Assistant Professor Myeloma Institute, Sylvester Comprehensive Cancer Center, University of Miami, Florida, United States
Introduction: Early intervention for High-Risk Smoldering Multiple Myeloma (HR-SMM) achieves deeper and more prolonged responses compared to newly diagnosed MM (NDMM). It is unclear if this benefit is due to treatment of a less complex entity or inaccuracy in clinical HR-SMM definition.
Methods: To gain biologic insight into treatment outcomes, we performed the first whole genome sequencing (WGS) analysis of treated HR-SMM for 27 patients treated with carfilzomib, lenalidomide, and dexamethasone (KRd) and R maintenance (NCT01572480). We pooled genomic features with 24 patients with HR-SMM treated with Elotuzumab (Elo)R+/-d; (E-PRISM) and compared to 701 patients with NDMM from CoMMpass.
Results: After a median follow-up of 24.6 months, median PFS was unreached. After 8 cycles of KRd, 21 (78%) achieved negativity for minimal residual disease (Flow-MRD; LOD 10-5). At 1 year of maintenance, 48% sustained MRD-negativity and 7% lost MRD-negativity. Accrual began in 2012. 3 patients would today be reclassified as MM per 2014 IMWG criteria. One such patient had the only biochemical progression. Otherwise, 11% were HR by Mayo2008 criteria, 52% by Mayo 20/2/20, 67% by PETHEMA, and 78% by RLM criteria (Rajkumar et al. Blood. 2015). 67% met criteria by 2 or more scores and the median 5-year risk of progression per Pangea was 19% (range 5-82).
Across pooled HR-SMM, frequency of HR IgH translocations was similar (t(4;14), t(14;16), t(14;20); p>0.05) as compared to NDMM from CoMMpass. Driver genes (Rustad et al. Blood Can Disc. 2020) were interrogated together with copy number variation at their loci. Mutations of RAS pathway genes (KRAS, NRAS, and BRAF) were diminished in SMM (22% vs. 48%; p = < 0.001), as were gains at the MYC locus (8q24; 6% vs 25%; p < 0.001) and gains/amps at 1q (19% vs 33%; p = 0.039). Aberrations at key tumor suppressors were less common in HR-SMM (p < 0.05): CDKN2C (4 vs 15%), CYLD (8% vs 28%), MAX (8% vs 25.0%), NFKBIA (4% vs 15%), RB1 (20% vs 49%), TENT5C (12% vs 29%), TP53 (4% vs 14%) and TRAF3 (4% vs 20%). There was no biallelic inactivation of TRAF3 as compared to 10% in NDMM (p = 0.010). In a genome-corrected comparison, APOBEC (SBS2+SBS13) mutational signatures were diminished in KRd WGS compared to 60 dara-KRd-treated NDMM (Maura et al., ASH 2022; 37% vs 87%, p < 0.001) and in E-PRISM vs CoMMpass (17% vs 45%, p = 0.006).
Finally, pooling the HR-SMM treated with KRd and Elo-R+/-d, gain/amp1q was associated with a composite of MRD-positivity, loss of MRD-negativity at 1 year, and progressive disease (39% vs 11%; p = 0.047).
Conclusions: In patients treated on 2 parallel clinical trials for HR-SMM, we found a uniform and relative simplicity in genomic features, which may explain the superior outcomes of contemporary trials. These results support the use of genomics to contextualize advantages of early intervention in SMM (i.e., to avoid overtreatment of non-progressors and to better identify cases likely to progress without therapy).
