The Safety and Effectiveness of Revlimid

A few weeks ago, the FDA issued a safety announcement concerning Revlimid, indicating its concern that longer-term exposure to the drug increases the risk that the patient will develop additional hematological malignancies (translation: leukemias and lymphomas). This isn't exactly shocking new news, but it does betoken a heightened level of concern and awareness of the problem. Of course, in my case, "longer-term exposure" is exactly what we are hoping for, since the idea is that I will continue to take Revlimid as long as possible, until it stops working.

But we already knew that the answer to the "how safe" question is "not very". Lenalidomide (Revlimid's chemical name) is a derivative of thalidomide, which was originally introduced in the 1950's as a sedative. Thalidomide was prescribed to large numbers of patients, among them pregnant women, who proceeded to produce tens of thousands of babies with severe birth defects, until the drug was withdrawn in the early 1960's. It was one of the most spectacular failures in the history of the pharmaceutical industry. But in the 1990's, thalidomide was resurrected as a chemotherapeutic agent effective against none other than our old friend, multiple myeloma. Subsequently a derivative, lenalidomide, was introduced for the same purpose, but with better responses and fewer side effects for many patients. Today, both thalidomide and lenalidomide are being prescribed for myeloma, but they are distributed in a tightly controlled fashion. Every 28 days my oncologist generates, and the insurance company approves, a prescription for Revlimid capsules, quantity 21, in 25mg strength. Eventually I am contacted by the specialty pharmacy, and I receive the same "counseling" from a pharmacist every time: I am warned against donating blood or sperm, and against engaging in sex with "a woman who is pregnant, or who could become pregnant", unless I use a condom. The pharmacist then transfers me to a patient service line at Celgene, the manufacturer of Revlimid, and I take a "survey", which is the same every time: I answer questions about whether or not I have donated blood or sperm, and whether or not I have engaged in unprotected sex with "a woman who is pregnant, or who could become pregnant". Only after I have successfully jumped through all of these flaming hoops can I be shipped the goods.

Beyond this, Revlimid carries warnings regarding, among other side effects, deep vein thrombosis (blood clots) and tumor lysis syndrome (TLS), which covers a grab bag of metabolic disturbances, the most dangerous-sounding of which is acute renal failure.

So Revlimid is a dangerous drug, maybe more dangerous even than we were thinking. Given the risks, definite and possible, should I be "allowed" to take it? In the binary world of mass media health and science reportage, drugs are either "safe" or "unsafe". No gray areas, please. No nuances allowed. And the FDA is the God of this Manichean religion, sitting in judgement over which may enter the Heaven of Safe Drugs and which are consigned to the Hell of Unsafe Drugs. For many drugs, the end of the line comes in the Phase I clinical trial. The Phase I clinical trial has nothing to do with assessing the efficacy of the drug under test. The question "Does Revlimid do anything good for multiple myeloma patients?" was not asked, let alone answered, in the Phase I clinical trial. The only objective of the Phase I clinical trial is to determine whether or not the drug is going to hurt or even kill people. Those laundry lists of "possible side effects" that come with prescription medications are generated by the Phase I clinical trials. If a patient in the non-control arm of the trial (the group of patients actually getting the drug under test, rather than the placebo) gets a nose bleed during the trial, then "nose bleed" is going to appear in the list of "possible side effects" for this drug -- whether or not the drug actually had anything to do with the nose bleed. Because, in fact, there's no way to know for sure. And if patients in the non-control arm die during the trial? Then the drug is pretty much done for. And in fact quite a few promising drugs have not survived their Phase I trials for precisely this reason. Pharmaceutical industry professionals of my acquaintance assert, with the utmost seriousness, that should it have been subjected to the FDA's approval process, aspirin would not be available in the United States today. It's simply not "safe".

And given its litany of problems, no doubt many people would be surprised to learn that the FDA has approved the use of a drug such as Revlimid for any purpose whatsoever. Probably, it is flying under the radar: few are the patients who want or need to use it, and these few are sufficiently desperate to resort to it in spite of the dangers. In all probability, they are more likely to die without it than with it. So the all-powerful FDA has allowed this, calculating that repercussions will not return to haunt it. But now it's getting nervous about it, as the safety announcement shows.

There is no way that a mass-market drug like Lipitor or Viagra would be permitted to reach the market with a rap sheet as long as Revlimid's. That sounds right, except that there are bound to be gray areas in which certain drugs could benefit a relatively large number of patients, but the FDA has ruled that out, because it doesn't want to be raked over the coals by the media and by Congressional sub-committees later, if it guesses wrong. Better to keep this stuff away from the unwashed, who don't know what they're missing anyway. The FDA is rarely made to suffer for keeping dangerous drugs out of the hands of people who might be helped by them.

