The Borrowed Time Zone

2014: Better Times Ahead, I Hope

noreply@blogger.com (Mark Shaffer) — Mon, 06 Jan 2014 03:38:00 +0000

I may return later to provide an account of the ordeals of the past two months, but rather than get bogged down in all those messy details at this point, I will simply set out the current situation.

I am tethered 24x7 to a portable IV pump that is dosing me with the antibiotic oxacillin every four hours. This will continue through the month of January, at the end of which time blood cultures will presumably reveal no trace of the staph infection that caused so much havoc. I have a daily ritual in which I replace the empty IV bag with a fresh one. Once a week a nurse arrives at the house to replace the dressing around the PICC line in my left arm (installed during my hospital stay) to which the pump is attached, and to take blood for any tests ordered by the infectious disease doc running this show. The major side effect I am struggling with here is the fact that the oxacillin is killing the good bacteria in the gut that is required for proper digestion, alongside the bad bacteria. I am trying to counteract this effect with probiotics supplements. My appetite varies from poor to fair; I am supplementing occasionally with bottles of Ensure.

I am two weeks into what is at least for starters a four-week program of physical therapy designed to get the left knee that was sliced open in pursuit of the staph infection going again. So far the therapist in charge of my case is happy with progress in this area.

Chemotherapy was finally reinitiated on December 19. The protocol is not what I was thinking it would be a couple of months ago. It involves the novel agent carfilzomib (brand name Kyprolis) and the steroid dexamethasone, both administered via IV. I get these on days 1, 2, 8, 9, 15 and 16 of each 28-day cycle. So far I can discern no meaningful side effects, other than maybe some temporary temperature boosts caused by the dex; this effect is nonetheless bothersome, since given the staph infection situation I must constantly be on the lookout for fevers.

In the pain management area, I am sticking solely to acetaminophen, and that only occasionally, for example if the left knee is preventing me from sleeping. I emerged from the hospital popping oxycodone on top of twice-daily slow-release oxycontin; I have weaned myself from both and am religiously avoiding any and all opioids, since they have the effect on me of constant daytime drowsiness, which renders me nearly useless, in terms of doing things. I was falling unconscious in my chair at any moment.

I am currently not working; all the time taken up by various medical appointments during the week make that impossible. Once the issues unrelated to chemotherapy are resolved, presumably by the end of January, a return to work should become much more plausible.

The New Treatment Plan: CyBorD --> CyCarD

noreply@blogger.com (Mark Shaffer) — Sat, 02 Nov 2013 02:03:00 +0000

It sounds like the name of some dangerous computer malware, or perhaps the latest secret NSA surveillance program. Instead, "CyBorD" is the name of the protocol that I will ~~soon~~ [not, as of 10/30/13] begin following as treatment against the advancing multiple myeloma. CyBorD indicates a combination of cyclophosphamide, bortezomib, and dexamethasone. It's also called VCD, using the names of the branded agents involved (Velcade, Cytoxan, and dex).

This proposal of the Christiana oncologist came as something of a surprise to me. None of these is, strictly speaking, a particularly novel agent. Velcade (bortezomib) is a member of the first generation of such agents that included for example Revlimid. It has been used successfully for a decade, very often as a part some sort of combination such as this. [10/30/13: Kyprolis/carfilzomib, the next-generation successor to Velcade/bortezomib, will be substituted for it.]

Cytoxan (cyclophosphamide) is really old-school; clinical trials involving it were first conducted in the late 1950's. It's the traditional type of agent that many people continue to associate with the term "chemotherapy"; it makes the patient's hair fall out, induces nausea, and so on. I was sufficiently concerned about the potential toxicity for a post-transplant patient such as myself that I brought the issue to the attention of the Johns Hopkins oncologist. He did not exactly endorse the idea, but it also raised no red flags for him. [But he did raise a red flag over Velcade; read on.]

