Waldenstrom's Macroglobulinemia: My story
By Steve Kirsch
My name is Steve Kirsch. I am a serial entrepreneur and philanthropist (see Steve Kirsch Wikipedia profile). I was recently diagnosed with a rare, incurable blood cancer that might kill me. I have enough time to change the outcome and I'm going to try to do that. This is my story.
I've had monoclonal gammopathy of undetermined significance (MGUS) since at least 2000 when a high sedimentation rate (ESR) caused my doctor to refer me to a hematologist, Steven Coutre at Stanford. The ESR is basically like the "check engine" light on a car. It signals that something is wrong. Coutre discovered I had an elevated IgM of 1260 (which explained the high Sed rate because the huge quantity of IgM basically skews the Sed rate test). MGUS is a fancy way of saying that there is something abnormal about the plasma B-cells (aka plasma cells) in my blood that is causing them to produce huge quantities of the IgM class of antibodies. These diseased plasma cells live virtually forever (it is believed that they originate from memory B cells which normally live for decades whereas normal plasma cells have a lifetime of months), they produce antibodies continuously, and they keep cloning themselves. On my most recent physical in 2007, my blood test indicated I was anemic. My Complete Blood Count (CBC) had a low hemocrit (HCT) of 31.9 (which explains my anemia), a low hemoglobin (Hgb) of 10.6, and a low red blood cell count (RBC) of 3.72. However, my platelet count (PLT) was high at 524, and fortunately my white blood count (WBC) is normal at 9.5. My metabolic panel showed a high globulin (6.8), a high total protein (9.6), a low albumin (2.8), a slightly high creatinine (1.2), and a high glucose (141).
On July 3, 2007, I saw Coutre again who, after looking at my blood tests and doing a physical exam, conjectured that my MGUS had progressed to full Waldenstrom's macroglobulinemia (WM) which is a type of lymphoplasmacytic lymphoma. He had warned me back in 2000 that this was a possible consequence of my MGUS. Light chain analysis shows my my IgM light chain is kappa (80% of WM patients are IgM kappa; the other 20% are IgM lambda). Electrophoresis showed that my monoclonal IgM (aka M-spike) has more than doubled to 2.7 g/dl (which is about 10 times higher than normal), and I have a high kappa/lambda ratio of 1.83 (most WM patients have a higher kappa) and a high Beta-2-Microglobulin of 2590 ng/mL. He advised me to do a bone marrow biopsy (BMB) to confirm the WM diagnosis which I did the same day.
Tip: The BMB isn't exactly fun. The CT- guided BMBs are usually less painful. But a really good physician can also do a good job especially if he drugs you up before the procedure.
On August 10, I inquired as to the result of the bone marrow biopsy test and they faxed me all my test results. The results of the biopsy are variable depending on where you take the sample from (your WM is NOT uniformly distributed) so one sample isn't really definitive. However, it's the best we have; it's the "gold standard." The biopsy confirmed Coutre's diagnosis with a 10% to 15% involvement of lymphoplasmacytic lymphoma. In other words, it's quite possible that I'm going to die soon. That was a real shocker. And wow, I didn't even getting a phone call from the doc telling me the bad news. I had to call them!
Today, according to all the peer reviewed papers I'm aware of, WM is, for most people, an incurable death sentence. The Shah of Iran, former Algeria President Houari Boumedienne, and former French President Georges Pompidou all died from WM. According to the medical literature, half the people die within 5 or 6 years from first diagnosis. 80% are dead within 10 years (see page 8). It is very serious stuff. You will likely either die from the disease or from the treatments you take in trying to fight the disease.
Fortunately for me, WM is a slow moving cancer and there are many people who have lived 20 years or more with WM. Today's treatments, such as Rituxan, LBH-589, RAD001, etc. dramatically increase the median survival time. The numbers cited in the peer reviewed papers are based on old data. The reality is that we won't know the latest numbers until the people who are on the current treatments die. So the currently published mean survival rate numbers are always backwards looking and somewhat on the pessimistic side. So that's the good news. I've probably got at least 10 years left.
