Postdoctoral Fellow Cancer Program, Broad Institute Cambridge, Massachusetts
Introduction: A newly characterized monoclonal entity, termed monoclonal gammopathy of indeterminate potential (MGIP), has been described in a racially diverse cohort of individuals at high risk for multiple myeloma (MM) through screening with matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS), a highly sensitive technique for detecting and quantifying monoclonal immunoglobulins (Ig). These cases predominantly involve low-level monoclonal gammopathies (MG) that fall below the detection threshold of conventional electrophoresis (< 0.2 g/L). Here, we aimed to determine whether MGIP precedes multiple myeloma and other hematologic malignancies, and whether it represents a true premalignant condition.
Methods: We performed MS on 2,194 serum samples from 491 individuals from the PLCO cohort, including 122 who progressed to MM and others with persistent monoclonal gammopathy of undetermined significance (MGUS) without progression. To further validate the persistence of MGIP, we also analyzed 932 samples from 461 individuals enrolled in the PROMISE screening study. Additionally, we performed single-cell RNA sequencing (scRNA-seq), single-cell B cell receptor sequencing (scBCR-seq) and whole-genome sequencing (WGS) on samples from individuals in the MS-tested cohorts, including PROMISE and PCROWD.
Results: We observed that MGIP consistently preceded both MGUS and MM, and the persistence of MGIP was further validated in the PROMISE study. Longitudinal MS testing revealed the presence of multiple co-occurring monoclonal proteins (M-proteins) in individuals who progressed to MM and demonstrated dynamic patterns over time, including occasional switching of the dominant clone and isotype class at the individual level. Using scBCR-seq, we confirmed the presence of MM clones corresponding to distinct MGIP-level and MGUS-level M-proteins within a MM patient. Comparing V(D)J amino acid sequences of germline and tumor clones of this patient derived from WGS and scBCR-seq, respectively, along with phylogenetic reconstruction based on posterior probabilities of copy number events from scRNA-seq, suggested that clones producing MGIP-level M-proteins diverged earlier than those producing MGUS-level proteins. In additional two cases with persistent MGIP, we identified B cell clones that produced MGIP-level M-proteins and harbored known lymphoma-associated driver mutations using WGS, scBCR-seq, and scRNA-seq data, further supporting the premalignant potential of MGIP.
Conclusions: We provide a comprehensive insight into low-level MG by demonstrating that MGIP is a non-transient, stable condition that precedes and may evolve into hematological malignancies. This study contributes to our understanding of clonal heterogeneity and dynamics prior to MM and may help guide future approaches for monitoring individuals at risk of progression.