Technically, CyBorD is a protocol approved for newly-diagnosed myeloma patients, rather than as salvage therapy for relapsed patients. But because I have never before been exposed to Velcade, I might be expected to respond to it as if I was a treatment virgin. Its operation is fundamentally different from that of Revlimid, which simply destroys myeloma cells outright. Velcade is more subtle, disrupting the internal processes of cell growth and division, thus preventing myeloma cells from behaving effectively as, well, myeloma cells. The principal danger of Velcade for me is the potential for increased peripheral neuropathy. Weekly subcutaneous injections, rather than twice-weekly IV (the original method of Velcade administration) is supposed to minimize this, but it will have to be carefully monitored.

[Not as of 10/30/13. Instead, the next-generation successor to Velcade/bortezomib, Kyprolis/carfilzomib, will be substituted for it. Peripheral neuropathy is evidently much less of a risk with this agent, which is the primary reason for the switch. It took quite awhile for the medical insurance company to swallow this change, because technically I am not supposed to get carfilzomib until I have failed bortezomib. The Christiana oncologist had to fight an extended battle to get the required authorization to move forward with it; hence the delayed nature of this post. This peripheral neuropathy risk was something that the Hopkins oncologist warned against when I discussed CyBorD with him; I believe he may have influenced the Christiana oncologist's decision to seek this modification.]

This is a complicated protocol, about which I have much more to learn. I will be taking pills (the dex), ~~getting subcutaneous injections of Velcade~~ getting Kyprolis via IV, and getting Cytoxan via IV, each on its own schedule. The first step in the process will be to attend a class at the oncologists' office to find out what is going to happen, and what I will be expected to do; the new campaign will begin the next day. This will occur in the coming week.

I will also be continuing with bisphosphonate therapy, but I am being switched from Aredia to Zometa. I will be learning about this as well.

Meanwhile, I am very happy with the current pain management regimen, which combines dexamethasone with slow-release Oxycontin. I struggle with waking up a couple of times each night, and some of my work days recently have begun at 4 AM, but my appetite is great, and my energy levels are very high.

Hopkins: No Second Transplant

noreply@blogger.com (Mark Shaffer) — Fri, 11 Oct 2013 01:30:00 +0000

On Thursday October 10 we made our way to Baltimore to visit the director of the stem cell transplant program at Johns Hopkins. He is not in favor of performing a second transplant on me. In fact, he says that in many cases he has begun to discourage the use of even first-time transplants, in favor of some of the novel chemotherapeutic agents that have appeared in recent years. He specifically mentioned pomalidomide and carfilzomib, both of which I have discussed in earlier posts. Compared with them, a second transplant, and for that matter increasingly even a first transplant, does not do so well in cost/benefit terms -- where "cost" is an expression not so much of money but of risks, side effects, and recovery time; and "benefit" is an expression of the quality of the response and the time to progression. To use his formulation, the novel agents are gradually transforming "a bad nasty disease that kills people" into "a bad nasty chronic condition". They are in no sense curative. But we'll have to take what we can get.

He will communicate his views to my Christiana oncologist, who I am scheduled to visit next week.

Obviously I am relieved by this verdict. None of the proposed regimens will involve anything like the ructions that would be caused by a transplant. I think Huong may be even happier than I am about it; after I started talking about the possibility of a second transplant, I thought I heard her get her suitcases out to start packing.

Meanwhile, daily life has not remained on hold. I continue to work, and I am eating and sleeping normally (although the dexamethasone has me a bit wired, and is causing night sweats). The dexamethasone is doing a good job of keeping down the pain. I can still drive motor vehicles. I confess to not having returned to my normal fitness regimen, as I'm a bit paranoid about the spinal deterioration. Since the myeloma is no longer under control, that cannot be doing anything other than getting worse. Huong is encouraging me to investigate aquatic therapies, which seems like a good low-impact idea.

An Unplanned Hospital Stay

noreply@blogger.com (Mark Shaffer) — Wed, 09 Oct 2013 00:42:00 +0000

The insidious nature of myeloma has revealed itself once again, as if we needed to be reminded of it. A couple of weeks before my visit with the oncologist last month, I began to experience some new pain in the right hip and upper right leg. The pain was hardly debilitating, but it was noticeable, and I mentioned it to the oncologist. She ordered an MRI of the lumbar spine, which revealed some new lesions, indicating myeloma activity. "But we have to give the higher dosage of Revlimid a chance to work", she said. Meanwhile, the new pain remained, but it didn't seem to be spreading or getting worse.

