IMS 2025 | The discovery of MGIP: an early and premalignant stage in the evolution toward multiple myeloma

Using highly sensitive mass spectrometry, we recently identified a very low level of M protein below the standard detection level, which is 0.2 g per liter. We named this as MGIP. So the discovery of MGIP led us to two important questions. Firstly, does MGIP persist over time before myeloma diagnosis? And secondly, is it truly from clonal plasma cells? So firstly, to address the first question, we used the PLCO cohort, which screens healthy individuals collecting up to six serial samples and later tracks for cancer. So using the PLCO cohort, we analyzed more than 2,000 serum samples from about 500 individuals, and of those, 122 were myeloma progressors. The others were MGUS but non-progressors. Using the PLCO cohort, we were able to identify 37 of them had MGIP, and 84% of MGIP were either persistent or even progressed to the MGUS level. And we looked deeper into the growth dynamics of each M protein before myeloma diagnosis. And we found the pattern, which is called shifting dominance, where different M proteins compete over time, and one eventually leads to the myeloma. So we have an example that IgG M protein was at the MGIP level in the first sample. And then eventually that grows to become the major M protein at near diagnosis, while the others disappear or appear or persist at a low level. So this suggests that myeloma emerges from an oligoclonal background, competing over time with one that eventually takes over. And then we also compared myeloma progressors and non-progressors. We applied a Bayesian growth model, and then we found that those MGIP M proteins progressing to the MGUS level, in myeloma they had higher growing potential compared to the MGUS non-progressors. And interestingly, they were exclusively IgG or IgA. So there’s a second question, where MGIP comes from. We leveraged the PCRD and PROMIS cohort. And we matched the mass spec peaks to the single cell level, single cell B-cell receptor sequencing. And we found one multiple myeloma patient with MGIP and MGUS level mass spec peak. And then we, using that mass spec peaks to match the single cells, we found heterogeneous clones within the multiple myeloma. One is for MGIP and two for MGUS, and half of them actually have no heavy chain there. So after we found the heterogeneous clones within the myeloma, we tried to evaluate whether which clone comes earlier than the others. And then we found that MGIP clones were closer to the germline. And then we found that CMV probabilities across all the cells, MGIP clones were relatively having lower probabilities compared to the others. And finally, in the PROMIS cohort, we found two cases with persistent IgM-MGIP. And then we found this IgM-MGIP is derived from clonally abnormally expanded B cells in peripheral blood with genetic alterations, such as driver mutation in MYD88 and CREBBP. So altogether, this established MGIP as the earliest identifiable stage of monoclonal expansion in the hematological malignancy trajectory with the major implication for early detection or risk stratification and patient monitoring.

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