Waldenstrom's macroglobulinemia: Treatment ideas

By Steve Kirsch
August 11, 2007

In July 2007, I was diagnosed with a rare incurable blood cancer. I have slightly more than 5 years left. This page describes what I'm doing to try to save my life and the lives of others with this disease.

First, a very short course in hematology. Blood is composed of a yellowish liquid called plasma, red cells (which are the majority of cells which is why blood appears red), white cells, platelets (used for clotting). There are 5 different kinds of white cells: neutrophils, monocytes, lymphocytes, eosinophils and basophils. In turn, there are three major types of lymphocytes: T cells, B cells (aka B-lymphocytes), and natural killer (NK) cells. B-cells, which are created in your bone marrow, are critical to your immune system since it is these cells that produce antibodies that fight off disease. Each B-cell has a unique receptor protein (known as the BCR) on its surface that will bind to one particular antigen (an antigen is a molecule that stimulates an immune response). Once a B-cell encounters its cognate antigen and receives an addition signal from a T helper cell (this is ususally, but not always required), it will then differentiate either into a relatively short lived plasma B cell (aka plasma cell) or a long living memory B cell. In this disease, we are interested in the former: the plasma cell. So plasma cells are large B cells that have been exposed to an antigen and are now secreting large amounts of antibodies in order to attack and destroy an enemy (whereas before activation, the B-cells only express surface bound IgM). In WM, it is these plasma cells which multiply out of control and produce excessive amounts of the IgM antibody class. There are 5 different classes of antibodies: IgA, IgD, IgE, IgG, and IgM; the IgM class antibodies are produced quickly and in high volume when a pathogen occurs and before IgG take over the longer term work of destroying the pathogen. These diseased plasma cells invade your bone marrow and other parts of your body. For example, one person unable to walk, reported two tumors in their foot and a PET scan, then MRI, then biopsies revealed their heel bone and soft tissue tumors were all completely infiltrated with WM cells.

The only good news in all of this is that if my body becomes infected with the one specific disease that matches my antibodies, I'm completely immune because I have more defenses against this one disease than anyone else on the planet. The bad news is there is no way to tell what I'm immune to! Each person with WM is immune to something different.

Our first step is to figure out what is different about these B-cells. Because a bone marrow transplant from a human into a mouse induced the disease, it probably means that there isn't something external to the the bone marrow that triggers the disease. However, we can't totally rule that out because it could be that the original triggering mechanism lies outside the bone marrow and then, one triggered, the disease is self-sustaining through multiplication of somatic cells. The cause therefore is one of four things:

  1. the B-cells themselves are created with a genetic defect (e.g., because the stem cells or other B-cells that create the B-cells are also defective or that the stem cell is told by some outside force to create a genetically defective B-cell),
  2. the B-cells are genetically perfect, but there is either an antigen or something elsewhere in the bone marrow such as a mast cell that is sending instructions into those B-cells to make or allow them to produce high IgM antibodies
  3. the B-cells were created without any genetic defects, but something external to the cell changed them during the maturation process so they are now genetically defective
  4. one or more of the above

There are many papers such as Gene expression profiling of B lymphocytes and plasma cells from Waldenstrom's macroglobulinemia indicates that WM B-cells are indeed genetically different. Deletion of the long arm of chromosome 6 is the most common cytogenetic abnormality found in WM. Therefore, it must mean that at least 1 or 3 is true, i.e., either the cells were born with a genetic defect or they "developed" their defects after birth. But just because these cells are genetically different, it doesn't necessarily mean that the genetic difference is the cause of the problem. That's the natural conclusion, but you cannot rule out the possibility that each of the genetic differences are all completely benign (or that it just creates a "susceptibility" to some molecule that is normally present in the blood) and that there is a "mystery antigen" that is causing the IgM flareup.

Our next step is determine, if it is a defect, whether it is "at cell birth" or an "acquired" defect that happens after a perfect B-cell is born. I'm not sure how you do that, but there must be a way. This step may not be required but it might be helpful in eliminating treatment options.

