Thalidomide

This Washington Post (actually rehashed AP wire service) article revisits the thalidomide disaster, in the context of the controversy over the original German manufacturer's recent "apology" to the victims, fifty years after the actual events. The article stands on its own merits; but at the very end, it mentions that thalidomide is currently used to treat multiple myeloma, which it identifies as a "bone marrow cancer". Gah.

Carfilzomib

Progress in the treatment of multiple myeloma is slow (let us not speak of "cures" here). Over the past couple of decades, the options developed, aside from the nuclear one (bone marrow or stem cell transplant), are the three FDA-approved agents thalidomide, lenalidomide (Revlimid), and bortezomib (Velcade). These, and various cocktails combining them with each other, with steroids, etc., comprise the universe of weapons commonly used against this cancer.

A few weeks ago, a fourth contestant entered the lists: carfilzomib, called by the brand name Kyprolis by its manufacturer, Onyx Pharmaceuticals, received FDA approval for the treatment of multiple myeloma. As usual, formal approval is for an absurdly narrow scenario, namely for patients who have developed resistance to two of the other therapies and who showed progression within 60 days of completing the last therapy. The clinical trial on which the approval was based involved just 266 such patients. On such slender scientific threads do our fates turn. Of course, the restrictions imposed by the approval are a polite fiction; having received approval for some usage, carfilzomib can now in reality be used by oncologists for any use that seems to them likely to provide some benefit, as indicated by further research. Fortunately.

Back To Aredia

The latest test results show that kappa free light chains are now only very slightly above normal. The kappa/lambda ratio is well within the normal range. So our concerns in this area have eased. But there's always something to worry about. This time, it's glucose, which suddenly spiked up well above the normal range. So I'm supposed to fast for next month's tests. These will also include a thyroid test. I have been noticing my weight drifting downwards again for the past few months. Since there is no evidence of myeloma activity, the possibilities include something going on with the thyroid... or the emergence of a second cancer. We will check the first possibility next month, meanwhile watching for any changes in the weight trend. If it becomes necessary to go on a cancer fishing expedition, the first step would be a CT scan.

Meanwhile, next week I resume Aredia infusions. It has been a year now since I ceased the monthly infusions I was getting. But the oral surgery that prompted this action is now more than seven months past, so it should be safe to resume them. And the spinal MRI carried out in April indicated some weakness around T8 that could be shored up. This time, though, I will be getting infusions only quarterly.

Generic Revlimid?

To completely understand the market and regulatory environments in which Revlimid exists, I would probably have to quit my day job and devote myself to full-time study for an extended period of time. Even then, I'm probably not smart enough to fathom the deepest complexities involved. But let me now take a quick stab at what I think I know about the concept of "generic Revlimid" at this point.

0. Have I mentioned how expensive Revlimid is? It is costing the health insurance company $100+K per year to keep me tuned up with it.

1. Celgene's annual Revlimid revenue is < $2 billion. In the larger scheme of the global pharmaceutical industry this is chump change, but it looms large for Celgene, representing 50-ish% of annual revenue. For the foreseeable future, Celgene really really needs this cash to continue to roll in.

2. Celgene has a protective wall of patents around Revlimid. The earliest of these expires in 2019, but Celgene appears to believe that it has defensible patents that would prevent the production of a "legal" generic version through 2026. That qualifies comfortably as "the foreseeable future".

3. Patents aside, a manufacturer of a generic version of Revlimid (at least one that could be sold legally into the US market) would have to demonstrate "bio-equivalence" of its product with Revlimid. Part of the process of so demonstrating of course involves obtaining samples of the "real thing" for purposes of comparison.

4. A couple of the big Indian generic manufacturers are working on their own versions of lenalidomide (the chemical name of Revlimid). These companies appear to believe that Revlimid's patent wall will be breached in 2019. But they are unable to obtain the requisite samples of Revlimid, because...

