Spanish Expert Recommends Early Treatment For High-Risk Smoldering Myeloma (IMW 2013)
During a session at the International Myeloma Workshop (IMW) held in Japan earlier this month, Dr. María-Victoria Mateos of the University Hospital in Salamanca, Spain, discussed whether smoldering multiple myeloma patients should be actively treated.
The current standard of care is to monitor smoldering myeloma patients and to begin treatment only when their disease progresses to symptomatic multiple myeloma.
However, in Dr. Mateos's opinion, smoldering myeloma patients who are at high risk of progressing to symptomatic myeloma should be offered early treatment.
During the IMW, Dr. Mateos presented updated results from a study she and other Spanish researchers have been conducting, showing that Revlimid (lenalidomide) in combination with dexamethasone (Decadron) delays disease progression and improves overall survival in high-risk smoldering myeloma patients.
Based on these results and other recent research, Dr. Mateos believe high-risk smoldering myeloma should be called "early multiple myeloma," which leads to the following new treatment paradigm: early treatment for early multiple myeloma patients.
Dr. Mateos's recommendation, however, is likely to be viewed as controversial by many myeloma specialists, as most continue to recommend against active treatment of smoldering myeloma except in cases where a patient is participating in a clinical trial.
Background
Smoldering, or asymptomatic, multiple myeloma is a precursor to multiple myeloma in which the patient experiences none of the symptoms typically associated with active (symptomatic) multiple myeloma (elevated calcium levels, kidney failure, anemia, or bone lesions).
Smoldering myeloma is characterized by an excess of monoclonal protein in the blood and urine. A diagnosis of smoldering multiple myeloma is made when a patient’s monoclonal protein level is at least 30 g/L or the proportion of plasma cells in the bone marrow is at least 10 percent, but the patient does not experience any of the typical myeloma symptoms.
The risk of progression from smoldering myeloma to symptomatic disease is around 10 percent during each of the first five years after diagnosis, and decreases to 3 percent per year for the following five years, and to 1 percent per year thereafter, which means that the median time to progression is about five years.
Although smoldering myeloma patients are at a higher risk of developing active myeloma than the general public, the current standard of care is the so-called “watch and wait” approach, in which smoldering myeloma patients are regularly monitored and treatment only begins once the disease progresses to multiple myeloma.
However, certain factors have been shown to be associated with an increased risk of progression to symptomatic disease in patients with smoldering multiple myeloma. These include: a monoclonal protein level exceeding 30 g/L; plasma cells exceeding 10 percent in the bone marrow; an elevated level of abnormal plasma cells in the bone marrow; an abnormal ratio of small parts of antibodies (known as an abnormal free light chain ratio); the presence of chromosomal abnormalities in the plasma cells; and lower-than normal levels of one or more types of immunoglobulin.
Studies at the Mayo Clinic and in Spain have found that patients with several of these risk factors can be considered to have "high risk" smoldering myeloma, meaning that the patients have a higher risk of progressing to symptomatic myeloma than other smoldering myeloma patients.
In a Spanish study, for example, smoldering myeloma patients with several "high risk" disease factors had a median time to progression of about two years.
Previous Research On The Treatment Of Smoldering Myeloma
Dr. Mateos mentioned that several clinical trials during the past 30 years have investigated the effects of melphalan (Alkeran) plus prednisone, thalidomide (Thalomid), and/or bisphosphonates in patients with smoldering multiple myeloma. According to Dr. Mateos, none of these trials supported early treatment of smoldering myeloma patients.
For example, an Italian trial in the early 1990s looked at whether early treatment improved survival among patients with what, at the time, was known as "Stage I" multiple myeloma. Most of those patients today would be classified as having smoldering myeloma.
In the trial, half the patients were treated with melphalan and prednisone immediately, while the other half had treatment deferred until they showed signs of disease progression (at which point they, too, were treated with melphalan and prednisone).
Median overall survival in this trial was actually higher for the patients who received deferred treatment (71 months) compared to those who received treatment immediately (64 months).
Dr. Mateos noted during her presentation, however, that these older trials did not distinguish between standard-risk and high-risk smoldering multiple myeloma patients. She explained that standard-risk smoldering patients might not benefit from treatment, whereas high-risk patients might.
Current Research In High-Risk Smoldering Myeloma
Due to the possibility that high-risk smoldering myeloma patients might benefit from early treatment, Dr. Mateos and her colleagues initiated a trial that included only high-risk patients.
In the trial, half the 125 patients were randomly selected to receive an initial nine cycles of treatment with Revlimid plus dexamethasone, followed by Revlimid maintenance therapy, while the other half received no treatment until their disease progressed to active myeloma (see related Beacon news).
The updated results of this study continue to show that the high-risk smoldering patients who received treatment immediately had better outcomes than the patients who did not receive treatment until disease progression.
Time to disease progression is longer for the actively treated patients (not yet reached at a median follow-up time of 40 months, versus 21 months), as is overall survival at five years after diagnosis (94 percent versus 78 percent).
