Waldenstrom's macroglobulinemia: How to cure WMThere are 3 major options for a cure to WM:
I used to believe #3 was the best option for a cure. I currently believe #4 is best. See The approach I'm taking to cure my disease Here was my fomer reasoning (that is now obsolete): A new miracle targeted drug would be great. Suppose we could engineer an antibody that only attached to WM cells and killed them instantly. We'd have a perfect killing machine. Gleevec for CML comes to mind. So this is possible. Somewhat of a long shot since there are very few wonder drugs but 6,000 (?) different cancers. Aggressive use of traditional drugs (chemo drugs and Rituxan) can be used to permanently cure WM. Unfortunately, you'd have a high chance of dying along with the WM if you use any of the traditional remedies. The only way you have a chance to cure WM with traditional drugs is to use so much of the drugs so as to drive your B-cell counts to zero for at least a week if not 2 weeks to make sure they are all dead. At that point, your WM cells will also be zero. But you will probably die too. So this is an option, it's just not a great one. The point is this: the traditional arsenal just doesn't have the drugs you need. A single semi-targeted drug plus a chemo drug (which is untargetted) will NEVER kill WM without risk of killing the patient. Never. Doesn't matter how you combine them or how you dose them. Think about it. Every drug is hitting all your B-cells at a minimum. So to wipe the WM, you have to reduce your B-cell count to near zero. That will probably kill you. You need at least two different drugs where the damage has nothing in common other than killing the WM cells. The traditional arsenal doesn't give you that. So it should come as no surprise that CHOP, rCHOP, etc. treatments never produce complete remissions that last. WM always comes back. It is mathematically guaranteed not to work (unless you kill all your good B-cells too)! The third option is something no one is doing right now in humans. It cures WM the same way you got it: relatively slowly. But it doesn't do it with one drug. It does it by continuously rotating a set of drugs at very low dose over a long period of time. This minimizes side effects and the WM cell counts decrease exponentially over time (on an absolute basis, faster at the beginning; slower at the end; but on an exponential basis, the decay half-life time is constant over time as long as the drug concentrations are the same over time). This is because the only thing all these drugs have in common with each other is that they all affect the odds of survival of a WM cell and ONLY a WM cell. Therefore, collateral damage to other parts of the body are minimized because while the other drugs are administered the body has time to recover from the earlier drugs. The more drugs we use, the less the collateral damage because you increase the recovery time for good cells. Here's the analogy. Suppose you have a casino (your body) that has cash (WM cells) all over the place. The casino got all that cash over a long period of time because every time someone played, they lost a little money because the odds are slightly in the house's favor. The cash in the casino fluctuates from month to month. Sometimes it is down, sometimes up, but over the long term, it is slowly growing. Just like when you play blackjack... your stake varies up and down over time, but if you play long enough, your stake is going to disappear. You want to rob the casino of all that cash without the casino noticing and changing their behavior. So on day one, you send in enough customers (drugs) that know how to cheat so that the odds are in their favor. They play for a day at the craps table. Then a different set of customers come in on the next day and they are experts at cheating at roulette. The bottom line is that every day the casino now is losing money (WM cells). But the side effects are minimized since any given part of the casino is only under "stress" for one day before returning to normal. This analogy isn't quite perfect, but you get the idea. So the first step is to come up with a list of new drugs that have a short time constant and differentially affect WM cells more than other cells; the less collateral damage the better. The next step is to prune the list so that the ONLY thing these drugs have in common is the damage to the WM cell. So if you have a drug that affects all B-cells, you should try to make sure that all the other drugs you choose do not affect normal B-cells. It doesn't have to be perfect, but the fewer the commonalities the better. So Rituxan is not such a great drug. It is differential in that it affects WM cells more than other cells, but it is not very selective (affecting all B cells) and it has a long half life in the body. Chemo drugs are worse. They