Risk-Adapted Therapy For Multiple Myeloma
In the last 10 years, we have witnessed dramatic changes in the treatment of multiple myeloma that have provided hope and optimism to myeloma patients worldwide.
We have a better understanding of the biology of the disease and an array of approved and investigational new drugs with excellent clinical activity.
Importantly, we have also come to the realization that myeloma is not one genetically distinct disease, but a clinical condition with many distinct molecular subtypes. Indeed, there are subtle differences in clinical presentation among the various subtypes.
More remarkable, however, are the dramatic differences in long-term outcome, even when all available new drugs are used aggressively early in the disease course as some academic centers have tried to do.
These differences in overall survival are the reason why understanding risk-stratification and risk-adapted therapy is so important for patients with multiple myeloma.
What do we know about risk factors in myeloma?
All things being equal (i.e., patients of similar age and functional status), there are some genetic abnormalities that appear to be associated with a shorter duration of response to therapy and shorter survival (high-risk myeloma). These include deletion of chromosome 17p- and translocations t(4;14), t(14;16), and t(14;20), all of which can be detected using a bone marrow test called "fluorescent in situ hybridization", or "FISH."
On the other hand, patients who have extra chromosomes ("hyperdiploidy"), translocation t(11;14), or translocation t(6;14) appear to have longer duration of response to therapy and better survival (standard-risk myeloma).
FISH is not the only way to assess risk status. Risk can also be assessed using other techniques like karyoptyping. Some centers use a full gene expression profile (GEP) to assess risk. Overall, approximately 75 percent to 80 percent of patients with myeloma have standard-risk disease.
What does risk stratification mean for patients? Can we overcome high-risk myeloma? Are these risk factors useful in the era of novel agents?
First of all, no one can predict outcome in a given patient. There are many high-risk myeloma patients I know, who have lived 10 to 15 years or longer.
Second, with recent advances I believe we are indeed starting to overcome some types of high-risk myeloma―at least to some degree. For example, studies at the Myeloma Institute for Research and Therapy (MIRT) at Little Rock, Arkansas, show that with modern therapy, patients with the t(4;14) translocation can on average expect almost similar outcomes as patients with standard-risk myeloma.
Third, although one can be tempted to dismiss risk stratification as an outdated concept or as an antiquated idea born prior to the arrival of new drugs, we must be careful not to throw the baby out with the bathwater. The “Total Therapy” studies at MIRT show clearly that certain cytogenetic groups still need help: t(14;16), t(14;20), and deletion 17p. More importantly, these studies show that not all patients need the same intensity of therapy. Whether such groups are best identified by FISH or GEP (or some futuristic technology) remains to be seen. But each method does identify a subset of patients that merit consideration of special treatment approaches and careful counseling.
How do we deal with this information about risk stratification? How has the myeloma field reacted?
There are two points of view that are being hotly debated. Both points of view come from well-meaning and thoughtful investigators.
One point of view is that all patients need to be given the best treatment options early in the disease course, and our goal should be to achieve a complete response (CR).
The opposing point of view is that it is time to abandon the “one size fits all” approach, and rather approach the treatment of a given patient based on the underlying risk stratification. I subscribe to the latter viewpoint, and I will give 3 reasons why:
First, in a perfect world, if we had treatments that have a good chance of curing myeloma, there is no question that most of us will encourage patients to put up with major (sometimes life-changing) side effects to pursue that possibility. But we don’t. Unfortunately, the treatments we have against myeloma, while incredibly effective in controlling the disease for a given time period, eventually fail. Moreover, all have side effects. The more drugs we administer, the more the toxicity. While patients with high-risk features may be willing to take on risks of increased side effects to achieve good disease control, patients with standard-risk myeloma who have an average expected survival in excess of 7 to 10 years may have little reason to take on the risks of serious side effects without proof that such treatments actually make them live longer.
Second, not everyone needs a CR. While many studies show that patients who achieve a CR live longer than patients who do not, these studies should not be construed as proof that CR is an important goal of therapy. Such logic has actually been shown to be flawed for decades in the cancer field, but rises periodically like the Phoenix. In fact, in any study, based on pure statistical considerations, patients who “respond” always look like they lived longer than patients who did not, even when the drug in question is useless. In my mind, CR is a bit like a mediocre prognostic factor for most patients with myeloma―not the specific goal of therapy.
In any case, CR in myeloma is seldom a true CR unlike say, large cell lymphoma. There are almost always residual myeloma cells even in CR patients. That is why almost all patients still relapse. The one thing trying to get a CR can however guarantee is more side effects. Now, this does not mean CR is not desirable―quite the contrary. Patients who achieve a CR should no doubt be pleased. But patients who fail to achieve a CR should by no means lose hope or feel disappointed either.
The best data today with current therapy shows that patients with standard-risk disease actually live the same length of time whether they achieve a CR or not. On the other hand, achieving a CR seems to be important for patients with high-risk features. Based on these considerations, I try and use available treatments in a sequential manner in standard risk patients with an emphasis on quality of life, while in high-risk patients I am more willing to pursue aggressive therapy.