Until late last week, that is. On Thursday October 3, I began feeling not so well during the day, with pain spreading up into the old problem areas of the thoracic spine and lower ribs. But what was really disturbing was that by that evening I was experiencing faint echoes of the spasms that sent me to the hospital for the first time, four years ago.

So we dropped all of our Friday plans in favor of an impromptu visit to the oncologist's office. She quickly settled on the need for a thoracic MRI -- exactly what I was hoping for. But my timing was terrible. The cancer clinic is not a 24x7 operation, and there was no possibility of getting the MRI there before the imaging department shut down for the weekend. Not wanting to just send me home until Monday in a potentially dangerous state, she sent me to the hospital instead.

Miraculously, the ER was practically deserted on a Friday afternoon, and I was more or less swiftly admitted into the hospital and installed in a bed in the Oncology ward. The oncologist stopped by on her way to begin a week-long vacation -- bad timing again -- to announce that "We're done with Revlimid" -- but that she had not yet decided on the treatment path forward.

The neurosurgeon who had done the original balloon kyphoplasty on T8, and who has been monitoring me sporadically ever since, also stopped by to say that he would not be working that weekend, but that he would need to look at the results of the yet-to-be-done MRI, and in any case any necessary surgery would have to wait until the following week. As it happened, I was summoned to appear before the MRI machine not long after his departure.

And then I sat in my hospital room for two days, while nothing else happened, either good or bad. Of course Huong spent a lot of time with me, and she and the iPad together succeeded in keeping me from going mad with boredom.

On Monday October 7, the neurosurgeon called to announce that, while the thoracic MRI showed new lesions and additional compression, there were no new spinal fractures. He indicated that he was unwilling to undertake any surgical procedures whatsoever in my case at present, as any such procedures would be very invasive, involve much recovery time, and could not be counted on to be actually beneficial. His preferred strategy would be to manage my pain while minimizing further damage, i.e. by forcing back the cancer again.

The ball was now firmly in the court of my oncologist's backup -- a man I have never met and have spoken to exactly once, on the phone. He began by telling me what I already knew, that there are now many chemotherapeutic agents available for use against myeloma, and choosing amongst them would be an educated guessing game. And then he hit me with something completely unexpected: "But if I was conducting your case, I would consider a second transplant, because you are still young and strong enough to handle it, and you responded very well to the first one, which would lead me to believe that a second one would be your best chance for another extended remission."

I was frankly speechless, but eventually managed to reply that the Johns Hopkins transplant artists had already expressed their opposition to so-called tandem transplants. To which the backup oncologist replied, "There is little evidence that tandem transplants are sufficiently beneficial, but that is not what we are talking about here. A tandem transplant involves a brief recovery time between the transplants; they are done back to back. Your first transplant was four years ago. This would just be a second transplant." As it happens, I have already set up a near-future appointment with the director of the Hopkins transplant program to discuss the recent developments in my case, and when I told the oncologist this he said, "Excellent. Ask him if he can do another transplant."

So that is my current plan. I am going to ask the Hopkins oncologist if he wants to subject me to the unspeakable horrors of the peripheral blood stem cell transplant a second time.

Meanwhile, I was discharged from the hospital on Monday evening. The pain is being kept at bay with 4 mg doses of my old steroid friend dexamethasone, taken twice daily, which suppresses any swelling of the spinal cord; and I have oxycodone for breakthrough pain relief.

Daratumumab: The First Myeloma "Breakthrough Therapy"

noreply@blogger.com (Mark Shaffer) — Sun, 29 Sep 2013 01:46:00 +0000

I haven't been keeping up with my myeloma research in recent months, but I'm making up for lost time now.

In 2012, the Food and Drug Administration Safety and Innovation Act (FDASIA) was enacted. Section 902 created a new category of "breakthrough therapies" that the FDA is supposed to accelerate through its approval process, so that they can reach patients much sooner than would ordinarily be the case. These therapies must represent significant improvements over existing therapies in the treatment of serious or life-threatening conditions. Since at least some clinical evidence of improvement must be demonstrated in advance, the requirements for the "breakthrough" designation are more stringent than for the older alternative "fast track" designation, which can be granted based on preclinical evidence, if the therapy "fills an unmet medical need", i.e. there are no existing therapies at all. At least in theory, a breakthrough therapy could be released to patients after Phase 1 or 2 clinical trials.

