Experts Examine Predictive Value of MRD, Maintenance Strategies in Myeloma

Nina Shah, MD

On an episode of OncLive^® On Air, Nina Shah, MD, an associate professor of medicine in the Department of Medicine at the University of California San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, along with Sandy Wong, MD, an assistant clinical professor in the Division of Hematology/Oncology at the UCSF School of Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, discussed the predictive value of minimal residual disease and a potential course of treatment for a patient with revised International Staging System I (ISS-I) multiple myeloma.

In this exclusive interview, 2 unique cases were presented. In the first case, Shah described a 54-year-old man who presented with back pain and mild anemia, which later on resulted in a diagnosis of revised ISS-I multiple myeloma. Although this patient appeared to be a perfect candidate for a clinical trial, Shah reviewed all available options, including lenalidomide (Revlimid) maintenance.

Shah: Today, we will be discussing a case where a 54-year-old man presented with revised ISS stage I disease; this was diagnosed when he presented with back pain, mild anemia, and was found to have a compression fracture at the T4 vertebra. Ultimately, his labs showed a protein of igG kappa of 2.5 g/dL. He had a slightly elevated kappa change, but nothing too remarkable. The anemia was very mild, around 11, and he had normal renal function and normal calcium.

He ultimately got a bone marrow biopsy which showed 40% plasma cells with the translocation 11;14. Notably, his other imaging showed a possible lytic lesion in the pelvis, but nothing with immediate fracture. He was then diagnosed with revised ISS-I disease. His beta-2 was normal, he had no adverse cytogenetic factors, a normal lactate dehydrogenase, and his albumin was within the normal limits. He was initially treated with bortezomib (Velcade), lenalidomide,dexamethasone (VRd) for 4 cycles and he achieved a very good partial response (VGPR). His M-protein went down from 2.5 g/dL to 0.2 g/dL.

He then went on to a high-dose chemotherapy/autologous stem cell transplant program with melphalan 200 kg/m2 and was still in VGPR after the transplant with an M-protein of 0.1 g/dL. After the transplant, we did a bone marrow around the 90-day mark and it showed no evidence morphologically with plasma cells; the flow was negative, as well. However, we sent the bone marrow off for next-generation sequencing (NGS) and that did show minimal residual disease (MRD) positivity.

Dr. Wong, what you would do in this situation?

Sandy Wong, MD

Wong: If there is a clinical trial option, this patient would be a perfect candidate. Outside of a clinical trial, there are not enough data to say that we can use MRD to change our maintenance strategy. Given his disease risk and his absence of high-risk cytogenetics, I would put him on lenalidomide maintenance.

Shah: I think I would choose the same. Lenalidomide maintenance is a standard of care that is certainly supported by the CALGB data and the meta analyses of 3 different randomized, controlled trials. Data from these trials show that there's a benefit with lenalidomide no matter what category the patient is in. Obviously, we know that high-risk patients do worse, but they still benefit from lenalidomide maintenance. That would be 1 option that's supported by data.

A second option would be consolidation, either with VRd, and if you wanted to be more aggressive, carfilzomib (Kyprolis), lenalidomide, and dexamethasone. The thought being that the patient is MRD positive, do we want to make that better? However, we really don't have any data, as you pointed out, to support us.

In fact, this person presents very similar to the average patient on the BMT CTN 0702 trial, which had induction therapy dealer's choice, and then a melphalan 200 mg/m2 for transplant in patients who were randomized to either get a tandem autologous transplant and then lenalidomide maintenance, 4 cycles of consolidation, and then lenalidomide maintenance or just lenalidomide maintenance. There was no difference in those arms. In this case, I really couldn't make a true argument for consolidation; there wasn't even MRD as a decision-making point in that trial.

I also appreciate that you mentioned clinical trials because we are conducting the AURIGA trial (NCT03901963) here at UCSF and it's being conducted at many sites around the United States. In this trial, patients who achieve a VGPR or complete response after transplant, are restaged as per standard of care. If that bone marrow, after the transplant, does show at least 1 in 100,000 positive clones by NGS-MRD analysis, that patient is eligible.

In that clinical trial, patients are randomized to standard-of-care lenalidomide maintenance, versus daratumumab (Darzalex) and lenalidomide maintenance with the primary end point being conversion to MRD negativity is 12 months of maintenance. As such, that would be my choice if the patient was interested in clinical trial; however, in absence of that, I definitely would proceed with lenalidomide maintenance. Any other thoughts, Dr. Wong?

Wong: The PRIMeR trial, which used next-generation flow cytometry, was a subanalysis of the STaMINA trial (NCT01109004). In the data that have been presented, it seems that after being on maintenance, some patients converted from MRD positivity to negativity. It’s hard to tell from just 1 time point how these patients eventually will fare. We all thought MRD positivity portends a poor prognosis compared with those who are MRD negative; however, I think this is an evolving picture. People are doing more serial MRD testing. One hypothesis is that in the future, we will see that of those who are MRD positive some will become negative after more exposure to lenalidomide maintenance.

I would also point out that, in the EMN02/HO95 trial (NCT01208766), they did MRD testing by next-generation flow cytometry in patients who got at a least VGPR before the start of maintenance and during maintenance. Results showed that some patients do convert from positive to negative after receiving 1 year of lenalidomide maintenance. As such, you have 2 studies that basically show that with lenalidomide maintenance specifically, you can see that conversion.

Shah: This question of MRD is really important and it’s something that we all talk about so much because we'd love to have this information, but for what? In the absence of a clinical trial though, we don’t know what to do with it. Even though we're talking to our patients about MRD positivity, conveying that on a curve that might mean they would do less well than if they were MRD negative, we don't know whether it's worth intervening to make them MRD negative; it might just be reflective of the person's disease biology. Furthermore, not all patients with MRD positivity are the same.

Wong: Absolutely. In the absence of the clinical trial and of mature data, it is too preliminary to change our treatment just yet [with regard to MRD].

Shah: Yes, I want to shift into this newly diagnosed theme for a minute because, as you know, the MASTER trial (NCT03224507) is one where patients are receiving KRd and daratumumab induction, transplant, and consolidation. The idea is that when they have 2 sequential points where they have MRD negativity, they'll come off the study just be observed; this is by NGS at 10-5 cutoff. I really like this study design because it's using MRD intelligently. I found it interesting that, let's say patients do great on the trial, the question is, maybe it's the patients with MRD negativity who should be on lenalidomide maintenance?

We assume that just because a patient is MRD negative that they don't need maintenance but maybe it's those who are doing great that will continue to do great even with lenalidomide maintenance. What do you think about that?

Wong: You have a great point. We don’t have the data to support it one way or another, but there is a possibility that the scenario will play out. We'll know for sure once these trials are complete.

To hear the second case, listen to the OncLive^® On Air episode now.