aren't selective toward WM cells and kill everything. When used with each other, there is 100% overlap. The only good thing about chemo drugs is they have a short lifetime. You'll never permanently cure WM with chemo drugs unless you kill all the white cells and then find a way to revive them, e.g., a bone marrow transplant. The theory matches practice. Newer drugs such as Velcade, Perifosine, enzastaurin, etc. are both selective to WM cells and have a short lifetime. (is this right?) So you give these drugs, one at a time, in rotation, at a dose that is sufficient to reverse the odds so they are in our favor. The stronger the dose, the faster we can kill WM but the more likely the side effects are. So we'll have to play with the dose. It will either be a very mild dose over a year or more, or a stronger dose over a shorter time. We'll have to see which has the fewest side effects. The more drugs we can rotate, the better since it gives the body time to recover from the collateral damage and minimizes side effects. Drugs with fewer and non-permanent side effects could be used in higher doses. So what happens is that the WM cells are constantly hammered by each of the drugs. But any other cell in your body are only being affected by ideally at most one drug out of the rotation. It is sort of like a gamma knife where the 200 rays aren't strong enough in any single direction to do damage, it is only at the point where all 200 rays intersect that the damage happens. Same here. The WM cells are the only ones that are hammered by every single drug; each drug is hitting a different mechanism for WM cell survival and multiplication. Other cells are only affected by one, maybe two drugs. We rotate the drugs so that the collateral damage to any other cells are minimized and have a chance to recover before they are hit again. The other cells never really get hit hard enough or long enough to cause any change from normal levels. The WM cells, on the other hand, are being hit continuously so that they slowly decrease in number over time. So the key parts are:
It's possible that a single cocktail of all drugs might actually be better than serially cycling through the drugs. With a cocktail, the amount of each drug we'd have to use will be quite small. So the collateral damage will be quite minimal, but it will be continuous over time. So it's possible that the ultimate solution might be some combination of a cocktail and serial rotation, e.g., serially rotating cocktails. But it's not so simple because even if you find a drug that only affect the WM cells with minimal collateral damage, there is a good chance of drug resistance. To a cell, a drug is simply another new environment that, given the opportunity, it will adjust to. That is because cancer cells are constantly mutating.. So the danger in more subtle approaches is that the cells will adapt enough that they don't die. These may eliminate some drugs from consideration. But we know there are lots of drugs (such as protein kinase inhibitors such as Gleevec) that maintain their efficacy and can be used at low doses over long periods of time where the cancer is unable to mutate to bypass the pathway. Wouldn't it be remarkable if there was a natural hormone, for example, which when restored to normal levels shifts the chemical balance such that the odds are in our favor for WM cells decreasing? The longer the period of treatment, the greater the chance of mutation. So you'd like to kill it as quickly as you can subject to the time constants The drugs used can work indirectly too, e.g., by shifting cytokines and chemokines in the blood and marrow. Hypoxia can also shift the odds. Maybe high cholesterol, or aspirin, or Sudafed, or iron, or vitamin C, etc. can shift the odds of a WM cell dying. All we need is a set of those drugs and chemicals that can tip the odds in our favor. The bottom line is that people have been trying to kill WM with a sledgehammer. That will never work because you can never hit all the cells without killing the patient. It's smarter to be patient and use a combination of drugs that shift the odds so WM cells are more likely to die than to live and kill it slowly over time. Today, few people think of curing cancer by just slightly shifting your normal body chemistry to change the odds and killing it slowly over time with a continuous rotation of a large number of low dose drugs, each drug hitting a different support mechanism and having different collateral damage. Maybe it is time to consider this. This can be tested in mice. To get started, we should have NCGC test all the FDA approved drugs against the WM cell line. This has never been done. The more drugs we have in rotation, the better. In theory, you only need two good drugs to cure WM. Two drugs are sufficient, but more are better. You probably can't