Using MRD to Inform Treatment Decisions in Transplant-Eligible Myeloma

Rafael Fonseca, MD

As more transplant-eligible patients with multiple myeloma experience deep, durable responses with novel quadruplet regimens, the question of how best to use minimal residual disease (MRD) in guiding treatment decisions and duration has become more pronounced, according to Rafael Fonseca, MD.

“We really cannot accept a doublet regimen, and perhaps soon we will not accept a triplet regimen as part of frontline therapy for [patients with] myeloma. I’m personally moving toward [approaching treatment in] the frontline [setting] with very effective and intense combinations,” Fonseca said. “It’s clear from multiple clinical trials that the best results happen when you put your best foot forward and you start with the best [therapies] from the get-go. Don’t save drugs for later. [Use] the best combination and try to induce the best responses.”

Fonseca said that after day 100 is when he typically measures MRD in patients who undergo transplant, as well as in any other patient who achieves a very deep, durable complete response (CR). If MRD negativity is sustained, determining whether maintenance therapy can be stopped in that patient is an area of active discussion. Moreover, the question of how to proceed with a patient who completes initial therapy and remains MRD positive remains open.

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on multiple myeloma, Fonseca, interim director of Mayo Clinic Cancer Center and director of Innovation and Transformational Relationships at Mayo Clinic, discussed several clinical trials that support the use of quadruplet regimens in myeloma, the utilization of MRD in clinical decision-making, and future directions for research.

OncLive^®: Several notable trials have been conducted in the frontline setting, both in transplant-eligible and -ineligible patients. What do these efforts indicate about the current state of treatment and where the paradigm is headed?

Fonseca: Clinical trials in the multiple myeloma space can be broadly categorized into those that are going to be important for patients going through stem cell transplantation and for those going through conventional combinatorial therapy without transplant.

In the first category, we’ve seen the CASSIOPEIA study [NCT02541383] with daratumumab [Darzalex] plus bortezomib [Velcade], thalidomide [Thalomid], and dexamethasone, which at the global level has been very important in [that the combination has elicited] deep responses. Most recently, we’ve seen updated presentations and publications for GRIFFIN [NCT02874742], which is [with] a combination of daratumumab plus lenalidomide [Revlimid], bortezomib, and dexamethasone [RVd]. We’ve seen the MASTER trial [NCT03224507], which includes daratumumab plus carfilzomib [Kyprolis], lenalidomide, and dexamethasone [KRd] vs KRd alone. In this case, [the triplet includes] carfilzomib instead of bortezomib. Also, the FORTE trial [NCT02203643] did not use a monoclonal antibody, but it did use one of the state-of-the-art backbones for frontline therapy, which is KRd plus transplant. All [these trials] show the same thing.

When you look at the groups of patients enrolled in these trials, those who have the deeper responses do better, whether they are measured through the International Myeloma Working Group criteria or through MRD methods, f low cytometry, or next-generation sequencing. Those outcomes really translate into better time-dependent variables, such as would-be progression-free survival and, ultimately, overall survival.

As we think about the transplant-ineligible candidates, perhaps one of the most important [studies] is MAIA [NCT02252172], which [examined] a combination of daratumumab plus lenalidomide and dexamethasone. We’ve seen this before, with the same antibody but combined with bortezomib, melphalan, and prednisone in the ALCYONE study [NCT02195479]. Both were randomized phase 3 studies that [tell the] same story: deeper responses and longer duration of disease response. I hold the belief that a group of these patients with multiple myeloma who achieve deep responses, and in particular those who have sustained MRD negativity, will ultimately convert to cure.

Quadruplet regimens are clearly eliciting these impressive responses. Are 4 drugs necessary to achieve that benefit, considering the toxicity that accompanies these combinations?

[The question of] whether 4 agents are necessary [has been asked] in light of toxicity. However, I would say that the incremental toxicity is quite minimal. We deal with greater problems with toxicity when we talk about proteasome inhibitors, as well as corticosteroids. Also, clearly, an added expense is incurred for the treatment of patients with these extra medications; I’m really interested in seeing the longterm outcomes from a pharmacoeconomic perspective.

If some of these patients are able to convert those deep responses into durable ones, and then, ultimately, prevent relapse, the downstream benefit of that could be enormous. That is not to minimize [the concern regarding toxicities]; every drug must be taken quite seriously. When you add a new drug, whatever the drug is, you always add toxicity, and you don’t know if you add benefit. However, that is the reality for all the drugs we use. The [class that] is at play right now is monoclonal antibodies, and these agents are generally well tolerated by patients.