Third, I am concerned about surrogate endpoints such as progression-free survival (PFS) and time to progression (TTP). These endpoints sound nice, and even have relevance when it comes to regulatory drug approval studies. However, in most clinical trials, trying to determine the timing of treatments or to define the optimal combinations, such endpoints are not as informative as overall survival. The optimistic results with these endpoints which tempt us to pursue a “one size fits all” approach can have unintended consequences. After all, how long a patient lives is not just dependent on efficacy, but on safety as well. If we use all the available drugs early on, what do we do at relapse? Further, for many patients, quality of life trumps longevity in terms of priority, and it helps to have an individualized, risk-adapted approach. For example, why take even a 5 percent risk of severe neuropathy in the first four months following the diagnosis of myeloma if one has a high probability of living longer than 10 years?
Before I close, I would like to be specific about what I mean by risk-adapted therapy. In standard-risk patients, I favor initial therapy with a regimen such as Revlimid (lenalidomide) plus low-dose dexamethasone (Decadron). If such patients are transplant candidates, I would collect stem cells early in the disease course, but leave the timing of transplantation open to many factors including patient preference. CR would be great, but not essential. In high-risk patients, I would favor initial therapy with a Velcade (bortezomib)-containing regimen followed by autologous transplantation (if eligible) and then maintenance with a Velcade-based regimen. CR will be pursued as a specific treatment goal, and I will consider changing drugs if needed to achieve that goal.
Myeloma is a complex disease, and the above concepts are modified according to the individual situation and will evolve with time. I must emphasize that I prefer clinical trials over standard treatments whenever possible.
We have much work left to do. The strides made in the last decade are spectacular compared with most other cancers. I think in the near future we will have options that are safe and highly effective, which will make treatment approaches more uniform. My sense, though, is risk-adapted therapy is here to stay, but it will become more precise and more accurate in the next few years.
Dr. S. Vincent Rajkumar is a professor of medicine at the Mayo Clinic in Rochester, Minnesota. His research focuses on clinical, epidemiological, and laboratory research for myeloma and related disorders.
Dear Dr. Rajkumar, thank you for this excellent article. It's a remarkable point for the Beacon to have renowned experts at their site. (Thank you, Beacon-Team!) Excellent Text. Why? You can understand it as a patient, but it gives us also insights in the status quo of advanced myeloma therapy. Of course, we as patients have always this final question: Do you think with a targeted therapy a steady control of our disease will be possible in the next 3 to 5 years? If you're 35 years old as me and many under 60 in our group, 10 years sounds excellent but...you know....20 sounds much better, of course. Could you give us a hint, what milestones has to be reached to make myeloma(s) a chronic disease? We know, that you're not the oracle of Delphie, but what obstacles (cancer stem cell, genetics) do you think are the most important ones. Thank you very much!!!! Peter
-Dr. Rajkumar, as Peter says: Outstanding Text! Thank you!!! For us it's sometimes hard to know the status quo, because there're so many insituts out there, using the "cure"-word in their title: The "Cure-Myeloma-project", "the cure-controle"-debate, the "race to cure" (...) "Cure" seems just a term for fundraising, not an achievable goal, that could be reached in the next 5 years. The most of us realapse within 3 to 5 years. Even targeted therapy will not bring us much nearer, I learned. Best regards, Tom
Dr. Rajkumar - Thank you for this excellent article and for taking the time to share your insights with the Myeloma Beacon community. I have found the Beacon to be invaluable to me in helping to understand what my husband is dealing with in regard to his high risk myeloma. You and your fellow doctors who contribute their time and insight to the Myeloma Beacon are doing a very great service to all of us.
An interesting article that highlights the continuing debate in the myeloma community, patients, families, physicians and researching physicians.
Quality of life issues are important to consider, but I will tell you that when my mother, age 62, and 12 years of fighting 5 different cancers faced that hurdle, it made sense. When my husband at age 48 and otherwise healthy was diagnosed, quality of life was no where on our radar. We were looking for aggressive treatment to rid him of this disease. Rightly or wrongly, we just were not thinking that broadly.
My biggest frustration continues to be the lack of up to date information by treating physicians around the country in the hematology field. It is still be disseminated quite regularly that a low risk myeloma diagnosis is a three, perhaps five year (with transplant) survival situation. As you have alluded, this is very outdated and I believe, quite a disservice to newly diagnosed patients, desperately trying to overcome a cancer diagnosis that they most likely never heard of.
Finally, one of the obvious concerns I have, is that in treating my husband aggressively at age 48, his chances of developing serious complications from the treatment in years down the line will be great. Although I am quite happy to report that he is doing very well, worked through his entire treatment, and continues to work full time.
Are you doing maintenance therapy after SCT with your patients and what are your thoughts on that? It is another raging debate in our experience. Arkansas does a standard 3 year (but will continue as long as you can tolerate it) and our at-home doc who administers it, completely disagrees with maintenance therapy theories as a whole in cancer treatment. However, it is quite prevalent in tumor cancers as well.
Thank you for your article.
