Experts Publish Consensus Risk Classification For Multiple Myeloma
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.
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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.
Related Articles:
- Importance Of Factors Affecting Multiple Myeloma Survival Changes With Patient Age
- Early Use Of Radiation Therapy Associated With Shorter Survival In Multiple Myeloma
- Researchers Shed More Light On Risk Of MGUS In Close Relatives Of People With Multiple Myeloma
- Revlimid, Velcade, and Dexamethasone, Followed By Stem Cell Transplantation, Yields Deep Responses And Considerable Overall Survival In Newly Diagnosed Multiple Myeloma
- Sustained Complete Response To Initial Treatment Associated With Substantial Survival Benefit In Multiple Myeloma
I was diagnosed with Multiple Myeloma in mid June of this year (2013). I see my Oncologist next Tuesday and plan on asking him what risk factor I am. I have been treated with Velcade since my diagnosis. Is there a reason why he shouldn't be able to tell me? He seems to focus on my light chains and tells me that they are practically normal, now. He has told me I have CML Leukemia, also, and he can't do anything to help me with that until we have a taken care of the Multiple Myeloma, which I find a bit confusing, since the Multiple Myeloma is incurable.
This is still pretty new to me and I'm still trying to figure out the right questions to ask. I have asked how much time do I have (which I would think is an automatic question to ask). I can't get an answer. Like Tom Petty sings, 'The waiting is the hardest part'.
What is value of Free Light Chains in prognosis of MGUS?
Tropicdiver,
It is a very complex disease/treatment. Once the get your myeloma fully under control, they will deal with CML Leukemia. I was diagnosed in 2010, after treatment my myeloma levels were very low, and I have felt great since. Eventually it will get worse, but I will then try one of the many new treatments.
Eventually you may be able to figure out an estimate of how long you have, but you need to get both conditions under control first. Some people have a relatively easy time dealing with myeloma, while others don't. Since your light chains are so low, you are doing well already.
My recommendations are patience, and lots of reading on this site regarding all your treatment options.
Good luck
David
Thanks for the questions and comments.
Tropicdiver - Based on what we have heard from other patients, your experience is not unusual. Many patients are not told their risk classification by their physicians. This is one of the reasons, we suspect, that the expert panel published this risk classification, so that it can be more widely known and more regularly used.
If you go back over the tests that were done when you were diagnosed, you will probably be able to find on your own the information you need to determine your initial risk classification. If you can't do it on your own (it's not always easy), bring your test results with you to your appointment on Tuesday, along with a printout of this article, and have your doctor work out with you what your risk classification was at diagnosis.
We should add that David is right to point out that, regardless of what your risk classification was at diagnosis, the fact that you have responded well to your treatment is a very good sign. (Thanks David!)
A.Franklin - The key issue when it comes to the prognosis of MGUS patients is their risk of progressing from MGUS to symptomatic multiple myeloma. There are two systems right now for classifying MGUS patients into different groups based on their risk of progression. One system is from the Mayo Clinic, and having an abnormal free light chain ratio is one of the factors in that system. The other system is from a group of Spanish researchers, and that system does not make use of the free light chain ratio.
You can read more about the different systems in this publication:
http://asheducationbook.hematologylibrary.org/content/2012/1/595.full.pdf (full text available at no charge)
I realize there is a benign purpose in this type of information, but it is the kind of stuff that disheartens me and I try not to retain it. My husband's disease has been aggressive and resistant and he has chromosome 13 deletion, but he has survived remarkably well overall for six years and we are still fighting the good fight. He is not a statistic, he is unique in his skin.
So I wonder exactly what is meant by the statement that a "low risk patient has a median overall survival of more than 10 years from diagnosis."
In particular, what type of treatment does this reflect?
