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EMN 2021 | Overcoming microenvironment-induced resistance in myeloma

Enrique M. Ocio, MD, PhD, Marqués de Valdecilla University Hospital, Santander, Spain, gives a summary of his talk on overcoming microenvironment-induced drug resistance and novel agents in heavily pre-treated patients with myeloma. Dr Ocio highlights two approaches to overcoming resistance; targeting microenvironmental features, such as CXCR4, directly, or using novel agents such as the peptide-conjugate alkylator melflufen, CELMoDs, BCL-2 inhibitors or MCL-1 inhibitors, all of which have microenvironmental effects. This interview took place during the 2021 European Myeloma Network (EMN) congress.

Transcript (edited for clarity)

One of the main points or one of my main talks here would be talking about the microenvironment and how to overcome the resistance induced by the microenvironment. Now, currently we have many different agents and combinations acting for multiple myeloma. We have to also take into consideration that we should not only target the myeloma itself, but also in the context of the microenvironment because this microenvironment can induce drug resistance, induce proliferation and antiapoptotic signals...

One of the main points or one of my main talks here would be talking about the microenvironment and how to overcome the resistance induced by the microenvironment. Now, currently we have many different agents and combinations acting for multiple myeloma. We have to also take into consideration that we should not only target the myeloma itself, but also in the context of the microenvironment because this microenvironment can induce drug resistance, induce proliferation and antiapoptotic signals. So, it’s very important to target them.

There are two main approaches, there’s one to target directly or specifically microenvironmental features such as CXCR4, cytokines such as, cytokines such as IL6 or IEF-1. There have been attempts with that. Probably they have some activity in combination, but I think the activity as monotherapy is not very good. and the other approach is to use the currently, the dosed drugs that we know that they are active in myeloma, that they are being studied and evaluated, some have been approved, and we know that all these drugs have a microenvironmental effect.

And here we can speak about, for instance, alkylators such as the novel alkylator melflufen that we know that increases or creates an immunogenic environment. We have of course the CELMoDs that we know that they have a clear activity in the microenvironment and also in the immune system. We have BCL2 or MC1 inhibitor, also are together with ERK pathway inhibitors. These are pathways that are increased or are activated in the context of the microenvironment.

So, there are many different targets or agents that we are using that would work both in the plasma cell but also in the context of the cellular microenvironment, and this is good. This is something we have to take also, to be aware of and take into consideration.

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