The International Waldenstrom's Macroglobulinemia Foundation (IWMF) is emphatic that you are more likely to die with WM than from WM. That's absolutely true. A retrospective study of 337 patients done in 2006 by Dr. Irene Ghobrial, et al. (Br J Haematol. 2006;133:158-164) showed a median disease-specific survival of 11.2 years (from time of eligibility for treatment) and, more importantly, a median survival from all causes of 6.4 years from the date of diagnosis. That last number is troubling since the 6.4 year timeframe would include people treated with newer drugs such as Rituxan which was approved November, 1997. However, it's skewed in terms of age so since WM strikes later in life, your mean life expectancy is pretty low at those ages, even if you didn't have WM. If you measure from the time of diagnosis (rather than start of treatment), then it is 12 to 19 years.
So statistically, once you are diagnosed with WM, more than half the people make it past 6.4 years, even though most of the deaths are not from the WM itself. More meaningful would be the median survival from all causes for people who are diagnosed at my age. Unfortunately, that number isn't readily available. Not that it would make a difference though. As of December 2007, my WM had progressed to affecting my vision so treatment isn't optional. I'm on the treatment train and so my objective is to halt or reverse this disease without killing the patient.
At the Atlanta IWMF conference in 2007, Joanne Pavia asked, "We're told we don't die FROM WM, but WITH it. Yet we also see lifespans mentioned. If the WM isn't killing us, what is?" Almost all the doctors weighed in. They basically said it's the treatments that weaken our systems, our organs, in addition to the WM itself, and we contract other illnesses, sometimes as a result of those treatments, that do us in.
While you have WM, the symptoms can range all over the place. A lot of people don't miss a beat and have virtually no symptoms. Others report symptoms (from either the WM or the treatments) including peripheral neuropathy (often caused by Velcade and by unnessary chemo such as Vincristine and other "-ines"), the WM and can be so bad that you cannot work), blurred vision, fevers, weakness, mental fog (which can inhibit productive thinking and reasoning), severe anemia, enlarged spleen and liver, enlarged internal abdominal lymph nodes, liver damage, severe fatigue, anemia, nose bleeds, transient stabbing pain, low energy, nasty attitude, sweats, loss of appetite, weight loss, rashes all over your body, swelling and pain in elbow, hands, or feet (that even morphine won't stop), permanent muscle weakness, more likely to get an abnormal type of shingles (often due to Fludarabine), coma, blindness, deafness, and so on. And WM can morph into other bad diseases like Diffuse Large B-Cell Lymphoma (DLBCL). So depending on the person, it can range from not noticeable to severely debilitating. Some drugs increase your susceptibility to shingles. When the IWMF recruited fundraisers from the membership, they found that 20% were so disabled that they couldn't work.
I'm 50 years old as I write this. I checked my prognostic factors using this paper summarizing the survivability data (see the last page). Risk factors include age, level of beta-2-macroglobulin, low hemoglobin, and low platelet count. According to that paper, I have slightly more than 5 years left. However, that paper is based on old treatment protocols so the survivability prognosis is better today than it was but I don't know how much better. Statistically, I have to acknowledge the fact that, while unlikely, it is possible that I'll be unable to see my youngest daughter graduate from high school. It's possible that I won't even be around even to see her graduate from elementary school. This is a great disappointment for me. But what really hits home for me is thinking that my youngest daughter may not have a Dad who is around long enough to see her graduate from elementary school and that my second youngest daughter will have a father who might be dead before her high school graduation. And that I will be leaving my wonderful wife Michele with a family of three kids to raise solo. All those wonderful plans we had about how we were going to spend the rest of our lives together...those plans have...well, shall we say... changed.
WM is a rare blood cancer. Less than 1,500 people per year are diagnosed in the US. Funding from the government is almost non-existent because the numbers are so low it's considered an orphan disease (the only researcher in the country with an NIH grant for WM is Irene Ghobrial at DFCI).
Despite the description of this disease by Dr. Jan Waldenström in 1944, until very recently, very little progress into the pathogenesis and treatment of this disease has occurred over the past 63 years. Thanks to the dedicated work of research groups at Dana Farber and other locations, fundraising efforts by people associated with the IWMF and the RFW, and generous gifts from wealthy WM survivors such as Peter Bing, there has been a lot of progress that has been made on this disease over the past 10 years.
