Dr Shaji Kumar Discusses Biological Foundations of New Multiple Myeloma Research

By understanding the biology of myeloma tumor cells, researchers can better develop therapies, including drug combinations, that target the complex mechanisms at play in the disease, according to Shaji Kumar, MD, professor of medicine at the Mayo Clinic.

Transcript (slightly modified)
How can combinations of drugs sometimes result in better responses to treatment?
Now, myeloma is a very heterogeneous disease, so when we look at the myeloma cells even at the time of diagnosis, there’s a lot of heterogeneity. Most of it is driven by the genetic abnormalities, so we know that there’s a whole wide spectrum of mutations that we can find in myeloma, both newly diagnosed and relapsed.
What we have seen is that myeloma progresses, and they go through response and relapse. There’s increasing numbers of clones and sub-clones that develop, so this clonal evolution also allows the myeloma cells to become more resistant to the current therapies. So, by using combinations, there’s the potential that we can limit this clonal evolution in myeloma, and that can translate to better outcomes. 
We already have some evidence to that effect. We know in the newly diagnosed setting, a combination of a proteasome inhibitor and an immunomodulatory drug is better in terms of improved overall survival in patients with myeloma. We also know in the setting of relapsed myeloma, when we use triplets, which again incorporates a proteasome inhibitor and an immunomodulatory drug for example, they have a better progression-free survival and in some studies a better overall survival compared to just using 2 drugs. Finally, we also know by measuring minimal residual disease these triplets can actually give much deeper response compared to the doublets that we have been using in the past.
Why is research on the biology of multiple myeloma necessary for developing novel treatments?
Myeloma has a variety of different biological events that happen in the course of evolution from a monoclonal gammopathy of undetermined significance to symptomatic myeloma. The changes are not restricted to the tumor cell itself; we believe there are significant changes that are happening in the immune microenvironment as well as the microenvironment in the bone marrow, which includes the angiogenesis-type changes, the stromal cells in the bone marrow, which all help support the myeloma cells’ survival.
So, understanding the changes in the tumor cell alone will not allow us to control the disease long-term; we also need to understand what changes in the microenvironment. Once we understand what the changes are, then we could target therapies to either reverse some of those changes or specifically target abnormalities in the tumor cells which will allow the tumor cells to be killed more efficiently.
There are already some examples from the studies that have been done in the recent past. For example, we know that there are mutations which are more commonly seen in myeloma as they progress, so current generational clinical trials are looking at how we can incorporate targeted agents into the treatment of myeloma, especially in combination with the currently available therapies which are effective. We know that the immune microenvironment is suppressed in myeloma, so by using drugs such as the checkpoint inhibitors and combining that with some other drugs we already have, we can improve the outcomes.
Clearly, learning more about the biology is the only way we are going to develop therapies that can potentially cure this disease in the future. 
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