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Heavy/Light Chain Ratios May Be A Prognostic Marker For Myeloma Patients

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Published: Apr 11, 2012 1:02 pm; Updated: Apr 16, 2012, 10:25 am

The results of a small Spanish study indicate that heavy/light chain ratios may be a prognostic marker for myeloma patients.

Specifically, the Spanish researchers found that multiple myeloma patients who experienced elevated heavy/light chain ratios after achieving complete remission following a stem cell transplant had longer progression-free and overall survival rates than patients who did not experience elevated heavy/light chain ratios.

According to the study investigators, these results show for the first time the association between a heavy/light chain ratio and sustained remission in myeloma patients.

However, larger follow-up studies may be needed to corroborate these findings before the heavy/light chain test becomes a standard prognostic tool for the treatment of multiple myeloma.

“The results [of the current study] are hypothesis-generating, not practice-changing. The heavy/light chain test will need to be validated in larger, prospective studies before it can be used in routine clinical practice,” said Dr. Peter Voorhees of the University of North Carolina at Chapel Hill, who was not involved in the study.

“Additionally, the heavy/light chain ratio needs to be compared with other prognostic markers available in myeloma [such as free light chain ratios and measurement of minimal residual disease using flow cytometry] to determine if it provides additional information beyond what is already available,” he added.

Multiple myeloma is a cancer of the plasma cells, cells that produce various types of antibodies that fight infection. These antibodies, also known as immunoglobulins, are each comprised of two heavy chains and two light chains. There are five types of heavy chains, abbreviated as IgG, IgA, IgM, IgD, and IgE. There are also two types of light chains, called kappa (κ) light chains and lambda (λ) light chains.

Patients with multiple myeloma overproduce a single type of plasma cell and therefore overproduce a single type of antibody, known as monoclonal or M-protein, which then accumulates in the blood. Different types of myeloma are classified according to the type of M-protein that accumulates in the blood.

IgG myeloma is the most common form of the disease. IgA myeloma is the next most common form, followed by IgM myeloma. IgD and IgE myeloma are rare.

A recent tool called the heavy/light chain test allows experts to determine the ratio of each pair of heavy chains to light chains in myeloma patients. For instance, the fraction IgGκ/IgGλ is the ratio of IgG antibodies with κ light chains to IgG antibodies with λ light chains.

“Recent evidence shows that the heavy/light chain ratio could be a useful prognostic tool [for predicting progression to multiple myeloma] in patients with MGUS. It could also be used in the initial stage at the moment of diagnosis,” said Dr. Carlos Fernandez de Larrea of the Hospital Clínic of Barcelona in Spain and one of the study authors.

Plasma cells typically produce an excess of light chains, which build up in the blood and are called free light chains. Another prognostic tool called the free light chain test, which measures the amount of free light chains in the blood, has been shown in previous studies to predict the prognosis of survival in patients with newly diagnosed multiple myeloma (see related Beacon news).

According to Dr. Voorhees, “The advantage of the heavy/light chain test is that it does not appear to be affected by oligoclonal banding [the presence of multiple types of immonuglobulins] or kidney function, whereas the free light chain ratio is affected by both of these issues. Additionally, the heavy/light chain test is a blood test and does not require a bone marrow sample.”  

According to the Spanish researchers, the achievement of a complete remission, which is defined by the absence of the original M-protein, is currently the most significant prognostic factor for myeloma patients.

However, they speculated that heavy/light chain ratios may provide an additional prognostic tool for myeloma experts.  

In this study, researchers sought to determine the prognostic value of heavy/light chain ratios – IgGκ/IgGλ, IgAκ/IgAλ, and IgMκ/IgMλ – in myeloma patients who were in complete remission after receiving a stem cell transplant.

The study included a total of 37 myeloma patients with a median age of 57 years. Approximately half of all patients (51 percent) had IgG myeloma, 24 percent had IgA myeloma, 8 percent had IgD myeloma, and 3 percent had IgM myeloma; 14 percent of patients produced light chains only.

All patients were in complete remission after receiving a melphalan (Alkeran)-based stem cell transplant.

At the time of the analysis, 89 percent of patients were still alive, and 30 percent had relapsed.

The researchers then determined the heavy/light chain ratios for each patient and divided patients into two groups for each heavy/light chain ratio depending on whether they had values above or below the median value.

They found that for patients who had IgG myeloma, those whose IgAκ/IgAλ and IgMκ/IgMλ ratios were above the corresponding median values had higher progression-free and overall survival rates than those whose IgAκ/IgAλ and IgMκ/IgMλ ratios were below the median value.

For patients who had IgA myeloma, those whose IgGκ/IgGλ ratio was above the median value had higher progression-free survival than those whose IgGκ/IgGλ ratio was below the median value.

According to the Spanish researchers, their findings suggest that the heavy/light chain ratios are an indicator of immune recovery rather than minimal residual disease because all patients were in complete response, which is defined as the absence of the original M-protein.

 “A relative elevated heavy/light chain ratio emphasizes the importance of an immune reconstitution after autologous stem cell transplantation in patients in complete remission,” said Dr. Larrea.

“Therapeutic options that enhance the immune system in these patients would be useful. However, no specific changes [to standard myeloma regimens] can be addressed now due to the absence of available specific treatments,” he added.

