IMS 2024 | The mutagenic impact of radiotherapy & chemotherapy in multiple myeloma and lymphoma

In multiple myeloma, one of the concerns is that we give a lot of mutagenic chemotherapy and radiotherapy to patients at all stages along the disease course. And typically we use radiation up front or at some point during relapse to try and control plasmacytomas or extramedullary disease that’s causing symptoms. So this is palliative radiotherapy. What we don’t know is what impact on the genome these therapies that we’re giving are causing. Do radiotherapy and chemotherapy cause mutations and indels that are going to cause resistant disease? And so we aimed to evaluate this. We looked at over 500 patient samples from patients both with lymphoma and with multiple myeloma at the newly diagnosed setting and in the relapsed/refractory setting that were treated with chemotherapy and radiotherapy. What we found is on the surface, the profiles, the mutational indel profiles actually looked kind of similar. But if you look very closely and look at just the patients that are treated with chemotherapy and radiotherapy, there’s actually an increase in some of the indels that have previously been associated with radiotherapy. And that was of interest to us because previously it’s not been shown that chemotherapy can cause this kind of signature. It’s only been shown for radiotherapy. And more so, it’s only been shown in patients that have relapses or secondary tumors at the exact site of their radiation exposure. What’s not been looked at before is what happens if you treat a plasmacytoma and you sample the bone marrow years later, do those radiation-induced mutations and indels move to that extra site of disease? And so what we found then is that, in fact, we saw that patients that had chemotherapy-associated mutations from platinum and from melphalan, which are ubiquitous in multiple myeloma, and also from radiation, were in fact these patients that had these mutagenic chemotherapy signatures. The next step then was to do an actual experiment where we exposed cell lines to both platinum and to radiotherapy. And what we did then was to select a single cell that had survived the treatment to expand it to a colony big enough that we were able to perform whole genome sequencing on. Using this method you can basically fix all of the mutations that you induce with your therapy to clonal dominance. And so when we do whole genome sequencing you can get a very very pure signature of the treatment-related mutations. And so for the first time what we were able to show is that not only does radiotherapy cause a certain indel signature called ID8 in these lymphoma and myeloma cells, but in fact, platinum does as well. So it’s the first time we’ve seen something like this. Moving back to our patients, we’re able to use this knowledge to glean some information about how we can use these signatures to chart the course of the disease once patients have been treated and ultimately relapse. So a really good example, a vignette, if you will, is that we had a patient that had a plasmacytoma in the neck and also in the head. They were irradiated, received about seven different lines of immune modulator therapy, anti-CD38 therapy, and ultimately had a relapse years and years later. A bone marrow biopsy was done at a completely unrelated site in the hip as opposed to the site of relapse, sorry- as opposed to the site of radiation, and we were able to see those radiation-induced mutations at that unrelated site. So as to say that what happens is that when you get a mutagenic chemotherapy or radiotherapy, you can select for one surviving cell that’s exposed to these treatments that develops the mutations that are associated with the treatment, and you can see the entire body’s relapse. And this really brings us to the point that we’ve known for a long time is that when we use these therapies that potentially have mutagenic effects, we really need to go for broke. If you leave a surviving cell, that cell is going to take its resistance forward and cause your relapse many years later and result in resistant disease that will be difficult to eradicate.