Interview with Guido Tricot, MD, PhD

What is the recommended screening and diagnostic algorithm that you would suggest for multiple myeloma or monoclonal gammopathies?

In our opinion, initial workup needs to include identification of myeloma markers in the blood and urine, such as M-protein analysis, quantitative serum immunoglobulins and also serum free light chains. I would also include bone marrow aspirate biopsy with cytogenetics and either FISH or gene expression profiling, and MRI and/or PET/CT scan.

Would you recommend that the sFLC assays should be included in the diagnostic criteria for multiple myeloma or monoclonal gammopathies?

They should be part of the initial workup since they provide information on what the likelihood is that the disease will rather rapidly progress to overt myeloma. The more normal the free light chains are, the more likely it is that the disease is benign.

Would you analyze the patient's urine at the time of the screening?

We initially request a 24-hour urine on all of our patients, and for the initial screening I recommend a urine protein electrophoresis and then urine immunofixation electrophoresis.

What additional information could urine provide in conjunction with the serum at the time of initial screening or diagnosis?

The importance of the urine collection in myeloma has markedly decreased with the introduction of the serum free light chain testing. However, there are occasional patients where we see discrepancies, where the serum free light chain analyses are slightly abnormal yet the patient still has quite a bit of monoclonal protein in the urine. I've seen this situation four or five times out of 2000 patients. It's a very small fraction but there are some patients where there is a discrepancy between the two.

Would this be in part due to impaired renal function?

Even with an impaired renal function, you would think that the free light chains would also increase in the serum. These particular patients have a good amount of abnormal protein in the urine and yet still have a normal or slightly abnormal free light chain measurement. For example, a patient could have a Freelite kappa of three [grams] in the serum, and have eight grams of M-protein in the urine at the same time. That's not what you would expect. This is the exception and not the rule. This occurs in less then one percent of the patients. It still exists, however.

In your clinical practice, how often do you use serum free light chain analysis (sFLC)? When screening (query myeloma)?

In the initial treatment phase, we use it very often. When we give our initial cycle of intensive chemotherapy and with transplantation, we use it basically three times a week to see how quickly we see a response to the treatment. As you know, the sFLCs have a much shorter half-life than the IgG or IgA. It will therefore decrease much faster than intact immunoglobulin. This shorter half-life allows us to assess much faster whether the patients are responding to the treatment or not.

Do you change the treatment based on your sFLC result?

Yes, absolutely. If we see that we don't have an adequate response on serum Freelite, we may not continue with second cycle of the same treatment. It just doesn't make sense.

Would you share an example where sFLC has influenced a change in treatment option?

As I indicated, we would not repeat a treatment cycle that resulted in either minimal reduction or a short-lived reduction in serum free light chains.

What would you suggest as the optimal use of this assay in clinical practice?

I think sFLC should be performed at least twice a week to assess how well the patient is responding to the treatment, and here at the University of Utah we do it three times a week.

Are there any other areas where you find Freelite useful?

Yes, absolutely. Well, in my mind one of the major applications of the sFLC assays is to initially assess how aggressive the myeloma is. You can have a patient with an IgG kappa myeloma with an IgG of six grams, but the Freelite kappa is hardly abnormal. You know such patients are more likely to have a rather benign type of disease. Yet another patient with one gram of IgG, but a Freelite kappa of 200 mg/L or 300 mg/L is more likely to have an aggressive disease. You are more likely to find abnormal cytogenetics as well as other diagnostic markers suggesting a more aggressive disease. If you entertain the diagnosis of MGUS or smoldering myeloma and you see a Freelite kappa that's over 100 mg/L, usually you know this is not MGUS. Further testing with MRI and PET/CT 2 scan will more likely reveal that you are dealing with overt myeloma. I think Freelite gives you a much better indication on the risk of MGUS than anything else.

Does the high sensitivity of Freelite make it useful in therapeutic dose titration?

Our philosophy has never been to titrate down in doses. If something is working well, you take a risk by reducing the dose, thereby inducing resistance to the drug. However, it's extremely helpful to see if our patients are responding or not responding, and Freelite response is critical. If something is working you don't change it. If something is not working, you do change it.

In your experience, is normalization of FLC prior to a bone marrow transplant predictive of post BMT remission and the duration of this remission?

That's not what we've found. In general, patients with the highest kappa/lambda or lambda/kappa ratios have the worst outcome. We also note that patients who have a very quick response to treatment [as indicated by a rapid decrease in the absolute concentration of sFLC], in general did worse than the ones who had a more gradual and slow response in their light chains. So to have rapid response in your free light chain concentration, and to be almost normal by the time you go to transplantation, is not always associated with the longest duration of response. Some patients who go down very slowly, but ultimately normalize the involved serum free light chain tend to stay in remission. Attempts to have patients already in remission prior to transplantation was not a helpful strategy.

Suppose you were to compare the gradients of the decline of serum free light chain following successive courses of therapy. Intuitively, decreasing successive gradients might represent increasing tumor resistance to therapy and might be an early predictor of treatment resistance and failure to achieve remission. What are your thoughts on this, or do you have data that might support or refute this notion?

After a first cycle of the same treatment, one patient's Freelite may decrease by 50 percent while in another patient it decreases by 90 percent. We cannot say that the patient with 90 percent decrease is ultimately going to do better than the patient with 50 percent. However, at the next treatment cycle, one should again see the same decrease respectively. If in the next cycle with the same chemotherapy less than a 50 percent decrease is observed, you know resistance is starting to build. Alternatively, it is a bad sign to see the Freelite values increasing before the next cycle, suggesting relapse.

How often does sFLC increase before SPEP or IFE become positive in relapse post BMT?

In some cases it does [increase], in some cases it doesn't. In my opinion, the Freelite results are most likely to be the first sign of trouble. They increase before you see serum M-proteins or any other indicator going up. However, we must keep in mind that we have some very benign types of myeloma where one may have high M-proteins and very little serum free light chains. Here you will see that the IgG is likely to go up first before the light chains increase since it's a slowly proliferative disease with a good balance between the heavy and light chains. Not a lot of excessive light chains are produced and therefore, the Freelite results will look relatively normal. Further, the lower the Freelite results the more likely it is that you are dealing with a slowly progressive disease rather than benign types of myeloma.

Do you think that Freelite can serve as an early marker of recovering immune competence post BMT either following allo or auto transplants?

Usually you see both recovering which would indicate that there is some type of immune recovery. But that doesn't mean the immune system is in any way working fine. We see some patients where free light [chains] increase while the CD4 count remains very low. Is the CD4 count also increasing or not, and are both light chains increasing, or only the light chain secreted by the neoplastic plasma cells? If the abnormal light chain is going up, and the CD4 count stays low, you know this is relapse. If they both go up, you know it's either immune recovery or it's a renal problem.