• Tristan Manalac for Biospace: Amgen’s Tavneos troubles continue as NEJM retracts pivotal publication. First came FDA questions about data integrity. Now the academic authors are confirming the data tampering, though per the now retracted study they did “vouch for the completeness and accuracy of the data, the complete reporting of adverse events, and the adherence of the trial to the protocol. All the authors participated with the sponsor in the design of the trial, the analysis of the data, and the writing of the manuscript.” I wonder if people who sold this rotten pile of garbage to Amgen will offer a refund. So it goes…
• Carl Zimmer and Marco Hernandez for The NYT: This Cell Feeds, Grows and Reproduces. And It’s Manmade. “Dr. Adamala named her creation SpudCell, after its potato-like appearance. Rather than patent it, she and Dr. Endy are organizing a community of scientists to focus on making SpudCells more fully alive and adapting them to new kinds of experiments.” Bravo! Maybe science isn’t a complete lost cause.
• M Auerbach, MY Lim, GM Rodgers, and T DeLoughery for Sensible Medicine: When Normal Isn’t Normal: Non-anemic Iron Deficiency. A very academic group of authors makes a very good case for treating low iron levels in the absence of overt anemia. This is in response to an earlier text which poo-pooed the practice as “overmedicalizing normality”. Adam Cifu from Sensible Medicine proposes randomized controlled trials, though if symptoms of low iron are as diverse as restless leg syndrome, “brain fog” and craving for ice it would be a challenging endpoint to establish. Boy, isn’t medicine hard.
• Titotal (pseud): The best cause will disappoint you: An intro to the optimisers curse. ⊕ [Note: ᔥAndrew Gelman ] Mathematical demonstration of why effective altruists are, at the end of the day, a bunch of bozos. And not just them: America is the land of hyperoptimizers and if Taleb’s Incerto wasn’t a convincing enough case for why that doesn’t end up well in the long run, well, here is a much shorter Substack post that shows one facet of the problem.
• Ed Conway: The Apple-Banana Paradox. On the incredible flattening of banana prices in the last 25 years, and the incoming threat of another fungal infection that could wipe out the current Cavendish banana monoculture. On the other, could this be an opening for a Honeycrisp of bananas? One can hope.

• Max Kozlov for Nature: Inside the new political screening that’s stalling NIH grants. The plot to murder American science in the style of Rasputin (poisoned, shot, shot again) is well under way, and this is the slow-release poison. Choke off funding, dissuade people from thinking about federal funding, see the number of scientists drop for years to come.
• Vinay Prasad: Marc Tessier-Lavigne and Jose Baselga. To be clear, there are many things wrong with American science and Prasad in his review of the book How To Rule the World presents some good examples, but you don’t treat a serious diagnosis by killing the patient.
• Andrew Gelman: Bayesian Workflow exists as a physical book! An example of what’s right in science. I will be ordering a copy.
• Ann Lee for the Guardian: ‘David Bowie was a crazy workaholic’: Labyrinth at 40 – an oral history. ⊕ [Note: ᔥBill Harris ] An oral history done the right way, about a genius person in a genius movie.
• Catherine Ruth Pakaluk for The NYT: Life Is Better With Siblings. Sure is — just ask Jennifer Connelly from The Labyrinth! Joking aside, this is a serious case for large families and one with which I largely agree, though the double-digit census of children in some of the families mentioned gave me pause. [Note: The old George Carlin bit about idiots and maniacs applies. ] Regardless, for most people the right number is greater than two, and for almost everyone it is certainly greater than zero.

