Additional Treatment To Deepen Response Prior To Transplantation May Not Improve Survival In Newly Diagnosed Multiple Myeloma
A recently published study may change the goals many myeloma specialists use to make treatment decisions for newly diagnosed myeloma patients planning on having a stem cell transplant.
The study also has potentially broader implications. Indeed, it may influence ongoing debate on a fundamental controversy about how multiple myeloma, in general, should be treated.
The authors of the new study looked at data for 539 myeloma patients who failed to achieve even a partial response to their initial (induction) treatment regimen after diagnosis.
After their initial treatment failed, some of the 539 patients went on to have a stem cell transplant without any additional treatment. The rest of the patients received additional treatment with other myeloma therapies before also going on to a stem cell transplant.
Not surprisingly, the additional therapy received by some of the patients before their transplant meant that those patients had deeper responses before and after their transplant than the patients who went straight from their first treatment to a transplant.
But, when the authors compared the survival of the two groups of patients, they found no difference. The progression-free survival and overall survival for both groups were basically the same.
In other words, among the patients in this study, treating some of them longer and with more treatments to deepen their response did not provide any survival benefit.
These results, the authors of the study conclude, “indicate that transplant-eligible patients who achieve a suboptimal response to initial induction therapy should move on to [their planned transplants] rather than receiving additional … therapy in a quest to deepen the level of response.”
This summary of the study's findings is echoed by Drs. David Vesole and David Siegel of the John Theurer Cancer Center in Hackensack, New Jersey, in a commentary that accompanies the new study. The study, the two myeloma specialists write, makes it clear that “additional hammering of patients with sequential cycles of ‘salvage’ chemotherapy should not be pursued” prior to an initial stem cell transplant.
This approach to the treatment of transplant-bound myeloma patients is different than the one used today by many myeloma specialists, who make pretransplant treatment decisions based on a goal of achieving a target level of response prior to transplantation.
Broader Implications Of The Study
There also are potentially broader implications of the new study, because it touches on issues related to a key question that myeloma specialists and patients today face: Should achieving the deepest possible response be a goal when treating multiple myeloma?
Many believe the answer to this question is an unequivocal “Yes”. As evidence in favor of this position, those who support it point to studies that have shown that myeloma patients who achieve a deep response to treatment live longer than patients who do not.
Those who feel the answer to the question is not always “Yes” – or even an outright “No” – argue that the evidence in favor of the “Yes” position is flawed. They believe that, in many cases, the patients who live longer because they achieve a deep response to treatment do so because their disease is less aggressive than the disease found in patients who do not respond as deeply to treatment.
Depth of response, supporters of the “No” position argue, is not the cause of longer survival. Instead, it is a sign of how well a patient’s disease responds to treatment.
The answer to whether or not a deep response should be the goal of myeloma therapy has important implications. If it should be the goal, then, for many patients, treatment regimens probably should include more drugs, and treatment should continue longer, than currently is the case. Making these kinds of changes, the argument goes, will lead to more patients achieving a deep response, which will improve overall survival times.
The answer to the depth-of-response-as-target question also influences how one should think about issues such as transplantation, consolidation therapy, and maintenance therapy – all of which have deepening of response as a one of their goals.
Of course, a key reason there is controversy about depth of response as a goal for myeloma therapy is because few studies have provided evidence that directly addresses the issue.
Therein lies the potential broader significance of the new study. In a limited – but still important – context, it shows that targeting a deeper response to treatment did not provide an additional survival benefit to patients.
Yes, there are limitations to how much one can conclude based on the new study. It was a retrospective study, so patients received different treatment regimens for different lengths of time. Also, one cannot know for certain why some patients were given additional therapy prior to their transplant, and others were not.
Just as importantly, all the patients in the study received a stem cell transplant. This is one reason why the authors of the study – as well as the authors of a commentary accompanying the journal article – focus on the implications of the study for pre-transplantation treatment.
Nevertheless, despite the study’s scope and the limited claims its authors make about its implications, it is hard to see the study results not providing ammunition for those who argue against depth of response as a universal target during myeloma treatment.
