematologic malignancy,” said Tabbara, professor of medicine, director of the Blood and Bone Marrow Transplant Program, and Fellowship Training Program, George Washington University Cancer Center. “It is an evolving situation and more prospective studies will define the role in multiple myeloma, ALL, and AML.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Tabbara discussed the role of MRD testing in multiple myeloma, ALL, and AML, as well as emerging regimens in all 3 malignancies that are changing standards of care.

OncLive: In multiple myeloma, what regimens are being used for transplant-eligible patients?

Tabbara: The most standard regimen used in the United States is a combination of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone—known as RVd. Other regimens are available and are starting to be used more, including carfilzomib (Kyprolis), lenalidomide, and dexamethasone—which appears to be another powerful regimen.

Newer studies suggest that adding monoclonal antibodies to this regimen, such as daratumumab (Darzalex), may improve the outcomes of those patients and could [yield] more durable responses.

How do those regimens differ for transplant-ineligible patients?

For those who are ineligible for transplant, a combination that has been used is lenalidomide and dexamethasone, which seems appropriate for somebody who is older with comorbidities. Also, there is “RVd-lite” that can be used with some good benefit.

There are newer studies combining chemotherapy with monoclonal antibodies, such as daratumumab, in these patients.

Is there an end in sight to the number of therapies to combine, or will there now be trials of 5-drug regimens?

We have chemotherapy, immunomodulatory (IMiDs) drugs, proteasome inhibitors, steroids, and monoclonal antibodies; we will wait for a newer set of drugs with different mechanisms of action to combine 5 drugs. If we have that, maybe then we can say, “We can cure multiple myeloma.”

With so many potential regimens to choose from, what factors do you take into consideration when deciding which one to use in clinic?

Usually, the decision is made based on the patient's situation: comorbidities, age, and extent of disease. Also, the patient’s decision is a factor. We have so many options and some are associated with certain toxicities [so the patient will decide against a particular treatment regimen].

Where does MRD come into play here and why are you testing for it?

MRD in myeloma is still at its beginning. There are retrospective studies that show MRD can predict patients who are going to relapse. Now, there are some prospective studies showing that MRD-negativity tends to correlate with better outcomes. At this point, there are no definitive guidelines to tell us how to use MRD status in those patients.

For example, perhaps a patient who has MRD-negative disease does not need maintenance therapy or needs to continue therapy. Perhaps, we can stop [treatment once] achieving MRD-negativity, but there are no studies yet to answer that question.

Currently, is every patient receiving maintenance therapy?

Correct, that is the standard now—definitely posttransplant. There are some good, randomized studies showing that maintenance therapy is very important in improving progression-free survival and possibly overall survival (OS) in patients with multiple myeloma.

Right now, this is independent of MRD status of the patient, but I hope we can determine who will benefit from maintenance therapy depending on their MRD status in the future.

What is the biggest challenge in the frontline setting of multiple myeloma, and what steps are being taken to address it?

The challenge is to figure out what the best first-line therapy is. Is it a combination of a monoclonal antibody plus carfilzomib instead of bortezomib, or in combination with ixazomib (Ninlaro)? We know that a proteasome inhibitor is needed, but we don't know which one is the best. Moreover, which IMiD is the best? Is lenalidomide better than pomalidomide (Pomalyst) or vice versa?

If we use the most aggressive therapy upfront, what do we do if the patient relapses and we have used all of our effective drugs? Some people believe that it doesn't matter, [that you can] give everything effective upfront and keep that patient in remission for as long as possible. Then, figuring out what to do is the next step.

Where would you say you fall in the conversation of using the most effective drugs upfront versus holding back in case of relapse?

It depends on the patient. If the patient is younger with excellent performance status, no comorbidities and specifically, a bad disease, I would use everything that is effective upfront— maybe even a quadruplet therapy. That person can tolerate that treatment and I want to give them the best outcome. An older patient may not be able to tolerate that same aggressive therapy.

Shifting into the leukemia space, what is the role of MRD in ALL?

MRD status is an important topic in ALL. Many studies show that unlike multiple myeloma, there are some definite clinical studies to show that achieving MRD negativity in ALL is important in terms of patient outcomes.

