Chromosomal Abnormalities May Influence Myeloma Symptoms At Diagnosis
Findings from a recent retrospective study conducted at the Mayo Clinic indicate that chromosomal abnormalities may influence which symptoms a multiple myeloma patient has at diagnosis.
For instance, the researchers found that newly diagnosed myeloma patients with the chromosome 14 translocation t(14;16) are more likely to have kidney damage, while patients with extra chromosomes are more likely to have bone disease or anemia.
They also found that patients with t(14;16) who did not have kidney damage survived significantly longer (a median of 44 months) compared to those with kidney damage (9 months). The researchers state that the high rate of kidney damage in patients with t(14;16), and the negative impact that kidney damage has on survival, may explain why patients with t(14;16) often have short survival.
Based on their results, the investigators conclude that the presence of chromosomal abnormalities not only plays a role in the prognosis of multiple myeloma patients, but also in the symptoms present at a patient's diagnosis.
They add that their findings may also support the notion that multiple myeloma should be considered a collection of genetically diverse disorders, rather than a single disease entity.
However, they state that further studies are needed to confirm their findings.
Background
Chromosomal abnormalities are the result of structural changes in the chromosomes of a patient’s myeloma cells.
These changes may occur through deletions, insertions, duplications, or movement of chromosomal regions. Some patients also have missing or extra copies of entire chromosomes.
Previous studies have shown that certain chromosomal abnormalities, in particular t(4;14) and del(17p), negatively affect the survival of myeloma patients who have these abnormalities (see related Beacon news). Patients with these chromosomal abnormalities are considered to have high-risk myeloma (see related Beacon news).
However, according to the investigators, little is known about the relationship between these chromosomal abnormalities and the symptoms – such as elevated calcium levels, kidney damage, anemia, or bone lesions – that myeloma patients show at the time of diagnosis.
Therefore, the researchers decided to investigate the relationship between chromosomal abnormalities and myeloma-related symptoms at diagnosis.
Study Design
The investigators retrospectively analyzed the records of 484 newly diagnosed myeloma patients who were seen at the Mayo Clinic within 90 days of their diagnosis between January 2004 and December 2009.
All patients had chromosomal analysis performed via a technique known as fluorescent in situ hybridization (FISH) either within one year preceding their myeloma diagnosis or within six months following diagnosis.
The researchers categorized the patients into four groups depending on the myeloma-related symptom or symptoms they showed at diagnosis: bone disease (34 percent of patients), anemia (15 percent), kidney failure (8 percent), and a combination of these symptoms (43 percent).
They explained that elevated calcium levels were not considered as a separate category because patients with elevated calcium levels almost always also have bone disease; these patients were therefore categorized into the bone disease group.
Study Results
Among the patients included in the analysis, 42 percent had trisomies (an extra copy of one or more chromosomes), 30 percent had chromosome 14 translocations (rearrangement of a part of chromosome 14 with part of another chromosome, such as t(4;14) or t(11;14)), 15 percent had both, and 13 percent had no chromosomal abnormalities.
The researchers found that trisomies were more common in patients with anemia (45 percent), patients with bone disease (42 percent), and a combination of symptoms (44 percent), compared to patients with kidney failure (19 percent).
Chromosome 14 translocations, on the other hand, were much more common in patients with kidney failure (51 percent), compared to patients with a combination of symptoms (31 percent), patients with anemia (28 percent), and patients with bone disease (25 percent).
In particular, the t(14;16) translocation was present in only 5 percent of all the patients in the trial, but it was detected in nearly 14 percent of the patients with kidney failure.
When the researchers analyzed the data by the presence of individual chromosomal abnormalities, they found that 25 percent of patients with the t(14;16) translocation had kidney failure. Patients with t(14;16) and kidney failure had significantly shorter median overall survival (9 months) than patients with t(14;16) who did not have kidney failure (44 months).
As a result, the researchers contend that the reason why patients with the t(14;16) translocation have poor outcomes is because of the high share of patients with kidney failure. However, since a very small number of patients had this translocation in the study, they recommend a larger study comparing the presence of this translocation with the rate of kidney failure at diagnosis.
On the other hand, the share of patients with bone disease was high among patients with the translocation t(11;14) (35 percent).