• Keller, Murray, Ivory & Cabreros for The NYT: The Deadly Rise of Giant Trucks and S.U.V.s. A beautifully-illustrated case for America’s king-sized vehicles being the main culprit for increased pedestrian deaths. The careful reader will remember that this “Big SUV hypothesis” was also highlighted by Brian Potter a while back, though it didn’t explain all of the increase. And of course my conspiracy theory may also be true, although if there are people who said a while back “hey, these big A-pillar will lead to more pedestrian deaths” and then there are more pedestrian deaths, well, there’s a conspiracy theory for you.
• Adam Cifu: Advice for Internship. July already? Seems like my last day of residency was but a few years ago, but now, it’s been a full dozen years as of today. And I’ve given up sharing tips almost as long ago.
• Casey Handmer: In Defense of the Marginal Baby. Handmer presents the case for having more babies, with which I agree wholeheartedly. I do not share his enthusiasm for a contraption some call a “Snoo”, a preposterous subscription-based baby rocker.
• Charlie Stross: The Golden Age Of (sic!) Bond Villains. Stross shares the afterword for a reprint of his book The Jennifer Morgue, which is about a billionaire who wants to unleash a Lovecraftian horror in order to rule the world. It was written in 2009 and yes, some idiot billionaire — probably one from the Dialog crowd — must have confused it for an instruction manual. Anyway, Stross’ “Interview with the Entrepreneur”, the entrepreneur in question being Bond arch-nemesis Ernst Stavro Blofeld, is a thing of beauty.
• Ian Finder: UHF X11. A beautifully pixelated window system built for visionOS and Apple Vision Pro. Due to my newfound aversion to Apple I haven’t touched my own AVP in almost a year. This has persuaded me to pick it up again, for the novelty if nothing else.

Yesterday, I received the strangest of emails. It was nominally from the founder of a physician services company, one of those that will, for an undisclosed “signature membership” fee, help doctors with contract negotiation, financial planning, estate management and such. Fine. Stylistically I doubt that the founder, or indeed any human, has had much input on the contents, which were this: sign up for a free 3-day online course and your host, an “expert on lead generation and trust-building” will teach you how to increase revenue and influence in order to get more patients to your clinic. He once, and I am quoting directly from the email here, “helped a little-known surgeon go viral, ⊕ [Note: This is most likely a reference to John P. Williams, a breast cancer surgeon and the creator of the YouTube channel Breast Cancer School for Patients. He was the chair for two and a half years. ] fill his waiting room, and become the White House–appointed chairman of the President’s Cancer Panel.”

Crikey.

This gave me flashbacks from October 2023 when the annual meeting of a medical society which looked more like a TED talk than a serious clinical conference shook me so much that I wrote about it. Yes, of course doctors should learn to become influencers, as well as entrepreneurs and art critics, and also counselors on the matters of faith, car safety and gun violence, everything — everything! — but experts in medicine, which up until 1986 encompassed “the science and practice of caring for patients and [various aspects of] their injury or disease”, but then in the 1970s and 80s, all diseases apparently eradicated and injuries no longer needing treatment, started to include health promotion. And who can possibly be against promoting health?

Something else lamentable happened a half-century ago: in 1975, “the Federal Trade Commission (FTC) accused the profession of ‘restraint of trade’ and legally persuaded doctors to permit advertising amongst their clan”, as noted in the Journal of Medical Ethics. Yes, you have read that right: under threat of legal action, doctors were persuaded to advertise. Up until then, the Code of Ethics of the American Medical Association explicitly forbade it, those 19th century idiots not knowing what was good for them. Or their business. Is there a difference?

Let me postulate that, prior to that faithful — or was it faithless? — decade, the medical profession was defined as sharply as a scalpel and doctors had a notably different status from other professions. Justifiably so, was it not, for people who asked you about bowel movements and sexual habits, and poked and prodded various bodily orifices. [Note: Ah, but I wrote this sentence in the past tense, for both probing questions and the actual probing are done less and less in doctor’s offices, unless it is probing with an intravenous needle to inject that expensive drug, or to insert a medical device. Note how more of the former probing would have led to less of the latter. ] With an increase in scope, the equation of medicine to a business like any other, and one grave of an old physician at a time, the profession has slowly been getting blurrier. So blurry, in fact, that one can exclaim how “there is nothing wrong with healthcare that getting rid of doctors won’t fix” at a tech summit keynoted by Tony Blair ⊕ [Note: ↬John Naughton ] and get applause instead of jeers. So blurry, are they not, that they are just asking to be rubbed out!

