Relevance of polyclonal plasma cells and post-therapy immunomodulation in measurable residual disease assessment in multiple myeloma

Background Immunophenotypic profile and post-therapy alteration in antigenic expression were evaluated in normal, reactive, and aberrant plasma cells (NPC, RPC, and APC) for impact on measurable residual disease (MRD) assessment in multiple myeloma (MM). Methods Samples from non-MM staging marrow (n = 30), Hodgkin's lymphoma (n = 30) and MM (n = 724) were prospectively evaluated for expression profiles of NPC, RPC, and APC using antigens recommended in consensus guidelines. Results Polyclonal NPC-RPC demonstrated aberrations for all antigens evaluated with a higher frequency of aberrancies in post-therapy samples compared to treatment naive samples (p < 0.001%). Immunomodulation in APC was observed in 79% of post-therapy samples with a change in expression of 1, 2, and >= 3 antigens in 19.9%, 15.6%, and 43.5% samples, respectively. In 13.4% of samples, APC showed no aberrancy and aberrant status was assigned based on cytoplasmic light chain restriction (cyLCR) alone. 9% samples with an admixture of NPC and APC displayed normal cytoplasmic kappa to lambda ratio (cyKLR) when the percentage of APC of total PC (neoplastic plasma cell index, NPCI), was below 25% and 50% for kappa and lambda restricted cases, respectively. Conclusion The panorama and high frequency of antigenic aberrations on polyclonal PC signify the importance of MRD assay validation on a large cohort under normal and reactive conditions. Frequent Immunophenotypic shifts in APC re-confirm the redundancy of baseline immunophenotype for MRD evaluation. Small clones of APC may be missed by assessment of cyKLR alone and therefore, surface marker aberrancy supported by cyLCR is required for definitive assignment of residual APC.

Automated summary

This study evaluated the immunophenotypic profile and post-therapy alteration in antigenic expression of normal, reactive, and aberrant plasma cells in multiple myeloma, and its impact on measurable residual disease assessment. The results showed that polyclonal plasma cells exhibited aberrant antigen expression, which was more frequent in post-therapy samples. Immunomodulation was observed in post-therapy samples, with changes in antigen expression in a significant proportion of samples. These findings emphasize the importance of validating MRD testing under normal and reactive conditions.