I think the key to making myeloma more of chronic disease lies in persuading the patients immune system to mount an attack on the myeloma, as it often does after an allo-graft. I think this would be especially effective after a reasonable response to induction therapy or SCT. Vaccine induced production of myeloma antibodies has apparently been achieved in some recent trials on heavily pre-treated patients who's disease was refractory to all other therapies. No serious/ permanent side effects were reported. This has surely got to be the next generation of treatment and needs to be persued relentlessly!
Prof. Rajkumar, 10 big "thank you's" from our myeloma group. We need such very important articles from renowed experts. Anyway a view in the near future would be great. Would it be possible to name in a short comment (thank you Charly!) the most emerging and promising agents/approaches for us? We heard about immunotherapy/vaccination, new inhibitors and enhanced targeted chemotherapy, more efficiant transplants with stem cells that are growed artificially. Do you think the life expecency of low risk myelomiacs could be enhanced with that remarkably? Thank you again! Patrizia
I appreciate the comments. Mr. Parker, you are right. Ten year survival is not adequate. In order to make this truly a chronic disease where patients can expect a full length of life, we need additional new classes of agents that are effective. Currently we have 5 classes of agents that are unquestionably active in myeloma: alkylating agents (eg., melphalan, cyclophosphamide), steroids (eg., prednisone, solumedrol, dexamethasone), Imids (thalidomide, lenalidomide), proteasome inhibitors (bortezomib), and anthracyclines (eg., liposomal doxorubicin). The drugs on the horizon carfilzomib and pomalidomide that have shown clear single agent activity are not from a new class, but represent improved versions of the classes I mentioned. What we need desperately are brand new classes of drugs with good single agent activity. I think we are close. There are some promising candidates. These same requirements are needed for a cure as well. The main obstacle is that we have not identified a clear cytogenetic lesion in myeloma that causes the disease as we have in the case of chronic myelogenous leukemia. Ms. Puente, there is unfortunately no consensus on maintenance therapy. We evaluate each patient and decide on a case by case basis. Finally, I do believe that we have many promising leads that have potential in myeloma, eg., the HDAC inhibitors, elotuzumab, and some immunotherapy approaches.
Dr. Rajkumar, thank you again for answering.
That are our milestones. We hope, that some myeloma agents are already in the market an could brought faster to the patients. For example Dr. Croce published Research about microRNAs in mm. The agent, that could be used, Nutlin, exists.
Or take the immunomodulative advances in HIV and the drugs there. My doctors speculated, that they could
be used in MM also but they' ve no capacity, to test them in cell lines.
One beacon reader, Tom, told me about moores law. Perhaps the speed, that we need to survive comes from the tests, that are now possible with the better transgenic mice models, that could simulate human bones better. A Breakthrough is around the corner.
Dr. Rajkumar - our group wish you all the best!!!
Peter M. Parker
Thank you, Dr. Rajkumar. A very encouraging article!
Thank you Dr.Rajkumar
I was really pleased reading your articles and listening to your online lectures , i need your advice about a regimen used for MM treatment, i send e.mail to mayoclinic , don't know if it will be forwarded to you, or if i can contact you through other mail address
Thanks, Dr. Rajkumar. UAMS claims with its Total Therapy 3 that some patients can alerady be considered cured. My thought is, as long as the tumor cells are not completely eliminated and we don't have something similar to the T-cell gene therapy pioneered by U Penn to keep them at bay, the cure is a bit misleading. Patients also run the risk of running out of drugs when the disease does come back. What's your view?
Regarding the potential of using the U Penn method to treat MM, are you aware of any ongoing effort in the academics or cancer institutes? How many years are we looking at before that becomes a reality? - Thanks!
Ben S.,
You are describing the real problem that Myeloma patients have. Our Immune systems do not view the Cancer as dangers to our bodies. Our Immune Systems even try to help the Cancer cells survive. See attached link:
http://www.sciencedaily.com/releases/2009/10/091005123043.htm
An Allogeneic SCT can accomplish what the T-cell Gene pioneered at UPenn did. Here is a link to an article about Allo's in Myeloma.
http://www.haematologica.org/cgi/content/full/93/9/1295
It is an interesting article. Take note of the paragraph about Molecular remission. They discuss a small study of 29 patients, 14 did Allos and 15 did Autos. Here is a sentence that shows some of the Allo patients whose "new" immune systems are killing Cancer cells without the aid of Chemo:
In three of the allogeneic transplants, molecular remission occurred more than 3 years after the transplant, while late molecular remissions were not seen in autologous transplant recipients, indicating a GVM effect in the allogeneic transplants.
I did a full Allo. I was in my first CR when I did it. When I was tested after the Allo, I was in Strident CR. I do not know if it was the Chemo or the "new" Immune System that did it. Hopefully it was from the GVM effect, as that would likely mean a longer Remission than if the Chemo got me there. Of course, there are risks associated with doing the Allo.
Here is a link to an excellent article about the "Cure/Control Debate" in Myeloma that Dr. Rajkumar wrote. It is great that Dr. Rajkumar shares all this great information with us patients.
http://bloodjournal.hematologylibrary.org/content/118/12/3205.full
Best of luck,
Mark
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