Deep Sequencing Impacts Treatment Landscape for MM

At the 2019 Lymphoma & Myeloma Congress, Gareth Morgan, MD, PhD, NYU Langone Health, New York, NY, discussed deep sequencing and how it is improving the treatment landscape for multiple myeloma (MM).

Transcript:

Dr. Gareth Morgan:  Hello, my name's Gareth Morgan. I'm a professor of hematology, and I'm director of myeloma research at NYU Langone Health here in New York City. I was asked to talk today about whether deep sequencing can improve the treatment of multiple myeloma.

While up until about this point, that's been a debatable point, the purpose of my talk today was to make the point that now is the time when this is starting to make a difference. There are now tangible treatments that you can direct the use of based on the sequencing derived from the patient. The best example of this is in the 4;14 myeloma, which is about 15 percent of all cases.

These cases are particularly sensitive to treatment with what's called a Bcl-2 inhibitor that's got a specific name, venetoclax. This is a drug that's available. There are clinical trials that show it works in this subgroup of patients. This group of patients seems to do extremely well with this drug, so it's a paradigm-shifting event.

Then the question is are there other sub-groups. Sequencing finds that about 50 percent of all cases have mutations in a pathway called Ras or Ras-MAP kinase. We've shown previously that you can treat these patients. Even if they've not been responsive to chemo, they'll respond to the BRAF or Ras inhibition with a MAP kinase inhibitor, so pretty interesting.

Are there others? Yeah, but these are quite rare events. There are fusion gene products, NTRK. There are IDH1 and H2 subsets of disease. The deal is only something like two percent of all cases have the mutations.

To be able to investigate that, you need to do things called basket studies. There's an MMRF basket study called MyDRUG, which I think sets a paradigm for the community.

We treat everybody the same in terms of their risk status. It's now possible to tell which patients are high-risk and which are low-risk. Arguably, we can treat these double-hit myelomas differently. We can treat p53. Another lesion, which is called amp 1q, is also responsive to apoptosis inhibition like venetoclax, only this case, they respond to an MCL-1 inhibitor. Over the next few years, I expect MCL-1 inhibition and targeting that to 1q amp cases, which is about eight percent of all cases, is going to give us a marker and a new treatment.

The point of the whole talk was we're starting to see myeloma as maybe six different diseases. The treatment for each of those diseases should be different. We're starting to have treatments that work for each of those different segments.

The last part of the talk was around immuno-oncology. All of these have been about chemical drugs, in some way. The big buzzword is around, "Can you use the immune system to fight the cancer?" Now sequencing doesn't just look at the sequence. It looks at the sequence of many different cells. That's called single-cell sequencing.

We're starting to use this single-cell sequencing to look at the whole bone marrow biology and then use that information to do precision immuno-oncology, which is going to be a major thing in the next 10 years.

With all of these approaches, we'll start to see a continued improvement in myeloma outcomes, so more people have their disease controlled long-term, and more people achieve functional cures. I think it's really exciting for patients, and it's a great time to be working in this area.