MRD Testing in Stage II Multiple Myeloma

C. Ola Landgren, MD, PhD:At my institution, at Memorial Sloan Kettering, every patient typically receives 6 cycles of combination therapy if they are candidates for a potential transplantation. After 6 cycles, we do a bone marrow biopsy. And if they have reached a complete response, we always check for MRD status. Many clinics around the country here in America, they don’t have access to MRD, and that’s also true outside of the United States. I do predict that more and more centers will start using MRD, and as I mentioned before, I think that, potentially, MRD results could guide the next step in terms of treatment.

I have worked on MRD assays since about 2010. I worked on flow cytometry-based assays, and I have worked with sequencing-based assays. We are also developing proteomic-based assays, where we look for proteins in blood and urine. At this point, we use flow cytometry-based assays in the bone marrow in parallel with sequencing-based assays based on bone marrow samples as well. The flow cytometry is more available around the world because flow cytometry machines are basically available in every hospital. Sequencing is not easily available around the world. Flow cytometry has lower sensitivity. If you do it perfectly right, you can, at the highest level of detection, find 1 cell in 100,000. That’s the maximum that a method can deliver. Sequencing can find 1 cell in 1 million. If you look through the series that we and others have—including the French study that I did mention before and the Dana-Farber study, where we are participating—we see that there is a difference in the duration of freedom from disease, the progression-free survival. If you compare patients that are negative—1 in a 100,000 versus 1 in 1 million—there is no doubt that sequencing is a better technology and it delivers longer duration of freedom from disease. There are also data from metaanalysis reporting sequencing being associated with longer overall survival.

At this point, the main limitation for sequencing is the availability. I do think in the coming 1 to 2 years, we will start seeing available assays that can be run in the local centers for sequencing. I also would like to add that I mentioned the blood-based test. I think there will be a lot of development. The new technologies are amazing. You can find single circulating cells. You can find proteins. And we have a lot of resource data that we have not yet published, showing that you can track the disease in the blood. And I think that would be great. Patients don’t have to do bone marrows. Also, you could also use imaging. PET/CT is part of the current guidelines for tracking for MRD. The current PET/CT that we have around the world using FDG as the PET tracer is not optimized to a myeloma. In fact, around 30% to 40% of patients with myeloma bone disease are, unfortunately, PET-negative already on diagnosis.

So, if you want to treat the patient and repeat PET/CT, if it was negative to begin with, it could continue to be negative. And if it was positive in the beginning and now is negative, it could still be false-negative. What I’m try to say, and trying to get at here, is that we need better tracers that are more designed to track myeloma cells, if you want to really use PET/CT for tracking.

The patients come back after about 1 year, which is a very short duration of maintenance. The average patient that’s treated with a 3-drug combination, followed by an autologous transplant and put on maintenance therapy, lasts for about 4 years. So, 1 year is clearly short. Whatever therapy is used, patients who relapse within the first year, that’s a usually very aggressive disease that’s going to be hard to deal with, whatever therapy we use.

Also, this patient presents with symptoms beyond the labs. Looking in more detail, the patient has evolving kidney failure. And if you pay attention to the details of the light chains, you see that the kappa light chains are passing the threshold when they start becoming toxic for the kidney, which usually goes from 50 mg/dl and higher. So, the light chains are probably trying to clog the kidney. This patient has a lot of disease activity going on.

Case Scenario 1:

January 2015

• The patient is a 61-year-old male who was diagnosed with ISS stage II MM.
• Performance status 0.
• At diagnosis bone marrow shows 40% light chain restricted plasma cells, FISH cytogenetics show hyperdiploid phenotype.
• M-spike of 3.2 g/dL IgG kappa, serum free light chains kappa 60 mg/dL, lambda 1.5 mg/dL, ratio=40
• Bloodwork show beta-2 microglobulin=4.2 mg/dL, Hg=8.2 g/dL, creatinine=0.9 mg/dL.
• PET/CT shows multiple focal bone lesions in upper and lower extremities and in L2 and L3.Bone lesions have increased SUVs.
• Based on these data and diagnosis of standard risk he was started on lenalidomide, bortezomib, and dexamethasone (RVD) induction.
• He achieved a partial response with RVD.
• He then had an autologous stem cell transplantation and achieved MRD negativity.
• He was started on lenalidomide maintenance of 10 mg.

April 2016

• Patient was experiencing back pain, loss of appetite and weight loss.
• Blood work show beta-2 microglobulin=4.0 mg/dL, Hg=9 g/dL, creatinine=1.5 mg/dL.
• M-spike is 0.5 g/dL, serum free light chains kappa 60 mg/dL, lambda 0.6 mg/dL, ratio=10.
• Performance status 1.
• Based on these criteria he was diagnosed with standard-risk multiple myeloma.
• He was started on daratumumab, bortezomib, and dexamethasone.