OA-20: Genomic profiling of high-risk smoldering myeloma patients treated with a curative strategy: a biological study of the phase II GEM CESAR clinical trial.

Introduction: Smoldering multiple myeloma (SMM) precedes multiple myeloma (MM). The risk of progression of SMM patients is not uniform, thus different progression-risk models have been developed, although they are mainly based on clinical parameters. Genomic predictors of progression have been defined for untreated SMM, but their usefulness in the context of trials evaluating upfront treatment in high risk SMM (HR SMM) has not been explored yet, precluding the identification of baseline genomic alterations leading to drug resistance.

Methods: We carried out NGS and FISH studies on 57 HR SMM patients treated in the GEM-CESAR trial (NCT02415413). CD138+ plasma cells were isolated from the bone marrow; after DNA extraction, a custom NGS panel was used to sequence 145 Kb from 666 target regions, allowing the detection of SNV and indels located in 38 genes previously reported in the literature as relevant in MM. FISH studies included probes to detect the following alterations: t(4;14), t(14;16), del17p, t(11;14), 1q gain or amplification (+1q), del1p and structural aberrations in the MYC locus.

Results: According to the 2014 IMWG definition, 44 patients met the current criteria to be considered HR SMM at diagnosis, while the remaining 13 cases, originally classified as ultra‒high risk (UHR), had active disease at baseline following the actual criteria.
The median number of SNV/indels per patient was 1 (range: 0‒9), with 11/57 patients (19.3%) harboring no alterations in the studied genes. The mutational profile of these patients was enriched in alterations involving well-known drivers in MM (KRAS, NRAS, DIS3, FAM46C). MAPK pathway gene mutations were the most abundant (52.6%), followed by those belonging to RNA and protein processing (22.8%). In 7 patients we identified more than one SNV and/or indel in the same gene (multihit mutations).
Concerning cytogenetics, frequencies were closer to symptomatic MM, although some aberrations were enriched in HR SMM compared to the general SMM population [t(4;14) and +1q]. On the contrary, 1p deletions were infrequent (3.8%) and double-hit TP53 alterations absent. Interestingly, FGFR3 mutations were frequently accompanied by t(4;14): 7/8 cases with FGFR3 mutations also harbored the translocation.
Previously described risk factors of progression in SMM (mutations in the MAPK pathway, structural alterations affecting MYC and aberrations in the DNA repair pathway) did not predict early biological or clinical progression. In our cohort, NRAS mutations (HR: 5.45, 95% CI: 1.57‒18.93, p=0.008) and the co-occurrence of t(4;14) with FGFR3 mutations (HR: 6.75, 95% CI: 1.87‒24.34, p=0.004) were associated with a higher risk of biological progression.

Conclusions: The mutational profile of HR SMM patients is similar to symptomatic MM. If validated in larger studies, t(4;14) plus FGFR3 mutations, or NRAS mutations, could be used to predict resistance and a shorter time to disease progression.