In May 2013, the FDA designated daratumumab a breakthrough therapy against refractory myeloma, i.e. myeloma that has become resistant to the existing mainstream therapies, such as bortezomib and lenalidomide.

Phase 2 trials were announced earlier this month.

2013 Test Data

noreply@blogger.com (Mark Shaffer) — Sat, 28 Sep 2013 01:58:00 +0000

The most recent round of tests had mixed results. Monoclonal proteins continued their upward march, but Kappa free light chains declined. I am in the middle of only the second cycle of the increased 25mg Revlimid dosage, so we must give that time to work. Another UPEP test was also done; this failed to show enough protein concentration to allow UPEP evaluation, which is a good thing.

Here is a summary of the tests so far this year. Note that anything other than "None" is undesirable for the monoclonal proteins; the normal range for Kappa free light chains is 3.3 - 19.4 mg/L, and for the Kappa/Lambda ratio, it is 0.26 - 1.65.

Test Date	Monoclonal Spike (g/dL)	Kappa Free Light Chains (mg/L)	Kappa/Lambda Ratio
1/22/13	None	16.3	1.38
2/18/13	"Faint"	19.6	1.34
3/18/13	0.2	21.6	1.41
4/18/13	0.3	19.7	1.31
5/17/13	0.3	21.3	1.46
6/27/13	0.4	23.1	1.24
8/6/13	0.7	23.4	1.50
9/13/13	1.0	18.6	1.58

Le Bleu et le Blanc (apologies to M. Stendhal)

noreply@blogger.com (Mark Shaffer) — Wed, 14 Aug 2013 00:52:00 +0000

As everyone knows, before being brought under control the cancer did substantial damage to my spine, with the result that I require the use of a cane to walk any distance. Consequently, I am in possession of an official blue-and-white handicapped parking pass, property of the State of Delaware. I would give anything to get my pre-cancer physique back (not that it was any great shakes, but I miss it just the same), but I have learned over time that my "cripple card" is the key to previously unsuspected benefits the world over. So now I always make sure I have it with me whenever I am traveling, even if I have no expectation of driving or parking in the course of my sojourn.

When I arrive at the airport, I have my card handy, because if I have to check luggage, and there is any kind of line for economy ticket holders (I am always one of those), if I wave the card around then typically I, along with my entire "entourage", will be directed into what is invariably a much shorter line for first class customers. I have never discovered the card to be in any way helpful in the security line. But at the gate, if I make myself known to the agents ahead of time, they will instruct me to join the priority boarding group. I have even had the experience of a gate agent rounding me up just prior to the first boarding announcement, and escorting me personally to the boarding pass check machine. How sweet is that?

In France, a ticket seller at a museum or other attraction has only to catch the merest glimpse of the blue-and-white card to immediately punch out, without further ado, two free tickets, one for myself and one for Huong. If there is a temporary exhibit requiring distinct tickets then I can get a couple of those as well.

The French are reputed to have practically invented the modern concept of "bureaucracy", and to have granted us the privilege of incorporating into our language the term unaltered; whereas the Italians are alleged to be intentionally lackadaisical towards (actually quietly contemptuous of) bureaucratic rules and procedures. Yet in this small area these nations seem to have exchanged their stereotypical roles, because in Italy, unlike in France, the blue-and-white card was occasionally carefully scrutinized, and certain of its details, along with those of the supporting Delaware ("The First State") driver license, were entered into one or more Italian databases. I have no idea why, although I speculate that this represents some attempt to head off the potential abuse of the card's substantial benefits, which were much the same in Italy as in France.

