Genomic Landscape of Multiple Myeloma and of its Precursor Conditions, and its Clinical Implications

Reliable strategies to capture patients at risk of progression from precursor stages of multiple myeloma (MM) to overt disease are still missing. In this study, we generated whole-genome sequencing (WGS) data from matched tumor and normal samples from 98 individuals from the PCROWD study (Precursor Crowd, NCT02269592). These individuals have either a precursor condition for MM, which can be a monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM), or an active multiple myeloma (MM). To do so, we enriched tumor plasma cells from the bone marrow by magnetic bead selection (CD138+), sequenced the DNA of these samples to a target depth of 60X (tumor), and analyzed them against normal white blood cells (peripheral blood mononuclear cells) from the same individuals sequenced to a target depth of 30X (normal). In our first publication [Alberge, Dutta, Poletti, et al., 2025], we integrated and homogeneously analyzed these data together with data from mostly publicly available datasets (phs003084 and phs000748) to reach 1,030 total samples. We used these data to identify recurrent coding and non-coding candidate drivers, as well as significant hotspots of structural variation, and used those drivers to define and validate a simple “MM-like” score which we could use to place patients' tumors on a gradual axis of progression toward active disease. Our MM precursor genomic map provides new insights on the time of initiation and cell of origin of the disease, on the order of acquisition of genomic alterations, and on mutational processes found across stages of the transformation. Taken together, we highlight here the potential of genome sequencing to better inform risk assessment and monitoring of MM precursor conditions.]]>
Inclusion Criteria: Patients with known or suspected precursor hematological cancer Including one of the following subgroups of diseases: Early MDS, including pathologically-confirmed MDS (IPSS Low/Int-1; IPSS-R Very Low/Low) and idiopathic cytopenia of undetermined significance (ICUS); Asymptomatic Multiple Myeloma (MM) and Waldenstrom Macroglobulinemia (WM) such as monoclonal gammopathy of undermined significance (MGUS) or Smoldering Multiple Myeloma (SMM); Monoclonal B cell lymphocytosis (MBL); Early stage asymptomatic low-grade lymphomas; or Other precursor conditions or clonal genetic abnormalities of the blood/bone marrow that do not meet criteria for symptomatic hematological malignancy, or patients exposed to prior chemotherapies (e.g., alkylating agents, platinum derivatives, taxanes, topo-2 inhibitors, anti-metabolites, systemic radioisotopes). Patients must be at least 18 years of age to participate in this research. Inclusion of Women and Minorities - In accordance with NIH guidelines, women and members of minority groups and their subpopulations will be included in this protocol.Patients enrolled on clinical trials for precursor diseases are included in this study. Exclusion Criteria: Evidence of symptomatic or active hematological malignancy. ]]>