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).