To me, the true advantage of the card has to do, not so much with free tickets (as attractive as they are), as with the ability to skip long lines of weary, sweaty tourists. Approaching the Colosseum or the Uffizi on a hot day at the height of the summer tourist season is a daunting prospect. The very long line of people seeking tickets makes the siren song of the tour guides ("skip the line") seem irresistible; but not to me, because I simply march past all of them directly to the Reserved Ticket window (or the Guided Tours entrance, or whatever it is), where eventually I am duly handed my free tickets, and then I... walk in. My companions may have to pay full price for their tickets, but they are at least spared the wait as well.

Incidentally, in some other respects the Italians lived up to their reputation for administrative carelessness. In the course of our recent visit we rode Italian intercity trains three times, and our tickets were checked only once (Typical occurrence: Conductor slouches into car, checks a few tickets, receives cell phone call, wanders off, is never seen again). We used the water buses of Venice for several days, and I was checked just once. In Venice the blue-and-white card was the only artifact I needed to use the water buses; there was no need even to parlay it into any sort of free pass or ticket. I think I'll be going back.

Official: Return to Treatment

noreply@blogger.com (Mark Shaffer) — Mon, 12 Aug 2013 02:49:00 +0000

This past Friday, Huong and I met my new oncologist for the first time. A woman of Indian heritage considerably younger than myself, she took immediate control of my case, and established that she would be substantially more aggressive than the old guy (whom she claimed as her mentor) had been. Once again the blood test numbers have crept up slightly, and she wants to head off the disease by, for now, restoring the 25 mg dosage of Revlimid. The reader may recall that this was my original dosage on returning from Johns Hopkins 3-1/2 years ago, but it was reduced to 10 mg in view of the second cancer development risk associated with long-term exposure to Revlimid. But now fear of the resurgence of the actual first cancer has overtaken the speculative fear of a second one. She is also shifting me to a full 325 mg aspirin daily, up from 81 mg, against the increased risk of blood clots arising from the higher Revlimid dosage.

For next time, she has requested that I undergo another UPEP (urine protein electrophoresis) test, to get a set of fresh baseline results for that.

Meanwhile, none of this is having much impact on my daily life. I continue to work and play as normal. I have just returned more or less intact from an arduous three-week trip overseas. My disease-related "issues" (back pain, fatigue, gastrointestinal instability) exhibit neither deterioration nor improvement in the recent past. The changes are, so far, completely test-driven.

No Symptoms, Yet

noreply@blogger.com (Mark Shaffer) — Sun, 07 Jul 2013 22:06:00 +0000

The question has arisen: Given the apparent progression, am I noticing any new or different symptoms? The short answer is "No". Other than the fact that my digestive tract seems more stable, if it weren't for the advancing test numbers, I would have no inkling that anything has changed. To use medical establishment terminology: "No clinical evidence."

Major Transition

noreply@blogger.com (Mark Shaffer) — Thu, 04 Jul 2013 00:21:00 +0000

The blood test numbers continue to edge up -- monoclonal proteins are now 0.4 g/dL, vs. 0.3 last month; and kappa free light chains are 23.1 mg/L, up from 21.3. Lamba free light chains also increased, though, so the ratio actually declined to 1.24, from 1.46. Nevertheless, this "progression" -- the oncologist allowed himself to utter the word this time -- is "real", not some noise in the testing process.

We agreed that, since in a couple of weeks I will be leaving the country for several weeks, now would be a bad time to make any changes to the medication regime. Given the seemingly glacial rate of progression, the risk that the disease will suddenly get out of control in that time is comparatively lower than the risks potentially arising from a change in medication. Also, there remains the psychological barrier: "Once you go from 'maintenance' to 'treatment', there is no turning back."

And having said that, with one engine on fire and the other one losing oil pressure, the oncologist strapped on his parachute and lept out of the open hatch. Shortly after my last visit with him, I received a letter from his group announcing his retirement, effective August 1. So my next appointment will be with a physician I have never met.

May: Additional Tests

noreply@blogger.com (Mark Shaffer) — Mon, 03 Jun 2013 01:00:00 +0000

For May, the oncologist added to the usual blood tests the more accurate 24-hour urine protein electrophoresis (UPEP), and an x-ray bone survey. The blood tests spoke of stability, more or less, with monoclonal proteins remaining at 0.3 g/DL, and kappa free light chains edging up to 21.3 mg/L, but the kappa/lambda ratio remaining in the normal range at 1.46.

