Last week a friend sent me a new “Blood” study discussing the “cure” versus “control” issue (abstract: http://goo.gl/q0DdI) As the full text tells us, and as we well know (!), there isn’t a standard protocol for the treatment of myeloma. There is instead a lot of what the study authors call “variation,” which is caused by availability and cost of new drugs as well as differing treatment philosophies and alternative interpretation of the available data. A few of the main questions in conventional treatment are: is it better to have a stem cell transplant or not, to use an aggressive approach or not, to start treatment early…or not?
Now, since this cure/control problem is so important and controversial, I REALLY feel that this article should have been made accessible to everyone. For free, I mean. So I’ve decided to report about it today. And yes, I’ll be quoting from it, too…otherwise you might not believe me. 😉
The full text is full of interesting points but, even though it wasn’t easy, I had to pick what I considered to be the most significant points. And I was forced to skip over others. Anyway, let’s jump right in. The first interesting thing I read is that both early and delayed stem cell transplants appear to have the same overall survival. Whoa. Pause for thought…serious thought.
Disease definition. Myeloma is still referred to as one disease. Well, that is simply wrong. And we all know it.
Myeloma includes a bunch of different diseases. I didn’t know this, but the International Myeloma Working Group is figuring out how to change the definition of myeloma. Right now. But until they come up with a new definition, the authors say, we need to recognize that comparison of recent trial results to historical outcomes may not be valid since the intensity of the diagnostic work up and the willingness to treat has changed over time, but the disease definition has not. Interesting…
Survival. No surprise here, but it varies with age, stage and how well a patient responds to treatment. The main goal in current MM treatment is complete response, or CR. But the study authors declare that This needs to change. Trying to achieve CR could result in unacceptable and unnecessary toxicity for some patients and come at too great a price. More pause for thought…
Oh, and they add that those who respond to treatment will always seem to do better than those who do not…whether the treatment works or not. Sheesh! Talk about an eye opener (for me, anyway)…
Complete response. In myeloma, CR means that there has been a profound tumor reduction. But most CR patients will relapse with time. The authors state that, on average, CR doesn’t last very long. Well, that’s “on average,” mind you. And we’ve all heard about Stephen Jay Gould, the Harvard professor (petit anecdote: as an undergrad at Harvard, I wanted to be in one of Prof. Gould’s classes, but it had a waiting list rivalling the Divine Comedy in length, so I opted for another science class. Now I’m sorry I never put my name on that list…drat), and his thoughts on cancer statistics and averages, right? Incidentally, if you have no idea what I’m talking about, then please read “Anticancer,” by Prof. David Servan-Schreiber, a brilliant neuroscientist and doctor who unfortunately died on July 24…of brain cancer. He was my age…Anyway, at the beginning of the book, he tells the Stephen Jay Gould story…fascinating…Of course, you can read Prof. Gould’s “The Median isn’t the Message,” too (available online).
Back to us. Another point the study authors make is that in most cases it is probably impossible (with the possible exception of allogeneic transplantation where true complete eradication is possible for a minority of patients), unnecessary, and prohibitively toxic to attempt to eradicate all clonal plasma cells. Indeed.
Furthermore, the tests used to define CR in MM are still inadequate and often vary considerably between laboratories. Ain’t that the truth!
Here’s a shocker: not every MM patient needs or benefits from achieving CR. The authors say that 85% of all MM patients fall into the “standard risk” category, and their survival does NOT depend on achieving CR. EIGHTY-FIVE PERCENT! The opposite, though, is true for high-risk myeloma patients, for whom it is terribly important to achieve CR.
And now for a bombshell that I wasn’t expecting. The authors claim that Despite dramatic improvements in CR and very good partial response (VGPR) rates, bortezomib-dexamethasone was not able to cause a significant improvement in PFS (neither statistical, nor clinical, in our opinion) let alone OS. Similarly despite the doubling of the rate of CR/VGPR with thalidomide and dexamethasone, or a tripling of it with the addition of lenalidomide to melphalan and prednisone induction there was not even a hint of a difference in PFS or OS. There was however significantly greater toxicity. (PFS means “progression free survival,” and OS = overall survival.)
No significant improvement in overall survival or progression free survival. Only greater toxicity. I’m still stunned. And in fact I read this article over the weekend but had to reread it today…I just couldn’t believe it. I mean, it sounds like a condemnation, really, of current aggressive therapies…and, whether you agree with the authors or not, this is amazing. Could it be time for a change in direction in myeloma treatment? Or am I reading too much into this study? That could well be. Let’s keep going.
