What is the role of genomics at relapse?

What is genomics and next generation sequencing?

genomics and next generation sequencing of myeloma cells gives us very specific information about what's happening inside the genes within the myeloma cell. And we do that also with fish testing, but with fish testing, we're looking at the inside of the myeloma cell, inside the genetic makeup. But we're looking for a handful of very specific common abnormal abnormalities in myeloma. When we do genomics, we're looking at the entire genome where all of the genetic material is, and we get a vast amount of information and we can see small mutations changes in the genome that we can't see with other testing like fish testing.

What is the role of genomics and next generation sequencing at relapse?

So what's the role of genomics in relapsed or refractory myeloma? So genomics is basically a way of looking at the genetic abnormalities that a person has in their myeloma. So I'd say first, the genomics are we're usually not talking about the kind of genetic abnormalities that a person gets from their parents and passes on to their child. These are only genetic abnormalities that are in a person's myeloma cells. And so the field of genomics and myeloma right now both newly diagnosed as well as relapsed, is really an evolution where we myeloma investigators are only now starting to get smarter about this. And what I mean by that is that currently we know that genomics in relapsed or refractory myeloma is prognostic. So it often gives us a sense of how myeloma is likely to behave, if it's likely to be more aggressive and respond not as well to therapy, come back sooner or if it's likely to be less aggressive, respond well to therapy, stay in remission for many years to come. And so we use that genomic information quite a bit. The more important thing is really using genomic information to choose therapies, and that's where we're not we're not quite there yet. There is one abnormality that we see sometimes it's called t 1114. So that's a specific chromosomal abnormality that we see in multiple myeloma in a minority of people that predicts a good response to a medication called venetoclax, which is not FDA approved for treating myeloma, but it's known to work. And that specific subtype. But beyond that, we really don't have great information telling us that certain genomic types of myeloma should be treated with certain types of therapy. So in terms of next gen sequencing, that's one way of looking at the genomics of a person's myeloma. next Gen sequencing is tremendously helpful in other types of cancers. So it's pretty standard in other types of cancers, not nearly as standard in myeloma. And I'd say that most of us really don't regularly get next gen sequencing only because it's not been well proven to make a difference or to really help us to choose effective therapies for myeloma. That's probably coming, but we're not quite there yet. So I don't routinely get it outside of certain specific circumstances which are usually research based. the role of genomics and next generation sequencing is really expanding in the relapse setting. And I predict that it's not only going to be expanding in the relapse setting, but also we're going to be using it in the newly diagnosed setting to help us better define risk. But in the relapse setting, I think it's important because we can learn and possibly have targeted therapies that we wouldn't have otherwise predicted. And an example is the BRAF mutation. If a in a BRAF mutation occurs in about 5% of patients with myeloma and now we have effective B-raf inhibitors and BRAF inhibitors plus other combination that can be used in patients with BRAF mutated myeloma. And so that's just one example where using genomics can give us a specific therapy to help a patient. And I think as we use more genomics in as we understand myeloma biology better, we're going to be able to use the genomics to help come up with therapies similar to the BRAF therapies for those patients who have the BRAF mutation. so when you relapse from multiple myeloma, there are a number of considerations.So it's different to newly diagnosed because you have the duration of the first remission that plays out into the nature of the relapse, the nature of the treatment.

Do you have side effects? What treatment was it? How long were you on treatment for? Are you resistant to that treatment?

And all of these play out in terms of your age, your frailty, how strong you are and how well you're able to tolerate the treatment? So these are all important things that you can sort of tick off in a box. But I think that it really is important that you assess the genetics of disease and relapse because there are treatment options that really depend upon the genetics of your disease. So you should know if you have an 1114 translocation because even in people with really aggressive relapse, if you receive venetoclax in the context of an 1114, you're likely to have a good and durable response. So I think that's really important. You need to know if you have a p53 mutation, whether you by clinically deleted at the P53 locus, because if you have a lot of that, the response to ALKYLATING agents and stem cell transplant is not going to be particularly good and you'd be better going with another treatment. More than 50% of patients that relapse have a mutation in the RAS map kinase pathway. There are potential therapies for that that are being developed and are used in the context of other cancers and receiving those, while maybe could be considered experimental, offers an important option for people at relapse and so my message would be there's a lot of information in the molecular genetics of your relapse. You know, I kind of didn't mention resistance to IMiD drugs, but it's possible to find mutations in the pathways that govern resistance to REVLIMID or POMALIDOMIDE. And if you have those mutations, maybe you should consider a different type of therapy or one of the new IMiD drugs, or the CELMoDs. So lots of information and important information that you can use to target therapy appropriately. what's the role of next generation sequencing? So I would say that the short answer is that everybody should consider that and actually it should be part of your initial diagnosis. So when you are first diagnosed with myeloma, you should actually have genomic testing and next generation sequencing done on your initial sample because they actually as part of the analysis and part of understanding, you know, the part of the utility of next generation sequencing, not only is can you identify new targets, and I'll come back to that in a second that your myeloma, your individual myeloma, may be sensitive to, but can we follow your myeloma over time? So, for example, in minimal residual disease testing, there is a genetic approach to do minimal residual disease testing. However, you have to know what your myeloma originally looked like to be able to use next generation sequencing or minimal residual disease, genetic minimal residual disease testing in order to use that test at the time of your best response. So I would say that everybody needs to, you know, at the time of diagnosis, if possible, get next generation sequencing to look at their myeloma. Now, the longer answer is that currently that information doesn't really change the way we manage patients because honestly, unlike a lot of other cancers like lung cancer or other cancers, we don't have a lot of good therapy that actually targets the mutation in myeloma that makes a difference. So knowing all of these mutations your myeloma might have we don't have any drugs that actually seem to work against any of those myelomas or those mutations. Now, again, that doesn't mean that in five years we won’t. So it is a good thing to get that information, characterization of your myeloma early as detailed as can be, because it may be that the next drug that comes out all of sudden targets a mutation that we had no idea that was going to be important but seems to be effective. And now we know all those patients that had next generation sequencing done, we can go back and say, Hey, you do have that mutation. We have a drug for you.