Dr. Mateos added that there are currently numerous trials being carried out in high-risk smoldering myeloma patients that include treatment with approved drugs such as Revlimid and Kyprolis (carfilzomib) as well as investigational treatments such as elotuzumab, siltuximab, BHQ880, and ixazomib (MLN9708).
She pointed, in particular, to a Phase 2 trial that is investigating the efficacy and safety of Kyprolis, Revlimid, and dexamethasone in high-risk smoldering myeloma patients. Initial results of the trial, which look very promising, were also presented at the IMW earlier this month. In particular, all patients included in the trial have responded to treatment (see related Beacon news). Time to progression and overall survival results for this study, however, are not yet available.
For further details of Dr. Mateos's presentation and the study she and her colleagues have been conducting, see the slide deck (PDF) of her IMW presentation, which she has made available as a courtesy to the Beacon's readers.
Related Articles:
- Diet May Affect Risk Of Developing MGUS And Risk Of MGUS Progressing To 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
- Importance Of Factors Affecting Multiple Myeloma Survival Changes With Patient Age
I'm unclear just what this group considers to be "high risk" from the description below:
These risk factors include a monoclonal protein level exceeding 30 g/L, plasma cells exceeding 10 percent in the bone marrow, abnormal plasma cells exceeding 95 percent, or an abnormal ratio of small parts of antibodies (known as an abnormal free light chain ratio). Smoldering myeloma patients with these risk factors, known as high-risk smoldering myeloma patients, have a median time to progression of about two years.
Does one have to meet ALL of the criteria or n number of the criteria to be considered high risk? The FLC ratio criteria also seems be to be pretty vague. It seems like they are simply saying that ANY abnormal FLC ratio would meet that specific criterion.
Thanks for your question, Multibilly.
The section of the article you quoted is just a description of one particular classification system for high-risk smoldering myeloma (the Mayo system) which happens to be commonly used in the U.S.
[Editor's note: The above statement is not correct. See clarification below in the next Myeloma Beacon staff comment. Note, as well, that the text Multibilly quoted also has been edited based on the comments here.]
The criteria for inclusion in the Spanish trial, however, were more akin to other main system for classifying smoldering myeloma patients, the PETHEMA system. There were four criteria used to determine a patient's eligibility to participate in the trial:
1. Bone marrow plasma cell percentage greater than or equal to 10%
2. M-protein greater than or equal to 30 g/L
3. Ratio of abnormal to normal bone marrow plasma cells greater than or equal to 95 percent
4. At least one immunoglobulin (Ig) level lower than the normal range
If a patient met both criteria (1) and (2), they were considered high-risk smoldering myeloma and could participate in the trial.
Also, if a patient met either criteria (1) or (2), but also met criteria (3) and (4), the were considered high-risk smoldering myeloma and could participate in the trial.
In her presentation, Dr. Mateos reported that about 45 percent of the patients in the trial met both the Mayo and the PETHEMA criteria for classification as high-risk smoldering myeloma.
Hope that clears things up a bit. Thanks again for the question.
Good afternoon Beacon Staff,
Could you post the MAYO risk stratification model as I was not aware they included "more than 95% abnormal PC" as one of their criteria. I thought MAYO listed >30 g/L m-protein, >10% BMPC and an abnormal FLC ratio 8 as their 3 major criteria for High Risk SMM? And isn't this the reason for the discordance amongst experts as to how they classify SMM as high risk? Hence, research continues in this very area to determine which model is more accurate? Thanks for this info.
Sorry the previous post did not identify my symbols for the FLC ratio ... I cannot remember the "less than" number, but I do know the "greater than" 8 is accurate.
My previous understanding of the Spanish study criteria just included the greater than 95% BMPC and immunopareses. Can you clarify this confusion on my end please. Did the Spanish researchers add additional criteria? Thank you.
Hi Dana,
Thanks for your question. You are correct that the Mayo classification does not include anything about the percentage of bone marrow plasma cells being abnormal. The explanation in our first comment above was incorrect.
As it was first written, the paragraph referred to in Multibilly's comment listed factors that were mainly those included in the Mayo Clinic classification of high-risk smoldering myeloma. But there was also the extra factor which you mentioned (levels of abnormal plasma cells in the bone marrow) that is not part of the Mayo Clinic classification.
The intention of the paragraph as it was originally written actually was to list off a number of factors which Dr. Mateos listed in her presentation as having been linked, in various research studies, to a higher-risk of progression in smoldering myeloma patients.
We've edited the section of the article to better reflect the original intention of the text. Thanks again for pointing out the error in our first comment.
Regarding the criteria for inclusion in the Spanish trial ... They were, in fact, as described in our first comment. Here is a description of the criteria from the abstract of an ASH presentation that Dr. Mateos gave in 2011: "The high-risk population was defined by the presence of both >PC 10% and MC >30g/L or if only one criterion was present, patients must have a proportion of aberrant PCs within the total PCsBM compartment by immunophenotyping of 95% plus immunoparesis."