5. Distribution of Revlimid is very carefully controlled by Celgene. You can't just stroll down to the corner CVS with a note from your oncologist and score 28 days worth of Revlimid for a mere $10K. You have to be known to Celgene, and convince them on a monthly basis that you continue to be worthy of receiving the magic beans; and you have to work through a specialty pharmacy that has contractual relationships both with Celgene and your health insurance company.

6. ...when the Indian generic manufacturers request samples of Revlimid from Celgene, of course their requests are ever so politely refused. Celgene's position is that it "is under no obligation to supply" potential competitors with samples of its products.

7. Of course the Indian generic manufacturers could obtain Revlimid samples on the street in 10 minutes flat for the right kind of cash. But that would do them no good, because if they were to submit approval applications to the FDA based on bio-equivalence studies in which such samples were used, Celgene would instantly sue the pants off everyone in sight, since obviously these studies could only have been based on "unlawfully obtained" samples -- i.e. samples obtained anywhere other than directly from Celgene itself.

8. So how is it that, here in the land of "free markets", Celgene can get away with controlling the distribution of this product so closely -- so closely that it can't be legally obtained otherwise than directly from the manufacturer? It does so, in fact, in order to comply with FDA regulations.

9. Revlimid, you understand, is a Very Dangerous Drug. It can't be allowed to come anywhere near "a woman who is pregnant, or who could become pregnant", because of a rather extreme risk of severe birth defects. A patient taking it is not allowed to donate blood or sperm. And so on. As such, it is required by the FDA to be covered by a Risk Evaluation and Mitigation Strategy (REMS), under authority conveyed by the FDA Amendments Act of 2007 (FDAAA). And of course the REMS for Revlimid involves very strict control by Celgene over its distribution, lest the stuff fall into the wrong hands, and cause the production of monsters.

10. The FDAAA explicitly forbids using a restricted distribution program to block or delay the development of competing generic products. But of course, in the event of war, it would have to be proven in a court of law that that is what Celgene is in fact doing in this case. And accomplishing that, inclusive of the appeals process, could take years. Maybe until 2026.

More Miscellanea

My apologies for leaving everything hanging for three months, but I've been busy. First, the most recent tests continue to show slightly elevated kappa free light chains, but only slightly. The trend is back towards the normal range. There is no evidence of monoclonal proteins. So the oncologist is pretty relaxed about things right now. He is suggesting that I resume the monthly Aredia infusions (discontinued almost a year ago, in preparation for the extraction of tooth #27), since a set spinal MRIs taken in April indicated some improvements vs. the lytic lesions generally (on one hand), but some additional compression of T8 (on the other). Assuming the medical insurance will work for this, we plan to do this in July.

We did manage to carry out a successful three-week reconnaissance of Indochina in May. Christiana Hospital turned out to have its own travel medicine practice, so there was no need to return to Johns Hopkins. The travel doc, apprised of my situation, made no attempt to dissuade me from making the trip. She provided us with the necessary vaccinations (e.g. Hepatitis A and typhoid fever), as well as with some prophylactic anti-malaria pills (taken starting before the journey and continuing for a week after returning) and antibiotics (Cipro) for "traveller's diarrhea", should it occur. In the event, no one got hurt or ill on the trip, and a good time was had by all.

The biopsies on the tissue samples taken during the recent endoscopy turned up nothing. The GI doc is standing by his diagnosis of mild, "non-specific" (code for "we don't know where this is coming from") gastritis, but otherwise apparently has nothing to offer, at least based on the results of the endoscopy. The Xifaxan he had me try impacted my symptoms not one iota. I may follow up, but based on twenty years of on-again-off-again experience with GI specialists, it wouldn't be with any elevated hopes.

Miscellanea

The bone marrow biopsy performed three weeks ago at Johns Hopkins came back negative: "No evidence of plasma cell myeloma". Unfortunately, the accompanying blood protein test was somehow botched, so I have to wait until later this month to have my anxieties around the results of the January test assuaged. Meanwhile, the Hopkins oncologist seems unenthusiastic about my idea of travel to Vietnam, punting me to the Johns Hopkins travel medicine team.