The International Waldenstrom's Macroglobulinemia Foundation appears to be the largest funder of research; to the tune of less than $2M per year. I looked at the list of contributors to the foundation. It is dominated by people who gave "In memory of ..." I cried when I read that. Then I imagined my name being added to that list in the not too distant future. How sad is that? A disease whose research is, in essence, being funded by a bunch of dead people.
You are probably wondering, "why doesn't the government fund this? After all, more people in the US die each year from Waldenstrom's than from terrorism!" See The real enemy isn't the terrorists for my opinion on this.
Due to the limited funding, there are less than 35 researchers in the whole world focused on this disease. There is an international meeting of everyone working on Waldenstrom's macroglobulinemia that happens every few years where researchers share their research. And there is a research group at Harvard that is spearheading national and international efforts to bring innovative basic and clinical studies to WM.
Even though the disease has been known for more than 60 years, there are still no FDA approved therapeutic agents for the specific treatment of WM. There are about a dozen different treatment options: chlorambucil and prednisone, and more recently, fludarabine (Fludara) and cladribine. All of these are chemo therapy that kills everything in sight and there can be permanent side effects (like kidney failure). There is also a relatively new drug Rituxan which is an anti-CD20 monoclonal antibody. Combining the drugs has shown to be more effective than a single drug. Alone they are all about equal in effectiveness. They can reset things for a while but eventually, the cancer always returns. And the remissions get shorter and shorter each time. Rituxan, which is the most targeted and has the least side effects can kill you within 24 hours after you take it (0.4% chance), it takes about 3 months or so before you know whether it is working, and typically only works for 8 months before symptoms degrade again but it is often only 6 months and some people have reported things start going bad again after only 2 months. So if it takes 6 months to get the max effect, then you'll be back where you started after 12 months (a very symmetrical cycle). Even if you go on "maintenance Rituxan," some people believe that can only be used safely for about 2 years. The good news is that maintenance Rituxan will somewhat extend your lifespan. But typically, only about half the people will receive a benefit. And many people are allergic to it and can no longer take it (even after being treated successfully many times). This is presumably due to the fact there are mouse antibodies in it (there is a human version coming out soon). There are other options such as stem cell transplantation (SCT) which is risky and has up to a 12 month recovery period and plasmapheresis (PP) which is supposed to be risk free, but only lasts a very short time and only affects blood viscosity. I know people who tried PP and found that the results were worse than the nerve damage without the treatment so they opted for the permanent nerve damage instead of the treatment. Each patient is different in their reactions to the treatments, there are no miracle drugs that almost always work, and all the treatments carry some amount of risk and side effects (sometimes permanent). So it's not like there are a lot of great options to choose from.
For a list of drug options, see Waldenstrom's macroglobulinemia: Drug options
Statistically, I probably have more than 5 years to live. What do I plan to do? Not the protocols that anyone else has used before. Those don't work. Here's a plan that I think has a great chance of stopping or curing this disease: My treatment plan.
Having been involved in medical research through the Kirsch Foundation, I know that medical research normally takes at least five years, and more often a lot longer, to find answers to problems, even if you do everything right as we did with Catalyst for a Cure which has made remarkable progress in finding a cure for glaucoma. So if my treatment plan doesn't work and we have to do more research, it's possible that whatever I do to find a cure may likely be too late to save my own life.
But that doesn't mean I shouldn't try. I remember as a kid learning the old saying that "nobody ever won a chess game by resigning." Who knows. Maybe I will get lucky.
I believe that people make their own luck. I think my best chance of survival is to advance the science by intelligently directing funds into research that is likely to do the most good including bringing in fresh eyes from outside the field.
It appears that there is very little money being applied to the research and the research is focused more on finding the best treatments rather than in understanding the underlying mechanisms that cause the disease.
My strategic bet is that if we are to cure this disease, it won't happen by doing the same things over and over and expecting a different result.
That's why I developed my treatment plan.
In parallel with that, I'd take much the same approach we did with Catalyst for a Cure: raise the funding, find a chair for the Science Advisory Board who is world class, find researchers in complementary fields, get an animal model, and focus the entire collaborative effort on first understanding the cause and the mechanisms, e.g., by profiling changes in gene expression using micro array analysis.