Was there a master plan to eliminate a profession and make it into an ordinary trade? I doubt it. It was, as ever with Americans, a pinch of short-term gain and a dash of performance artistry in the stew of unintended consequences. But how oh how to unstew it now?

As seen in the official email communication from the American Society of Hematology:

Milos, if you’re sitting for the hematology boards this November, you don’t just need more resources — you need a structured plan that fits alongside your fellowship and life.

AI slop is the clipart of our age. This too shall pass, one would hope.

• Sasha Gusev: Thoughts on AI in academia. They are good ones. Extra points for leading me to an article from Sam Kriss in Harper’s Magazine about some magnificently agentic stupid people spending away their youth in San Francisco.
• Ruxandra Teslo: Manufacturing requirements are killing cell and gene therapy. The FDA wants companies to make at least two batches of product at the highest standard of manufacturing before approving it for commercial use. You should know this before starting your clinical program, especially if you have manufacturing that’s expensive, so maybe make two small batches instead of a big one? Just a thought. Separately, none of this would be an issue if there was momentum towards considering cell & gene therapy more of a blood bank/cell processing thing than a commercial drug. But then you couldn’t charge as much, could you?
• Regan Penaluna for Nautilus: Lessons in Chemistry, 19th-Century Style. Frustratingly, it takes Penaluna four paragraphs to mention the full name of Jane Marcet, the woman whose book “Conversations on Chemistry” inspired Michael Faraday — first paragraph mention! — to pursue science. The headline is also too broad: this was 1806, pre-Victorian times and barely 19th century. An extraordinary woman. Also: I want that book.
• Kristen French, also for Nautilus: Solving Feynman’s Formula for Eating Well, Parking Your Car, and Finding a Mate. How Feynman’s scribbles in a Thai restaurant lead to a paper in the Proceedings of the National Academy of Sciences, with mathematical proof of a common-sense inkling: more possible choices and more time should lead to more experimentation in order to discover “the best” of anything.
• Adam Mastroianni: Stop eating Lady Gaga’s Oreos. One of Mastroianni’s best, hinged on one key insight: Americans used to see themselves as temporarily embarrassed millionaires. High fortune now being so out of reach for many that it is simply unimaginable, they now see themselves as temporarily anonymous celebrities instead, which is why we have become more tolerant of celebrities hawking Oreos and less tolerant of billionaires. Also, good confirmation that I did not imagine the period when artists were trying very hard not to be labeled as sellouts.

Repugnant.

Abby Care — the listing is alphabetical so it sits at the top — “empowers families to deliver exceptional care”. More specifically, it “trains family members to become paid caregivers for loved ones with disabilities or special needs” and “provides training and community support to deliver better care at lower cost”.

Mysteriously, it also brags about accepting major health insurance providers. Piecing together the fluffy prose on their website and their simple 3-step process ⊕ [Note: Step 1: Get certified with Abby Care through no-cost training. Step 2: Begin care enrollment (with Abby care support for employment, payroll and administrative coordination… Wait, payroll?) Step 3: Deliver quality care. ] it seems that Abby Care wants to be the Uber of home health aid for people who have a family member in need. The proposition is that, since you are already doing all these things for your loved one, you may as well train to do it even better (great!) but also bill your loved one’s medical insurance for it for the “care” you “deliver” (wait, what?) and let Abby Care take a cut (ick!)

The website is also full of community, whether it’s “family-to-family connection and support”, “navigation of community programs and resources” or a statement that “Abby Care brings families together through shared experiences, practical support, and ongoing connection”. Yes yes, you can make this abomination into a community in the same way you can run dirty tap water through reverse osmosis and add back electrolytes to make it taste like a crisp mountain spring. But only one of those comes free, conditional on 1) it existing and 2) you getting to it; RO is significantly easier to obtain provided you have the electricity to run the machine, money for regularly replacing the remineralization filter, and tolerance for wasting four gallons of water for every one you drink.