Overall, patients with bone disease had a significantly longer median overall survival (59 months), compared to patients with kidney failure (42 months). The researchers explained that patients with bone disease may have longer survival because they may typically be diagnosed earlier in the course of their disease.
For more information, please refer to the study in the journal Leukemia (abstract).
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Gentlemen: I found your analysis of the paper quite interesting but I am wondering in this age of genomics whether this is an anachronism? It is interesting that we are publishing papers on FISH testing instead of gene array studies. Could it possibly be that the medical community can't make sense out of this wonderful new "omics" technology. It seems that everyone that looks at it comes up with a different result. FISH lives.
Thanks for your comment Gary.
The most likely reason why the researchers looked at chromosomal abnormalities, as measured by FISH, is because those results were readily available in the records for a large number of patients. No new FISH testing was carried out for this study. Instead, the researchers were able to rely on tests already carried out when the patients were diagnosed.
It would have been a much bigger, more expensive, undertaking to carry out more advanced testing on bone marrow samples from the patients included in the study -- assuming the research could even have gotten access to most of those samples.
Genomic analysis of the initial bone marrow or plasmacytoma biopsy in MM provides useful information over and above FISH testing. Scecific genome guidelines therapies can then be offered, esp. In high risk patients.
It will probably not replace FISH testing though, for the reasons you cite. It is very useful in correlating symptoms and prognoses to specific chromosomal abnormalities, as this paper elegantly demonstrates. Thank you Beacon staff!
Jan
Well, the study appears to put a much finer point on chromosomal-based prognostications ... but leaves us unfortunately with the usual "blunt objects" for treatment.
However, when the genomics of MM lead us to a more targeted therapy with fewer toxicites, well, then we will be talkin'! But, how far away is that?
The purpose of this study was not to determine the best test for prognosis, or to determine best therapy based on genetic abnormalities. We are conducting those studies, and they require different designs. The specific purpose of this study was to add one more dimension to the argument that what we call "multiple myeloma" is not one disease, but a collection of several unique diseases.
What makes something a unique disease as compared to a variation of the same disease? For example, CLL and mantle cell lymphoma were usually considered one and the same, till we found that mantle cell lymphoma had a unique clinical course and prognosis, unique cytogenetic abnormalities, and a difference in response to therapy compared with CLL. When we undertake a task as big as saying myeloma is not one disease, and we try to define each of these different diseases separately - we need a collection of arguments similar to the one used to split mantle cell from CLL; or various myeloid disorders from CML; or various acute leukemias into unique diseases.
This is the latest in a long series of studies that we and others have undertaken to examine this question. And there will be more to come. But we can already demonstrate that from most practical definitions used in other cancers we are not dealing with one disease.
For example, the progression from SMM [smoldering multiple myeloma] to MM is different depending on the cytogenetic subtype; the response to therapy is different; the prognosis is different; and now we show that even the clinical presentation is different.
As another example, we now have data that the t4;14 myeloma is as different from other types of myeloma to warrant consideration as a separate disease: it has a time to progression from premalignant to malignant (SMM to MM) that is much shorter; it presents with less bone disease; it responds better to Velcade; it requires Velcade based induction, maintenance, as well as stem cell transplant to have outcomes comparable to t11;14 or trisomies; and the prognosis is quite different without optimal therapy.
Each study is a small piece of a very large puzzle.
[Editor's note: Dr. Rajkumar is one of the co-authors of the Mayo research study discussed in the article above.]
Thanks, everyone, for the additional comments and feedback.
For those who may be interested in the study that Dr. Rajkumar alludes to showing that t(4;14) in smoldering myeloma is associated with a shorter time to progression to symptomatic myeloma, here is a link to the related Beacon research summary:
"Chromosomal Abnormalities May Identify Smoldering Myeloma Patients At Higher Risk of Progression"
Thank you, Dr. Rajkumar, for clarifying the intent of the study...."The specific purpose of this study was to add one more dimension to the argument that what we call “multiple myeloma” is not one disease, but a collection of several unique diseases." Your statement provides me with a take-away that is considerably different than the summary at the top of the thread.