Next, we need to understand whether it is the sheer number of plasma cells that is the problem, or that the number of plasma cells is normal but they are just secreting IgM much faster than normal. My best understanding from the papers is that the abnormal plasma cells do not die (normal plasma cells don't live very long).

Then we need to understand whether these IgM antibodies all look alike or are they different?

Once we have an understanding of how the disease operates, our last step is to determine what the best treatment path is. There are at least 16 possible treatments avenues to consider that I can think of off the top of my head:

  1. repair the genetic defects in the circulating B-cells, e.g., gene therapy
  2. kill just the defective B-cells, e.g., something like Rituxan (which unfortunately kills both the defective and healthy B-cells since both exhibit positive CD20)
  3. Prevent the defective B-cells from being created, e.g., it's possible (but unlikely) that the stem cells that create the B-cells are perfect and that there is some environmental factor that causes the perfect stem cell to create a defective B-cell either when it is first created or sometime during the recombination/maturation process of the B-cell. Drugs such as Belimumab prevent the creation of all B-cells, rather than just the defective B-cells which is what we want.
  4. fix the defective stem cells so they no longer creates defective B-cells, e.g., gene therapy or SCT
  5. kill the defective stem cells so that defective B-cells will no longer be created
  6. destroy the IgM that gets created by the defective B-cells (this may be completely useless other than reducing serum viscosity)
  7. remove or somehow neutralize the mystery antigen that is stimulating the B-cells to produce IgM (assuming there is such a mystery antigen)
  8. inject something that will bind to the defective B-cells and keep them busy until they are dead so that they do not produce IgM.
  9. Get rid of the supporting infrastructure or inhibit communication with cells (such as bone marrow mast cells) that are enabling the support of lymphoplasmacytic cell growth. In any cancer, the cells need a support structure in order to support the higher than normal growth. Also, there may be some kind of signaling mechanism that tells these defective cells to grow. If you can either remove the guy sending the signals, or inhibit the signals from reaching the receiver, you may be able to stop the growth of the cancer. Similarly, there may be cells or other supporting infrastructure that the cancer cells need to survive and multiply. In traditional cancers, for example, the cancer needs to grow excess blood vessels in order to supply the evil troops with food. So if you can cut off the energy supply to the malignant cells, they will die of starvation or neglect.
  10. understand why the body develops resistance to the existing chemo treatment and circumvent it so that treatments may be repeated as necessary to keep things under control. This likely isn't a very viable strategy for at least two reasons: 1) if this was easy, we'd have antibiotics that people don't develop a resistance to and 2) the more stress you put healthy organs under, the greater the chance they will fail on the next treatment.
  11. Prevent the defective B-cells from replicating (currently, I don't understand whether the stem cells create all the B-cells or whether the stem cells create some B-cells and those B-cells replicate or both)
  12. Cut short the normal lifespan of the defective B-cells, i.e., so that they die sooner than the life of a normal B-cell
  13. Prevent the defective B-cell from living an extended life (this assumes the defective B-cells live longer than normal B-cells or replicate forever or replicate at a more rapid rate than normal)
  14. Reduce the number of replications of the defective cells, e.g., either entirely prevent the defective cell from replicating itself or do something that impedes the defective cells from replicating out of control either by slowing down the rate of replication or the total number of offspring.
  15. Figure out a way to make more IgM cells class switch into some other class such as IgG. I have no idea if this would be effective; if you could do it, it would be much more of a treatment than a cure and it isn't clear that the cure would actually be an improvement.
  16. If the B-cell is T-cell dependent, then if you can stop the T cell from helping out a diseased B-cell, the plasma cell will not be created. On the other hand, if the T-cells are the problem because they are defective and when a defective T-cell activates a B-cell to create a defective plasma cell, then we need to understand that more.

And here are some things I'd like to understand better:

  1. Is the disease is due to oncogenes that have been turned on or by tumor suppressor genes that have been turned off?
  2. There are many DNA changes in WM cells. Which one(s) are significant, if any?
  3. How important is the excess production of interleukin-6 (by the dendritic cells in the bone marrow) to the disease? Is reducing the IL-6 production effective in slowing WM?