Mr. Market has a knack for finding an inherently good thing people do out of altruism, sense of obligation or sheer humanity, then putting a price tag on it, taxing it and adding on a 15% service fee to boot — just look at what happened to Airbnb. The only reason some galaxy-level brain at Sequoia isn’t funding a child care scheme similar to Abby Care is that there is no equivalent in health insurance for the care of children. Otherwise I have no doubt that there would be a platform — it is always a platform — for parents to take care of each other’s progeny in return for some meager returns which the platform owners will garnish, laughing all the way to the Silicon Valley Bank.

The monetization of everyday interactions is not new — it first became salient to me after reading the 2019 book Capitalism, Alone by Branko Milanović, which the Wall Street Journal described as “an implausibly dystopian vision of global capitalism’s future.” I am sure the finance whizzes at the WSJ would not find this entire thing repugnant, but I truly wonder about the prevailing opinion among everyone else.

Since the Acquired podcast was so heavily recommended by John Gruber and Ben Thompson on Dithering, I thought I would give it a try. Half an hour into an almost four-hour episode about Epic EMR, I am not impressed.

The style is in the uncanny valley between spontaneous and fully scripted, where the two co-hosts simulate a dialogue in the style of NotebookLM. I could actually tolerate that part: “The Rest Is History” podcast has the same shtick and I’ve listened to quite a few episodes. What I can’t stand is sloppiness about facts (ahem), and this is what one of the hosts uttered as an introduction to why medical records have become so important:

The important thing to realize from all this is that the vast majority of patients do not feel the cost of their healthcare directly in the United States. Those costs are so laundered through private insurance companies and Medicare and Medicaid, that most people think about any given health encounter as being paid for by someone else, by a part of some system.

If you’re trying to unpack how did our healthcare become 18% of GDP versus 11% of the UK GDP or a staggering 6% of Singapore’s GDP, albeit at a much smaller scale, why are we 18%? A big thing you have to understand is psychologically every healthcare encounter is that the system is paying for it. I’m paying into the system, the system is paying for it, but what does it cost? What do I actually pay? It’s a big abstraction.

This is, of course, hogwash. Citizen of the UK and Singapore are even further removed from knowing how much their health care costs — Singapore has a mandatory government-funded “base” coverage with voluntary private coverage on top, and the UK of course has the NHS which is funded straight from the budget — so anyone trying to blame the American healthcare disaster on patients, the implication being that they are spending money like drunken sailors because they don’t know what anything costs, is trying to pull wool over your eyes.

I would also push back strongly against the first paragraph. No one — underlined, bold, in all caps NO ONE — in the United States of America things that their health encounter is being paid by someone else, because the deductibles are high, so are the co-pays, the insurance premiums are staring at your from the pay stub, and at the end of each encounter with the “health” “care” “system” comes the Explanation of Benefits. I mean, who is this podcast even for?

Oh.

“Acquired tells the definitive history & strategy of the world’s greatest companies” says the home page, not realizing that there is a difference between history and hagiography. These guys are doing the latter, to much back-patting from the buy, borrow, die class which eats that stuff up. I’ll pass.

Go to openevidence.com and you will see, right under the elegant logo and a free text box prompting you to ask a medical question, an immodest tag line: “America’s Official Medical Knowledge Platform”. The boast sits above an enviable lineup of official partners: The New England Journal of Medicine, Journal of the American Medical Association, National Comprehensive Cancer Network, Cochrane Systematic Reviews. If you were a clinician in need of information these would be the first places to go, ⊕ [Note: Save, perhaps, for a few journals in the JAMA network, and I write this as someone who has published in and reviewed for JAMA. ] but now there is no need because OpenEvidence will do it for you, for free and — unlike those poor community doctors whose practices can’t afford an NEJM subscription — with full access to all those journals.