Interestingly, the UPEP test showed no monoclonal proteins at all; but "polyclonal free light chains and polyclonal IgG seen". Taken together, nothing the oncologist takes as meriting any kind of alarm.

The final impression on the bone survey was equally bland: "Stable metastatic bone survey compared with 12/29/2011." There was not even any additional compression of T8 noted, which is one of the things I was fearing. The worst that could be said was: "Stable lumbar spine with degenerative changes in the lower levels", which probably could be said of any male in his late 50's.

On the whole, there is just nothing to get excited about at this time.

April Tests: Inconclusive

noreply@blogger.com (Mark Shaffer) — Sun, 28 Apr 2013 17:29:00 +0000

For some reason, April's test results were slow to arrive at the oncologist's office this past week (first time this has ever happened). We have them now, but are perhaps not much the wiser for it. Kappa free light chains backed off slightly, and are now barely above the top of the normal range; the kappa/lambda ratio is well within its normal range. On the other hand, the monoclonal spike in the gamma region edged up to 0.3 g/dL.

The oncologist continues to keep his powder dry. He still does not want to change anything -- yet. But he mentioned for the first time the possibility of "changing the dosage". That would mean boosting to 15 mg or 25 mg Revlimid, from the current 10 mg. Attentive readers may recall that on my return from Johns Hopkins 3 years ago I was started on 25 mg, which was subsequently reduced to 10 mg in view of the increased second cancer risk associated with long-term Revlimid exposure. But we may have to assume that risk once again.

Beware The Tests of March

noreply@blogger.com (Mark Shaffer) — Wed, 27 Mar 2013 02:04:00 +0000

The myeloma blood tests are "headed in the wrong direction", to use the expression of the nurse practitioner who reviewed this month's results with me. The free light chain numbers are virtually unchanged. But the SPEP comment reads: "Monoclonal spike seen in the gamma region = 0.2 g/dL." For IFE we have: "Monoclonal IgG Kappa seen."

Few phrases are as calculated to stoke the long-term myeloma patient's anxiety as "monoclonal spike". An ocean of bad memories lap at the veteran's feet. The notion that the cancer cells themselves seem to be multiplying is bad enough; but then one visualizes the garbage that they pump out, clogging the delicate filters of the kidneys, freezing the struggling musculature of the heart, crushing the shielding of the nerves as if in a slowly tightening vice. The tormented osteoclasts resume their mindlessly feverish drilling of the bones. The patient's mind and spirit are once again imprisoned in a body that is its own worst enemy.

In these circumstances, the oncologist's rationalizations are comforting: 0.2 g/dL is still minuscule; two data points don't make a curve; and so on. Only in case next month shows significant further deterioration must we consider taking evasive action. Wait until next month.

Generics, Authorized and Otherwise

noreply@blogger.com (Mark Shaffer) — Wed, 06 Mar 2013 03:11:00 +0000

Last summer's discussion of generic Revlimid attracted an unusual amount of attention, so I thought I would expand a bit on the regulatory environment for generics.

In the United States, competition law is administered and enforced by two distinct government entities: The Federal Trade Commission and the Department of Justice Antitrust Division. The relationship between them is complicated, and I am greatly oversimplifying here, but in general the FTC pursues the enforcement of antitrust and consumer protection laws in civil courts, while the Antitrust Division has the power to bring criminal charges in cases of violations of antitrust laws. In recent years, maneuvers undertaken by patent-holding pharmaceutical companies and their generic-making competitors have attracted the attention of the FTC, and prompted legal actions by it.

Consider the hypothetical case of MegaFarma Inc., the holder of patents on, and exclusive manufacturing and marketing rights to, a very expensive therapeutic agent, wigglidomide (brand name Skeezix). Skeezix is coming off patent soon, and a maker of generics, LoPillCo, is known to be working on a much less expensive, bio-equivalent version of wigglidomide, to be pushed onto the market the moment that happens. There are a couple of things that MegaFarma thinks it might do to delay this event.

