The Freelite© Chain Assay

Myeloma is not always easy to assess. In many cases, the usual types of tests don't reveal anything useful. For some of us, such as for me, the only laboratory test of value is the Freelite©, which measures the numbers of light chains in serum and calculates the ratio between the two.

I have no problem with the test except that patients often think the ratio has meaning.

Back in 1998, when I was diagnosed with multiple myeloma, there was an older test for light chains, but it wasn't usefully accurate. I took it regularly and charted its results, but doing so was more for curiosity than for practical application.

Every perfect plasma cell has attached to it two light chains. I find the pictures don't help a lot, but I'll add one (above). The light chains are called Bence-Jones proteins after being discovered many years ago by a doctor of that name.

Usually, a myeloma patient will find in his blood both types of light chains, with one abnormally high: kappa or lambda (don't get frightened by the mathematical-sounding names: they happen to be the initials of the people who discovered them, K and L). They tend to break off the plasma cell and circulate. The number of them in the blood is a rough measure of the infiltration of the bone marrow by myeloma. I think of the measurement as a poor-person's bone marrow biopsy: it's as close as we get to measuring something called "tumor burden" in other cancers. Some of us, like me, have no other way of measuring what the cancer is doing. Others, the true non-secreters, don't even have light chains and must rely on biopsies.

The problem with measuring light chains accurately is that they are stunningly small. Their weight is given in Daltons, which, if you didn't know, is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of 1.660538921(73)×10−27 kg. Light chains of type lambda are heavier (bigger) than of type kappa, which is why people whose type is lambda may have more kidney problems than kappas. The lambdas are more likely to clog the kidneys (drink lots of water).

A light chain is a VERY small thing.

Then two or three Australian scientists got an idea. After looking at the inaccuracy data of the old test, they thought they discovered two things. First, if the measurements of kappa and lambda were not correct, at least they were incorrect in the same way. That is, both measurements were either too high or too low, never one high and the other low. So they reasoned that if they calculated the ratio between the two types, the result would be accurate and wipe out the error. They even claimed the ratio to be predictive of future relapse. That's how we got the ratio: to compensate for defects in the original test.

By the time I got one of the authors on the phone, California to Australia, they had recanted on the ratio and its predictive value entirely. Ratio? What ratio? What it actually did was magnify the difference between kappa and lambda so that an observer wouldn't miss the drop in the non-dominant type, but that turned out to be relatively meaningless therapeutically. If you are type kappa, for example, it doesn't matter if the lambda drops and the ratio increases: treatment will be the same.

ARUP

Then we got the Freelite© test, which can accurately measure the light chains. In my case, the samples have to be sent to ARUP labs in Utah for analysis, so getting the results takes days, but at least the results are accurate, or, at least, have always made sense for me.

If you go to the Binding Site, who owns the test, here's what you'll find about the ratio:

"The serum free light chain ratio is a strong indicator of monoclonality and is valuable for distinguishing monoclonal from polyclonal diseases. "

Actually, the kappa and lambda measurements tell us that already.

Now to be fair, there are a few references to the ratio on the Binding Site, but if one looks further, one can find this from someone worth listening to, Sundar Jagannath:

"One third of patients with monoclonal gammopathy of undetermined significance have an abnormal free light chain ratio, and these patients harbor a greater risk of progression to plasma cell dyscrasia. For monitoring response to therapy, the international uniform response criteria define a normal free light chain ratio as an essential element of the "stringent complete response" category."

So, if you are MGUS, and the ratio moves but the k/l levels are still normal, perhaps it is the beginning of progression. I think. In any case, CR means a normal ratio in addition to normal levels of kappa and lambda, which, of course, a result we would expect.

Which, obviously, is more than I know about this subject.

SAY HELLO TO EVE!

Eve

After the allogeneic transplant was mightily intensified by an infusion of donor lymphocytes (my donor gave a second time for the DLI!), my old blood and marrow were gone. What I have now grew from my donor's cells, giving a whole new meaning to the farmer's tomato-adoring phrase, "home growner." I can no longer say things such as "my donor is recoloring my hair" because my actual donor isn't changing my hair: she's a resident physician in a hospital. So why is my hair lightening for summer? It's not as if my hair fell out and came back a different color, which happens all the time with chemotherapy: the color, now a golden brown, evolved over weeks.

