Should Myeloma Patients Panic If They Do Not Achieve A Complete Response?
Over the last year or two, I have seen an increasing number of patients with multiple myeloma who are deeply worried that they have “failed” treatment because they are not in “complete response” (CR). This phenomenon is gaining further steam with recent interest in “minimal residual disease” (MRD).
In fact, with numerous educational programs, daily emails, and ubiquitous lectures touting a new regimen with even higher complete response rates, I am now almost as worried as them. Of course, the cause of my worry is not that patients have not achieved the magical complete response or minimal residual disease-negative status, but at how misinterpretation of data can lead to needless concern, unnecessary chemotherapy, increased side effects and cost of care, and even harm.
A lot of the recent hype surrounding complete response and minimal residual disease-negative status is the result of two factors.
The first is that prior to Revlimid (lenalidomide), Velcade (bortezomib), and other new drugs, a complete response was seen in less than 5 percent of patients treated with standard-dose therapy. Now, this rate is climbing steadily with each new study, making investigators giddy with optimism.
The second factor is more subtle. It is based on a proliferation of studies in which patients who achieve a complete response or minimal residual disease-negative status are reported to live longer than those who do not achieve these levels of response.
On the surface, these two factors suggest that we can achieve complete response in more patients than before, and we should try our best to get to that point because patients in complete response live longer than those not in complete response. However, there are numerous caveats to this superficial interpretation of the data.
In newly diagnosed patients treated with induction, stem cell transplantation, and Revlimid maintenance therapy, the proportion of patients who get to a complete response is approximately 30 percent. Does this mean that 70 percent of myeloma patients have “failed”?
Even with more expensive triplet induction regimens such as Revlimid, Velcade, and dexamethasone (Decadron) (abbreviated as RVD), only 40 percent of newly diagnosed myeloma patients achieve complete response. An aggressive seven-drug induction regimen followed by two back-to-back transplants, and three years of maintenance used in the “Total Therapy 3” regimen results in a complete response rate of 55 percent.
Should one-half of newly diagnosed myeloma patients panic that they have not reached a complete response? That would be over 10,000 worried patients each year in the United States alone. The short answer is no; absolutely not.
Multiple myeloma is a remarkably heterogeneous disease; the outcomes vary dramatically depending on the patient’s chromosomal abnormalities. The type of myeloma one patient has may be completely different than the myeloma another patient has; it may not even be the same disease.
I am sure patients participating in support groups have seen and pondered about the marked differences in how fellow patients seem to respond to the exact same therapy.
Thus, the first point I would like to make is that myeloma is way too complex to have one set of rules. In some patients, a complete response is critical for long-term survival; while in many, lack of a complete response has no impact whatsoever on long-term outcome. There are countless patients with myeloma who have a persistent monoclonal (M) protein after initial therapy who live for years without progression and without needing additional therapy.
A classic study by Dr. Bart Barlogie’s group looked at the impact of complete response in patients according to their chromosomal abnormalities in their myeloma cells. His group found that most (more than 85 percent) of patients with myeloma lived the same length of time whether they achieved a complete response or not. Only in very high-risk patients, as defined by gene expression profiling, could one see the possible importance of complete response.
How then do we interpret the numerous studies that find superior survival in patients who achieve a complete response? In simple terms, what these studies show is that the achievement of complete response identifies patients with biologically better-risk myeloma.
These studies cannot be interpreted to mean that modifying (or adding) therapy in order to achieve complete response prolongs life. Such studies are yet to be done.
It is one thing to say that achievement of complete response is a prognostic marker, but quite another to take that to mean we need to treat patients until they reach complete response. It is also incorrect from a statistical standpoint to compare the outcomes of patients in complete response versus those not in complete response, since all early deaths that occur before patients have time to respond will be included in the “no complete response” group. Even landmark analysis methods, which attempt to correct this problem, may not fully rectify the biases that occur. Therefore, most study designs assessing the importance of complete response are fundamentally flawed.