In a "pay-for-delay" agreement, MegaFarma would simply bribe LoPillCo to delay the introduction of its generic wigglidomide for some period of time. During that time, MegaFarma's domination of this particular market would remain unimpaired, LoPillCo would get substantial sums of cash for doing literally nothing, and everyone is happy. Everyone, that is, except the consumers (and notably the much-maligned medical insurers), who would continue to pay the usual elevated prices for Skeezix. And the FTC. The FTC is not at all happy with pay-for-delay, and in at least one case has chased the appeals process in a case against such an agreement all the way to the Supreme Court.

A somewhat subtler move for MegaFarma would be to introduce, or rather threaten to introduce, its own "authorized generic" wigglidomide, i.e. a repackaging of Skeezix itself as a generic, when it goes off-patent. Doing this could be assumed to be deleterious to LoPillCo's business model around wigglidomide. In fact MegaFarma has no desire to win a race to the bottom of the market for generic wigglidomide; what it really wants is a "No-AG" agreement with LoPillCo, in which LoPillCo would delay the introduction of its generic for some period of time, at the end of which MegaFarma would not counter with its own generic, thus leaving to LoPillCo unmolested (at least by MegaFarma) control of the market for generic wigglidomide. The FTC is unhappy with No-AG agreements as well, for pretty much the same reasons, and has undertaken similar actions against them.

These agreements are not an occasional problem. By law, agreements between brand and generic companies resolving patent disputes must be filed with the FTC; of 140 such agreements filed during the fiscal year ending 30 September 2012, the FTC believes that 40 of them involve some form of pay-for-delay or no-AG. It estimates that these agreements cost consumers an estimated $3.5 billion annually.

Finally, MegaFarma may choose to try to evade the generic competition altogether, rather than reach some sort of rapprochement with it. Thus, the phenomenon of "product hopping", a term applied to a process involving the dropping of a branded product altogether, and its reintroduction into the market in some slightly altered form -- rarely if ever a therapeutically improved form, incidentally -- thus moving the target for LoPillCo rather late in the game. News flash: The FTC doesn't care for this gambit, either, and has said so in court.

The Myeloma Blood Tests

noreply@blogger.com (Mark Shaffer) — Tue, 26 Feb 2013 02:22:00 +0000

This month's myeloma blood test results moved slightly off center. Since I don't recall previously discussing all of these tests, now would probably be a good time to do that.

I do remember mentioning the free light chain tests a year or so ago, the last time they attracted this kind of attention. This time the kappa free light chain number is a shade over the top of its normal range, while the lambda and kappa-lambda ratio numbers are normal. These tests are simply measuring the concentrations in the blood of these molecules, in milligrams per liter.

The other two tests seem more subjective in nature. They involve an examination by a trained analyst of "pictures" representing the behavior of blood proteins that have been subjected to certain processes.

In serum protein electrophoresis (SPEP), blood proteins are placed at one end of a agarose gel to which an electrical current is applied. Different proteins migrate to different locations in the electrical field on the gel; if monoclonal proteins are present in significant quantities, they will show up as a dense, narrow discrete band in the gel. Of course, depending on the patient's situation, this band may be more or less dense, and more or less narrow; this is not a binary, yes/no the patient does/doesn't have myeloma test. In my case, the analyst's comment says: "A very faint discrete band."

The immunofixation electropheresis (IFE) test attempts to further validate the presence of monoclonal proteins by identifying the heavy and free light chain components involved. The electrophoresis is repeated in five "lanes" on the gel; to each lane an antibody specific to one of the three heavy chains or two light chains is applied. An antibody reaction will cause a telltale precipitation band to be left behind in that lane. A band in a heavy chain lane, paired with a band in a light chain lane, identifies a specific type of monoclonal protein. In my case, the analyst's comment says: "A very diffuse IgG Kappa band seen."

Obviously, experienced hematologists could express differences of opinion regarding the significance of such phrases as "very faint" and "very diffuse", when used in this context. For his part, my oncologist, a phlegmatic, conservative sort, seems at least outwardly to be unimpressed by all of this. We will run these tests again next month, he says, and we will see.

