MRD Assessment of Response to Myeloma Therapy

Ajai Chari, MD:After stem cell transplant, typically we do restaging at somewhere between day 90 to 100, and that would include the usual labs, a 24-hour urine collection, imaging to ensure that there’s no radiologic disease, and, finally, the marrow sample. In bone marrow, we now not only look, histologically, to see if there’s any clonal plasma cells left, but there’s also increasing interest in using more sensitive methods to look for minimal residual disease (MRD).

This is an important area of investigation, and there’s 2 major types of MRD testing. One is flow-based, and the other one is next-generation sequencing. There are some pros and cons to both of them. Next-generation sequencing has the advantage that it is not as variable dependent. For flow cytometry, when the aspirate is pulled out, we have to try to get it to the lab quickly because the plasma cells are labile. And then, we need to also check how many cells are being counted and how many markers are being tested. With all of those quality control issues, it’s not as well standardized. Next-generation sequencing, in some ways, is more easily standardized. However, the caveat is, you do need that initial clone from the patient to be able to detect that in the minimal residual disease state. Flow cytometry doesn’t require that. Every patient, theoretically, is evaluable for flow, but if a patient didn’t have the initial clone for next-generation sequencing, they may not be evaluable for MRD.

The other big difference between them is the sensitivity of the test. It’s thought that next-generation sequencing can get up to 10^-6, or 1 in 1 million. Whereas, with flow cytometry, depending on the data, the number of the cells counted and the channels or the number of antigens tested can be 10^-4or 10^-5. So, those are some approaches, and the question is, as a community doctor or even for any physician, one of the things we’re always taught in medical school is if you do a test, how will it change your management of your patient? And I would say, in 2017, we don’t have an answer for that. That’s why I think this is still in research.

And part of it is, as somebody once said, we know if somebody has a hemoglobin of 8 g/dL, it’s going to be pretty reproducible from lab to lab (when you go around the country). We know that patient is quite anemic. But, when you have a test like flow cytometry, which is so user dependent, is maybe subject to so many quality control issues, and is not yet well standardized, you may very well get different results at different centers and at different time points (perhaps even from different sides of the marrow). We didn’t even mention that the marrow really is contingent on all the other tests being negative. So, in other words, you need to have serum being negative, urine being negative, and very importantly, radiologic studies being negative. What if your marrow is negative but there’s still an osseous lesion that’s lighting up on the PET scan?

There is this well understood concept of macrofocal disease, where you can have little pockets of myeloma but the marrow may be negative. We don’t want to be making decisions based on incomplete data. So, I would say that this is an important area of investigation. And the other caveat that we didn’t mention yet about MRD is the importance of molecular risk. I would like to think that if MRD is negative, it means the same thing for any patient—that it’s a great result. However, we know that MRD negativity may not mean the same thing in high-risk patients, which means we have to really think about those patients. And even if it’s MRD-negative, we can not necessarily assume that all is well.

And lastly, getting back to the concept of changing of therapy, it would be nice to know, if a patient was MRD-positive, we should escalate the therapy? And perhaps equally interesting, if you have a low-risk MRD-negative patient, can we stop therapy? I don’t think we have any prospective studies to answer these questions, but it’s an area of investigation. And probably, in the community, if a patient was having difficulty tolerating maintenance therapy for some reason, or was averse to doing it, and you were doing the MRD test, perhaps it would be reasonable for that patient to not do maintenance therapy. But again, acknowledging this is outside of evidence-based practice.

So, going back to this patient, whether she was MRD-negative or not, in 2017, we don’t know that we would change our management of lenalidomide maintenance—the use of lenalidomide maintenance or the duration of lenalidomide maintenance.

This patient (who was taking lenalidomide maintenance) was doing quite well. She was working full-time. She had grade 1 neuropathy but actually had a good quality of life. And then, in August of 2016, we noticed that on laboratory testing, although her calcium was normal, her creatinine did bump up to 1.3. She did become slightly anemic to a hemoglobin of 10.3 g/dL. She did not have any known new bone lesions, but her paraprotein testing also showed that her free light chains were rising and her serum M-spike was now detectable at 1.3. She clearly has had a relapse of her myeloma on lenalidomide maintenance, and the question becomes, what do we do now?

The progression of myeloma can come in 2 flavors, broadly speaking. One is a biochemical progression, which would be purely paraprotein related. And by myeloma clinical trial criteria, the numbers that we would look for typically would be an M-spike of, depending on the isotype, 0.5 for IgA (immunoglobulin A), 1.0 for IgG (immunoglobulin G), free light chains becoming more than 100 mg/L, or the 24-hour urine collection now showing more than 200 mg/day of Bence-Jones protein. You can have patients with that isolated biochemical relapse, which may be very slow and indolent. Conversely, you can have a very fulminant relapse with the CRAB (calcium, renal failure, anemia, bone lesion) symptoms that we were just discussing. And perhaps, even worse, you can have extramedullary disease, high LDH (lactate dehydrogenase), and circulating plasma cells. So, we have to understand that the relapse of myeloma can come in that entire spectrum, and it’s important to consider that when making decisions about treatment.

Transcript edited for clarity.

Biochemical Progression of Stage II Myeloma

July 2011

• A 61-year-old Caucasian female was diagnosed with stage II multiple myeloma
• Genetic testing showed t(14:16)
• At the time she was treated with lenalidomide, bortezomib, and dexamethasone (RVD) induction therapy followed by autologous stem cell transplantation
• She achieved a near complete remission with RVD and transplant
• Based on her high-risk cytogenetics, the patient was placed on lenalidomide maintenance therapy

August 2016

• On routine follow up, the patient reports having mild fatigue but continues to work full-time; she has grade 1 neuropathy
  • M-protein, 1.3 g/dL
  • SFLC, kappa, 150 mg/L
  • Hb, 10.3 g/dL
  • Creatinine, 1.3 mg/dL