The Role of Genetic Testing and Targeted Therapy
MAY 05, 2020
Ola Landgren, MD, PhD: Myeloma is genomically a very heterogeneous disease. Unlike, for example, chronic myeloid leukemia, where you have the BCR-ABL that led to the TKI [tyrosine kinase inhibitor], the Gleevec discovery. That’s not what myeloma is. For myeloma, on average when you have a newly diagnosed patient, you can—if you use whole genome sequencing—identify between 5 and 10,000 mutations. You can use hierarchical clustering to aggregate this information into subsets and subclones, and you will see that the patient has many different subclones that carry a different type of mutation. You cannot use a targeted drug that goes after mutations. You cannot. Currently in the clinic we still use 1980s technology. We use the so-called FISH [fluorescence in situ hybridization] assays. And we have merged our program away from the karyotyping; we do SNP [single nucleotide polymorphism] arrays.
Some groups still do the karyotyping. They use karyotyping and FISH. We do SNP arrays and FISH assays. We just published a paper in 2019 showing with a targeted DNA-based assay, a capture assay, that you can capture everything with FISH assays and SNP arrays. For that matter, also FISH and cytogenetics or FISH and karyotyping with this DNA-based assay. Plus, you will get all the mutations in 1 assay. We published that in Blood Cancer Journal in 2019. There are a couple of groups that are developing similar platforms. We now have follow-up showing that you also can identify the majority of the VDJ sequences, which is what you use for longitudinal tracking for MRD [minimal residual disease]. You probably can capture everything that FISH assays, cytogenetics, SNP arrays, and MRD work-up do in just 1 assay. Then you can choose whatever you like to follow over time.
You can probably do MRD tracking separately if that’s what you want to do, or maybe you have just 1 assay going forward. Still, there’s work to be done beyond the bone marrow-based applications. Everything I just said right now refers to bone marrow-based assays. Can you use cell-free DNA? Can you track these sequences in the blood? The answer is yes, a diagnosis in myeloma can capture these things for the most part in the blood. But once you start treating the patient, the amount of DNA goes down. So your sensitivity is way too low in the blood to reliably use the blood. You have to unfortunately still do the bone marrow-based assays. But there’s a lot of new development. The mass spectrometry-based protein assays also complement these genomic assays for tracking low-level DCs [dendritic cells]. So some formal blood-based monitoring I think will be reality very soon in myeloma.
Simon Murray, MD: That’s very interesting.
Transcript Edited for Clarity