The Revlimid Paper Chase

noreply@blogger.com (Mark Shaffer) — Sat, 16 Feb 2013 05:22:00 +0000

No doubt you are used to getting a bit of paper whenever you go to the local pharmacy to pick up a prescription. Nowadays typically there is included with even the most seemingly innocuous of nostrums a "Medication Guide", printed on fan-folded tissue paper, that describes, unreadably and at considerable length, how to take the stuff; how not to take the stuff; all the bad things that could happen, maybe, if you dare to take the stuff; what to do and whom to call if any of these bad things happen; and so on.

But you never, ever read any of this mind-numbing material. Am I right?

News flash: This stuff isn't for you, the patient; it's for every one else involved in the process of delivering the products of the pharmaceutical-industrial complex. It's a liability-limitation mechanism. If something bad happens to you as a result of swallowing a few billion milligrams of Skeezix 100mg tabs, and an ambulance-chaser persuades you to sue the manufacturer, the defense's attorney will want to know whether the plaintiff actually read all this stuff, as required, and fully understood the risks involved. No? Well then: Your honor, this is clearly a deplorable example of the irresponsible misuse of a product the safety of which, when used as directed, has repeatedly been demonstrated blah blah blah.

Every 28 days the UPS man brings a little box to my door. It contains a plastic bottle containing 28 pills, and a quantity of paper. Some of the paper is packing material. But there is also the usual Medication Guide... and 16 standard 8-1/2x11 pages of additional stuff, mostly identical every time, and mostly recycled without much ceremony by yours truly:

An invoice (one page), in the quantity of my minuscule co-pay. The true invoice, for something like $10000, is not included; that is sent to the medical insurance company. I can see it only if I log into my account on the medical insurance web site.

"Important Drug Information" (4 pages). In effect a reprise of the material of the standard Medication Guide, but organized in a different manner, and "personalized" with my name, my oncologist's name, my pharmacy account number, etc.

"Medication Guide" (3 pages). Yet another copy, in a different format, of exactly the same material as the Medication Guide mentioned above.

"General Information about Cancer" (7 pages). Answers such burning questions as "Are there cancer treatment side effects?" (Ummm... Yeah.); and "Do I need to finish my chemotherapy even if I feel better?" (Nah, that's for sissies, pilgrim. But the last page warns against doing anything without asking your doctor first. So we're covered, counselor.)

And finally, a whole page of "Helpful Information Regarding Your Prescription", including such gold as "How do I convert the convertible cap to a non-safety cap for easy opening?".

What a comfort it is, to know this is possible.

Pomalidomide

noreply@blogger.com (Mark Shaffer) — Mon, 11 Feb 2013 03:19:00 +0000

The multiple myeloma treatment arms race has really been heating up. Practically on the heels of FDA approval of Onyx's carfilzomib (branded as Kyprolis) comes approval for Celgene's latest thalidomide derivative, pomalidomide (branded as Pomalyst). Once again this entry is fenced about by theoretical restrictions (only for patients who have failed at least two other treatments, please) that will yield in practice to further research. Unsurprisingly given its lineage, pomalidomide seems to do better with a low-dose dexamethasone amplifier. Also unsurprisingly, these new agents are doing nothing to reduce the cost of treatment; both will run more or less the same $10000/month as my old reliable Revlimid.

Thalidomide

noreply@blogger.com (Mark Shaffer) — Tue, 04 Sep 2012 01:52:00 +0000

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

noreply@blogger.com (Mark Shaffer) — Wed, 08 Aug 2012 02:09:00 +0000

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

noreply@blogger.com (Mark Shaffer) — Fri, 13 Jul 2012 23:33:00 +0000

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?

noreply@blogger.com (Mark Shaffer) — Wed, 20 Jun 2012 00:14:00 +0000

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

noreply@blogger.com (Mark Shaffer) — Sun, 10 Jun 2012 22:52:00 +0000

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

noreply@blogger.com (Mark Shaffer) — Tue, 20 Mar 2012 01:29:00 +0000

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

noreply@blogger.com (Mark Shaffer) — Sat, 10 Mar 2012 00:46:00 +0000

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

noreply@blogger.com (Mark Shaffer) — Sat, 21 Jan 2012 15:56:00 +0000

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.