https://www.onclive.com/web-exclusives/landgren-explains-crucial-role-of-mrd-in-myeloma
Landgren Explains Crucial Role of MRD in Myeloma

Brandon Scalea

C. Ola Landgren, MD, PhD
C. Ola Landgren, MD, PhD
It is becoming clear that minimal residual disease (MRD) negativity is a crucial prognostic factor in patients with multiple myeloma, said C. Ola Landgren, MD, PhD.

It has been known that MRD has a role in clinical trials, but as more data become available, that role has become more clearly defined. For years, researchers have evaluated different platforms for detecting MRD in patients, and are now able to do so with the use of next-generation sequencing (NGS).

On September 28, 2018, the FDA approved the first NGS assay, ClonoSEQ, as a test for MRD in patients with acute lymphoblastic leukemia (ALL) or multiple myeloma. The clinical validity of the assay was shown in a retrospective analysis of samples collected from a clinical trial that enrolled 273 patients with ALL and 2 trials involving 323 and 706 patients with myeloma, respectively.

For the trials, researchers used the assay to evaluate MRD at various disease burden thresholds and determined that MRD status correlated with event-free survival (EFS). EFS was longer and EFS rates were higher for MRD-negative patients. These findings were similar for progression-free survival (PFS) and disease-free survival among patients with myeloma.1

Other data have shown that MRD negativity is indicative of longer PFS, irrespective of the treatment regimen used in a patient, said Landgren, chief of the Myeloma Service, Memorial Sloan Kettering Cancer Center, which is encouraging in the relapsed/refractory setting of myeloma.

Despite many options, there is still not an optimal therapy to use in the relapsed/refractory setting; however, chimeric antigen receptor (CAR) T-cell therapy has shown some promise in the space. For example, preliminary data from the phase I CRB-401 trial demonstrated that a BCMA-directed therapy, bb2121, induced a complete response rate of 50% in a heavily pretreated patient population. The median PFS was 11.8 months with a duration of response of 10.7 months. The phase II portion of the trial is ongoing.2

In an interview with OncLive, Landgren discussed the role of MRD negativity and the emergence of CAR T-cell therapy in multiple myeloma.

OncLive: What is the role of MRD in multiple myeloma?

Landgren: MRD is currently moving into many disease areas. In multiple myeloma, this has been going on for more than 10 years. Now, we are at a point that MRD plays a crucial role in clinical trials; it is an important clinical outcome. We have data from multiple studies and 2 meta-analyses showing that MRD negativity is indicative of longer PFS. We know that MRD negativity is a highly clinically meaningful prognostic marker in clinical trials. MRD negativity has been tested against cytogenetics and other important clinical markers and data show that MRD negativity is a stronger prognostic factor.

Additionally, there are now clinical trials showing that patients who achieve MRD negativity both in the newly diagnosed and relapsed/refractory settings have similar clinical outcomes; this is independent of the treatment arm they were on in the respective clinical trials. Simply, a 3-drug regimen versus a 2-drug regimen was being tested in a randomized matter. In both arms, there were patients achieving MRD negativity at some point. We looked at the patients' PFS outcomes. Data show that the patients who receive the more aggressive regimen have outcomes [similar to those who receive] the less aggressive regimen, as long as they achieve MRD negativity. 

Is there a specific assay for MRD testing that should be used across practices?

For a long time, researchers have been looking at different platforms for doing this. Some groups were in a laboratory trying to decide if we should use polymerase chain reaction primers based on the sequencing and the development of patient-specific primers. Over the years, the molecular field has evolved and moved forward very fast.

Data consistently shows that V(D)J sequencing seems to be very similar across all the myeloma cells in a given patient; it varies from patient to patient, but it is rather similar within 1 patient. Myeloma is a very heterogeneous disease, but V(D)J seems to be similar across the board. Using [the NGS] assay, you can get a good idea of a patient's genomic signature. This was FDA approved in 2018, and we have adapted our technologies to fit this. 

What factors do you take into consideration when deciding what the right treatment is for a patient?

It is a complicated question to answer, and there really is not an optimal, go-to therapy. This is why it is important in particularly difficult-to-treat patients to get a second opinion at a specialized clinic. There are so many options these days. [One factor to consider is] the rapidity of the relapse, and this is sort of biomarker-based. On the other hand, if a patient gets acutely sick and there are symptoms such as pain and kidney failure, this would require a completely different approach [than you would use for] someone who has indolent disease. 

You also see that patients favor the more convenient therapies. They won't want to come all the way to the clinic multiple times a week if there is an easier option available. Therefore, patients will typically favor the oral therapies. Patient preference is a major factor [that should be considered when choosing treatment]. 

How are CAR T cells being used in multiple myeloma?

[Data pertaining to the use of] CAR T-cell therapy in [patients with] multiple myeloma was first published in 2013. The researchers had identified BCMA as a potential target using CAR T cells for multiple myeloma patients. Just a few years later, the same research group at the National Cancer Institute published the first study that evaluated BCMA as a target. As a result, several trials exploded all over the world looking at BCMA and CAR T cells. All these different products out there use the same target, but what differs between them is [how they are developed].

All of these studies seem to show that the use of CAR T cells can lead to encouraging responses in very heavily pretreated patients [with multiple myeloma]. There were patients who received 7 or more lines of previous therapy and did not respond; these patients usually would not last more than 2 or 3 months on any other FDA-approved therapy. Patient responses with CAR T cells are lasting somewhere between 12 and 18 months. There is no doubt that it works and it seems to be superior to other regimens, but there are a lot of issues that need to be improved on.

For starters, the development of CAR T cells is quite complicated and it is done in a personalized way; it needs to be made more efficient. Also, the actual delivery of the CAR T cells is something that needs to be improved. Having patients stay in the intensive care unit taking up several beds is not practical; this needs to be done in an outpatient setting. 

The unanswered question is how these therapies will do if they are moved into an earlier setting. The obvious thing to do would be to develop CAR T cells for newly diagnosed patients with high-risk histology. Currently, the projected overall survival for these patients is anywhere from 1 to 3 years. The hope would be that CAR T cells could drastically change that. Unfortunately, to date, about 10% to 15% of all newly diagnosed patients fall into that category. 

Lastly, there are a lot of improvements that can be made to the CAR T cells themselves. For example, they can be "armored." There are things that can be done to make them more active and durable in the body. The targets also need to be further developed.

We will probably reach a point where there is a combination of targets. CAR T cells also continue to have competition with other therapies that go after the same target. For example, there are monoclonal antibodies and bispecific antibodies that also go after BCMA. 
References
  1. FDA authorizes first next generation sequencing-based test to detect very low levels of remaining cancer cells in patients with acute lymphoblastic leukemia or multiple myeloma [news release]. FDA. Published September 28, 2018. https://bit.ly/2OWPpnX. Accessed November 29, 2018.
  2. Raje NS, Berdeja JG, Lin Y, et al. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: Updated results from a multicenter phase I study. J Clin Oncol. 2018;36(suppl; abstr 8007).
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