do it with one drug (unless you are lucky enough find a drug that targets a pathway that is totally unique to the disease with minimal effects elsewhere and that is going to be VERY unlikely). But two drugs are sufficient as long as the only thing they have in common is they both impact the bad WM cells. So for example, you apply drug A for a week. The WM cells go down and so does cell group A. Then the next week, you apply drug B. During this time, the cells in group A will recover back to their normal level while those in cell group B are being hammered. Since the only cells in common between cell group A and B are the WM cells, the WM cells decrease every week while the other cells all remain close to the level they were before the treatment. Two mobilizers:
Six drugs:
Other potentials:
So for example, you'd set the dose of each drug at a level not to cause any immediate or long term side effects. You'd dose once a week, with a different drug each week for the first 4 week, then continue the same rotation pattern. To be safe, you'd set the dose so that normal cells recover in a week, i.e., a conservative dose. The mobilizers would be alternated every week since there are only two of them and again, administered at a level that doesn't accumulate side effects. This just enhances the treatment so it isn't strictly required, but it does speed up the kill which is good for minimizing resistance. Only drugs that alone are shown in test doses to reduce the disease in the individual should be used since there is no point in suffering unknown side effects from drugs which aren't effective. You also need to retest each drug periodically since it's possible that the drug can stop working. It's possible that combining all 4 drugs and then waiting for the things to return to normal may be a lot more effective since you may get synergy. However, it may also trigger unknown and unpleasant drug interactions. So it's worth trying in mice. To determine dosing in mice, you look for signs that something is wrong: weight loss, skin changes, fur changes, etc. Current plan of attackI like drugs that are targeted and live a short time and are proven effective in WM. That's means I'm down to one drug: Velcade. But WM is slow moving, so I have time. Velcade has a half life of 9 to 15 hours. And it takes the body at least 10 days to recover from a round of treatment. 1.3mg/m2 is found to be too high in some patients. 1.0mg/m2 reduces neuropathies but is ineffective against the cancer. The other thing I'd do since I can't get AMD3100, is to see if G-CSF mobilizes WM cells into the bloodstream. It takes a week of daily injections for AMD3100 to maximally mobilize the WM cells. So that's probably too high a price to pay. Giving Velcade at 1.3mg/m2 1x/week has proven effective. People have been doing this on maintenance in multiple myeloma for 2 years without any problems. If there are neuropathies, you can decrease the dose or increase the time between the doses, e.g., once every 2 weeks. By keeping the disease at a low cell count, you minimize the chance of it reoccuring. Since WM cells live for 2 to 3 days, it means that bombardment with a 1x/wk dosing schedule doesn't provide any additional benefit. It is purely increases the number of cycles. By hitting it more often, you are just increasing the kill rate. But since WM is really slow moving, this isn't required; it's not like you are going to lose a lot of ground in the interim. Because there is no known mechanism of resistance to Velcade and no new cumulative toxicity with extended therapy, it should be quite a safe and effective choice. The trick to keeping your remission is to continue treatment past when the IgM's return to normal. After all, even if you kill all the WM cells, there could be a stem cell lying around. Using the rate of decline and the IgM level at the start of treatment, you can then estimate how long it takes to kill all the WM cells (if you can calculate an absolute cell count from the concentration). You need to keep treating until the cell count drops to zero, e.g., bone marrow examination. I'd bet that 1x/month of velcade would be more than adequate as a maintenance regimen. There is no reason to delay treatment. The earlier you treat it, the sooner you'll be cured and the less chance for side effects caused by the high IgM. Velcade is about $1,000 per bottle. It might not work at all. Dosing at 1.0mg/m2 is probably going to be ineffective. Dosing at 1.6mg/m2 is probably ok for the first few doses. You want to hit it the hardest at the start since that is where you can kill the most cells. A few patients taking Velcade + Rituxan have had a complete remission after only a few cycles. Same is true for CPR. everyone's response to these drugs is quite variable.
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