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723 Genomic Profiling of Smoldering Multiple Myeloma Classifies Molecular Groups with Distinct Pathogenic Phenotypes and Clinical Outcomes

Program: Oral and Poster Abstracts
Type: Oral
Session: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: Genomics
Hematology Disease Topics & Pathways:
Genomics, Adults, Translational Research, Plasma Cell Disorders, Diseases, Lymphoid Malignancies, Biological Processes, Pathogenesis, Study Population
Monday, December 13, 2021: 3:15 PM

Shankara K Anand, MS1,2*, Mark Bustoros, MD3,4, Romanos Sklavenitis-Pistofidis, MD5, Robert A. Redd, MS6*, Eileen M Boyle, MD, PhD7, Yu-Tzu Tai, PhD8, Carl J Neuse, MD9*, Selina J Chavda, MBBS, BSc, MRCP, FRCPATH10*, Cody J. Boehner, BS8*, Mahshid Rahmat, PhD8*, Benny Zhitomirsky1*, Andrew Dunford1*, Ankit K. Dutta8*, Chip Stewart, PhD1*, Lorenzo Trippa, PhD6*, Tineke Casneuf, PhD11*, Efstathios Kastritis, MD12*, Brian A Walker, PhD13, Faith E Davies, MD7, Meletios A. Dimopoulos, MD12, P. Leif Bergsagel, MD14, Kwee Yong, MD, PhD10*, Gareth J. Morgan, MD, PhD7, François Aguet, PhD1*, Gad Getz, PhD1,15* and Irene M. Ghobrial, MD8,16

1Broad Institute of MIT and Harvard, Cambridge, MA
2Boston University School of Medicine, Boston, MA
3Division of Hematology & Medical Oncology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY
4Division of Hematology & Medical Oncology, Weill Cornell Medicine/New York Presbyterian Hospital, New York, NY
5Department of Medical Oncology, Dana-Farber Cancer Institute, Brookline, MA
6Department of Data Science, Dana-Farber Cancer Institute, Boston, MA
7Perlmutter Cancer Center, NYU Langone Health, New York, NY
8Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
9University of Münster School of Medicine, Münster, Germany
10Cancer Institute, Department of Haematology, University College London, London, United Kingdom
11Janssen Research & Development, Beerse, Belgium
12Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
13Melvin and Bren Simon Comprehensive Cancer Center, Indiana University, Indianapolis, IN
14Division of Hematology, Mayo Clinic, Scottsdale, AZ
15Center for Cancer Research, Massachusetts General Hospital, Boston, MA
16The Center for Prevention of Progression of Blood Cancers, Dana-Farber Cancer Institute, Boston, MA

Introduction: Multiple Myeloma (MM) is an incurable plasma cell malignancy commonly preceded by the asymptomatic stage smoldering multiple myeloma (SMM). MM is characterized with significant genomic heterogeneity of chromosomal gains and losses (CNVs), translocations, and point mutations (SNVs); alterations that are also observed in SMM patients. However, current SMM risk models rely solely on clinical markers and do not accurately capture progression risk. While incorporating some genomic biomarkers improves prediction, using all MM genomic features to comprehensively stratify patients may increase risk stratification precision in SMM.

Methods: We obtained a total of 214 patient samples at SMM diagnosis. We performed whole-exome sequencing on 166 tumors; of these, RNA sequencing was performed on 100. Targeted capture was done on 48 additional tumors. Upon binarization of DNA features, we performed consensus non-negative matrix factorization to identify distinct molecular clusters. We then trained a random forest classifier on translocations, SNVs, and CNVs. The predicted clinical outcomes for the molecular subtypes were further validated in an independent SMM cohort of 74 patients.

Results: We identified six genomic subtypes, four with hyperdiploidy (>48 chromosomes, HMC, HKR, HNT, HNF) and two with IgH translocations (FMD, CND) (Table 1). In multivariate analysis accounting for IMWG (20-2-20) clinical risk stages, high-risk (HMC, FMD, HKR) and intermediate-risk (HNT, HNF) genetic subtypes were independent predictors of progression (Hazards ratio [HR]: 3.8 and 5.5, P = 0.016 and 0.001, respectively). The low-risk, CND subtype harboring translocation (11;14) was enriched for the previously defined CD-2 MM signature defined by the B cell markers CD20 and CD79A (FDR = 0.003), showed upregulation of CCND1, E2F1, and E2F7 (FDR = 0.01, 0.0004, 0.08), and was enriched for G2M checkpoint, heme metabolism, and monocyte cell signature (FDR = 0.003, 0.003, 0.003, respectively). The FMD subtype with IgH translocations (4;14) and (14;16) was enriched for P53, mTORC1, unfolded protein signaling pathways and plasmacytoid dendritic cell signatures (FDR = 0.01, 0.005, 0.008, respectively). The HKR tumors were enriched for inflammatory cytokine signaling, MYC target genes, T regulatory cell signature, and the MM proliferative (PR) signatures (FDR = 0.02, 0.03, 0.007, 0.02, respectively). The APOBEC mutational signature was enriched in HMC and FMD tumors (P = 0.005), while there was no statistical difference across subtypes in the AID signature. The median follow-up for the primary cohort is 7.1 years. Median TTP for patients in HMC, FMD, and HKR was 3.8, 2.6, and 2.2 years, respectively; TTP for HNT and HNF was 4.3 and 5.2, respectively, while it was 11 years in CND patients (P = 0.007). Moreover, by analyzing the changes in MM clinical biomarkers over time, we found that patients from high-risk subgroups had higher odds of developing evolving hemoglobin and monoclonal protein levels over time (P = 0.01 and 0.002, respectively); Moreover, the absolute increase in M-protein was significantly higher in patients from the high-risk genetic subtypes at one, two, and five years from diagnosis (P = 0.001, 0.03, and 0,01, respectively). Applying the classifier to the external cohort replicated our findings where intermediate and high-risk genetic subgroups conferred increased risk of progression to MM in multivariate analysis after accounting for IMWG staging (HR: 5.5 and 9.8, P = 0.04 and 0.005, respectively). Interestingly, within the intermediate-risk clinical group in the primary cohort, patients in the high-risk genetic subgroups had increased risk of progression (HR: 5.2, 95% CI 1.5 – 17.3, P = 0.007). In the validation cohort, these patients also had an increased risk of progression to MM (HR: 6.7, 95% CI 1.2 – 38.3, P = 0.03), indicating that molecular classification improves the clinical risk-stratification models.

Conclusion: We identified and validated in an independent dataset six SMM molecular subgroups with distinct DNA alterations, transcriptional profiles, dysregulated pathways, and risks of progression to active MM. Our results underscore the importance of molecular classification in addition to clinical evaluation in better identifying high-risk SMM patients. Moreover, these subgroups may be used to identify tumor vulnerabilities and target them with precision medicine efforts.

Disclosures: Bustoros: Janssen, Bristol Myers Squibb: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria. Casneuf: Janssen: Current Employment. Kastritis: Amgen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Walker: Bristol Myers Squibb: Research Funding; Sanofi: Speakers Bureau. Davies: Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Beigene: Honoraria; Janssen: Honoraria. Bergsagel: Genetech: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: human CRBN mouse; GSK: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Yong: BMS: Research Funding; Autolus: Research Funding; Takeda: Honoraria; Janssen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; GSK: Honoraria; Amgen: Honoraria. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Getz: Scorpion Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; IBM, Pharmacyclics: Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

*signifies non-member of ASH