A preface to this post: last year, in reviewing my options for Medicare coverage (surely one of the driest sets of posts I've done--at least I hope so!), I made a post with the title "Drugs." Didn't think twice about it. Every so often I check to make sure there are at least a few people still reading: the few, the proud . . .
Anyhow, one post stands out for alleged readership, with roughly ten times more hits than average. You guessed it---"Drugs." So, in the spirit of experimentation, I've got a new really dry subject to cover, namely new MM drugs just approved and in the pipeline, and I'm pretty sure that I can boost my stats just by putting the word drugs in the title of the post. Sorry, everyone who is trolling for mind-altering substances. Nothing to see here. You've heard of the dark web?
I'm not planning any changes to the current chemo regimen (Ninlaro, Revlimid, dexamethasone), since it's working very well at present, but there's no reason to think it will work indefinitely, so I keep an eye on new developments in the pharma pipeline. Myeloma is proving to be fertile ground for drug discovery and there are lots of interesting things out there, including one new FDA approval and several that are pretty far along in clinical trials--in fact, there are so many different approaches that seem to be bearing fruit that it seems like a kind of golden age in myeloma treatment. Golden ages are best judged after many years have passed, of course, so maybe it's just a lighter version of the darker ages that have gone before. But there is real progress--hard to judge while you are in the midst of it--but undeniable.
For example: in this post, the proportion of patients like me ("high-risk") surviving for a standard treatment (Single ASCT) is about 30%, 4 years after diagnosis [For the record, I am just about exactly 4 years post-diagnosis.] Given what we knew at the time, we chose a second transplant, and that seems to have been a wise choice. But that barely scratches the surface of what has changed over the last few years.
Most of what is new is that a bunch of different attacks on myeloma cells look to be working. I wanted to say "are bearing fruit", but that's almost exactly wrong. Tumor fruit is not to be borne. In any case, here's a quick rundown of what's newish.
1) Xpovio (that's the brand name), selinexor (that's the generic name). The only new FDA-approved drug for MM since 2015. An interesting story in several respects: 1) new mechanism--the drug interferes with nuclear export within cells, meaning that cells can't get the new stuff they've made out of their nuclei fast enough, leading to death; 2) it works comparatively well for patients who have exhausted all other possibilities, including those like me who are considered high-risk; and 3) it almost didn't get approved because there were a surprising number of unexpected patient deaths, balanced against the bleak prospects of those patients if they had no other options.
2) Monoclonal antibodies. Back in 2015, two monoclonal antibodies were approved by FDA. One, daratumumab (brand name Darzalex), has been a big winner in terms of patient responses, market share, and name recognition. It targets CD38, an antigen that most myeloma tumor cells express. The other, elotuzumab (Empliciti) targets a different antigen (SLAMF7), and also looks to be working well, but needs a bit of help from some of the other myeloma drugs. One major thing about the the monoclonal antibodies is that they have some major effect by themselves, but they can also be used to target anything from chemotherapy agents, to biologics, to nuclear warheads (really!) that will attack the tumor cells. More on this to come.
3) CAR-T. There are something like a half-dozen trials of chimeric antigen receptor T-cell (CAR-T) therapies in MM, and most of them look really good so far. The idea is that you harvest T-cells from the patient, culture them in the lab and attach a new receptor to the T-cells that will more-or-less specifically recognize a myeloma tumor, attach to it, and kill it. As of today, CAR-T therapies have been approved for some leukemias and some lymphomas. The upside is that they might actually cure the disease. The downside is that they are so expensive ($500k+) that they have not been widely adopted so far.
In myeloma, the trials so far have yielded very positive results, even in patients who have failed multiple rounds of treatment. It seems likely that approvals for one or more of these will be granted within a year or two. The expense issue will still be there, and the competition might be fierce, but I am looking forward to having this as an option.
Just this week, the abstracts for the December 2019 American Society of Hematology meetings have been released. It looks like several of the CAR-T trials that have been in progress have continued to have great results.
4) BiTE. Bi-specific T-cell engager. A newer, potentially much cooler approach is to make compounds that have myeloma-specific antigens on one end, and T-cell targets on the other. These function as matchmakers, bringing together the presumably fatal attraction between the tumor cells and the T-cells. Unlike CAR-Ts, they don't need cells cultured from the patients, a big plus. So far, there is a big minus as well, because the half-life of the BiTEs is very short, so in trials patients have needed to be infused continuously for 28 days. That would be hard.
I haven't seen any updates yet for this trial, but I will post them if/when I do.
There's a similar new technology, called T-cell effectors, that are also showing promising early results. The idea is similar--the molecule is engineered to bring together the antigens on the tumor with the T-cells that will kill them.
5) CRISPR. The first human cancer trials of a CRISPR-based approach to treatment for myeloma have just begun at the University of Pennsylvania, with two myeloma patients and one lymphoma patient enrolled. The good news is that all the patients are still alive after 9 months, and the edited cells are still present. It's way too early to say how this will go, but so far it's looking good.
6) Conjugates. This is a rapidly growing area, in which a monoclonal antibody targeted to some tumor antigen (CD38, BCMA, etc.) is used to introduce something toxic to the tumor cells. There are a huge number of possibilities, from basic toxins to apoptosis-inducers to radioactive compounds. Definitely an area to watch (the approach could work for many cancers).
7) The stuff that's already approved, but I haven't needed it yet. This is a pretty big list by now. It's headed by Darzalex and Empliciti, but there are other newly approved drugs that could replace drugs I already take if they fail. The Ninlaro could be replaced by Kyprolis, Revlimid by Pomalyst. Sadly, there is no better replacement for my particular nemesis, dexamethasone.
As long as the current regime keeps me in the complete response category, and the Rube Goldbergian system that pays pharmaceutical companies too much for their highly variable investments in research and (especially) development continues to pay out, I have the luxury of waiting out the results of these many, many studies.
More to come.