Which brings us to the topic of "effectiveness", which is the subject of the later-phase trials. This is where the gray areas become very murky indeed. Technically, Revlimid is approved, in combination with dexamethasone, only for myeloma patients who have failed at least one prior therapy. I have now been prescribed the drug not once but twice in circumstances that do not fit this description: once with dexamethasone as induction therapy for a stem cell transplant; and once without dexamethasone as post-transplant maintenance therapy. When this inconvenient truth is brought to their attention, oncologists merely shrug. This kind of thing is routine, universal practice in American medicine. Once a drug has been approved for any purpose whatsoever, it will never again be approved for any other, irrespective of any subsequent research that may support such usages. Formal clinical trials done in support of an application for FDA approval are so expensive and so drawn out that no one ever does more than one set of them for a given drug, if they can avoid doing so. Physicians feel free to dispense a drug for unapproved uses if current research supports them. But they, not the FDA, make these decisions. Hence my experiences with Revlimid to date. As one of the aforementioned pharmaceutical industry professionals commented to me: "You're in the real clinical trial, right now."

The thalidomide disaster gave birth to the FDA's existing approval process for drugs. But the problem with thalidomide wasn't the absence of this approval process, the problem was a lack of adequate testing. There can be no doubt that drugs like Revlimid need to be tested and retested, early and often. What I question is the FDA's power to arbitrate what drugs can or cannot be made available as a result of these tests. Why aren't the results of drug tests simply made available to the physician community, so that they can decide whether and how to use the drugs? They are doing this job anyway, for drugs that have managed to successfully negotiate the FDA's highly politicized approval process, as my experience with Revlimid shows. To me, the FDA's control of this process appears to be less about assuring safety and efficacy than it is about control.

Geraldine Ferraro's 12-Year Benchmark

With the death of Geraldine Ferraro, multiple myeloma claimed its most prominent American victim in recent memory -- perhaps ever. Huong asked me whether I was bothered by this. I suppose she guessed that I might consider it to be an unwelcome harbinger of some kind. Anyway, the answer is "No", and not because I'm an insensitive lout (although that could be another reason).

When Ms. Ferraro was first diagnosed, in the late 1990's, her chances of surviving five years were deemed to be slim; her chances of surviving ten years were, for all intents and purposes, nil. In the event, she managed to hopscotch past the Devil for even longer than that, on the backs of powerful new therapies that became available in the intervening years.

Short of a cure -- and curing myeloma would require the kind of breakthroughs that merit Nobel prizes -- the goal of clinical oncologists today is to render this disease as manageable as, say, Type II diabetes. The gallows humor version of this says that "success" is lodged in making the patient survive long enough to be killed by something else. That remains a goal, as Ms. Ferraro's demise makes clear, but there is every reason to believe that I will be able to live a relatively normal life for many years to come, by shifting from one therapeutic regime to another over time, following her example. Yes, I will likely have to battle undesirable side effects. There will be uncomfortable moments when Plan N is found to be no longer working, and Plan N+1 has not yet succeeded in replacing it in a stable manner. I may eventually have to resort to something previously untried. But on the whole, it would really be a little surprising, to me, if I cannot do better than Geraldine Ferraro's 12 years before I'm done, since I should have access to options not yet conceived in her time.

Boosters

Yesterday my immune system advanced to "adolescent" status, at least in terms of childhood immunizations. I made my way to the office of my primary care doc to receive boosters for four of the five vaccines I received during my most recent visit to Johns Hopkins, in January. My primary care doc is of course not a pediatrician, but she does have patients young enough to need these boosters, so she had them on hand. I will get the last installment of these when I return to Hopkins for the last time (well, the last time related to the transplant, at least), for my 24-month checkup.

Cancer Research: Vital To The Nation's Defense?

Apparently so, since Congress has continued to fund it via Dept. of Defense budgets for almost 20 years, and will do so again for fiscal 2011, according to this Washington Post article. Of course, this is in addition to the usual avenues of funding for such research, such as the NIH. Money quote: "Breast cancer is a 'huge issue' for women in the military." Yeah, I get it, but...

12-Month Transplant Checkup

Wow. I knew it has been awhile since I updated this blog, but I didn't realize that it has been more than two months. That's good news though, really, because nothing exciting enough to report has occurred since then, and on this blog, excitement equates to trouble.