There are several studies [of MRD status] that have been published. The summary that all of them show is that MRD status is a key predictor for relapse and overall survival in those patients. [MRD status] is important after induction, after consolidation, or after a stem cell transplant.

There are multiple studies in both children and adults that show benefit from achieving MRD-negative status. Recent studies use polymerase chain reaction to look for MRD status; other studies look at next-generation sequencing.

There is no consensus on what defines MRD negativity. Is it 10^-3 or is it 10^-4? There are studies on both sides, but it is clear that the less presence of leukemia cells, the better the outcome.

You mentioned the different settings that MRD status is being tested in. Could you elaborate?

It is being tested after induction therapy, which shows that patients who do not achieve MRD negativity after induction have poor prognosis. Some of those patients may not be salvaged by transplant, so that is a big point for achieving MRD negativity early on. We know that MRD positivity after transplant is associated with very poor prognosis; everyone will relapse after transplant if they have MRD-positive disease.

An important study is a preventative study of blinatumomab (Blincyto) in patients who are MRD positive after induction therapy. In who achieved MRD negativity after blinatumomab, about 80% of those patients did very well compared with those who did not achieve MRD-negative disease. This is a very important trial, and blinatumomab received FDA approved for that indication.

Thus far, this is really the best available agent that we have good studies on [for MRD-positive patients]. Additional chemotherapy regimens or different combinations may achieve that but the chances are much lower than with blinatumomab.

Moving onto AML, could you highlight the advances we are seeing in that space?

[There are multiple] newer agents [being introduced] in AML. One is CPX-351 (Vyxeos) which was approved by the FDA in comparison to what we used to call standard of care 7+3 chemotherapy. [CPX-351] is very effective in patients with a bad prognosis through therapy-related leukemia and leukemia evolving from myeloid dysplastic syndrome. Those are the worst types of AML, and it seems that CPX-351 does much better in terms of OS compared with standard of care.

The use of targeted therapy for FLT3-positive patients [has seen growth as well]. We have a few agents that target FLT3: midostaurin (Rydapt), quizartinib, and a newer agent, gilteritinib (Xospata), which are shown to be effective in relapsed patients with FLT3-positive AML. An additional targeted therapy is gemtuzumab ozogamicin (Mylotarg) in CD33-positive patients in combination with chemotherapy. The last treatment option is [ivosidenib (Tibsovo)] in patients with IDH1/2-positive disease. We have targeted therapy for each one of those mutations.

Where did this sudden surge of developments come from?

It was the understanding that AML is not one disease. Ten years ago, we thought of AML as one disease where everybody received 7+3 induction therapy. In the last 10 years, data showed that AML is heterogeneous. There are certain mutations that we knew existed but didn’t have targeted therapies for. Now, we have several targeted therapies for each mutation and the field is growing further. Definitely, 10 years ago versus now, there has been a complete change in the management of AML.

What is the role of MRD in AML?

It is not as well established as in ALL. There are some studies to show that achieving MRD negativity in AML can affect prognosis, but there are no randomized studies and no clear guidelines on how to use the MRD status in AML in terms of treatment, consolidation therapy, or maintenance therapy. That is an area of the field that is being explored. All the newer clinical trials are incorporating checking for MRD status in those patients.

Are patients being tested upfront for FLT3 and IDH1/2 alterations?

That is where things have changed in terms of managing AML. We should do all these tests upfront at the time of diagnosis, but it takes a week for some of those test results to come back. By then, we have already started treatment in those patients. Based on those results, we may need to modify treatment.

Would you potentially hold off on treatment for a fit patient with a good performance status?

We try to, but there isn’t a good study to tell us how long we can wait. Most patients with AML are sick at presentation so, usually, we cannot wait 1 week [before giving treatment]. Perhaps we can wait 1 or 2 days, but not a whole week.

Would you say that these alternations are mutually exclusive or is it possible that a patient with a FLT3 mutation could also develop an IDH1/2 mutation?

Some patients have both [mutations]. Sometimes patients have FLT3 mutation and an NPM1 mutation. NPM1 is a good prognosis factor, whereas FLT3 is not as good of a prognosis. The presence of the two may give us a neutral prognosis, so they can coexist in the same patient.