Progression free survival. PFS can help determine if a drug or treatment is working or not and is useful to determine the efficacy of new drugs. But PFS indicates a period at the end of which the patient must start taking the next drug (or regimen). Prolongation of OS in MM is almost always associated with prolonged PFS, but not the other way around. Treatment of MM is like a marathon, rather than a sprint. It is for most patients (i.e., non high-risk MM) a chronic malignancy, in which patients relapse repeatedly, and using all active drugs early on may be the equivalent of a marathon runner running the first mile at breakneck speed. He/She may finish the race at the same time as a runner who spreads out the energy a little better, but the remaining 25 miles would have been a lot more pleasant.
There is more: the use of PFS as a surrogate endpoint to justify earlier and more prolonged use of new treatments results in more people taking treatment (or an extra drug/intervention) when they do not need it. Wow…
And if OS is not affected by, say, early versus delayed treatment, and the risk of toxicity, perhaps irreversible toxicity, is high, then even an improvement in PFS may not be enough. The authors at this point bring up the thorny issue of second cancers with lenalidomide maintenance. There are now emerging data, and an FDA warning, that the use of lenalidomide as maintenance may increase the risk of second cancers. The authors warn that we need to be cautious. Not all patients benefit in the same way from taking lenalidomide. Some may even be harmed. The only reason to administer lenalidomide is if there is an OS advantage, and so far, the authors tell us, we have no firm data to that regard, although that seems to be the preliminary outcome of a clinical trial (in progress)…too early to tell…
This is an extraordinary statement…
The authors insist that OS is more important than PFS: If survival is the same eventually, what exactly is the point of improved PFS by giving an additional new drug early in the disease course? Is there not an increased risk of toxicity when more drugs are combined? Is there not a risk that patients are subject to potentially irreversible risks earlier in their life? Again, I am stunned…
And so we get to the final Cure versus Control paragraph. The “cure” proponents like the idea of whacking myeloma early in its development, when it is most vulnerable. The “control” proponents believe instead that the aggressive approach should be taken only for high-risk patients (those who have the 17p deletion and so on). “Standard” patients should be offered treatment that minimizes toxicity and maximizes QOL (=quality of life).
Younger patients may opt for early intensive strategies such as allogeneic transplantation accepting high treatment related mortality in exchange for a chance at long-term survival. It is obvious, though, that the authors are opposed to overly aggressive treatments: While early use of multi-drug combination strategies and maintenance therapy improve CR and PFS, we need to strive for clear evidence of OS improvement to change practice.
In the end, almost as an offering of peace to the “cure” proponents (that is how it seems so to me, anyway…again, I could be wrong), the authors write that they support well-designed investigations of both the curative and control approaches. We do see the merits and arguments of the curative approach, and we recommend head-to-head trials comparing the two strategies.
In time, they add, they hope that patients will be cured, not just “controlled.”
That is my wish, too…
UPDATE: Lori’s comment made me go back to the article. Ah. I should have put the “younger patients” quote into a slightly larger context, and I apologize for not having done so yesterday (my only excuse is that I’m very tired in this period…superduperbusy, trying to do a zillion things before heading off on holiday…can’t wait!). Context: here the authors are referring to “high-risk subgroups.” Not to “standard” folks. Basically, the authors recognize that these subgroups may require more aggressive treatments, and that is when they mention the example of younger patients perhaps opting for allo transplants in spite of all the dangers involved (high mortality etc.). Hope that clears up the matter. Again, my apologies…
Margaret, thanks for this great write up. I’m still absorbing some of what you have surmised. 85% of MM patients are LOW RISK. Low risk patients have more choices in how they proceed with their treatment. They can manage or SCT. It becomes a personal choice, though often it is totally directed by the doctor’s opinion. So it seems to me to still come down to how old they are, other health issues, quality of life before, physical condition before and their treatment goals. For instance one of the reasons to go aggressive for us, wasn’t just that Dave was young (48) but also that he was healthy and strong enough to take it. Waiting may have made that harder and harder for him.
Early on I was told that “stage” does not determine survival, but only indicates level of impact of the disease. Different from other cancers, this makes total sense to me, though staging is still often cited in survival stats. It’s more important I think for their DNA analysis to be done to determine that risk factors and survival prognosis. I have long thought though that VGPR could gain higher acceptance, while CR would still be more optimum.
