COMy 2026 | Genomics and immunotherapy: reshaping high-risk multiple myeloma treatment

So, we have defined risk very recently. The Myeloma Society and IMWG came up with a new definition of risk. And this is a simple definition. It includes deletion 17p with 20% clonality or p53 mutation. Presence of t(4;14), t(14;16), and t(14;20) translocation with either deletion 1p or gain of 1q and then bi-allelic 1p loss and 1p plus 1q gain and then high beta-2 microglobulin. However, we know that there are patients who are functionally high risk. They may not carry clearly these features, but their survival is shorter. And then there are patients, even within this group, who do not do well with a very acute course. Consider around 5 to 7 percent who we call ultra high-risk. And we are beginning to define them with a new definition. Most likely multiple presence of these high-risk features together constitute that group, but we have to further define it. The critical part is that because they do not do well, we are now modifying our treatment to get them into better remission and then get better outcome. So what are those treatments or what are those changes? Now, the central to all of this is that any category, standard risk, hig- risk, ultra high-risk, we must try and get MRD negativity at 10 to minus 6 in the clinical sense. That will help us overcome the risk. The problem happens is the high-risk patients do not achieve this very easily. And this is where intensification of treatment comes into the picture. So, for example, we have wonderful new treatments now. We have bispecific antibodies. There are two types. A third one is likely to be approved hopefully soon. We have CAR T-cells also of multiple types and they induce deep responses very quickly and we are beginning to consider use of such treatment earlier on for ultra high-risk patients to get them MRD negativity. And then we are beginning to develop innovative maintenance treatment where we would include bispecific maintenance, for example, to sustain this remission. So utilization of immunotherapy earlier on and its use in maintenance testing is the newer innovation that we are beginning to implement to specifically target this high-risk patient population, ultra-high-risk and/or functional high-risk patient population. Now, with development of these treatments, but more importantly, also recognition of a lot of other genomic features in patients. We have patients with certain mutations, BRAF mutation, KRAS and NRAS mutation. We have patients with translocation t(11;14) and t(4;14). Now we know what is abnormal in this patient molecularly or genomically and we are beginning to have drugs against them. So development of NSD2 targeting drugs, development of cyclin-1 targeting drugs or CDK1 targeting drugs are becoming important in some of the subsets of patient population. Similarly, the newer advances are beginning to target long non-coding RNA. There is one other discussion in our session, which is where we can use a drug to degrade an RNA that is causing the problem or producing a protein. And one discussed was MYC. MYC is not easy to target as a protein, but we can target its RNA using this specific new drug called riboTAC. And using that, we can target a lot of myeloma patients who have a high MYC expression. And so there are great advances in this area. There was also discussion about deletion 17p, high-risk disease. There is a new target identified called PKMYT1, which was discussed. And that target, there’s a drug for it which works very well in patients who have 17p deletion and so utilization of such drug is beginning to be coming about and use of sequencing to define the risk to do the genomic changes is becoming standard. I think this two together is going to change how we treat patients specifically with genomics in mind.

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