PLASMA CELL CANCER CLASSIFICATION from "LEUKEMIA"

Experts Publish Consensus Risk Classification For Multiple Myeloma Published: Sep 13, 2013 5:24 pm An international panel of multiple myeloma experts, known as the Inter­national Myeloma Working Group (IMWG), recently released a consen­sus statement on risk stratification for patients with multiple myeloma. Risk stratification refers to the classification of patients into different cate­gories based on likely disease outcome. The new IMWG risk stratification, for example, has three risk categories: low-risk, standard-risk, and high-risk. In the new system, determination of a patient’s risk classification is based on three factors: a patient’s disease stage according to the Inter­national Staging System (ISS); the presence of certain chromosomal abnormalities in the patient’s myeloma cells based on results of so-called FISH testing; and patient age. Patients who are ISS stage II or III and whose myeloma cells contain the translocation t(4;14) or the deletion del(17p13) are classified as high-risk. About 20 percent of patients are expected to fall in this category at the time of diagnosis, with median overall survival of two years from diagnosis. Patients who are ISS stage I or II, under the age of 55 years, and whose myeloma cells do not contain t(4;14), del(17p13), or 1q21 gain are classified as low-risk. About 20 percent of patients also are expected to fall in this category at diagnosis, with median overall survival of more than 10 years from diagnosis. The remaining 60 percent of patients are classified as standard-risk, with median overall survival of seven years from diagnosis. Despite agreeing on how to classify patients into low-risk, standard-risk, and high-risk groups, the expert panel does not recommend that their stratification be used to determine a myeloma patient’s initial therapy. Some major treatment centers – notably the Mayo Clinic – favor a “risk-adapted” approach to myeloma therapy, in which a myeloma patient’s initial therapy is guided by their risk classification. The expert panel, however, does not believe that such an approach is generally warranted at this time. In addition to the risk stratification described above and a discussion of risk-adapted therapy, the newly published consensus statement presents the experts’ current opinions on the need for risk stratification and explains the criteria that can be used for risk stratification. The Need For Risk Stratification According to the consensus statement, one of the foremost reasons for risk stratification is to inform a patient of his or her prognosis. It allows physicians to provide an expected survival time in answer to the patient’s question, “How long do I have to live?” (see related Beacon article on myeloma prognosis). Secondly, the experts argue that risk stratification may pave the way for risk-adapted therapy. In risk-adapted therapy, a patient’s treatment is tailored to their risk category. For example, high-risk patients receive more intensive treatment than low-risk patients (see related Beacon article). This approach aims to minimize side effects while maximizing the benefits of treatment. Risk-adapted therapy is commonly used for acute myeloid leukemia and Hodgkin lymphoma, diseases in which low-risk patients can be cured with non-intensive treatment. However, there is an argument that this approach does not apply to myeloma, since myeloma is still considered incurable. Instead, all myeloma patients should receive the most effective treatment available. The researchers suggest that the identification of low-risk myeloma patients, who are likely to live 10 years or longer, may strengthen the case for risk-adapted therapy in myeloma. The investigators also note that risk stratification provides a useful framework for testing new therapeutic strategies. For instance, they suggest that strategies without high-dose chemotherapy and stem cell transplantation can be tested for low-risk patients, while more potent strategies need to be tested for high-risk patients who have poor outcome with current treatment strategies. Factors That Can Be Used For Risk Stratification In order to arrive at meaningful risk stratification criteria, the experts considered a number of factors that have been found to be associated with poorer myeloma prognosis. They divided these risk factors into host-related factors (related to the patient) and tumor-related factors (related to the myeloma cells). Age The researchers conclude that the most important host-related factor in determining myeloma risk is age. Several previous studies have shown that younger age at myeloma diagnosis is strongly associated with longer survival (see related Beacon news and the Beacon’s recent article on multiple myeloma survival by race and age). Chromosomal Abnormalities And Gene Expression Profiles According to the consensus, the most important tumor-related risk factors are the presence of certain chromosomal abnormalities and the gene expression profile of the patient’s myeloma cells. Chromosomal abnormalities are changes in the structure of the cell’s genetic material. These changes can occur through deletions, insertions, duplications, or the movement of pieces of genetic material. The experts note that the translocation t(4;14) and the deletion del(17p13) are consistently associated with poor survival across a number of studies. The effects of the translocation t(14;16) and 1q21 gain on disease prognosis have remained controversial. However, the researchers note that the lack of 1q21 gain could be useful in identifying patients with good prognosis. Since a number of studies have revealed variations in prognosis even among individuals with chromosomal abnormalities, the experts conclude that the use of chromosomal abnormalities as a stand-alone risk factor may not be optimal. However, they