Genetic Plasma Cell Signatures In High-Risk Smoldering Myeloma Versus Multiple Myeloma Patients.

8003 Background: Smoldering myeloma (SMM) is an ill-defined clinical myeloma precursor state. Recently, treatment studies targeting high-risk SMM patients have been conducted, showing promising clinical outcomes. Limited information is available on the biology of SMM. Using samples from a prospective clinical trial based on carfilzomib, lenalidomide and dexamethasone (CRd) (Korde et al. JAMA Oncology 2015), we showed near complete response (CR) or better in 28 of 45 (62%) patients with newly diagnosed multiple myeloma (NDMM); in high-risk SMM patients we reported stringent CR in 12 of 12 (100%) and 11 of 12 were MRD negative. Here, we sequenced the patients on our clinical trial and provide novel insights on tumor cell biology. Methods: We performed whole exome sequencing (median 125x, range 105-184x) and RNA sequencing of plasma cells obtained from baseline bone marrow samples in 39 patients with NDMM and 12 patients with high-risk SMM. Results: Whole exome sequencing on the 39 patients with NDMM identified a total of 2273 non-synonymous variants (median 53, range 26-139). Amongst the 12 SMM patients, 692 non-synonymous variants were identified (median 44, range 26-124). Previously reported recurrently mutated genes in multiple myeloma patients (BRAF, DIS3, FAM46C, IDH1, INTS12, IRF4, KRAS, NRAS, PRDM1, TP53, TRAF3, CYLD, RB1, ACTG1, LTB, HIST1H1E and MAX) were observed in 16 of 39 (41%) NDMM patients. In the high-risk SMM cohort, we did not detect any non-synonymous mutations amongst these genes. Conclusions: Amongst patients with NDMM and high-risk SMM enrolled in a prospective clinical trial of treatment with CRd, we confirmed previously reported recurrent mutations in NDMM. While the number of non-synonymous variants was similar in the two groups, none of the high-risk SMM patients had mutations in these genes. Our novel results suggest that at least a proportion of high-risk SMM patients have different molecular profiles compared to NDMM patients, which could have implications for risk determination and initiation of therapy. Additional analysis including clonal heterogeneity and subclonal architecture will be presented at the meeting. Clinical trial information: NCT01402284 and NCT01572480.