How is MRD being used to direct treatment decisions in clinical practice?

MRD is no longer investigational. What the community can debate is how they’re going to use MRD to [inform] decision making. We have an FDA-approved assay that has been validated. Other [methods] are being explored, as well. We have flow cytometry with EuroFlow, as well as mass spectrometry methods. The question is: How do we bring a new biomarker into the decision-making process?

From a physician’s perspective, some might ask, “What am I going to do differently?” I’ll give a couple of answers to that. First, I routinely measure MRD after day 100 in patients who undergo transplant, as well as in any other patient who achieves a very deep and durable CR. Patients are in a much better position with a reduced risk of relapse if they are MRD negative, so that’s very important information.

Another remaining question is: If you have MRD negativity that is sustained, at which point can you eliminate maintenance therapy? That is actually something that has to be decided individually. We [may choose to] stop maintenance therapies [for many reasons], including [because of] symptomatic changes or toxicities. I don’t envision that MRD negativity would ever be the sole determinant of whether one continues treatment or not, but it does build into the information you have as you treat patients. If I have a patient who has a long-standing CR but is having more fatigue or diarrhea and they are MRD negative, perhaps both the patient and I would have a greater comfort in discontinuing the medicine. In contrast, if the patient is tolerating [maintenance therapy], experiencing some symptoms, and they are MRD positive, they may want to proceed further until we have data from additional clinical trials.

Also, what do we do when someone completes initial therapy and remains MRD positive? A French study published in 2018 by Aurore Perrot, MD, PhD, of the University of Toulouse, showed that if you are able to convert a high-risk patient into an MRD-negative status, their prognosis is better than if you have a standard-risk patient who remains MRD positive. Several abstracts presented at the 2020 American Society of Hematology Annual Meeting and Exposition showed that additional treatment post induction and post transplant seems to improve the outcomes of patients with multiple myeloma.

As we complete the next series of studies and we have adaptive clinical trials, such as the MASTER trial, there is going to be a future where we won’t stop with intensive therapy, but you have to finish the job and get those patients to convert to MRD negativity.

What impact do negative studies, such as the phase 3 TOURMALINE-MM2 (NCT01850524) study, have on the treatment landscape? Do such regimens still have roles?

The TOURMALINE-MM2 trial has shown proof of principle that the addition of a proteasome inhibitor is better. When you look at this in a different setting—[for example], the frontline or even the maintenance setting—they [show benefit]. It’s good to know that you have an extra option.

If I have a patient who goes on maintenance treatment with ixazomib [Ninlaro], would they be better off with lenalidomide? The short answer is that in general, most of the maintenance trials would suggest that your first choice is lenalidomide. However, in some circumstances that may not be either sufficient or the best route for patients who have high-risk myeloma. For instance, when we do maintenance therapy [in these patients], we like to combine ixazomib with lenalidomide. That’s something I do routinely for my high-risk patients, [and I see] good results and good tolerance. Some patients logistically cannot come to a treatment center, be that for frontline or for maintenance [treatment], [so in those patients] the all-oral regimen would be highly beneficial.

For me, I don’t think the numbers, or the hazard ratios, are as important as the fact that we know we have an active proteasome inhibitor that when used in combination is going to have superiority. However, again, when we start looking at the net effect, perhaps it is not as high. I also believe that one could make the argument that the cell-killing ability of bortezomib or carfilzomib is higher, but the convenience has made this a very important tool in our ability to fight multiple myeloma.

What are some future directions for research?

Several studies show that consolidation of stem cell transplants appears to improve patient outcomes. This notion that we have treated myeloma with 4 cycles of treatment and then do a transplant, [followed by] subsequent years of treatment with maintenance therapy—there’s really no logical basis for that. It’s just a historic adaptation of what was done in the past with vincristine, doxorubicin, and dexamethasone. Transplant, in many ways, was an accidental discovery. I believe all this will be challenged.

Do we still do 4, 6, or 8 [cycles]? Do we keep going until we have MRD? Do you change to a different regimen post transplant if you have someone who remains MRD positive? Obviously, this will take time, but the field has shown consistently that better responses result in better outcomes for patients with multiple myeloma.