LLM 2021 | Patient-specific targeted therapy in myeloma: t(11;14) and venetoclax
Rafael Fonseca, MD, Mayo Clinic, Phoenix, AZ, gives an update on patient-specific targeted therapy in multiple myeloma, including the history of the discovery of the specific genetic subtypes of myeloma with a focus on the translocation t(11;14). According to several studies, this translocation represents a unique subset of patients that initially was thought to have a relatively favorable prognosis. However, the progress made on new treatments for myeloma didn’t seem to be as significant as it was for patients without this specific translocation. Additionally, this group of patients appears to have a different form of myeloma that expresses lymphoid markers, with less mature cells that signal through different anti-apoptotic pathways. Patients with translocation t(11;14) favor signaling through BCL2 in contrast with most forms of myeloma, where the signal is through MCL1. Hence, BCL2 inhibitors, such as venetoclax, are viable treatment options for those patients. This interview took place at the Lymphoma, Leukemia & Myeloma Congress 2021.
Transcript (edited for clarity)
At the lymphoma leukemia and myeloma conference, I was given the opportunity to present an update on the work that has been done to target a specific chromosome translocation in multiple myeloma. Of course, the background is critically important, then that is where we talk about the history of the discovery of the specific genetic subtypes of myeloma with a particular emphasis in the chromosome translocation t(11;14)...
At the lymphoma leukemia and myeloma conference, I was given the opportunity to present an update on the work that has been done to target a specific chromosome translocation in multiple myeloma. Of course, the background is critically important, then that is where we talk about the history of the discovery of the specific genetic subtypes of myeloma with a particular emphasis in the chromosome translocation t(11;14). The t(11;14) was the only translocation that could be identified originally in standard karyotypes and subsequently was carefully mapped by my colleagues, Dr. Bergsagel and Martha Casey. We went on to describe the clinical features, attributes, and outcomes of patients who have this specific translocation. And originally it was thought to be a good prognosis translocation, but unfortunately, as time went by the progress that we were making for the treatment of myeloma at large, didn’t seem to be as great as it was for other tumors, for other patients who have this specific translocation.
Now we’ve learned also that this group of patients seem to have a different form of myeloma, it’s myeloma that’s a bit younger if you may. So it’s myeloma that expresses lymphoid markers, the cells are less mature, they have more scant cytoplasm, and importantly, they signal through different antiapoptotic signals. Very specifically, patients with translocation(11;14) favor signaling through BCL2. Now, this is in sharp contrast to most myelomas where their signaling is through MCL1. And the good news is that we do have inhibitors for BCL2. The prototype for this, of course, being venetoclax. So I had the opportunity also to do an update regarding the treatment of myeloma with venetoclax, and the special emphasis that has been placed on this being applied to for patients with this translocation and the literary with just very, very good results.
So we’re hoping that this would be the first of several other ways by which we can do a more targeted or a more precise approach for the treatment of myeloma. But we already see the harvesting of the first set of results that would indicate that as we figure out the other signaling pathways and mechanisms for the rest of the genetic subgroups, hopefully, there is a future where we have specific targeted agents like we do now with venetoclax, where there’s a subtype of the disease.
Read more...