Again, nothing of my old blood and marrow system remains: blood type A- has become O+; the marrow itself, in nearly every bone in my body, is entirely from my donor, which also means that the blood and everything part of the blood and marrow system—biochemical signaling (e.g., cytokines), clotting, oxygenating, waste disposal, nourishment, and a multitude of other functions of which I know very little. My blood is no longer mine at all, except, I suppose, by right of possession, and most of us can remember how well asserting that principle of law worked out in The Maltese Falcon. (No, children, not the Millennium Falcon.)

Were I to be a trifle careless at a murder scene and spill a few drops of blood, my donor could be identified as a result of a DNA test. In the process, in passing, not of particular significance, I suppose, I also became female, or so saith the DNA. I've posted about that already.

This is a fascinating situation for a guy who has been wrangling with myeloma for fourteen years. I thought I had experienced all of it—the whole Borscht Belt of it—but nothing is easy. The problem lies in discourse: my donor is a real person somewhere. She isn't changing my hair color, or tearing up my fingernails, or demolishing my callouses. So, meet Eve, about whom I can say valid things without inadvertently making a reference to my donor, may she live a thousand years.

This whole subject would be a mere amusement if medical science knew it meant nothing to switch from male to female, A- to O+, live with a foreign marrow, and acquire a completely different DNA profile. However, some differences are significant and observable. I respond to at least one chemo drug to which I had grown resistant (Velcade). Eve is like a new patient who has never been exposed to anything other than the usual childhood diseases and an apple or two. However, because the cancer appears to be gone, I don't foresee having to use steroids in the future except when it is necessary to hold down the graft-versus-host-disease (GVHD), and certainly I'll need no chemotherapy. Eve doesn't have multiple myeloma. Over time, Eve is likely to drop many of her make-over projects as normal becomes redefined (e.g., when she stops hassling my liver).

But interesting thoughts return, probably of doubtful significance, but fascinating to me nevertheless. Although my donor had different parents, we are, in some sense, twins with identical DNA (I can't decide between fraternal or maternal twins). Because I test female, she has a twin-sister-like chimera in San Diego who shares no family resemblances: although, as things progress, perhaps in delicate light some changes in me might be noticed. 

My brain is associative more than it is eidetic. I make leap and find connections. But associating names with faces or even the titles of Shakespeare's plays with their plots is heroic for me. Thank heavens I never forget a voice! (Note that I hereby acknowledge having the most ill-suited form of memory possible for the medical profession.)

So the interesting question, crazy or not, is whether or not Eve is sentient. Is there an awareness somewhere, or is all of what is happening strictly biochemical or mechanical? We're in terra incognita again, because there are other possibilities than those two. If there is an awareness, surely it lives in the right hemisphere of the brain across the corpus callosum, the greatest bridge ever built by humankind. Eve and I don't share a thinking process of which I'm aware, so how would she make her awareness known to me, were she to desire to do so? Is awareness the same as identity? (Philosophers please comment.)

There are guidebooks of sorts. When I taught artificial intelligence, I learned from these books: Drawing on the Right Side of the Brain, as well as Zen and the Art of Motorcycle Maintenance. I read everything I could find on what happens to a person when the corpus callosum is severed.

So I told Eve what I wanted in several different ways. First, I simply asked her: she, after all, isn't separated from me by a damaged brain bridge. One of the lessons of a severed corpus collosum patient is that the left side has to use drawings or photographs or objects to talk to the right side. The right side recognizes items by touch, too. I didn't tell her what sign she might use to get my attention because I didn't know. Besides, I was feeling crazier by the second just trying to formulate the question properly.