I continue to maintain that in the absence of data from appropriately designed randomized trials, targeting complete response (or minimal residual disease-negative status) as a therapeutic goal for individual patients remains an unproven strategy for most patients with myeloma. It is a strategy worth testing in clinical trials, but it is not considered the goal of therapy in standard clinical practice.
Patients with low-risk myeloma can do just as well without achieving complete response. In addition, patients with a long history of monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM) prior to the diagnosis of myeloma often do not achieve a complete response with therapy, but usually do very well regardless.
Studies are ongoing now to refine the meaning of complete response in myeloma by increasing the stringency of the definition. For example, modern flow cytometric and molecular methods can be used to detect residual malignant myeloma cells even in patients who are in conventional complete response. The term “minimal residual disease-negative” refers to absence of residual cancer cells by these newer methods. However, this is a moving target; minimal residual disease-negative in myeloma does not automatically mean zero myeloma cells; it just means that no cells are detected up to the limits of resolution of the test.
I am actively involved in projects looking at innovative methods to detect minimal residual disease, and in studying the value of minimal residual disease-negative status. But I would be the first to acknowledge that we are far from having proven the importance or the specific role of these endpoints. In addition, one should be careful in separating an interesting hypothesis that needs to be tested in clinical trials from proven fact that is ready for incorporation in clinical practice.
Why not try and achieve complete response or minimal residual disease-negative status in all patients, whether or not the value of such metrics is proven? After all, why would anyone not want to eradicate all traces of myeloma?
One good reason is that we want to avoid unnecessary chemotherapy.
Let us consider a patient who has achieved a partial or very good partial response after a course of therapy. Modifying therapy or adding drugs in order to achieve a complete response in such a patient often results in more side effects and lower quality of life.
Similarly, choosing regimens for standard clinical practice based on “the highest complete response rate” would do the same: there is no free lunch. These strategies would be acceptable if there is clear proof that such an approach prolongs survival, but they would be unacceptable if driven by incorrect interpretation of data.
At this point, there is reasonable evidence that newly diagnosed myeloma patients with high-risk chromosomal abnormalities should be treated with sustained complete response as a clear therapeutic goal. But data supporting a similar approach in most other patients with myeloma is weak.
Second, regimens that produce higher complete response rates are typically more expensive, and are more cumbersome.
In many countries, patients and their families pay the entire cost of cancer drugs; some may go bankrupt trying to obtain these treatments. If there is clear evidence of meaningful survival improvement, it would be justifiable not to spare any reasonable costs. But it would be sad to have patients and their families cope with dual (health and financial) setbacks based on surrogate endpoints and inadequate data.
Finally, it is just not worth the mental worry.
We hematologists have no reservations recommending additional therapy to large cell lymphoma patients who fail to achieve complete response with standard therapy. But in that disease the meaning of complete response is quite different than in myeloma.
For most patients with myeloma, not achieving a complete response should not be construed as failure. Part of the reason for this paradox is that the term complete response as defined in myeloma carries nowhere near the same implication as a complete response in large cell lymphoma or childhood leukemia. Part of it, more importantly, is because we are dealing with a heterogeneous condition in terms of chromosomal abnormalities.
To argue against complete response is not an easy task. My goal is not to minimize the reassurance that patients in complete response get with that knowledge. Achieving a complete response, especially a sustained one, is indeed a good prognostic marker. But that does not mean that patients who fail to achieve that benchmark should panic; neither does it mean that they need to change course and try a different treatment regimen.
In fact, a large subset of patients who do not achieve complete response will live just as long as patients who do.
Dr. S. Vincent Rajkumar is a professor of medicine and chair of the Myeloma Amyloidosis Dysproteinemia Group at the Mayo Clinic in Rochester, Minnesota. His research focuses on clinical, epidemiological, and laboratory research for myeloma and related disorders.
Thank you for this excellent column. I have never achieved complete response, but I am doing very well nearly eight years after diagnosis.
