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ASH 2025 | MGIP as a stable premalignant entity preceding hematologic malignancy
Irene Ghobrial, MD, Dana-Farber Cancer Institute, Boston, MA, discusses the concept of monoclonal gammopathy of indeterminate potential (MGIP) as a stable premalignant entity preceding hematologic malignancy. She highlights that MGIP is a clonal condition with the same B-cell receptor sequences as monoclonal gammopathy of undetermined significance (MGUS) and myeloma, and that over 80% of MGIP cases progress to MGUS or smoldering myeloma. This interview took place at the 67th ASH Annual Meeting and Exposition, held in Orlando, FL.
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Transcript
The same monoclonal gammopathies that we’ve been detecting by multi-TOF with binding site, once you have a detection level below what we use for MGUS or smoldering myeloma, we term that monoclonal gammopathy of indeterminate potential, which is a lower level. It’s not too low, so it’s still monoclonal, it’s not polyclonal. And here, what we said is, let’s go back to the PLCO samples...
The same monoclonal gammopathies that we’ve been detecting by multi-TOF with binding site, once you have a detection level below what we use for MGUS or smoldering myeloma, we term that monoclonal gammopathy of indeterminate potential, which is a lower level. It’s not too low, so it’s still monoclonal, it’s not polyclonal. And here, what we said is, let’s go back to the PLCO samples. PLCO is a cohort that was recruited in the United States over 20 years ago for other cancers, but we have the plasma samples. And Ola Landgren had previously looked at those patients who have multiple myeloma and went back to earlier samples and indeed found that every patient with myeloma must have had MGUS. So we took those same patients but went even earlier by years and years for their earlier plasma samples, the earliest one available. We also saw in all of the people who have MGUS what is their earliest sample and tried to track those over time. So we have multiple serial samples and we found indeed, many of those patients will have a monoclonal gammopathy below the level of detection that we have right now, and we call that MGIP. And those MGIPs, in over 80% of them, are sustained and increase and go on to develop MGUS or myeloma. And more interestingly, we took some samples, and we did single-cell sequencing as well as whole-genome sequencing and, indeed, identified that the clones of MGIP are clonal with the same VDJ sequencing, the same BCR sequences of plasma cells, and, indeed, by whole-genome sequencing in an IgM sample, they were also clonally related to a lymphoma sample. That tells you that, indeed, MGIP is clonal, that it has the same BCR sequences, and it persists in over 80% of the samples to go on to develop MGUS or smoldering myeloma. Interestingly, we also found that originally we find a lot of those are IgM, but they clonally shift and become IgG as you progress, which could potentially be because of the isotype class switch. So all of that together tells us that we may have a precursor condition before MGUS, which we now termed MGIP, a la CHIP, which is the clonal hematopoiesis of indeterminate potential. And there is so much to be done to understand this more.
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