These criteria have elements of the PETHEMA (Spanish) classification system for high-risk smoldering myeloma embedded in them. That's why we said in our first comment that the criteria are "akin" to the PETHEMA criteria.
But, as you can see, the criteria also have elements of the Mayo classification in them. In some senses, they are almost a cross of the Mayo and PETHEMA criteria.
Let us know if you have any further questions.
Thank you, and yes, I agree - it does seem to have a cross of the Mayo and PETHEMA criteria...thank you for clarifying and revising the article. This disease is confusing enough to me as it is ! All the best to you.
Hi
Glad to hear Pol are doing so well.... my significant other was diagnosed with mm in 2010. But Dr. Said had been found in '07 during a lung biopsy. He never returned multiple calls from Dr. So ill assume it had been growing since then he did his Rev/dex tx : chemo :radiation: and since has had a sct. He has had renal failure. After all this once. . Just a lil background info. My? is when you say not on Meds anymore u are talking about Rev/dex. Not the morphine etc... or the drugs treating side effects. Just to let u no he is hoping his own and gonna turn 69 in July. God bless
Thanks crystal s.
It's so clear that people at high risk should be given the early treatment. I can't see the argument against it to be honest, maybe I'm just missing something.
Good Afternoon Beacon Staff,
I have a follow up question please. Did this study or any recent/ongoing SMM progression risk study include a Plasma Cell Labeling Index (PCLI) as one of the parameters to determine proliferation rate. I understand this test can be used to determine rate of proliferation of the BMBpc's and wonder if any study is using it to determine SMM risk progression or is the PCLI an outdated test that the immunophenotyping assays used in the Spanish study (>95 aberrant PC %)has since replaced in SMM research.
Thanks in advance for your response !
Hi there,
The Spanish PETHEMA study has concerned me from the very beginning. Based on the PETHEMA classification, I would be considered high-risk SMM and would be eligible to enroll in that trial. But I wouldn't even consider doing so, for the following reasons...
1. I have been leading an active, normal-person life since my diagnosis with SMM (fall of 2005; MGUS diagnosis in 1999, btw), especially after I began taking curcumin (= Jan 2006). So I have been stable and smoldering for more than 7 years now, in spite of a high IgG, in spite of a high BM paraprotein level, etc. etc. etc. Just to give you an example, my husband and I just got back from Edinburgh, where we were climbing to the top of ruined castles and walking from morning till night. In other words, I have a very high quality of life.
2. The PETHEMA study never talks about its SMM patients' quality of life. How are they doing? We simply don't know. Overall survival doesn't give us any of the important details. I don't know about you, but QOL is very important to me!
3. The Mayo Clinic and PETHEMA cannot even agree on the definition of "high risk SMM." The Beacon published an article to that effect in Jan 2013. Uhm.
4. Many of the researchers involved in the PETHEMA study have very close ties to the pharmaceutical companies that produce the very drugs used on these SMM patients. One is even a Celgene employee (hello???). That's like having a safety study on a new Honda model...but the only people involved in the study happen to be Honda employees or people who have received money from Honda. Could we trust the results from such a study?
For these and many other reasons, I think that SMM folks with no CRAB symptoms are better off taking curcumin and/or other non-toxic, anti-MM, scientifically-backed supplements...and also being careful with their diets (no sodas, no aspartame, etc.) and stress levels.
I know it's hard, believe me!, and I know we all want to be proactive. But, in MY opinion, studies such as these can be very dangerous. As I said, it's just my own opinion...But it's also MY life.
Thanks for your comments, Dana and Margaret.
As best we can tell, Dana, the Spanish study is not making use of the Plasma Cell Labeling Index to help diagnose patients or track disease progress. We also have checked the details of one or two other trials similar to the Spanish study, and, once again, they don't seem to be making use of the PCLI.
We are, however, looking into this a bit more, and we will let you know if we hear anything more definitive.
Thank you Beacon Staff,
I would very much appreciate your follow up as I am very interested in finding out if the PCLI is of any significant value in trying to determine risk progression or track disease progress.
I have read the PCLI is not widely used, but it is due more to the lengthy process of performing the test as opposed to its prognostic value.
I am trying to determine if this is the actual case or if, in fact, this test has been replaced with a new diagnostic tool which has more significant value.
Good Evening Beacon Staff,
I am following up to see if you have found any additional information regarding PCLI and its application/significance in any studies. Can you provide any additional insight as to whether or not it is utilized as a tool to determine risk progression or track disease progress. Thank you.
I was treated with 25mg of revlimid and 40 mg of dexamethasone for 4 months and then had my stem cells harvested and stored.
What is your recommendation for followup treatment for my high risk smoldering myeloma? I have one hematolgist/oncologist recommending 10 mg
of revlimid and another suggesting no further treatment at this time only
blood work every month.
What would you recomnmend?
Thank you so much.
P.S.
I am 65 years old and was diagnosed May 2013