Multiple Myeloma - Episode 8

Case 2: Use of Genomic Sequencing in Myeloma


Ola Landgren, MD, PhD:May I ask you, is anyone still using gene expression? Nina, do you use gene expression on the bone marrow?

Nina Shah, MD:No.

Ola Landgren, MD, PhD:Do you do targeted sequencing? Do you do whole genome sequencing? Do you do anything else?

Nina Shah, MD:I really don’t, because I feel like—and I will fully admit—sometimes I just don’t know what to make out of those different groups of genomic data. Different groups have presented different things. And they’re not widely used. By the time I get the data, the patient has already started on something. It’s hard for me to use that data, so I don’t use it.

Ola Landgren, MD, PhD:Alfred, do you use gene expression, profiling, targeted sequencing, or whole genome sequencing?

Alfred Garfall, MD:When we do the diagnostic marrow at our center, we do targeted sequencing as part of an effort across all hematologic malignancies to do that. However, the data are not very useful for making clinical decisions. The gene expression profiling with the various tests—we never use those.

Ola Landgren, MD, PhD:You do the targeted sequencing. Do you do matched germline also, or only somatic profiling?

Alfred Garfall, MD:Somatic.

Ola Landgren, MD, PhD:Only somatic. And this is for somatic mutations? Is it also for VDJ sequencing?

Alfred Garfall, MD:No.

Ola Landgren, MD, PhD:So there is no signature generation for MRD [minimal residual disease] tracking going on at this point?

Alfred Garfall, MD:Correct.

Ola Landgren, MD, PhD:How about you, Ajai?

Ajai Chari, MD:Where I would be interested—and I’m not doing it now—is when we talked about 17p. FISH [fluorescence in situ hybridization] doesn’t give you the whole answer. What’s going on in that 17p locus? That would be very important, and I think would have actionable implications now.

Nina Shah, MD:If you even have a locus.

Ajai Chari, MD:But then the other question is, in the relapsed setting, this targeted sequencing can potentially identify novel targets using drugs from other cancers, although I think the success with that is limited. But at the end of the day, if you always ask that question—in regard to medical students, we teach them that if you’re going to order a test, be prepared to answer how it’s going to change your management. For the vast majority, similar to MRD, if it’s not changing your management, it’s fine to do it for academic purposes. But I think in the routine community setting...

Alfred Garfall, MD:I’ve done more of that targeting sequencing in the relapsed-refractory setting when you’re trying to generate more creative options for patients. I think it would be important to do it at the time when you’re thinking of using an outside-the-box targeted therapy like a BRAF or a MEK inhibitor. It’s probably better to do that sequencing at the time when you’re considering using it because those things can change over time and you can get allelic fluctuations over time.

Ajai Chari, MD:How about you, Ola?

Ola Landgren, MD, PhD:We do sequencing for the purpose of clinical trials. All of us at this table have small molecules. We have MEK1/2 inhibitors. We have BRAF inhibitors. We are looking for mutations in theMAPkinase pathway, and there could be other mutations as well. For that reason, we are looking for those types of options. We have started to do that a little earlier, also to have the data in case the patient continued to relapse. The timing obviously can be a factor that keeps patients out of the trials. If you don’t have the data available for targeted drugs, that may not be an option for that patient.

We just published a paper that we have for research purposes. We designed a targeted assay where we captured the entireIGHlocus and spread throughout the whole genome. Could this sequencing approach replace FISH and cytogenetics? We did 150 cases that we had all the data for. We were able to show more than 99%—both sensitivity and specificity. In addition, we had somatic mutations. We then could identify biallelic p53 inactivation. It’s not in clinical care, and I know there are other groups. I think Mayo Clinic has something. Dana-Farber Cancer Institute has something. I don’t know if your institutions have similar approaches. I think the field definitely is going in that direction, but I think more work needs to be done to standardize this.

Alfred Garfall, MD:I think, and we’re seeing it with venetoclax, it’s probably the first time a gene expression profile, a transcriptional profile, is predicting sensitivity to a drug in a really compelling way. And so it seems to be that the t(11;14) myelomas respond to venetoclax, but there probably is a subset of cyclin D1-driven myelomas that do not carry t(11;14), and those would presumably be sensitive to venetoclax. If we have more drugs coming out like that, [in which] we can tie sensitivity to specific gene expression profiles, I think we could see that testing become a bigger part of our mainstream care.

Transcript edited for clarity.