Study Design
The authors of the new study retrieved data for 539 newly diagnosed multiple myeloma patients from the database of the Center for International Blood and Marrow Transplant Research. The patients were seen at more than 80 different treatment centers, of which about 95 percent are in the U.S., according to Dr. Parameswaran Hari of the Medical College of Wisconsin, one of the study’s authors.
To be included in the study, patients had to have a stem cell transplant between 1995 and 2010, and the transplants must have been carried out within 12 months of the patient’s diagnosis.
In addition – and very importantly – patients could only be included in the study sample if they failed to achieve at least a partial response to their initial myeloma treatment regimen.
The researchers divided the 539 patients in the study into two groups: those who received additional treatment before their transplant (324 patients), and those who did not receive additional treatment and proceeded directly to the transplant (214 patients).
The median age at the time of transplant was 57 years for patients who did not receive additional treatment before transplantation and 56 years for patients who received additional treatment before the transplant. Almost 50 percent of the patients in both groups had stage 3 myeloma at diagnosis.
A majority of the patients received vincristine (Oncovin), doxorubicin (Adriamycin), and dexamethasone (Decadron) (VAD) as their initial treatment. More specifically, 60 percent of patients who did not receive additional treatment were treated with VAD as their initial regimen, compared to 47 percent of patients who received additional treatment.
Almost all the patients who did not receive VAD as their initial treatment regimen were treated with a regimen that included a novel myeloma therapy, such as thalidomide (Thalidomid), Velcade (bortezomib), or Revlimid (lenalidomide). This was the case for 32 percent of patients who did not receive additional treatment prior to their transplant, and for 39 percent of patients who received additional treatment.
Among patients who received additional treatment before stem cell transplantation, the majority (76 percent) received one additional line of therapy, 20 percent received two additional lines of therapy, and 4 percent received three or more additional lines of therapy.
More patients who received additional treatment (55 percent) had their transplants in the later period covered by the study (between 2005 and 2010), when more myeloma therapies were available, compared to patients who did not receive additional treatment (35 percent).
Study Results
Given how patients were selected to be included in the study’s analysis, it is automatically the case that none (0 percent) of the patients who went directly to a transplant after their first treatment regimen had achieved either a partial or complete response prior to transplantation.
In contrast, among the patients who received additional treatment after their initial regimen, 68 percent had at least a partial response before their transplant, including 8 percent who achieved a complete response and 60 percent a partial response.
After their transplants, more patients who received additional treatment before transplantation achieved a complete response than those who did not (19 percent versus 9 percent, respectively). The same pattern also held for partial responses (40 percent versus 33 percent, respectively).
Figure 1
Overall Survival - All Patients
(click on image to view a larger version of it)
However, despite achieving deeper responses before and after transplantation, the patients who received additional treatment before their transplant did not have better progression-free survival or overall survival than the patients who went straight to transplant after their first treatment regimen.
The four-year progression-free survival rate was 30 percent for patients who received additional treatment and 31 percent for those who did not. There also was little difference in the overall survival results for the two groups (see Figure 1 to the right).
Figure 2
Overall Survival - Novel Therapy Patients
(click on image to view a larger version of it)
The researchers also checked if their findings held up when they restricted their analysis to patients in their sample who received novel agents – either thalidomide, Velcade, or Revlimid – as part of their first myeloma treatment regimen. This test was done to address potential critics of the study, who might argue that the study’s results are not relevant to current treatment decisions, given that novel agents – rather than the older VAD regimen – are now the norm in the initial treatment of multiple myeloma.
Once again, however, there was no significant difference in overall survival between the no-additional-treatment and additional-treatment groups of patients. In fact, among the 195 patients who had a novel agent as part of their first treatment regimen, there was a (not statistically significant) trend toward longer overall in the 69 patients who received no additional treatment regimen before their transplant (see Figure 2 above).
For more information, please refer to the study by Vij, R. et al., “Impact of Pretransplant Therapy and Depth of Disease Response before Autologous Transplantation for Multiple Myeloma,” in Biology of Blood and Marrow Transplantation, February, 2015 (abstract).