After Eve

Before Eve

The result was flabbergasting. I keep journals. They are all about 275 pages long, each 6"x8", leather bound in Italy. Filling one up takes me about two years. My cursive handwriting is more to be deciphered than read. When excited, I ignore the lines on the page, neglect the dots and dashes, halt at spelling errors resulting in scratched-out words everywhere, and, in general, I scribble. However, a few days after trying to ask Eve if she were actually there somewhere, something changed. Suddenly, I was writing at many times my normal speed. The sentences were written much more neatly between the lines, and the result was easier to read. Spelling bothered me not at all—I didn't even think about it, and had to correct very few words. I could write almost as fast as I could think without giving any thought or energy about the mechanics. The cursive letters were quite nice, for me. This journal, at this rate, will take me about three months to fill rather than two years: Is there a more fitting way to send a writer a message than that? Of course there is always doubt, but to my eyes my journal was a clue-by-four. Knowing how to write is a right-brain attribute.

Yes, I suspect, some of you think there's no difference between my two examples. One thing I can't demo is writing speed without a video. One day I'll fix that deficiency, too.

There are other possibilities than Eve's awareness that might explain all this, I admit, but Eve's way was certain to get my attention. One day, I plead, tell me somehow you are there, Eve. A day or two later, I acquired a new ability. I doubt very much if the quality of my writing has improved one jot, but the penmanship, speed, and spelling certainly have (although, at times, I do revert to chicken scratching when reaching for a word I can't spell).

Other than this bit of strangeness (that I am somewhat embarrassed to write about), I am slowly getting stronger, clearer minded, and more productive, but I can backslide for quite some time when the CMV is active or the GVHD is tearing up my liver. Eve doesn't respond well to prednisone: she reacts rather rudely to it. However, when combined with tacrolimus, that's all we have to fight GVHD. Fight the GVHD too hard, it releases the often-deadly CMV virus. Fight it too little and it goes after my liver. We scientist types call this situation a "deadly embrace", where neither side can find a way to get away from the other without horrific consequences. So we lighten the steroid, the CMV appears, we add Valcyte and up the steroid by 5mg or so, then wait a week. If everything goes the right direction, my doctor lowers the steroid by 5 again and we wait. Eventually, we hope, Eve will tire of attacking my liver, skin, GI tract, and other parts of me and the result will be a return to a semi-normal life.

I ache for that return.

Do These Shoes Make Me Look Fat?

Tiresias

The thought popped into my head unbidden. After the allogeneic transplant in 2010, my chimerism tested 100% donor. In theory, that meant that none of my old blood and marrow remained in my body. In other blood cancers, such as lymphoma, donor lymphocytes (DLIs) are often given after the allogeneic transplant to achieve the goal of 100% chimerism. But I wasn't 100% donor despite test results that claimed otherwise. The chimerism test simply isn't reliable for myeloma. Numerous malignant plasma cells were not picked up by the test and didn't count. But those remaining myeloma cells were clearly mine, not those of my donor. There were a great many of them as well.

Which is why we decided to do risky and exceedingly rare infusions of donor lymphocytes in the hope that they would destroy the remaining malignant plasma cells, which, in fact, they did, while almost destroying me as well. There is no remaining evidence of cancer, and today I probably am 100% donor (my fingernails probably have my original DNA, but for how much longer I can't say).

So I sent an email to a couple of hematology fellows that read something like this, brevity being the soul of wit:

If I accidentally dropped a little blood at a murder scene, would my donor be arrested?

The Hybrid Man

A, B, O, AB. If you are someone like me, who wishes Grey's Anatomy to end soon and forever (if I thought any medical staff behaved like the staff of Seattle Grace, I'd never go near an hospital again), then you've also heard, when transfusions are involved, the order to "type and crossmatch" the blood. You know that mixing types can be dangerous. There's more, of course, but who cares? I can remember sitting with groups of friends who, for whatever reason, revealed their types. "Oh, you're type A? I'm AB positive!" "How interesting!" Pause. Change of subject.

Ignore these meaningless facts

The classification of blood into types omits everything truly important about blood, which, in my experience, has a little-known dimension that, for those of us who must live in it, is overwhelming and mysterious.