Finally, I don’t think any doctor would ever recommend the allo for younger patients just because they are younger. It would be paramount to malpractice with the high mortality. It is only used when there are no other options. I think that, at this time, it is highly provocative to even suggest it and that it will get “hit” in the medical community. How can they not be for aggressive therapies and then suggest something like that? I realize I don’t have the whole article.
Again, thanks so much for this! I’ll look forward to seeing more on it.
Great recap and amazing analyzing, Margaret. Thank you for your time and energy in sharing this. You know where I stand on the issue.
So no one mentions quality of life…..? Tells you what their values are.
I really believe that I shouldn’t have started treatment when I did. I was relatively symptom-free, with the exception of a poor immune system. I caught every bug that went around and had a feeling of general malaise. My serum monoclonal protein was quite high, but I think I could’ve hung on longer.
The way it worked for me was that I blew through about every available treatment in under 5 years, and then had to move on to SCT because I now had a pretty treatment resistant MM. However, I’ve had a very nice 4 year treatment-free run at this point, for which I’m extremely grateful.
From now on, I won’t do any treating unless I have symptoms that reduce my QOL.
It looks like the MM road is getting divided into a two-lane… those who feel that aggressive actions (U of Alabama group for one) right at the outset is the road to take and those who opt for management until there are no other choices is the other road.
First I think, sitting on the roadside as a caregiver, that the patient really must be brought up to speed (getting on this superhighway on a tricycle is flat-out deadly!) about his or her risk factors, entry level, and current treatment options as rapidly as is possible given the incredible systemic shock with the diagnosis.
Second, the family/support group must be educated as well to know what demands the options will place on everyone involved so that decision-making is not left to the patient alone. Not meaning that the patient shouldn’t be the final decider, but as in a small business, assessing family/support capabilities – i.e., with small children who cannot necessarily help or understand what is going on, taking a maintenance road for awhile might give the family time to more effectively plan the attack.
Third and finally, the patient must, must, must not rely on only one opinion and as one does when purchasing a car, one looks at several types (medical doctors) to see which one best suits the present (and likely to evolve) conditions. I know of one case where the patient was essentially forced to settle for government medical help and was seriously/negatively affected by this. Even in this arm-behind-the-back situation, a well-informed patient and his or her advocate might be able to push for more effective care. The patient I refer to has said, in retrospect, it might have been a better choice to move and go to another government facility in another city known to be more skilled rather than accept sub-standard care. Those are hard choices, but perhaps become part of the road map of a new diagnosis.
Hope these thoughts are helpful…
Margaret-
Great blog post. “No significant improvement in overall survival or progression free survival. Only greater toxicity.” I will be sure to forward your post. Thanks.
Fascinating article; thanks for presenting it! I have felt this same way since first diagnosed in 06: proceed with caution, and only when truly necessary. When my proteins get too high and threaten my kidneys, I have fallen back on Velcade/dex for a few months to knock the numbers down. I have only done this 2x, and my onc tells me my creatinine levels are lower than when I was first diagnosed. My bones are another matter, but I had a terrible, crippling reaction to Aredia, so bisphosphonates are out now. IMHO, not enough information is given to patients about potentially disastrous effects of some of the main drugs currently used. For example, few are told that Thalidomide and Revlimid can cause pulmonary hypertension – a fatal heart/lung condition. I think this article should be available to all MM patients/caregivers, too!
Seeing my sister die at age 40 after only 2 years battling MM, I agree wholeheartedly with your review of this article (I’ll read the whole thing soon). She was pushed to go with the newest combination therapy, usually reserved for those who had 1 relapse already. She got a CR, but it lasted all of 6 months. She was strong-armed into going to SCT, but by the time her disease was under control enough to do it, she’d been through all the heaviest-hitting drugs, she had already advanced to plasma cell leukemia, and her prognosis with the best SCT outcome would be about 6 months. She died from a complication from a head injury.
She had the most aggressive case any of her MD’s had ever seen. Perhaps aggressive therapy was called for from the start, perhaps had we opted for containment she’d have had better quality of life; of her last 2 years, only that 6 months of remission were spent without massive time in a hospital bed. Her doctors talked about almost nothing but getting that response up, not about quality of life (much) or of the fact that her OS was statistically the same no matter what. They’ve been brainwashed by the drug companies that the new drugs are “better” because they’re more potent somehow. It’s a VERY dangerous time to be a cancer patient if you rely on MD’s for your information.
For what it’s worth, I also wholeheartedly support the option of allogeneic transplant if the patient is willing to take the risk, and is young. Harsh drugs CANNOT cure. Allogeneic might. That is all the difference in the world, and reason enough to favor one without the other. I wish my sister had had the chance to use my stem cells (perfect allo match), but alas we didn’t get that far.