Related Articles:
- 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
- Stem Cell Transplantation May Be Underutilized In Multiple Myeloma Patients In Their 80s
- Early Use Of Radiation Therapy Associated With Shorter Survival In Multiple Myeloma
- Selective Digestive Decontamination May Reduce Risk of Infection In Myeloma Patients Undergoing Autologous Stem Cell Transplants
Thank you so much for this news and analysis. The broader implications of this study affect me directly.
Thanks, Maike and Navneet, for summarizing this very interesting article. Certainly it seems to present counter-intuitive results when we think in terms of the today's common practice of aiming for as deep a pre-transplant response as possible.
However, I'm not sure I completely agree that the "Broader Implications" discussed in the report follow directly from this study alone. You can think of two forms of "depth of response," depending on when it is measured. One is depth of response before the transplant. This paper provides evidence that that type of depth of response may not be as important as many people have been thinking. That, in itself, is potentially a hugely important result, as the review rightly points out.
The second form of depth of response is the "ultimate" deepest response that a patient ever achieves, measured whenever they achieve it. Presumably in most cases that would be post-transplant (if the patient receives a transplant), maybe even during consolidation or maintenance therapy if the patient receives those treatments. Many other studies look at this form of depth of response, and I think this is what we tend to think of when we think of depth of response.
The "Broader Implications" are, I think, talking about this second, more general, type of depth of response. The study (at least as summarized here and in the abstract) does not present OS as a function of the depth of response that was ultimately achieved. I think we need that analysis in order to say anything about the importance of this second, more general, depth of response. Did the full paper provide that analysis?
That said, the discussion in the "Broader Implications" section makes several important points beyond the scope of this study and reminded me of a Beacon physician column by Dr. Vincent Rajkumar in August, 2013. In that column, he argued that achieving a complete response in front-line therapy should not necessarily be the goal of every myeloma patient and his/her medical team (SV Rajkumar, "Should Myeloma Patients Panic If They Do Not Achieve A Complete Response?" Aug 10, 2013).
Thanks again for reporting on this study. At a minimum, it will be interesting to see how it affects pre-transplant treatment protocols in the next couple of years.
Makes one think that there is perhaps a better indicator of treatment response than M-protein values. Perhaps some other variable in the immune system is a more revealing indicator of the true status of the disease. The fact there is no statistical difference in overall survival, regardless of the depth of response to treatments before stem cell transplantation, tells me that the extra treatment to achieve a deeper response may be totally unnecessary.
Have there been any proposed studies or indicators of anything else that would give a truer picture of the state of the disease?
Thanks for the comments, everyone.
David - I'm glad you found the article helpful for your own decision making.
Mike - We do mention in our article that the patients who got additional treatment after their first treatment regimen had a deeper response – both before and after transplantation – compared to the patients who received only one treatment regimen prior to transplantation. As is mentioned in the article:
"After their transplants, more patients who received additional treatment before transplantation achieved a complete response than those who did not (19 percent versus 9 percent, respectively). The same pattern also held for partial responses (40 percent versus 33 percent, respectively)."
One thing we didn't note in that paragraph is that the post-transplant responses we mention are best responses post transplant, not just whatever response was measured, say, 100 days post transplant.
So I think this addresses, at least partly, the concern that you raise.
Eric - I am not sure the issue is with how response to myeloma treatment is being measured. Instead, what the study does is make it clear that, if two newly diagnosed patients both achieve the same level of response to whatever initial treatment(s) they are given, this does not mean you should expect them to have similar survival. It may matter how they got to the same response.
A newly diagnosed patient who achieves a very good complete response after six cycles of Revlimid and dex (two drugs), for example, should not necessarily be assumed to have the same prognosis as a second patient who is similar in age and other characteristics at diagnosis, and achieved a very good complete response after six cycles of Velcade, Revlimid, and dex (three drugs).
Although both patients achieved the same response, and are similar otherwise, it required a more intensive treatment regimen to get the second patient to the same level of response as the first patient. That probably says something about differences in disease between the two patients.