Their About page is even more effusive. “Our mission is to help doctors save lives and improve patient care.” Great! It goes on:

This year, more than 100 million Americans will be treated by a clinician using OpenEvidence. As a product, OpenEvidence is an AI copilot for doctors that helps them make high-stakes decisions at the point of care. OpenEvidence is the most widely used medical AI among verified U.S. clinicians. To date, we have supported over 200 million AI-powered clinical consultations from U.S. doctors and other frontline clinicians.

In a remarkably short period of time, OpenEvidence has become the default operating system of medical knowledge in the United States.

Underneath lies the Team, laden with Harvard and MIT affiliations, and long list of medical advisors ranging from Mayo, Hopkins and Mass General staff to prominent YouTubers.

It was a rather obvious idea, to create a specialized LLM chatbot which restricts its data sources to medical literature only, so when I first saw OpenEvidence, the way it presented itself (partnership with NEJM and JAMA, MIT affiliation) and the price (free for everyone with an NPI) I was pleasantly surprised that these institutions came together for the common good, to create our generation’s PubMed.

Hardy har har.

Scroll further down and under another immodest headline — “Supported by the Best” — sit the logos of Sequoia Capital, Kleiner Perkins, Blackstone, Andreessen Horowitz, Nvidia, Google Ventures and the like. Not listed on the website because there is no “Investor relations” page — that may spook the clinicians! — is the financial history. Earlier this year it raised $250 million in a Series D round at $12 billion valuation. Just three months before that it raised $200 million at $6 billion valuation. In total, it has received close to $700 million in funding over its four years of existence.

Yes, OpenEvidence, “the default operating system of medical knowledge in the United States” (their words, emphasis included), is a tech startup zipping through the first phase of enshittification, i.e. attracting users with a high-quality offering. I would argue that even the “high-quality offering” is a bit of a crock, but we’ll come back to that shortly. Let’s, for the purposes of this paragraph, go with the premise that the unique thing that OE provides is the “artificial intelligence” portion. Well, from what I understand the company relies on OpenAI, Anthropic and others for the actual compute and if that is the case they are one-step removed from the absolute carnage whose genesis Ed Zitron and others have been diligently chronicling. The default operating system of American medicine is an earnings miss away from the blue screen of death.

I won’t cry for the billionaires involved. I will, however, mourn the opportunity cost of so many smart physicians and programmers on their medical and technical teams spending their time on point-one-percenter enrichment instead of truly building our generation’s PubMed. It would not even require compute! The true value of OE is the curated collection and unrestricted access to peer-reviewed journals, treatment guidelines, and systematic reviews, supplements and all. Let me google all that — or better yet, look it up on Kagi — and I will not care at all for the LLM-generated veneer glued onto man-made knowledge. But good luck having NEJM, JAMA et al. open their vaults without the VC-backed carrot of (I suspect) God knows how many millions of dollars for access rights combined with the FOMO stick that Anthropic and OpenAI’s PR teams have been so diligently whittling.

Trigger warning for an LLM-sounding phrase: the mounds of AI slop added to OE search results aren’t just wasteful, they are dangerous. Back in the Triassic era when shmucks like yours truly were nursing their middle-finger calluses writing progress notes by hand you knew that every part of that note contained useful knowledge. With the electronic medical record mandate — thanks, Obama — much of it became an unreadable mix of computer-generated charts and copypasta; you had to look at the end of the note to find actual human thought, whether it is in the Assessment and Plan or the Attending Addendum section. Well, I can report from the front lines that much of the time even that one meager paragraph has become a copy/paste job carrying with it that distinct LLM waft.