Thank you Dr. Rajkumar. You have lifted a burden from my shoulders that has been there since not having reached CR after treatment and stem cell transplant. I think that will improve the quality of my life significantly.
Dr. Rajkumar, thank you so much for your article. This article hit right at home for me.
I'm 61 years old and was diagnosed last year started out with just dex and that worked for about 3 months until my legs and feet started to swell really bad. So I went off treatment until October and my new onc put me on Velcade / dex high dose with acyclovir to prevent shingles because I had chicken pox in the past and also I was on benazepril / hydrochlorothiazide for my blood pressure (I noticed that when I stopped taking the acyclovir - which is some kind of purine med and ben/hcl - purines are bad for this drug well it helped with my neuropathy, it started to ease up some, not recommending anyone to do this, but it did help me some) Anyway, I ended up with neuropathy and had to stop treatment, they sent me to physical therapy and it worked for the most part but I still have numbness in my toes but NO PAIN.
My M-spike at the time was 0.2 I was totally pleased but of course my onc wanted that ever allusive CR. and it stayed at 0.2 for 7 months. I'm all about the quality of life; at my age, I just want to enjoy whatever life I have left. That being said, after therapy, my IgG started to climb and at 7 months it was almost 2700 and he wanted me to go back into treatment. I told him I would, only if we tried lower dose Velcade / dex and I agreed on 1.4 Velcade / 20 mg dex once a week for 6 weeks.
It didn't work, but my neuropathy didn't get any worse, my IgG however was at 4055 as of last week. So he says he wants me to do Velcade 2.8 x 2 week, Revlimid 25 mg x 2 week dex 40 (only once a week for the dex) and then SCT. I'm very worried. But we will take it one day at a time.
Now all that said, I do have the t(4:14) and del(13), so I guess I am high risk. But even still I want to be able to walk without a cane or chair and use my hands and do things on my own and enjoy life and not be on mega dose pain meds. And, as you said, if there was a cure, maybe it would be worth it if as long as you were able at some point get back to life and enjoy it. But as I said I'm 61 if I was younger I probably could endure a little more.
Thanks so much
I've never hit a complete response and have lived almost 8 years with a varying degree of M spike levels. Diagnosed at 19! Been on RVD since April 2012 but have not hit CR yet...Hovering at .4 M spike but I'm at VGPR and very satisfied with my quality of life and choices I've made ... I've also never had a SCT either.
Thank you for this excellent article. Hit home -- REALLY hit home. So very appreciative to learn this information.
Thank you for this article. It's been 12 years since diagnosis and I feel like my years are numbered since I haven't heard of anyone that has lived longer than 16 years. I feel great and my counts are high, but stable. Articles like yours give me hope that I have many more years ahead of me.
Brenda
I am surprised you are only taking Velcade and Dex. Is there any reason you are not taking Revlimid in your treatment profile ? RVD has been a very effective regimen in combating myeloma. I was diagnosed in 2003 and started treatment 3 years ago. RVD had taken my M-spike down to 0.19. Unfortunately it has begun to rise in the past 8 months and my M-spike is now 1.19. My oncologist is now recommending SCT. However RVD has been an effective treatment for me and others.
Thank you for such a timely article. I was diagnosed in April 2013 and on RVD since then. I watch my M Spike tumble at first but the slope of the descent is flattening. I am preparing for a consultation with my lead onc tomorrow morning and very stressed out that I may not reach CR (have I stalled at 85% drop in M Spike?). Your words and facts have helped me calm down. I may be premature in panicing after six cycles, but I have read so many testimonials of people hitting CR in 4 cycles or less. Your reminder of the heterogeneous nature of multiple myeloma is a good touchstone.