I am in the midst of a two-week course of Xifaxan (Rifaximin), an antibiotic prescribed for me by the GI doc who recently performed upon me a combination colonoscopy and endoscopy. I was overdue for the colonoscopy, my second; I am on a five-year cycle for this procedure, since the first one turned up benign polyps. This time, no polyps of any sort. I requested the endoscopy to investigate a few nagging problems I have been having, including occasional trouble swallowing, the odd belching fit, and chronic abdominal bloating (some days, I look like I'm expecting). It's not clear whether these symptoms have anything to do with the chemotherapy, but in any case the GI doc is diagnosing mild esophagitis and gastritis, meanwhile awaiting the results of multiple biopsies.

Finally, my primary care doc ordered some X-rays of my neck and right shoulder; I have been having some pain in these areas that doesn't seem to want to go away. This makes me nervous, since as the reader may recall, the myeloma originally masqueraded as muscle pain that wouldn't go away. The X-rays didn't turn up any lytic lesions, though, and the primary care doc is pushing me off to an orthopedic specialist, if I want to pursue the matter further.

Johns Hopkins: The Final Chapter

I forgot to mention that I spent the entire day a week ago Thursday being poked, prodded and interrogated at Johns Hopkins for the last time (well, the last time that has anything to do with the stem cell transplant, anyway). This was the somewhat overdue two-year follow-up visit. As usual, blood and bone marrow were extracted for evaluation (still waiting for the results). And I was given the final round of childhood immunization boosters, so I am as close as I can get to having an adult immune system again.

The Hopkins oncologist waved off my concerns about the dangers of long-term exposure to Revlimid (increased risk of developing second cancers), saying that the benefits far outweighed the risks, and were in any case overwhelmed by the increased risks introduced by the transplant itself (first time I heard this, so there you go).

He also encouraged me to participate in a clinical trial that was offered to me recently by the Christiana oncologist (I think I probably forgot to mention this as well -- I'm definitely slipping). This is a trial of a vaccine for shingles. Although the post-procedure incidence of shingles is very high (30%+) for bone marrow and stem cell transplant patients, both oncologists think that if I was going to get shingles, I would probably have gotten it by now; but both also seem to think that participation in this trial is a good idea for me. I may have mentioned this before, but myeloma survivors are a valuable commodity in the cancer research community; for a number of reasons, myeloma receives proportionally more attention from the researchers than the raw percentages would suggest. Then again, maybe these guys are trying to prepare me psychologically for a future of clinical trials that will be my only resort, once I exhaust, inevitably, one by one, the standard treatment protocols.

Kappa Free Light Chains

The bad news is that, in the latest round of blood tests, my kappa free light chain number spiked, to 40% above the top end of the normal range. The good news is that this is not really bad news, yet.

To recap, plasma cells are in the business of producing the components of immunoglobulins, a.k.a. antibodies. These proteins are composed of chains of molecules, two "heavy" chains and two "light" chains each. There are two types of light chains, distinguished by the names "kappa" and "lambda". Normally, heavy chains and light chains are produced in more or less equal proportions, and assembled into antibodies. Light chains that have not been linked up with heavy chains -- "free" light chains -- are left floating around in the blood, and eventually are excreted in the urine. Too many free light chains of either type, or the wrong ratio between the two types, is taken to be an indicator of possible myeloma activity. In my case, the lambda number is normal, and the ratio is just under the top end of the normal range. The reason the ratio between the two types is significant is that there are conditions other than myeloma that can cause elevated numbers, but unlike myeloma, these conditions typically affect both types equally.

The oncologist is not yet worried, because this could be a one-time anomaly. Day-to-day variations in free light chain numbers can be substantial, affected by a number of factors, including for example hydration. To be considered truly significant, similar results would have to be repeated for successive tests. Beyond this, the numbers based on this blood test are not considered definitive; a much more accurate test, called "24-hour urine protein electrophoresis", would be carried out in order to justify taking any remedial action. I took this test not too long ago, and passed. So there is no cause for panic just yet.