I am not against using LLMs for progress notes — we have been using human scribes for decades to write up the facts of the doctor-patient encounter. But those are costly and your rural primary care physician certainly won’t have one, so why not delegate that work to AI? The assessment and plan, however, are where you infuse those facts with meaning and then act on them, which is the entire purpose of the physician’s job. Writing is thinking and millions of US medical professionals have decided to delegate the one job they have to AI while keeping all the moral and legal responsibility, reverse-centauring themselves willingly and with eyes wide open.

This may seem like a “the food is horrible and the portions are too small” joke — have I not just wrote that the whole thing will soon be dead? If you are a physician who values their brain and doesn’t copy off a clanker why should you care if either start relying on them and then get a rug-pull? Three reasons:

• Expectation-setting: those who copy will need 15 minutes per encounter, then 10, then 5, continuing to ingest slop and regurgitate it over patient notes even as it gets increasingly bad from more and more expensive compute.
• Asbestos exposure: as in, AI is the asbestos we are shoveling into the walls of our society, only the asbestos here is in the form of regurgitated slop we are putting into patient medical records. That, too, will take our descendants some time to dig out, although human life span being what it is it should be less than a whole generation.
• Thinking of the kids: some of my own highest yield learning moments were reading the attending addendum on my note, or the dictation of a particularly skilled specialist’s consult note; will the incoming generations of medical students and residents have the same opportunity?

So if your mission truly was to help doctors save lives and you weren’t a greedy son of a bitch would you not have made a non-profit to achieve that goal? It may not have been as slick as something coming out of Silicon Valley, but it would also not have the risk of blowing up if the financial winds turn and the funding flywheel stops spinning. After all, there have been many attempts to replace the government-funded Medline/PubMed combo, but none of them were that much (if at all) better to justify the cost.

As a fan of Ruxandra Teslo’s writing — 25 mentions to date! — it pains me to write that her recent article in “Works in Progress”, for which she shares the byline with Open Evidence chief product officer Amol Punjabi, had me wince about a half-dozen times too many to ignore. Worse yet, I agree with the thrust of the article: that China is eating America’s lunch in cell and gene therapy and will soon come for the rest of biomedicine. Heck, that is one of the main reasons I am soon going back to clinical medicine, seeing too many business flights to Shanghai and Beijing time zone Zoom meetings in my future ⊕ [Note: In case you were wondering, the correct number of each for me personally is exactly zero. ] had I continued down the industry path.

Alas, Teslo, Punjabi and whichever LLM did their research had cut too many corners on the way to the largely appropriate destination. Let’s count a few of them.

The old, cheap generic chemotherapy drugs still rock. A combination of two or three chemotherapy drugs developed in the 1970s and 80s is still the gold standard for treating testicular cancer. Chemotherapy has tamed what was once a pancreatic cancer-level death sentence into a diagnosis that doesn’t even have a “stage IV”. Speaking of pancreatic cancer: daraxonrasib, the K-Ras inhibitor which Teslo just a few weeks ago deemed a turning point, ⊕ [Note: That article was, however, still of much higher quality than the one discussed here. Or maybe I don’t know as much about K-Ras and pancreatic cancer as I do about CAR T-cells and myeloma. Could this be a case of reverse Gell-Mann amnesia on my end? ] doesn’t even come close to what bleomycin, etoposide and cisplatin did for testicular. I guess they don’t make turning points like they used to.

The transformation of oncology started long before mid-2010s. The article paints a simplistic picture of oncology’s history. First there was surgery, followed by, in the 1890s and the discovery of X-rays, radiation therapy. Blunt and unsophisticated chemotherapy which relies purely on the cancer cells’ propensity to divide faster than non-cancer cells came in the 1940s and 1950s. Finally, in the mid-2010s, after we learned more about the molecular biology of cancer ⊕ [Note: I guess that, if you wanted to show off your academic status, you should use a 10-dollar word like “underpinnings” here instead of the plain, grade school level “biology”, much in the same way you should find and replace every “use” with “utilize”. But that would, of course, make you a 10-dollar ass. ] came “immunotherapies” by which the article largely means CAR T-cell therapies in general and one in particular, ciltacabtagene autoleucel, known to friends as cilta-cel (generic name) or Carvykti (brand name and the one used throughout the essay; this is telling).

