Genomic Profiling to Contextualize the Results of Intervention for High-Risk Smoldering Myeloma

Early intervention for High-Risk Smoldering Multiple Myeloma (HR-SMM) achieves deeper and more prolonged responses compared to Newly Diagnosed (ND) MM. It is unclear if beneficial outcomes of interventional studies in HR-SMM are due to treatment of less complex, susceptible disease or inaccuracy in clinical definition of cases entered. Here, to gain greater biologic insight into treatment outcomes, we performed the first whole genome sequencing analysis of treated HR-SMM for 27 patients treated with carfilzomib, lenalidomide, and dexamethasone and lenalidomide maintenance ([NCT01572480][1]). Genomic features were pooled with another contemporary HR-SMM interventional study (E-PRISM; [NCT02279394][2]) and compared to those of NDMM. We reveal that across interventional cohorts, the genomic landscape of HR-SMM is uniformly simple as compared to NDMM counterparts, with fewer inactivation events of tumor suppressor genes, fewer RAS pathway mutations, lower frequency of MYC disruption, and lower APOBEC contribution. The absence of these genomic events parallels that of indolent precursor conditions with low chance of progression, possibly explaining the overall superior outcomes across these trials. However, there remains a subgroup of patients harboring genomic complexity for whom early intervention with potent triplet therapy fails to sustain response and who experience resistant, progressive disease. Overall, these results suggest that clinical risk scores do not effectively discriminate between genomically indolent and aggressive disease. Furthermore, our study supports the use of genomics to contextualize the advantage of early intervention in SMM and to consider novel approaches for those with the most aggressive precursor states. Key Points Treated clinical high-risk smoldering multiple myeloma is genomically heterogeneous but is mostly less complex than multiple myeloma counterparts. A small subgroup of high-risk genomic features is associated with disease progression despite early intervention with triplet therapy. ### Competing Interest Statement B.D. has received honoraria from advisory boards from Sanofi and Janssen and Independent Data Review Committee for Janssen. D.K. acknowledges research funding from: NCI/NIH, FDA, MMRF, DoD-PROMETHEUS (Murtha Cancer Center Research Program), Amgen, Celgene, Janssen, Karyopharm; has received honoraria for advisory boards and presentations for: Alphasights, Aptitude Health, Arcellx, BMS, Bridger Consulting Group, Curio Science, Karyopharm, MJH Life Sciences, MMRF, Plexus Communications, Sanofi; and served on Independent Data Monitoring Committees (IDMC) for: Aperture Medical Technology, Arcellx. O.L. acknowledges research funding from: NCI/NIH, FDA, LLS, Rising Tide Foundation, Memorial Sloan Kettering Cancer Center, MMRF, IMF, Paula and Rodger Riney Foundation, Myeloma Solutions Fund, Perelman Family Foundation, Amgen, Celgene, Janssen, Takeda, Glenmark, Seattle Genetics, Karyopharm; has received honoraria for scientific talks/participated in advisory boards for: Adaptive, Amgen, Binding Site, BMS, Celgene, Cellectis, Glenmark, Janssen, Juno, Pfizer; and served on Independent Data Monitoring Committees (IDMC) for international randomized trials by: Takeda, Merck, Janssen, Theradex. S.U. acknowledges research funding from Amgen, Array Biopharma, BMS, Celgene, GSK, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDX, Takeda; honoraria/consulting from Abbvie, Amgen, BMS, Celgene, EdoPharma, Genentech, Gilead, GSK, Janssen, Oncopeptides, Sanofi, Seattle Genetics, SecuraBio, SkylineDX, Takeda, TeneoBio; grant support from NCI, LLS, MMRF. None of the other Authors have conflict of interest to disclose. ### Funding Statement This work was supported by the Myeloma Solutions Fund (MSF), Paula and Rodger Riney Multiple Myeloma Research Program Fund, the Tow Foundation, Sylvester Comprehensive Cancer Center NCI Core Grant (P30 CA 240139) and the Intramural NCI Program. B.D. is supported by the Sylvester K12 Calabresi Clinical Oncology Research Career Development Program. FM is supported by International Myeloma Society, NIH, and American Society of Hematology. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Samples and data were obtained and managed in accordance with the Declaration of Helsinki and the Institutional Review Board of the University of Miami under protocol 20210398. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The dataset used for this paper is derived from public and newly sequenced sources: 27 SMM exomes were imported from dbGaP: phs001323.v3.p1. 701 MM exomes (from patients with RNA-seq and low coverage WGS data) were imported from the CoMMpass trial; IA 13. Data from the 27 newly sequenced samples are currently uploading on EGA and will be available upon publication of the manuscript. KRd +/- Dara: EGAS00001007404. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01572480&atom=%2Fmedrxiv%2Fearly%2F2023%2F08%2F31%2F2023.08.30.23294483.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02279394&atom=%2Fmedrxiv%2Fearly%2F2023%2F08%2F31%2F2023.08.30.23294483.atom