Case 3: Molecular Testing in Relapsed Myeloma

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARDAjai Chari, MD:Going back to the case, this patient had declined lenalidomide maintenance, which allowed us to use the lenalidomide-based backbone for her first relapse. But clearly, she’s demonstrating very high-risk disease with a very short relapse. Pei, from a pathology perspective, what may be the reason for these short remissions in her case?

Pei Lin, MD:As you mentioned earlier, the presence of the del(17p), which wasn’t detected at the time of the initial diagnosis, has now been detected. This has been seen in several situations. One scenario is that maybe this was a very small clone, at the very beginning, when we did the FISH [fluorescence in situ hybridization] testing. The sensitivity level wasn’t high enough, and we didn’t pick up the clone. Yet, after the treatment, maybe this particular clone gets expanded. Now we are able to detect it.

Ajai Chari, MD:To that point, I want to clarify the importance of doing plasma cell—specific FISH testing. Can you briefly comment on that?

Pei Lin, MD:Sure, absolutely. We now have the so-called enrichment. We use immunomagnetic enrichment of CD138 to enrich the plasma cells to perform the FISH studies. This will help to detect small clones. Still, each lab has different thresholds, or cutoff values, and these small clones may not necessarily get detected, even after enrichment.

Ajai Chari, MD:How about cIg [cytoplasmic immunoglobulin]—FISH?

Pei Lin, MD:That could also be helpful. Basically, the more enriched the sample is, the higher we are able to detect these kind of abnormal FISH results. In terms of the percentage of the cells, we have 50%. We have seen literatures reporting a different cutoff in terms of prognostic significance. I’d like to hear your comments on that. I have read the literature.

Our experience has been that if del(17p) is detected, in the broader context of complex cytogenetics, these patients do very bad and are actually comparable to patients who don’t have del(17p) but have complex cytogenetics. And yet, if they are detected in the background of normal conventional karyotype, it means something that is not as bad as those who have complex cytogenetics. So, what is the significance of detecting this abnormality using FISH? It’s a pretty high number—50%. I’d like to hear your comments, as well.

Ajai Chari, MD:What you’re alluding to is clonal burden of the del(17p). As you alluded to, some cutoffs have been as low as 20%. Others have been 60%. If we’re going to talk about risk, we really need to see a phase III study with control arms. The TOURMALINE study is a good example. When you have the low TP53 cutoff of only 20%, it looked like there was superiority. But, when you go to higher cutoffs, you lose that benefit. So, I think you need the control arms to prove that your cutoff is actually doing poorly, as you would expect.

Pei Lin, MD:Right. It needs to be a bit more standardized. Some institutions do enrichment, and others don’t. When you reportTP53deletions by FISH, which one are you reporting? Is it out of total cells that you are analyzing versus enriched plasma cell? What’s the denominator, so to speak? It’s very important to compare the data, to see the significance of it.

Ajai Chari, MD:With newer data showing that it’s not just the clonal burden but also the allelic burden.

Pei Lin, MD:Exactly.

Ajai Chari, MD:Is it the monoallelicTP53deletion or biallelic? This is a complex area. Again, it speaks to the importance of having control arms in these studies. Are you surprised? You alluded to the possibility of sensitivity failure and del(17p) being missed. What about clonal evolution?

Pei Lin, MD:It could be evolution, because they are chemotherapy- or drug-resistant.

Ajai Chari, MD:Have you seen that a lot in the relapsed/refractory setting?

Pei Lin, MD:Yes.TP53that was not detected at the beginning has appeared later in relapsed disease. This case highlights the importance of doing FISH forTP53at follow up. It’s likeFLT3in AML [acute myeloid leukemia]. It’s something that could be evolving. So, just doing routine testing based on what’s been detected at the beginning, which was t(11;14), is insufficient.

Transcript edited for clarity.