Look, I am no fan of Siddharta Mukherjee’s but at least his history of cancer, The Emperor of All Maladies got the sequence right. Rituximab, a monoclonal antibody which some still consider the original immunotherapy — after all, it acts mainly by siccing patients’ own immune cells and complement towards the target lymphoma and leukemia cells — was approved in 1997 after a Phase 1 trial that started in 1994. Trastuzumab, another monoclonal, was approved for Her2-positive breast cancer in 1998. Imatinib, a revolutionary wonder-drug which inspired dozens of me-too small molecule competitors, had its first-in-human study in 1998 and was approved just three years later, in 2001. Each needed just 3 years to get from the very first patient being dosed to FDA approval; remember that factoid it may become relevant in a few paragraphs. These were actual cures for lethal, aggressive cancers. But if the narrative is that China has accelerated the development of the first true advancement in cancer cures since the advent of chemotherapy let’s just pretend they don’t exist.

Myeloma treatment is not as brutal as painted. Although, of course, everything is in the eyes of the beholder, or rather the mind of the patient having to suffer through it. I do take issue with all three of the specific side effects that the essay highlights, as well as the time burden of myeloma is described. To wit:

Patients come in and out of the clinic for injections, take pills at home and undergo repeated blood tests, living according to a calendar organized around treatment days and recovery days. They also have to contend with the side effects of the medications. Dexamethasone can produce a sleepless agitation followed by a physical and emotional crash. Bortezomib often damages peripheral nerves, causing tingling and a burning pain in the hands. Daratumumab often leads to immune suppression, leaving patients more vulnerable to infections.

Dexamethasone is given in bursts and, thanks to the decidedly non-industry funded trials led by S. Vincent Rajkumar, at a much lower dose than before, minimizing these sorts of side effects. Similarly, bortezomib is now given less frequently and in different ways (under the skin instead of intravenously) to minimize nerve damage. And if you think immunosuppression is bad with daratumumab, well, try wiping out every antibody-producing cell in your body then waiting until you can get all of them back, and yes that includes needing to receive all your childhood vaccines again.

Separately, repeated blood tests are a sine qua non of multiple myeloma management, or really of any cancer management, even after a “cure”. If we aren’t monitoring for recurrence of the primary disease we are fussing over other cancers which may or may not be the result of the treatment itself, or of a person’s general propensity to have cancer. ⊕ [Note: In fact, two biggest risk factors for having cancer, other than a genetic mutation/hereditary syndrome, are age and prior personal history of cancer. ] And yes, that goes even for patients whose CAR-T treatment leads to durable complete remissions. Especially with CAR-T treatments which are known to cause cancer.

Speaking of which, cilta-cel/Carvykti is not a walk in the park either. Cytokine release syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS) are two particularly nice side effects of all conventional CAR-T therapies, Carvykti included. They are frequent and severe enough that most patients need to be treated in the hospital and be within driving distance for the next four weeks. Many end up being admitted to the critical care unit. CAR-Ts that target BCMA, like Carvykti, also cause profound immunosuppression (vide supra) and require patients to repeat their childhood vaccination series. Carvykti, however, is in a league of its own as on top of all that it can also cause Parkinsonism. This is not to throw shade at CAR-Ts, they truly are revolutionary. But let’s not condemn other myeloma treatments for their toxicity when the alternative is worse in some ways, about the same in others.