Having an animal model of WM is extremely helpful. For glaucoma, we had mice with the disease which was critical to making progress. Fortunately, we can now do the same with WM as described in this 2005 paper, A SCID-hu in vivo model of human Waldenstrom macroglobulinemia, where they transplanted human bone marrow into mice which then manifested the disease.
So we are actually in a very good position to make significant progress.
I've listed a bunch of questions we need to answer and treatment approaches than might be available.
However, the reality is that few people are going to get "excited" about giving massive amounts of funding to a disease that they have a low chance of getting. So I thought that the scope of the research would need to be broadened to "lethal orphan cancers" since the dollars a donor would give may very well end up saving their own life someday, just like it might save mine. But when I test marketed this concept with friends, they told me that if they were going to give a donation, it would be specifically for my disease in order to help out a friend. Therefore, a more generic mission would, to my surprise, make them less likely to give.
The objective of the effort is to develop "wonder drugs" for orphan lethal cancers similar what Gleevec did for chronic myeloid leukemia (CML). For that rare blood cancer which affects the same number of people per year as WM, nothing worked. It was a death sentence with only about 2 or 3% of patients achieving any kind of remission. With Gleevec, the statistics are reversed: 98% of patients achieve full remission without side effects and 87% have experienced a correction in the gene mutation that causes CML.
So it's been done before. The scientists working on WM believe can be done again for WM. We just need to put the necessary money and talent to work rather than starving them for research funds like we are now. That just makes no sense.
Today, my government spends nearly zero dollars on funding research for my disease . There is currently only one grant from the NCI specifically for my disease (to Irene Ghobrial at Dana Farber for $215,000 per year for just two years). In order for me to save my own life, I will also try overcome a more serious problem which affects us all: The real enemy isn't the terrorists.
The bottom line is this: while I am optimistic that I'll survive for a lot more than 5 years, and hopefully more than 10, I also must be realistic and cannot discount the possibility that it could be less than that. Nobody knows for sure. Nor does it matter. My "to do" list wouldn't change.
Fundraising for the disease
There are many ways to generate ideas for research projects for this disease. Here are a few:
Once there are people, ideas, and projects to fund, then are then two basic approaches for how to evaluate which ones to fund:
And there are two basic ways to give out grants:
Both approaches are useful and it isn't clear which is better. Since the IWMF is already allocating millions of dollars each year using the second approach, I thought it would be useful and complementary for me to help raise funds for the first approach. That way, we hedge our bets and have the most chance of curing this disease.
I am also a big believer in the "trust the judgment of a superstar." For example, in financial investing, the "group of smart guys approach" to investment decisions hardly ever beats the judgment of a single smart individual. For example, Yale beats every college in the country because there is one guy there (David Swensen) who is really smart who makes the final decision on every investment. It is not "investment by committee." It can be argued that investing in medical research isn't that much different. In fact, I am personal friends with the guy who runs the top medical investment fund in the country. He makes all the decisions.
If you want to help fund research, make a donation at the IWMF website.
My goal is that by providing another option for donors, that we will increase the total funds available for fighting the disease which benefits everyone with the disease. Because the SAB is very small, grant decision can be made very quickly when required. Some money might be used to sponsor critical clinical trials when necessary or support seed funding to a new idea even if it lacks sufficient data for a formal proposal.
It's quite likely that all of the funds raised may be used to attract and cultivate a few new researchers into the field who are executing a long-term coordinated strategic plan of attack and have a framework for collaboration. So there would be a focus on a team grant with a long-term plan rather than individual grants and sponsoring 3 or 4 people at different institutions over a 5 year commit period rather than projects. So it is like the Howard Hughes Medical Institute but with more coordination among the Fellows and a common long-term plan. By sponsoring a team of 3 new researchers over a long time period where the objectives and milestones are team oriented there is less incentive to keep secrets and more incentive to share information because everyone's funding is guaranteed over the long term, but the long-term continuation of funding is based on the team's progress. The Kirsch Foundation used this model quite successfully for glaucoma (see Catalyst for a Cure).
I'm also funding research done by Irene Ghobrial (pictured below) at Dana Farber through the Kirsch Laboratory for Waldenstrom Macroglobulinemia (see Kirsch Laboratory for Waldenstrom's Macroglobulenemia 2010 Annual Report).
My "to do" list