We traveled to Johns Hopkins on January 13 for my (somewhat overdue) 12-month transplant checkup. I have now obtained the bone marrow biopsy results, which the Hopkins oncologist describes as "awesome". The bottom line: "No evidence of myeloma".

After the tests were done, before we departed for home, I was given the first installment of my childhood immunizations. As you may recall, the transplant destroyed my existing immune system, replacing it with a brand new one more closely resembling the one I was born with. So for the past year I have been vulnerable to many diseases most adults have long since forgotten about, such as polio, diphtheria and tetanus. I received five injections, vaccinating me against the diseases just mentioned, plus hepatitis B, meningitis, and a couple of other less well known ones.

I will need boosters for all of these in March, but there should be no need to travel to Baltimore to get them; I'm guessing I will be able to get them all at Christiana. If so then I will not need to return to Hopkins until my 24-month transplant checkup, which I believe will be the last.

Meanwhile, there is just not much to say about my work experience of the past three months. It can only be described as "uneventful", which is of course blog poison. The days do drag out because of my need to take breaks, but I do not seem to be suffering much additional pain, knock wood. As for chemo brain effects, I don't see much that has happened that could be ascribed to anything like that. But maybe I have just forgotten all about it already.

Back To My Oar

The short version of this story is that I managed to survive my first two weeks back at work.

I work on the same product development team as before the onset of my illness, which has both comforting and disorienting aspects to it. On one hand, I'm familiar with much of what's going on; on the other hand, it's as if I have been suddenly transported forward in time about 18 months. Fortunately, the team is approaching the end of a product release cycle, so I'm engaged in such low-pressure activities as reviewing documents vs. software code, which allows me to reacquaint myself with the various software tools, without having to use them to actually create anything new at this point.

Going in, there are two open questions in my mind about my ability to do this. The first relates to the simple requirement that I remain more or less stationary for eight or more hours a day, usually in a sitting position. This involves pressures on ribs and spine that, eventually, begin to bother me, giving rise to the desire to stretch out in a prone position. Since I work at home there is no problem with this logistically; but, to get anything done, the bottom line is that I need to be able to somehow piece together a number of sufficiently lengthy work periods, with hands actually on keyboard. The lie-downs stretch out the work day. So far, this does not seem to be much of a problem, but it's way too early in the game to tell.

The second concern revolves around the question of "chemo brain". Almost since the day chemotherapies were first introduced, patients have complained of a variety of neurological side effects, generally adding up to a sort of mental fog, an inability to focus or concentrate. Historically, the medical community has tended to soft-pedal such complaints as psychosomatic, or in any case as dominated by the benefits of said therapies. The blood-brain barrier, it was thought, prevented the chemotherapeutic agents from affecting the brain much. But over time, the anecdotal evidence apparently accumulated to an extent that required attention from the research community. So far, the research tends to confirm that chemo brain is real, but may be a result of some combination of chemotherapies, of the cancers themselves (the latter possibility arises from the fact that even cancer patients who have been treated only by means not involving chemotherapy can exhibit the symptoms), or simply of the stresses induced by the fact that the patients have life-threatening diseases that make them feel real bad, and have to take drugs that make them feel even worse.

At the time of my stem cell transplant, and for some time thereafter, I could claim some chemo brain-like symptoms; I could stare into space with the best of them. I tend to think, though, that in my case a lack of mental stimuli, chronic exhaustion, and feeling just plain awful much of the time, were mostly to blame. As I have recovered, I have noticed the episodes that could be characterized as instances of chemo brain diminish in number, duration, and intensity. Again, although it's too early to tell for sure, I'm so far unable to detect any diminution in my ability to marshall the brain cells for the work at hand. Shoot, I may even be smarter. No, probably not.

October 2010 Notes

This month I resumed taking omeprazole, after being otherwise unable to shake some serious digestive tract disturbances. This was apparently the right move, because I am now feeling much improved in that area.

Meanwhile, once again my monthly test results were all deemed to be satisfactory by the Christiana oncologist. So, at my request, he composed and faxed to JDA a no-restrictions work release letter. I have arranged to resume my duties as a full-time employee of JDA, beginning November 1.

I have considered putting this blog on hiatus, until something "interesting" happens, rather than merely report good test results once a month. I'm now considering the possibility that returning to work will provide some grist for this mill. There may be a story here around an abnormal person attempting to resume a normal work life. If that doesn't sound compelling, and this is where the reader and I part company, then I can only convey my appreciation for sticking with me this far, which seems like a very long way already, to me.