Margaret, I’d like to Thank you for posting all this information. You’ve been so valuable to so many! Many Many Thanks for all your hard work!
I’ve read fairly often now that CR is no more beneficial than the PP level obtaining a consistent plateau.
‘those who respond to treatment will always seem to do better than those who do not…whether the treatment works or not.’ I found that really intriguing. 😀
Hi Margaret,
This is a wonderful post, and confirms what I personally believe and also the treatment that Mayo in Rochester has provided for me.
My myeloma is “standard risk,” and three years ago I presented with myeloma hot spots in several bones. I believe that in the USA the “standard of care” is to recommend a transplant for such a patient.
Nevertheless, I was offered a trial of pomalidomide with DEX (DEX decreasing to zero). I did not achieve a CR or even a VGPR, but M-spike went from 2.7 to 1 and has been stable since. A PET scan shows that there are no longer any active myeloma sites in my bones, and I feel healthy and strong. Further, all of the standard treatments (except pomalidomide) are still available when I need them. I did not go through the risk, expense, and difficulties of a transplant.
So that’s one vote for control as opposed to a more-toxic regimen. I’m a happy camper.
Yes I was told in my research that Myeloma was a bunch of ‘different diseases’ but when sharing this info, it is hard to get people to repspond, so one tends to stops sharing.
Definitely something that should be shared with anyone with multiple myeloma and their caregivers. Very important study, thank you so much for being on top of things and keeping us informed!
As always Margaret, you are the best, Beatrice
Lots of good stuff in here Margaret! I’ll have to digest it slowly! A couple of things jumped out at me right away… “those who respond to treatment will always seem to do better than those who do not…whether the treatment works or not.” I suppose this means that their improvement was simply psychological…since they “seemed” to do better but they really weren’t! So sad!
The next thing that caught my eye was, all the doubling and tripling of standard therapies made no difference! “not even a hint of a difference in PFS or OS!” The only thing progress was “significantly greater toxicity!” Tragic!
I look forward to reading the Stephen Jay Gould story. Thanks for all your hard work! Donna
Thanks for the clarification Margaret! Whew!
Ok – just back from being away so I need to read this again, and perhaps even send to my ND for comments. Next time I plan to start with comments 🙂
Thanks so much M for posting this. You are right it is quite the bombshell. Very important for all of us, regardless of any fences we sit on. Knowledge is power.
Any information on Estradiol for Myeloma ?
(one form mentioned 17-beta estrodiol)
excuse! –correct spelling:
17-beta estradiol
also: 2-methoxyestradiol
“Blood” reported on both of these as treatment for myeloma (not sure dates, nor articles)
Any further info./studies??
margaret, what a service you did in posting this. thank you so much. i read, re-read, also appreciated your readers’ comments. i agree, everyone should be able to get this article for FREE. for those of us who are lucky enough to have access to the highpoints and your excellent analysis, it’s mind blowing, head scratching, and as you pointed out in some segments, astonishing. but hannaO hit the nail on the head – knowledge is power! on first blush, it’s rather confusing and bewildering, but it provides a springboard to look for further comment, formulate questions, and share feelings and opinions. thanks so much margaret.
Margaret
Great summary.
I paid 35 dollars to have access to the Blood article for 1 day
It was probably the best 35 dollars I’ve ever spent
Every myeloma patient should be able to access something like this for free.
I was amazed at how Dr. Rajkumar toned down his comments in the Myeloma Beacon as compared to his strong comments in the Blood article on this subject.
This major international controversy should not be kept from us.
Informed decisions can make a significant difference
i have been on rev/dex for 11 months, i hate the dex and the side effects, last month doctor said time for stem cell transplant, i have had bad bad experiences with bm aspirations and biopsies i have so much fear i cant stand it, i hate the thought of a central line another biopsy and i have to live in the cancer house, high dose mephalan etc. i really dont want to do this. i am 53 have had iga lambda light chain mm for 5 or 6 years now. i have a few tumors am tired alot but more so from the meds. i am being pushed to do the stem cell transplant , someone please help me.
I’m recently diagnosed with MM, but without many of the symptoms (no anemia, normal calcium, 100% kidney function, normal M, IgA, IgG levels). The MM was found after surgery to remove a lesion on my 1st metatarsal, which turned out ot be a plasmacytoma. There are active spots (PET) on sternum and spine. Also, have lesions on clavicle, and skull. My Doctor at MD Anderson proposed an aggressive approach while my kidney, heart, pulmanary functions were strong. This gives me best chance for long term survival. Starting preliminary chemo in 10 days including Bortezomib, Cyclophosphamide, and Dexamethasone. Also included are drugs to control viral, bacterial infections as well as drugs for stomach upset.