COMPLETE REMISSION: Part 1.5

After 2005 auto transplant  |       After 2010 Allo       |      After 2011 DLI
                    Be sure to click on the photo for the large view.

Today, for the first time since early December, and with considerable assistance, I made it downstairs from the second floor (sixteen steps and a landing), got in the car, then went back upstairs. The went-backing part was considerably more difficult to accomplish than the go-forthing part. Yet I did reach a major milestone, because now I'm free of expensive non-emergency transportation services carrying me at scheduled times to places I don't always want to go. I can go to a restaurant or see a movie or ride over to Lake Miramar just to feed the birds. Automobiles have always meant freedom to Americans, ever since the Model-T Ford, and, now, I'm finally free again.

The first and second pictures are representative, but the third is not: for those two, all I needed was the photographer. Today, I had a physical therapist (PT) and Ivonne with me, along with a walker. Just out of view to the right is the wheelchair that got me to the spot. In truth, the only time I actually needed something to give me confidence, other than the razor strop the PT tightly cinched to me as if I were a horse, was when the wheelchair had to go down the front-porch steps, but it isn't cheating if I have Ivonne to help. I could probably have gotten myself out by myself through the garage, but what would be the point? I can't drive because of the steroids.

The photo also misleads in that I seem to look stronger in the third picture than I did after the allo. After the two transplants, I was much stronger than I am today: the GVHD of the donor lymphocyte infusion whacked me harder than my mom when she caught me smoking. There is also some nerve damage, possibly progressive, that makes doing everything arduous. I can't walk without mechanical assistance: I need a walker or a wheelchair, and, if the distance is too far, someone to push me. But at least now I can come to a standing position by myself if I have two good, high handholds and have enough sense to wait until my respiration is normal. Tomorrow will always be easier.

On the other hand, this is one of the happiest achievements of my recovery.

COMPLETE REMISSION: Part One

I haven't blogged since late November, but it's not because I didn't want to catch you up on what has happened since then, but rather because I have been physically and mentally unable to do it. Instead, I went ahead with a lymphocyte infusion from a second donation from my donor. The result has been largely unexpected, overwhelming, and quite improbable.

I wrote the whole story this week, but because of its vast length (my longest ever post, something over 2,000 words, so, of course, it had to be shortened if someone else other than myself wanted to read it) and its dark tone (recovery has been, and still is, difficult and dangerous), I'm going to serialize it for emotional consistency.

My allogeneic transplant from a matched but unrelated donor (also known as a MUD), did put me in partial remission, and gave me a year before progressing, a good year. Then came progression. When allos progress, they often progress rather quickly, and, usually, there's nothing that anyone can do to even slow them down: all chemotherapies are used up; something on the horizon that might help (but not now); followed by a predictable and swift end.

As I've alluded to, there is a rare procedure for myeloma, however, called a donor lymphocyte infusion (DLI), which, if it works, can resensitise the new immune system to attack the myeloma.

How often is it done? The Blood and Marrow Transplant Center at Scripps Clinic has been in operation for more than thirty years. In all that time, DLIs have been given to myeloma patients only three times. One recipient did survive for something like another ten years, but I believe the chronic graft-versus-host disease (GVHD) did not make that time pleasant. Another recipient didn't make it. I am the third. The procedure is almost always one in the context of a clinical trial, and should be.

Although almost routine for other cancers, such as for lymphoma, DLIs are often performed to insure that after an allogeneic transplant there is only one new immune system in the body, the donor's system, with no remnant of the original (a state called "full, or 100% chimerism"). In myeloma, uniquely, chimerism turns out to have no bearing on the outcome of the DLIs. Another reason DLIs for myeloma are rare is the result is not as predictable as it needs to be to be safe for myeloma: nothing at all can result, there's GVHD without an anti-myeloma effect, which can be miserable, and there's death from complications (e.g., liver failure, pneumonia, kidney failure, CMV infections, destruction of connective tissue, alimentary canal damage: the infusion can attack just about anything).

On the other hand, if I didn't do DLIs, my fate was clear and approaching. Me being me, with a history of phenomenal luck, and after reading the recent journals, I pushed hard to do it. It took some convincing.