However, determining the best therapy based on genetic abnormalities WOULD seem like the next logical step for such a study, or future study; one that could have a HUGE impact on how we currently choose which "blunt object' to use with any given patient?
Keep up the good work on this complex MM puzzle!
Steve - When you say "summary at the top of the thread", are you referring to the Beacon's article above, or one of the earlier comments?
Thank you Dr. Rajkumar for your wise clarification. Classifying the variant of MM is certainly important. However, for us patients, the real benefit will be targeted therapy, hopefully based on genomic analysis of our biopsies (or serum) studies. I visited with Dr. Keith Stewart at Mayo Scottsdale, and as you know, his lab is quite busy analysing hundreds of MM genomic patterns. Already, several new lines of therapy are emerging, such as BRAF and MEK inhibition. What is your prediction of the progress in this field? That would be a great column! With great appreciation for your work, Jan
Good Morning Beacon staff,
Is there any additional information/links that can expand upon Dr. Rajkumar's comment relating to the cytogenetic subtypes of SMM. I would like to understand which subtypes carry a higher risk to progression.
Thank you so much,
Best regards, Dana
Myeloma Beacon Staff said:
Steve – When you say “summary at the top of the thread”, are you referring to the Beacon’s article above, or one of the earlier comments?
Hi MBS, I was referring to the Beacon's article above. And thanks for bringing this important study to our attention!
Steve
Dana - The standard reference for the topic you mention is the study discussed in the Beacon article we mentioned earlier in this comment thread: "Chromosomal Abnormalities May Identify Smoldering Myeloma Patients At Higher Risk of Progression"
Steve - Sorry if our article was misleading in any way. We've been assured that it's a representative summary of the underlying journal article. We also mention explicitly in the introduction to our article that the study authors believe that "their findings may also support the notion that multiple myeloma should be considered a collection of genetically diverse disorders, rather than a single disease entity."
Myeloma Beacon Staff:
Where my initial confusion laid was that if the purpose of the study was, as Dr. Rajkumar clarified -- "The specific purpose of this study was to add one more dimension to the argument that what we call “multiple myeloma” is not one disease, but a collection of several unique diseases.", -- then that is what this reader would have expected a summary article would have addressed as its PRIMARY FOCUS -- the "specific purpose" of the study.
To this reader's mind, the MBS article only commented on that issue, i.e., MM as a "multiple disease", in a secondary fashion, almost as a parenthetical reference in the introductory paragraph -- hence my misunderstanding of the primary focus of the study.
Fortunately however, for all of us, Dr. Rajkumar clarified the intent of the study in his subsequent post.
Thank you again, Dr. Rajkumar!
Thanks for the feedback, Steve. Again, we're sorry if our summary of the Mayo study was misleading in any way.
Just to clarify, the "primary focus" of the Mayo study was, in fact, the content which was summarized in the Beacon's article: the study focused on the relationship between the symptoms myeloma patients have at diagnosis and their chromosomal abnormalities. This is reflected in
1. The title of the journal article written by Dr. Rajkumar and his colleagues, which is "Relationship between initial clinical presentation and the molecular cytogenetic classification of myeloma"
2. The goal of the Mayo study, which the authors describe as being "to determine the relationship between specific myeloma-defining event (MDE) and the cytogenetic subtype" (this is from the study abstract)
3. The content of the journal article itself, which focuses on exactly the sort of results summarized in the Beacon's article.
What Dr. Rajkumar described in his comment was the underlying motivation ("purpose") for the study, which is neither the "primary focus" of the study, nor is it something that occupies more than perhaps one full paragraph, in total, of the journal article.
Dr. Rajkumar's comment and explanation of the study's motivation were made because of initial comments in this thread which seemed to criticize the study for not doing things it never intended to do -- and which The Beacon never described as being the intention of the study.
We agree with you that it's been very educational to have Dr. Rajkumar drive home important potential implications of the study he and his colleagues did. That's why we thanked him in a comment we posted above (and in private correspondence with him).
Thanks MBS, for your further interpetations. I will be looking forward to when the entire article, "Relationship between initial clinical presentation and the molecular cytogenetic classification of myeloma” is available to all MM patients so that we can fully appreciate its insights and implications.
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