Stem cell to follow once we have CR or VGR. My MM is the rare form of IgD. The traditional blood and urine markers don’t apply….mine is stealthy except for the bone pain!
Gary-
I too was diagnosed with similar symptoms to you. The term used in my case was “non-secretory.” Aggressive therapy in my case (local radiation, induction chemo and a pbsct) resulted in making my mm more aggressive.
Further, my understanding of the C vs C article is that aggressive therapy does NOT, on average, result in longer survival- simply greater toxicity and side effects. To quote the study-
“No significant improvement in overall survival or progression free survival. Only greater toxicity.”
After several years of aggressive mm therapy and two relapses I was told that nothing more could be done for me. I then underwent antineoplaston therapy, acheived complete remission by 4/99 where I remain today. If I knew then what I know now…
http://multiplemyeloma.peoplebeatingcancer.org/
Please give serious consideration to the control philosophy.
David Emerson- mmer since 3/94
can you please explain some of the abverations like OS etc as I dont understand them. I feel a dill asking but if I dont ask I wont get the full gist of the information. I am the carer my husband has MM and is on Velcade and Dex and heaps of other drugs. He seems to be improving for the time being it is working. He lasted just over 3 weeks without a blood tranfusion which is great as he is anemic and has cronic kidney problems. But they seems to be holding there own. I apprecialte all the information I read. As knowledge is power and I find the Dr’s get a suprise when they find out that we read about MM and treatments
Margaret,
It would appear to me they don’t have to rename MM because it’s more than one disease. It’s already
MULTIPLE myeloma(s). Just wanted to respond to Lori’s comment:there are definitely MM specialists that recommend allos to their younger patients and do base it very much on their young age. My husband was one of those patients and he had 2 internationally known MM specialists both telling him he should do an allo and he did NOT have any of the cytogenic abnormalities that even made him a “high risk” case, nor was it any last ditch effort at that time. He was newly diagnosed. Their reasoning was that he was young and strong and had no other “co-morbidities” which many older MM’ers may have.
They told us that they didn’t think allos worked well or had that great a capacity to cure if done later when the patient was weaker from years of chemo and many times the m-spike cannot be gotten low enough for the allo to cure them at that point. They also feel they are more survivable when done early in treatment. They scared the heck out of us by basically saying, “it’s now or never” if you want to go for the cure. There are some who decide that risk is worth taking and they go for it. Due to the mortality rates and the high rate of relapse(they’ve seen plenty of both of these, I’m sure), Tim’s docs have pulled their recommendations back a bit from that time and when I asked one recently if they still rec. allos in frontline treatment, he told me it’s a case by case thing but that yes, when they have a patient who has the cytogenics that usually denote aggressive disease, they do talk to them about an allo. When Tim was making his decision a few years back about whether to do it or not(his sis is a match)this same doc said that it was the only known cure and he thought Tim had,
at best, 5 years if he did not do it and for a 43 year old, that was not enough. As far as what this report says about Velcade, I find it very hard to believe that they are finding no greater rates of PFS and OS. MM’ers have much better survival times these days and it is largely due, or totally due really, to Velcade and Revlimid coming on the scene.
Denise,
Regarding your last point about the survivals on Velcade and Revlimid – that’s just the point, isn’t it? Hard as it may be to believe, statistical analysis shows that they don’t really make for better survival. Sure there are people who do well with them, and those are the stories told by the MD’s and repeated to the point that we come to believe they are practically a cure. But unfortunately the numbers show the side less talked about, and not everyone does benefit from these drugs, or not for as long as they might expect. That’s the power of reports like this: they show the real numbers, even if they’re not what people/patients want to hear.
I understand what you’re saying Rob, but when there is documentation that people with MM are living longer now, then why is that? Of course, not all people respond to Velcade and Revlimid, but many do and how did the survival times go from 2-3 years to triple that and more? I know a lot of people on those 2 drugs who have been kept stable for years on them or gone into CR’s. My husband is just one of them. His IGG was 10 thousand at diagnosis. His auto did nothing. 4 cycles of Velcade put him into CR and he’s been off ALL meds for 3 + years now. What made the OS times increase, if it was not these drugs? They’ve done auto transplants for years. What else has changed?