BCMA CAR-Ts are, for most patients with multiple myeloma, not a cure. The essay cites 12-month results of the CARTITUDE-1 trial, where 76% of participants who received the cells [Note: But not including those enrolled to the trial who never got them, whether because they couldn’t be made, they were too sick to get them, or just plain died. This is how you play the denominator game. ] had no signs of myeloma at 12 months. Quote:

But what happened afterwards is perhaps even more striking: in the Abecma progression free survival curve, the line falls continuously. By contrast, in Carvykti, the line starts to plateau. Extended follow-up at five years confirmed that 33 percent of Carvykti patients remained disease-free.

This is false: there is no plateau. Figure 2 of the NEJM article describing these results has some numbers at the bottom not included in the Works in Progress essay. These represent the “number at risk” — participants who were still available for follow-up at a given time point; others have either progressed, resulting in an unwanted “drop” in the curve, or have not yet been followed for that long ⊕ [Note: There are actually more reason for a participant to be marked as a “tick” without dropping the line, i.e. to be “censored”, some more nefarious than others. For a good primer on this “informative censoring” see, for example, this article ] and are marked with a triangle here though more commonly they are merely a tick. The “plateau” is an artifact of too few participants getting to 24 months, only 9. It completely disappears in extended follow-up, with the curve continuing its descent at and past 24 months in Figure 2A, all the way to 60 months where a cluster of vertical tick marks precedes yet another mirage of a plateau, again with only a handful of patients being at risk. Let’s pray it ain’t so but I suspect that, if we were to continue following these participants to 10 years, the curve will continue going down and down and down.

You could make the same story about artefact plateaus about daratumumab as well. It, too, has been pushed up all the way to first-line treatment and even before overt disease; concerns about longer follow-up needed for what is usually a slow-burning disease remain. Compare and contrast to imatinib in CML in this recent essay from Vinay Prasad, who concludes with:

There is progress in both diseases but more in CML. CML is more clearly a success story. There is much room for progress in myeloma. Myeloma is not yet curative, sadly. Presenting survival over time is misleading and masks more complicated narratives.

Carvykti’s approval timeline was not gobsmackingly fast. Most misleading is the side-to-side comparison of the Chinese cilta-cel and its American predecessor, ide-cel development pathway. Ide-cel includes the development of CAR T-cells in general (1989–2012) and the first BCMA targeting proof-of-concept (2013). Cilta-cel emerged from Zeus’s head in 2014, like it didn’t require both CAR-Ts to be developed and BCMA to be validated as a target. The tag line of the figure is that “China’s BCMA CAR-T reached FDA approval just 11 months after the US, despite starting decades later.” Hogwash.

Note the development timelines: ide-cel’s first-in-human study started in 2014. [Note: I should know: I was there! Funnily enough I was the in-house fellow on call on the days when two of the first 3 participants received their cells and had the honor of escorting them to the intensive care unit that very night. Both had both their myeloma and all of bone marrow wiped out in the process. ] It received FDA approval in 2021, for a total of 7 years of clinical trials. Cilta-cel’s first-in-human was in 2016 with a 2022 approval; 6 years. Let’s finish up our mini-mental test: how long did it take for the FDA to approve rituximab, trastuzumab and imatinib, from the first patient dosed?

These are only the highlights, but going much deeper would be nitpicking. I don’t know whether this amount of laxity with the truth was intentional, but the essay is almost as misleading as a Seattle lady’s GPS, taking her straight onto light rail tracks. Once there, you can only go in two directions: forward, towards loosening up regulations to match China’s Wild West, or backwards, tightening up regulator requirements for Chinese assets and trials and punishing companies for doing business there. [Note: See how I ties going “forward” with less regulation and “backward” with more. This can easily be flipped to portray less regulation as going backwards, but I leave doing that in full as a fun exercise for you, dear Reader. ] What happened to going sideways? Diagonally? Up or down? What if it the time to approve revolutionary cancer treatments has doubled because the follow-ups aren’t as revolutionary? And then get drowned out further by the me-toos and the ghost drugs which make much better competitors in the biotech beauty pageant, where whom you know and where you came from is more important than the increasingly pliant, malleable and quicksand-appearing ground truth?

But sure. China.