Should Myeloma Treatment Be Fully Personalized?
Recently there has been a discussion among some myeloma patients concerning the need for fully personalized myeloma treatment. Is there a benefit to this type of approach? Intuitively, the answer is "yes." But I would argue that "no" is the better answer.
Let me explain. Yes, there are many variants of myeloma which could be considered individually and personally. These include secretory myeloma (IgG, IgA, IgD: Kappa/Lambda only ---); non-secretory myeloma, plasmacytoma, plasma cell leukemia, extramedullary disease and more. But there is a fundamental similarity in biology. Immunomodulatory drugs (IMiDs) (e.g. Revlimid and Pomalyst) combined with proteasome inhibitors (e.g. Velcade and Kyprolis ) produce excellent responses for most subtypes of the disease. Even in the relapsed/refractory setting, Kyprolis/Pomalyst/DEX produces responses (>/= PR in 70%), including in patients with high-risk 17P- disease. Long remissions occur for many patients.
Thus, although it is now known that myeloma cells have hundreds of mutations in different subclones, most of these are wiped out by newer novel combinations. The subclones which persist or recur are the ones that require special attention.
Fortunately, a new Flow MRD test, which is highly sensitive and can be used to identify and sort residual clones, is ideal for studying such resistant subclones. A vital element of the IMF's Black Swan Research Initiative is studying the patterns of resistant disease--which are already emerging--and using this knowledge to guide treatment selection. Figuring out how to mop up disease that remains after initial therapy is much more manageable, in my view, than attempting to individually tailor treatment at the outset.
It appears that broadly applicable relapse therapies can be developed. Studies from single cells or clones from individual patients provide clues for successful approaches that can be applied broadly to others with similar subclones.
The opposite approach of attempting to target each of many, many individual mutations is truly challenging and, I believe, ultimately not feasible. There are too many individual mutations and too much time and expense needed to develop multiple targeted therapies.
If key so-called "driving mutations" can be found, this will be the answer for new drug development. But, again, these therapies will be broadly applicable to treat patients with resistant disease and/or combined with current treatments to start curing patients! The anti-CD38 antibody therapies are examples of this type of more broadly applicable agent that can significantly contribute to better outcomes.
So, although studies of individual patients are extremely helpful, the goal is to have broadly applicable therapy--to "lump and not split" and learn more from treating larger numbers of patients together, not separately. Myeloma can be divided into apples and oranges and maybe even pears, but not a complete fruit cocktail, which would be counter-productive from the standpoint of both diagnostics and treatment.
The argument against fully personalized therapy is therefore very important in the way that myeloma research moves to achieve the best results for all patients in the most rapid fashion.
Stay tuned as the Black Swan Research project moves research in this direction!
Dr. Brian G.M. Durie serves as Chairman of the International Myeloma Foundation and serves on its Scientific Advisory Board. Additionally, he is Chairman of the IMF's International Myeloma Working Group, a consortium of nearly 200 myeloma experts from around the world. Dr. Durie also leads the IMF’s Black Swan Research Initiative®.