Hi Emilio, yes that's what my onc is going to start me on now is the RVD but at induction levels. And with my neuropathy that has me worried. It seems, though, you haven't had any problems with it and that's great, but I sorry to hear that your M-spike is going back up again. I actually was feeling fine and, other than anemia, my creatinine was back to normal and I don't have any bone involvement yet. But I do get stiff and have muscle cramps on my right side mainly, but I still do my at home physical therapy exercises and that helps. So I was looking forward to finding a part time job and maybe doing some volunteer work, because during the time when I was off of treatment for those 7 months I really started to feel better. Take care
Thank you Dr. Rajkumar for another important review, which affirms your view from your Dec. 2010 risk stratification article. You mention that one high risk group, identified only by gene expression profiling (GEP) (13 % per Dr. Barlogie's study from 5/2007) does indeed benefit from intensive therapy to achieve CR. The amount of associated genes, and the information gained by gene expression profiling, has multiplied in the over six years since the above University of Arkansas study was published. GEP is more available and more often very useful. Many new novel agents and unconventional therapies have become available to MM patients like me with recurrent high risk disease.
For example, the finding of a positive BRAF V600e mutation in 3% of MM patients (myself included) explains the short duration of remission experienced by this group. Yet it also provides for a new avenue of therapies based on BRAF inhibitors, and possibly MEF inhibitors. These meds, like Zelboraf, are now only FDA approved for metastatic melanoma, but recently have been found to be very effective in this MM subgroup (ref.: Cancer Discovery, August 2013). So I would really enjoy your opinion on the current application of GEP, or whole genome sequencing, in both newly diagnosed and recurrent MM patients.
Thank you again for your excellent reviews for the Myeloma Beacon and its many interested readers!
Dr. Rajkumar - thank you for the excellent article with its positive message. I am, however, a bit confused because this article seems to contradict the poster session that you co-authored with Dr. Pandey and a host of others for ASCO 2013. That poster clearly states "Achievement of a complete response (CR) to treatment is an important predictor of outcome for patients (pts) with myeloma (MM)." Am I failing to fully understand the message of either your article or Dr. Pandey's poster session?
Holt - I don't think there's necessarily a contradiction between what Dr. Rajkumar wrote in this article and what he wrote in the ASCO poster.
You can see that in his final sentences, where he writes:
"Achieving a complete response, especially a sustained one, is indeed a good prognostic marker. But that does not mean that patients who fail to achieve that benchmark should panic; neither does it mean that they need to change course and try a different treatment regimen. In fact, a large subset of patients who do not achieve complete response will live just as long as patients who do."
Those sentences really sum up the crux of his argument.
He's saying that CR is a good predictor, but it's not a *perfect* predictor.
And he's also saying that just because CR is a good predictor doesn't necessarily mean doing everything possible to achieve a CR is a good idea.
I don't think that either of those positions contradict what's in the ASCO poster he co-authored.
While I appreciate this article – and agree with it – there is still an unspoken reality in the following statement:
"In fact, a large subset of patients who do not achieve complete response will live just as long as patients who do."
"Just as long" still means DECADES less (at least for younger patients like myself) than someone without the fu$&!@#g disease, so excuse me for not jumping up and down with joy.
And in that regard, I also wonder whether reaching a CR in cases where one has favorable genetic and disease markers and tolerates chemotherapy well is still preferred to ward off nasty changes in disease course and perhaps realize additional benefits.
This atticle is very informative. Almost 50% of those doing Total Therapy III, perhaps the most aggessive therapy, will not achieve a CR. The point of all this shows that MM is still not curable, but it can be treated as chronic condition. People like Karen, me and many others can live years in a low level disease state held in check - in a remissive state.
When I say remissive state, I do not mean a full remission with no trace of the disease, instead it is held in check at a very low level and kept that way for several years. I find it encouraging that new treatments and new drug combinations are being developed, which use has changed the playing field and offers the very strong possibility that we can keep the disease in check for ever longer periods than ever thought possible just a few years ago. I am hopefull and even optimistic that these new inroads will allow patients to have a good QOL and a near normal life expectancy even though they never achieved a CR.