Dr. Larrea pointed out that he and his peers are now interested in evaluating the usefulness of the heavy/light chain ratio to predict relapse in myeloma patients in complete remission.

For more information, please see the study in Biology of Blood and Marrow Transplantation (abstract).

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4 Comments »

  • suzierose said:

    Hello Dr Vorrhees!!

    I understand your message about this data is not practice changing yet and I see that the article focused on the outcome of the comparative data between the 2 groups, i.e. a statistical observation as yet to be determined clinically significant.

    I read this ratio as Heavy chains divided by free light chain ratio..hopefully that is correct?

    I understand the free light chain assay tells us how many of the immunoglobulins are running around unattached to the heavy chain. And the more unattached chains the worse the disease process is as normally they are attached.

    My question is why would these new variables heavy/light chain ratio be predictive or prognosticators? What are these ratios comparing pathogenically in terms of disease process? How did they decide to make the ratio heavychain kappa to heavy chain lambda….vs. heavychain lambda to heavychain kappa…or why did they not create a ratio of heavychain to Freelightchain ratio vs. the individual lambda as a denominator?

    While I ReeeeeaLLY, REALLY prefer blood tests over bone marrow tests, :) how does using lambda as a denominator eliminate the problem of oligoclonal banding interference?

    IOW’s I read this ratio as Heavy chain divided by free light chain ratio..is that correct? If this is correct, can’t a clinician simply calculate that knowing the IG total and FLC assay numbers that are already done?

    For example, are these heavychain/lightchain numbers similiar to how we do cholesterol numbers? It is not total cholesterol but the ratio of high density lipoprotein (H) and low-density lipoprotein (L) to total cholesterol that matters? Where total cholesterol would represent heavy chain and H&L represent free light chains? So, going back to my original question, ..we know in the case of cholesterol that a High LDL is bad vs. a high HDL which would make overall total chlolesterol high…. is that the case here?

    IOW’s one type of free chain being higher (thus the denominator) worse than another type of free chain in MM? If so, why would that be?

    Sorry for this long message, but I am really curious as to why this test adds new information in terms of the disease process. ( even though it eliminates oligoclonal banding interference)

    I really and looking forward to your answer Dr. Vorrhess and saying Thanks for your time in advance.

  • Myeloma Beacon Staff said:

    Hello suzierose,

    Thank you very much for your follow-up questions on the article. We have forwarded them on to Dr. Voorhees.

  • suzierose said:

    Thank you Beacon Staff!!

    I think I may have found some answers.

    I thought they were dividing the IG by kappa/lambda ratio. They aren’t. The Ig kappa and Ig lambda are seemingly different entities. Found by slicing through the heavy and light chain region of the IG. The confusion arises because we often describe our MM as IGG kappa based on whether we have a high kappa vs lambda ratio. But here, they are not using FLC ratios as I assumed as a denominator. Rather they are using a specific region with the IGkappa attached.

    There is a nice picture (figure 32.1) that shows the area that is sliced to determine the Igkappa/Iglambda area as well as the light and heavy chain regions. In addition, there are normal median ranges for this heavy/light chain ratio..which is how it is being projected as a prognosticator factor based on normal ranges in this study.

    In terms of pathogenesis l also earned:

    ” HLC κ/λ ratios provide information about the tumour selective killing rates versus non-tumour plasma cell kill rates. This assessment of selective tumour killing rates may help with decision-making on effective chemotherapies.”

    http://www.wikilite.com/wiki/index.php/Analysis_of_Ig_heavy_chain/light_chain_pairs_(Hevylite™)

    This is my new understanding, perhaps Dr. Voorhees can tell me more and if I am missing critical points.

  • Dr. Peter Voorhees said:

    Dear Suzierose,

    Long time no speak! I hope all is well with you. In this study, the investigators determined that a higher heavy/light chain ratio of the uninvolved immunoglobulin was associated with improved progression free and overall survival. For example, for patients with an IgG kappa or IgG lambda producing myeloma, if they were in complete remission after transplant, a higher IgA kappa to IgA lambda ratio and/or a higher IgM kappa to IgM lambda ratio was predictive of a better outcome. Since they are measuring the ratio of heavy/light chain pairs that are not being produced by the myeloma, the authors believe that the establishment of a higher heavy/light chain ratio of the unaffected immunoglobulins may be a surrogate marker for improved immune reconstitution/recovery. They are not measuring residual antibodies produced by the myeloma. This test does not measure free light chains or use light chains to calculate the ratio.

    This study was small, so I would not over-interpret the results. Plus, they only looked at patients who had been through autologous stem cell transplant and were in a complete remission. I would not extrapolate these results to other patient populations. Lastly, the article is a bit misleading about this possibly representing a test that could replace a bone marrow biopsy. What I intended to get across is that some other tests that might be utilized after a transplant (PCR or flow cytometry to assess for minimal residual disease) require a bone marrow aspirate. There are other blood tests that get at the issue of immune system reconstitution after treatment of myeloma — normalization of free light chain ratio, normalization of unaffected serum immunoglobulins. Whether this heavy/light chain ratio is a better marker of immune reconstitution than these other blood tests remains to be seen.

    I hope this helps. Take care!

    Pete V.