I don't see any reference in the abstract to the chromosomal risk factors of the patients studied. It could be that 'high risk', 'intermediate risk' or 'low risk' factors, as determined by FISH tests would have some determination on this too. Also, the co-morbidities of the patients are not given. I suppose that, if there were studies of how patients with differing chromosomal risks, or issues such as heart disease, kidney disease, diabetes, responded to initial treatment, that could be used to determine as to why this result is obtained too. One question could be is whether those patients would have a poorer response to initial treatment.
Thanks, Maike and Navneet, for the thought provoking article.
Thanks for a great article.
I find it interesting that many people seem surprised by the results of this study, or are suspicious of the results. I may be mistaken, but I don't think it is anything new to say that you have to be careful about the conclusions you make based on studies that show that deeper responses to treatment are "better." This is something, for example, that the Beacon medical advisors often say in their forum postings. For example, Dr. Shain wrote in this posting,
"You can find numerous publications that demonstrate that the deeper the level of response achieved equates to improved outcomes, whether the response be PR, VGPR, CR, sCR or MRD negative disease. Currently, I consider the level of response to be more like a readout of myeloma disease biology – a measure of your myeloma's sensitivity to drugs."
I think that all myeloma specialists would agree that it is great to see someone get a complete response to their first myeloma treatment regimen. They all also would agree that the response bodes well for the patient's longer-term survival.
Where the views start to diverge, I believe, is on questions like: What if the patient had achieved just a partial response; should they receive additional treatment? Or, sure, the patient got a complete response – but should we treat the patient further until we get them to sCR or MRD negative status?
As I understand it, if depth of response should be a treatment target, then the answer to all those questions is "yes". Doctors who hold this view believe that deepening response leads to longer overall survival.
Doctors who, on the other hand, believe response is just a reflection of a patient's disease biology would probably answer the questions with either a "no," or "it depends". They would argue that adding more treatments, or treating longer, will have only short-term benefits. It may delay progression, for example, but not necessarily improve overall survival, and it could lower a patient's quality of life due to side effects.
Again, this is just how I keep the different views on the controversy organized in my head. As they say, "your mileage may vary".
"Multiple levels of heterogeneity exist in MM, providing tremendous clinical challenges in diagnosis, prognosis, treatment, and monitoring. The understanding of biological relevance of the heterogeneity at the molecular, clonal, and cellular level and how these relate to clinical heterogeneity will provide important mechanistic insights that will guide future development of diagnostic, prognostic, therapeutic, and monitoring modalities to further personalize treatment, improve treatment precision, and lengthen the survival of MM patients."
http://www.hindawi.com/journals/bmri/2014/232546/
So, it seems to me that, until medical science can come to a better understanding of the correlation of the various biological relationships as described above to the most efficacious treatments, we are, at best, comparing only unidentified fruit to unidentified fruit, as we still have insufficient understanding to consistently know whether we are comparing apples to oranges.
We have a loooooonnnng way to go in that regard, I'm afraid.
Best,
Steve
I'll bet insurance companies are watching this study and others like it very closely. As we become more of a government insured society, we have to be aware of bias that may exist in government funded research, who are otherwise viewed as third party "observers".
Just a random, paranoid, pre-weekend thought!
Good morning:
I understand that this article touches on debates that I have read and/or heard regarding one of forefront issues today on MM treatment. For the non-responders, those who do not fall under the "easy" of "no-brainer" category: What to do?? What next? When do you stop and try something else? There are MM experts with differing views, and for the top doctors, they can achieve superior outcomes for their patients based on their individual knowledge and understanding of the practice of their art, even though they have different philosophies.
As the authors of the article point out, however, the statements in this article and the preliminary conclusions do seem to contradict many recent studies/publications. The counter idea is in short: Better response, no matter how you get there, better outcome. This was touched on in the article. So the article sparked my interest and motivated me to re-review some of the recent literature that I had read, and after doing so, I have a couple of points that perhaps the authors can comment on in reply.
First: Is not this study obsolete??
