A 1,000-Genome Map for Multiple Myeloma and Its Precursor Stages, and Its Impact on Clinical Outcome
Authors: Alberge Jean-Baptiste , Dutta Ankit K. , Poletti Andrea , Coorens Tim H.H. , Lightbody Elizabeth D. , Toenges Rosa , Loinaz Xavi , Wallin Sofia , Dunford Andrew , Priebe Oliver , Boehner Cody J. , Horowitz Erica M. , Su Nang Kham , Barr Hadley , Hevenor Laura , Towle Katherine , Beesam Rashmika , Beckwith Jenna D. , Perry Jacqueline , Cordas dos Santos David M. , Bertamini Luca , Greipp Patricia , Kübler Kirsten , Arndt Peter F. , Terragna Carolina , Zamagni Elena , Hess Julian , Sklavenitis-Pistofidis Romanos , Stewart Chip , Getz Gad , Ghobrial Irene 
Published: December 2024

Introduction
Genomic alterations are common in multiple myeloma precursor stages, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). However, commonly used stratification systems do not include somatic alterations that play a role in the disease. To address this clinical need, we generated a comprehensive genomic map of MM and precursors by harmonizing and analyzing mostly WGS data from 1,030 patients. We used these data to define a simple MM-like score, that is able to discriminate which premalignant patients are at risk to progress.
Methods
We collected, enriched, and performed WGS of tumor plasma cells and matched normals from 138 participants with MGUS or SMM, including those in low, intermediate, and high-risk groups. We combined our precursor dataset with genomic profiles from MM (n=20) and external sources of 872 individuals with MGUS (n=18), SMM (n=62), and MM (n=792) for a cohort of 1,030 individuals with MM or a precursor condition. In 16 patients, we could perform WGS serially from the bone marrow or circulating tumor cells (n=39) and reassess the presence of mutations.
Results
To develop a simple score that reflects the similarity of precursor genomes to full-blown multiple myeloma disease, we searched among the 107 common driver events (occurring in &gt;1% of patients) and initiating translocations for ones that are differently altered in precursor conditions versus MM. We found 26 differentially altered events: only MAF and MAFB translocations were enriched in MGUS/SMM whereas 24 events were enriched in MM, including known drivers MYC, KRAS, FAM46C, del(1p) and gain(1q). We then defined a simple “MM-like” score for each tumor as the number of MM-enriched drivers minus the number of MGUS-enriched drivers.
As expected, the MM-like score in our cohort increased throughout MM development (MM-like score median of 1 in MGUS, 2 in SMM, and 3 in MM). Even among SMM patients, we found a gradual increase of the MM-like score from low- (median=1), to intermediate (median=2), to high-risk (median=3) groups that match the overall medians in MGUS, SMM and MM (p=2e-5).
We tested whether the MM-like score can be used to estimate risk of progression. Among untreated SMM patients characterized with WGS, an MM-like score greater than 2 was associated with a higher likelihood of progression (HR=5.3, P=0.03). Using an independent dataset of 87 patients with SMM, we were able to validate that a MM-like score greater than 2 was indeed associated with a higher risk of progression (HR=3.3, P=5x10-5).
11 patients who did not progress and for whom we performed longitudinal WGS, has stable MM-like scores over time, while three patients clinically progressed and their MM-like score increased at the time of progression (due to newly detected mutations in KRAS and NRAS). For the two remaining patients, their MM-like score increased, and we observed growth of the subclone that acquired the additional MM-like driver. In the first patient with MGUS/low-risk SMM, a novel hyperdiploid clone was detected in addition to a TP53 bi-allelic hit and t(11;14) translocation and was shown to increase in clonal fraction with tumor burden (light chains +104% within three years). In the second non-progressor with an increasing MM-like score, a novel del(1p) was detected, and other subclones in the phylogenetic tree either shrank or were stable over three years.
Finally, because the MM-like score can place tumors on a gradual axis of evolution towards a more genomically-mature tumor, we tested whether the MM-like score was also predictive of survival in patients treated with a newly diagnosed MM. To do so, we calculated the MM-like score in patients from the publicly available CoMMpass database. We found that an increased score significantly correlated with shorter progression-free survival (median PFS1: 3 years in high score, versus 5 years in low/intermediate score; p=1e-3) and overall survival (median OS: 4.5 years in high score, versus not reached in low/intermediate score; p=1e-5).
Conclusion
Overall, we demonstrate that it is possible to stratify precursor stages of MM by discovering drivers, detecting those that are associated with the stage of the disease, and defining a genomically-based score that can be used to assess risk of progression and is easy to implement in the clinic.