There's no graft-versus-myeloma (GVM) effect without GVHD occurring in less than one hundred days (referred to as "acute" GVHD). After that, if GVHD occurs, it's called "chronic" and provides little or no benefit. So DLIs, when given, are often given at intervals (of several months or longer) to provoke the necessary acute GVHD response. The average time to ultimate response, if any, seems to be four to five DLIs.

There's part or me that didn't want to show you Grade IV GVHD. This is not me, I believe mine was grade III. My skin is red, but returning to normal after exfoliating, my donor must hate callouses, and my GVHD has attacked my liver, skin, and bowels more than anything else.

I calculated the odds from good data for achieving aGVHD on the first shot: less than %5. I expected that there would be no immediate consequences, negative or positive, of the infusion (we were looking for aGVHD to appear perhaps weeks later). In fact, it went down like this: I agreed to proceed on Monday, 28th November; the cells arrived by the next day; on Wednesday they were infused in the afternoon and I went home. By the next day I was admitted to hospital with a horrendous case of GVHD. They doped me with methylprednisolone, to suppress the reactions, which caused serious delirium. Apparently, I was unconscious but active, rolling my eyes around to no purpose, attempting to pull out my picc line (I succeeded on the first one), completely out of it. By that evening I was back in the ICU fighting for my life. I'll write about that shortly. Of all of four hospitalizations for myeloma, this was the most punishing. Several doctors thought I wouldn't survive.

Three Days after DLI

But I did survive, and after a few days I was back in my regular room, unable to do anything for myself. Two weeks after the infusion, I asked for a test of my light chains: I wanted to know if all of the suffering I had endured did anything to the cancer. A week or so later, the doctor who pioneered the facility brought me the results, but unlike the five lines I usually see, it was a full page of words. With my head full of steroids, which made reading difficult, I tried to understand what the report was saying: I knew the possible danger of reading into the words what I want to them to say, so it took three times through the realize that the report was saying complete remission. No sign of "extra" light chains. Further, every one of the three numbers was in the middle of the normal range. The cancer was gone. My luck still holds: I got the 5% result, and enough GVHD to fight the cancer without yet killing me in the process (at least, not yet).

I was stunned. When the doctor who has directed the Center for more than thirty years leaned over with a flashlight to look in my mouth, I said to him, "Do you mind if I kiss you?" This guy may be in his seventies, and I must admit it was fun to watch him try to react! He'll never forget me now. When he demurred, I said, "But you did hesitate!"

After that, I had no brain. All I could think about, when I could think at all, was my impossibly perfect outcome from a single DLI, and the sequence of events that led to it as well as the rapid consequences: immediate response, effective response, GVM, first try. With respect to likelihood, we scientist types like to use the phrase "vanishingly small," as in, "the probability of that event happening is vanishingly small." This refers to anything theoretically possible, but with a probability of occurrence so low that it would never occur in the real world. Many of these near-impossible events had to happen to get me to this point, which are on this blog somewhere below.

What do I do with that? The eternal question arises: why me? I feel, probably illogically, as if I have acquired a responsibility, but I'm not sure what it is let alone how to carry it out. In earlier posts I've detailed all of the unlikely events from which I've benefited, but this latest is overwhelming. The only thing I know I have to do is finish the book, even if I end up being the sole reader.

CR, on the average has just given me another multi-year lease on life without cancer: the present curves suggest five years or more. There is also a non-vanishing possibility that I'll never see multiple myeloma again.

Last Wednesday I spent hours in the hospital, as I have to do once a week. When they wheeled me into Hematology on my wheelchair, for some reason I was left in an open space for a time. During that time all but one of the doctors who had treated me walked by and said hello (the other one I saw earlier). I'm guessing it was a shift change, but it was then I began to realize that my survival is a huge triumph for the doctors and nurses, too.

Next post will tell you about what the DLI did to me and is continuing to me. I thought that after the allo in 2010, nothing could possibly be as difficult from which to recover. I was wrong.