Ron
Thanks for all the comments. Greatly appreciate the sentiments and the feedback.
Jan Stafl, MD: The role of GEP and whole genome sequencing is still evolving. While GEP is a powerful tool for predicting prognosis, we are still not sure of its additive value compared to other markers. So we are not doing this on a routine basis. Whole genome sequencing can identify specific genetic abnormalities that can be targeted. Again, we are not doing it routinely because our understanding is still limited. I expect that whole genome sequencing will become a part of the evaluation of some patients with relapsed refractory disease at some point. My colleagues at Arizona are actively looking at its role as well the role of a custom chip. Sorry I am not able to give more clear information.
Holt: TerryH has answered this better than I could. When we write about prognostic markers, the goals are different. They are meant to generate hypothesis, validate testing, etc. For example, we are soon publishing a paper on stringent CR. These observations are based on studies with less rigor than the gold standard phase III randomized trial. We do these studies often to stimulate more research rather than change practice. So, sometimes the messages may seem confusing. The message I gave in this column is my consistent view on what CR means for patients in myeloma today, and what the therapeutic implications are.
Thank you for an excellent article. This helped put me at ease about EJ's condition.
Lyn
Thank you Dr Rajkumar,
I have been wondering of some aspects of the MRD project in predicting a better PFS/OS. Usually the pelvic BMB is used for the flowcytometry, but I am myself a perfect example of no MRD in hip BMB, but relapsing from sCR (clearly was not a sCR in hindsight) in one year with a plasmacytoma in my sternum under Revlimid maintenance. So active BM cites should be biopsied before even determining sCR and no MRD which is of course time consuming, expensive and unpleasant for the patient.
Sirpamah
I've been wondering for over 3 years if I'm in a partial remission, does that mean I have active cancer cells in my body that make me feel unwell, which I do. I'm an over 70 patient, generally in good health except for this lousy MM. I just feel so bad everyday. Docs tell me I'm doing sooo good. Not much information. Makes me crazy. When all this first began, I thought I'd be dead by now. I just keep going and going. Not sure I'm happy about it. Not fun to be sick day in and day out. Not many older patients contribute to The Beacon. I feel lonely, where are you?? Judy
Thanks so much for the article, Dr. Rajkumar. The timing is perfect for me. I had my 90-day post-ASCT checkup two days ago, and am waiting for results to tell me what kind of response I had. Your article will reduce my stress level for sure. And I just started the RVD consolidation phase, which explains why I'm writing this at 4:40 in the morning.
Thank you Dr. Rajukumar for an insightful article. I'm not in treatment with the exception of radiation for chest sternum 3 years ago. I have slight incident with lesions slightly showing at my pelvis, so my doctor wants to perhaps begin treatment, though things are stirring quietly I am concerned how this will effect my rather normal life now with myeloma, to think no true developments of complete response can be discouraging, but from the looks of it one can still have a relatively healthy long life then what was once considered.
Thank you
Thank you Dr. Rajkumar. It is important for patients and their families not to compare themselves too much with fellow myeloma patients. This article gives a realistic perspective to the so called norm and helps relieve the panic one feels at not reaching the remission percentages one reads about!
Laurie,
You may want to read this:
http://www.dana-farber.org/Adult-Care/Treatment-and-Support/Patient-Stories/James-Bond---Multiple-myeloma-clinical-trials-saved-my-life.aspx
I was diagnosed in 2011 at the age of 38. This article was one of the first I read while researching where to get treatment and it gave me tremendous hope and allowed me to look past the lifespan predictions I was seeing online.
After induction therapy and Autologous SCT I am in PR while on RD with Biaxin. My Dr is recommending to go back on Velcade and then do a donor transplant.
Nobody, not even the doctors will know when your time is. Live life to the fullest as best you can with this disease even though the challenges may be great. Look at Jim ... 12 years could turn into 20 or more!
Thank you Dr. Rajkumar for that article. I wanted CR but will have to work with PR and be positive.
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