Is VAD initial induction (on which the study is primarily based) used anywhere in the US any more?? I just looked up one old study where with VAD the % of patients reaching better than PR was 63% (37%, or over one third, not even reaching PR). For RVD and CyborD the >= PR is well above 95%, and almost 100% for KRD. If you get almost everyone to not only PR but VGPR with the new "good" meds (the novel agents), what does a study based the older "bad" meds have to do with today's NDMM treatment choices??
I understand that this is a retrospective study, which of course is potentially very valuable. By its very definition it is looking at the older data. In this case, my feeling is that it is too retrospective to have great applicability to today's situation.
Second: Are the conclusions a "stretch" to extrapolate from the data set under study??
This point is related to the first, as today's treatment options are more and better that even 5 years ago. As I read the study, I am very comfortable with the authors conclusions regarding the questionable value of piling additional treatment to VAD, when the VAD is not working. The study certainly seems to be complete and academically rigorous, and conforming to the same formats/approaches that all similar studies conform to.
The article however states that: "There also are potentially broader implications of the new study".
Although there as a relatively small element of novel agents included in the retrospective study, it is mostly based on VAD. To what degree can the authors be confident that a different initial base induction regimen (based on the best available novel agents) will have the same results?? Having read the article and the study I do not think that has been established. I think raising the question or putting forward the hypothesis that it might be worthy of further study with other initial induction regimens is reasonable, but suggesting that it should impact treatment decisions for a different induction regimen, seems to me an overreach.
Further, when considering both points, the big "hurdle" in days gone by was getting over the PR, and possibly reaching VGPR. In the period under study, VGPR was a rare thing. Today, VGPR response rates are in 70's and getting higher with new treatments, and the "hurdles" relevant today, are more along the lines of reaching VGPR, CR, and MRD -.
In any case, very interesting and thought provoking article.
Hi JPC,
I'm not sure that you are fully understanding or appreciating the significance of this study, and I think this is partly because you do not understand the previous research on the subject.
The authors of the current study never say that their results "contradict many recent studies / publications," as you write. The reason they don't say that is that there never really has been a study like this one.
Previous studies have only found that, for a specific treatment regimen, a better response is associated with longer overall survival. Previous studies have not addressed the more important question addressed by this study, which is: Is there a survival benefit to adding more treatment to get a deeper response?
This study addresses that more important question with a big dataset with patient outcomes particularly suited to answering the question.
You question the validity of the study to treatment decisions today because of the "small element of novel agents included in the retrospective study", claiming the study "is mostly based on VAD."
First of all, one third of the patients in the study were treated with non-VAD regimens including at least one of the modern novel therapies – Velcade, Revlimid, or thalidomide. Moreover, among the patients who got a second treatment regimen to deepen their response, almost 60 percent got a treatment regimen that included either Velcade, Revlimid, or thalidomide.
So claiming the study "is mostly based on VAD" is misleading, to say the least.
More importantly, if you believe that "deeper responses are always better for overall survival", why does it matter what the initial regimen is? A deeper response is a deeper response.
Trying to shift the focus to how many patients got VAD, and differences between VAD and current regimens, is just a distraction tactic. It sounds nice until you realize it doesn't matter to the central question: Does it improve overall survival if you treat patients with more agents to get a deeper response.
No matter how much you try to obfuscate the study's significance, it is very clear: Patients who got deeper responses because they got additional treatment did *not* have longer overall survival than patients who did not get extra treatment to deepen their responses.
By the way, when a study is described as "retrospective", this does not automatically mean the study uses old data. "Retrospective" just means that the study is not "prospective."
Both "retrospective" and "prospective" studies can involve data from many years ago. The difference is that a prospective study is explicitly designed and carried out to answer specific questions, such as "Is regimen A more effective than regimen B?", or "How effective is regimen A in a random sample of newly diagnosed patients?" Prospective studies are usually based on data from clinical trials.
A retrospective study, in contrast, analyzes data that was not specifically collected for the sort of analysis carried out in the study. A common type of retrospective study is a single-center study of all multiple myeloma patients who were newly diagnosed within a certain period of time. The data for those patients were not collected for a specific purpose or set of questions. However, they may still shed light on important issues.
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