The Importance of Having a Plan
February 16, 2017
The Importance of Having a PlanWRITTEN BY: Brian GM Durie MD
When a myeloma treatment or research plan comes together, it can be a great achievement. But it is unlikely to occur by chance. The goals and options need to be laid out very carefully ahead of time.
For patients today, we know that a combination of three drugs (triple therapy), if feasible, can produce deeper responses, and best remissions and survival. Thus, a strategy can be formulated: achieve the best response; consider a transplant (ASCT) and maintenance therapy; and be prepared with back-up options.
For researchers, success demands equally thoughtful planning. It is tempting to skip steps, which is why we see so many studies fail. My first myeloma research projects began years ago at the University of Arizona, where I learned that the first step which must not be skipped is to investigate prior research. My first steps took me in the direction of a brand new, very well-endowed medical school library, which had all background articles I needed to avoid prior pitfalls and be aware of often considerable prior research.
Homework pays off
In those days, about 10,000 myeloma articles were published annually (a number that has increased by 5- to 10-fold today). Two things were readily apparent about myeloma:
1. Sequential mutations of the myeloma cell chromosome/DNA occur over time. This prompted me to document this occurrence in my patients in 1985. Studies at that time showed that myeloma cells from patients with advanced myeloma had many, many DNA mutations which evolved over time.
2. Immune impairment: myeloma patients have an impaired immune system which contributes to the disease. In the mid-1980s, we showed in studies here and here that the immune abnormalities were multifaceted, involving T cells, NK cells, macrophages and other cell types.
Fast forward to 2012, when the Black Swan Research Initiative® (BSRI) project was being developed. Our team of investigators posited that if myeloma cells acquired multiple mutations over time, introducing therapy early is the best approach to avoid resistant disease, and immune approaches to therapy can be especially attractive.
Asking the right questions
For example, all the many mutations in patients with advanced disease are interesting, but not immediately relevant to what is happening early in the disease. What we now know is that all patients with myeloma previously had MGUS (monoclonal gammopathy of undetermined significance). So, the questions are: What causes MGUS? And why do 1% per year of patients with MGUS develop myeloma? This is quite probably because one or a small number of mutations—key or driving mutations—occur to produce that initial malignant transformation.
Suddenly, there is the possibility of an attractive research project. Instead of studying many, many mutations later in the disease, such as in the highly touted “Cancer MoonShot 2020,” a project STAT reports is now having difficulty showing value, the Black Swan Research Initiative has mapped out the possibility of a successful, targeted, early approach.
But where to find a lot of patients with MGUS and study the transition to myeloma? The surprising answer in 2016 turned out to be—Iceland!—where the special circumstances make it feasible to screen the entire population over age 40 years (120,000 people) and come up with 4,000 MGUS patients.
Elements of success
With this approach, we are fulfilling one of the major requirements for a successful research plan: there is high likelihood that data will be gathered which provides actionable information to improve patient outcomes. Precise early intervention will be achievable. Targeted and molecular approaches will be feasible, including the use of the attractive, very targeted CRISPR technology (recently the focus of patent lawsuits to gain control of this powerful approach). In addition, the precise immune changes early in the disease can be assessed with the potential for decisive intervention. Although the application of immunotherapies can be challenging and may not always work well, it is likely to achieve benefit combining immune approaches with other approaches.
And there you have it. In Iceland, hopes are high. Great outcomes are expected with early treatment, and, in addition, we will learn more about why patients with MGUS progress and even what caused MGUS in the first place!
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