And in this regard, does this fact mean that TOTAL THERAPY at Barlogie's Myeloma Institute is a bunch of toxic BS, because it's touted success is nothing more than what a low-risk patient would expet anyways? Consider the following statement from the UAMA website:
"Proven results: A patient diagnosed with low-risk multiple myeloma who is treated at the Myeloma Institute can expect to survive more than 10 years"
To all of the above, "local" Oncologists are not the best barometer for your myeloma treatment..Seek out an opinion of the best Like Ola Landgren at the NCI and his services are free as he's employed by the NIH in Bethesda MD,or consultation with the myeloma specialists at the Mayo in Scottsdale AZ. or Rochester MN. I have both and feel I'm receiving the best advise, and makes your local treatment on target..Most Oncologists ( and I have one in the family) are just not up to par with regard to the complexities of myeloma..
I have read the article several time and have a question. What is your risk if you are under 55, stage I or II, and DO have amp1q, del 13 and t(4:14) ?
To Jaksix
Based on the article, here is my interpretation:
If you have t(4;14) and are Stage II, then you would be considered 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."
But .. if you have t(4:14) and are ISS Stage I, then you would be considered standard risk:
"The remaining 60 percent of patients are classified as standard-risk, with median overall survival of seven years from diagnosis."
Perhaps the difference probably reflects the less advanced stage of disease as which MM was diagnosed in the second group...as reflected by the disease-burden related ISS parameters of serum albumin and beta-microglobulin levels.
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.
2 year median survival for a Stage 2 patient with 4:14 seems way too low. Velcade/dex should work in most at least that long, not including transplant or squeezing more time out of a variety of other options, most notably Kyprolis.
We tend to agree with you, Pat, and we're glad you pointed the issue out. We had toyed with the idea of mentioning something about it, but thought it best to discuss it in the comments.
We think that particular survival number may be influenced by the fact that the article was drafted by an international group of experts, and thus included many authors who do not currently have access to Kyprolis for their patients, cannot use Revlimid+Velcade+dex (or something even more aggressive) upfront, and who also may be limited in terms of the other options they can pursue at relapse, versus what is available to U.S. patients.
The other issue we need to keep in mind is that these numbers are for myeloma patients of all ages. While a high-risk patient who is younger may be able to fight the disease successfully for a number of years, it may be a lot tougher for the majority of myeloma patients who are over the age of 65, and for whom transplant often isn't an option.
Why so angry DM? I believe this article stated that the median for low risk is 10 years or more. I believe Ark/Barlogie predicts ~ 90% of low risk will see 10 years or more.
I was diagnosed about a month ago...I am finishing up my first 21 day cycle of Revlimid and Dex... Other than a little fatigue and irritability I am tolerating it OK... But I have asked the same questions of my Hematologist/Oncologist.... I sometimes get the feeling, that he is somewhat annoyed by the questions... Sometimes I get the feeling that if I continue to ask questions, he will tell me to seek another doctor..... (BTW I am 62 and diagnosed with Stage 1) MY view has always been that I want all the info available. (I am a retired Colonel U.S. Army) I would not think of conducting an operation without reading the plans first......
Chris, NEVER stop asking questions until you are satisfied.If your doctor is annoyed by your questions,find a new one. You have every right to ask all of the questions you want to. Thisis coming from a fellow patient.
By the way, thank you for your service and sacrifices!!
Scott - No problem... I had a meeting with my VA doctors on Friday. Both were stunned, as they are the ones who noticed the change in the blood tests. My private doctor is good, but I want to know the risk factors and the FISH results. BTW, the VA doctors scanned in the results of the private doctors tests. In their opinion, they stated in my VA records, that this was likely caused by the oil fires in Kuwait during Desert Storm. A good friend (who is both a PhD and MD, as well as a Special Forces Officer) was there at the time in Kuwait. He has the now declassified formerly "Top Secret" reports on the health impacts of the fires. He is going on record for me as well. One last thing, the VA says that Revilmid is on their pharmacology list and is available through them.
I am very interested in this article. I was diagnosed in September and I have had a difficult time getting my treatment plan together. Lots of waiting. I am waiting for an appointment to be scheduled to see a doctor at the Seattle Cancer Care Alliance for a second opinion. My doctor also does not like to talk about life expectancy. She says I am standard risk but I am stage II with the t (4:14). I am only 47. I read of other people starting treatment within a month of diagnosis yet I started my journey the beginning the first of August. My current doctor recommends treating with CyBorD. I just don't know why the delay all the time if I could be high risk.