suggest that combining information about chromosomal abnormalities with other factors could improve their prognostic value. Gene expression profiling simultaneously measures the activity of thousands of genes in a patient’s myeloma cells, creating a snapshot, or profile, of everything going on inside the cells. Previous studies have identified a number of gene expression profiles that are associated with poor disease prognosis. The experts note, however, that the clinical application of gene expression profiling remains limited due to three important factors: (1) the lack of a unified and standardized gene expression profile for myeloma cells, (2) the perception of a lack of reproducibility for the technique, and (3) the difficulty faced by physicians in analyzing and interpreting the complex data generated from gene expression profiling. To address the lack of a standardized profile, the IMWG is currently conducting a study that combines a number of known gene expression profiles to generate a unified set of profiles, which will then be tested. Disease Stage The International Staging System (ISS) uses a combination of b2-microglobulin levels and albumin levels in the blood to classify patients into three disease stages. Studies have shown that advanced disease stage is linked to poorer survival. The ISS, however, does not take chromosomal abnormalities into account. Based on more recent studies, the experts note in the consensus statement that a model that combines both ISS staging and chromosomal abnormalities could be more effective in predicting risk. They add that results from a recent IMWG analysis showed that ISS staging and the presence or absence of t(4;14) and del(17p13) can reliably segregate patients into three risk groups. Responsiveness Of Tumor To Treatment How a patient’s myeloma responds to treatment is a risk factor that can only be determined after treatment. According to the experts, not achieving at least a partial response to treatment – or at least a very good partial response to stem cell transplantation – is reflective of resistance to treatment and associated with poorer disease outcome. The experts state, however, that early relapse or an inability to maintain response to treatment is an indicator of very poor prognosis. Consensus Definition Of Risk Groups From among the various risk factors discussed above, the researchers sought to identify the most relevant factors to use for stratification. A study published by the IMWG in March showed that combining ISS stage with data about chromosomal abnormalities significantly improved risk assessment in myeloma. In particular, the study identified three key chromosomal abnormalities – t(4;14), del(17p13), and 1q21 gain, measured using the technique known as fluorescence in situ hybridization (FISH). The experts used the results of this previously published study to guide their final consensus risk stratification, which is as follows: High Risk – Patients who are ISS stage II/III and whose myeloma cells contain the translocation t(4;14) or the deletion del(17p13) are classified as high-risk. About 20 percent of patients are expected to fall in this category, with median overall survival of two years from diagnosis. Low Risk – Patients who are ISS stage I/II, under the age of 55 years, and whose myeloma cells do not contain t(4;14), del(17p13), or 1q21 gain are classified as low-risk. About 20 percent of patients are expected to fall in this category, with median overall survival of more than 10 years from diagnosis. Standard Risk – The remaining 60 percent of patients are classified as standard-risk, with median overall survival of seven years from diagnosis. The experts note that the two tumor-related factors used in the new stratification – ISS stage, which is based on b2-microglobulin and albumin levels in the blood, as well as the chromosomal abnormalities t(4;14), del(17p13), and 1q21 gain (measured using FISH) – are based on robust laboratory tests and are applicable to more than 90 percent of all myeloma patients. Experts Not Yet Ready To Recommend Risk-Adapted Therapy Despite the definition of what the experts believe is a robust risk stratification system for myeloma, the panel notes in its consensus statement that “We are still not in a position to recommend different treatments for patients in different risk groups.” Instead, the experts recommend that “all patients should receive the most optimal treatment tested in Phase 3 clinical trials and currently available,” with dose modification according to patient-related factors. The only exception stated in the consensus report is that the experts recommend the use of Velcade (bortezomib)-based initial and maintenance regimens for patients with t(4;14). The researchers made this recommendation based on several studies showing that Velcade-based treatment attenuates the increased risk associated with the t(4;14) abnormality. Although the experts do not recommend risk-adapted therapy at this time, they note that risk stratification can offer a useful framework for deciding among treatment options. For instance, they note that a low-risk patient could potentially choose a regimen with lower cost and toxicity, even if it was associated with slightly reduced efficacy. The researchers explain that such decisions are also dependent upon the treatment philosophy of the physician, who can take either a cure approach (aggressive treatment with the aim of achieving a complete response) or a control approach (less aggressive treatment with a focus on disease control and quality of life) toward treating the disease. The experts recommend that future studies should aim to further refine the risk groups defined in the consensus statement, based on the underlying biology of the myeloma cells. For further information, please see the consensus report in the journal Leukemia.