(PA-199) Elevated Non-Clonal Bone Marrow Plasma Cell Fraction at Diagnosis Is Associated with Improved Outcomes in Multiple Myeloma

Current risk stratification in newly diagnosed multiple myeloma (NDMM) primarily relies on interphase FISH cytogenetics and disease burden. In smoldering myeloma, a clonal/aberrant plasma cell fraction ≥95% is a recognized predictor of early progression, while a higher non-clonal plasma cell fraction (NCPF) is associated with improved outcomes. The prognostic impact of NCPF in NDMM remains understudied in the context of established risk factors.

Methods: We included patients with newly diagnosed multiple myeloma (NDMM) between 01/01/2013 and 01/31/2023. Non-clonal plasma cell fraction (NCPF), defined as the percentage of non-clonal plasma cells among total plasma cells, was measured using multiparameter flow cytometry (MFC) on baseline bone marrow aspirates. Immunophenotyping used CD19, CD38, CD45, CD138, cytoplasmic kappa/lambda light chains, and DAPI. Clonal plasma cells were identified as CD38+/CD138+, CD19–/CD45–, with light chain restriction and/or ploidy differences by DAPI. An NCPF of ≥5% was considered as NCPF-High and we hypothesized this to be associated with better prognosis. High-risk cytogenetics included del(17p), t(4;14), t(14;16), t(14;20), del(1p), and 1q gain/amplification. An adaptation of the 2024 IMS/IMWG classification was utilized for risk stratification (without the TP53 mutation data).

Results:

We included 798 patients, out of which 124 patients (15.5%) had a NCPF of ≥5% (NPCF-High). The median follow-up was 6 years and the estimated median overall survival (OS) was 8.2 years (95% CI: 5.6-6.4 years) for the entire cohort. Compared to NCPF-Low patients, the NCPF-High cohort had a lower BM plasma cell burden (median 20% vs. 50%, p< 0.0001), lower t(11;14) rates (14 vs. 24%, p=0.02) and a higher prevalence of hyperdiploidy (71% vs. 59%, p=0.025), with comparable rates of high-risk cytogenetics and IMS/IMWG high-risk status (25.2 %vs. 25.5%, p=0.94). The 6-year OS rate was 70.3% (95% CI: 62-79%; median OS not reached) for the NCPF-High cohort and 56.5% [95% CI: 52.2%-61%; median OS 7.6 years) for the NPCF-Low cohort [p=0.0096; HR 0.64 (95% CI: 0.46-0.9)]. In a multivariable analysis including NCPF-High, age of ≥75 years at diagnosis of MM, IMS/IMWG high-risk status, S-phase ≥2%, bone marrow plasma cells ≥50% and eGFR < 45 ml/min, the NCPF-High fraction was independently associated with a better prognosis [HR 0.64 (95% CI: 0.43-0.96), p=0.03]. The median progression-free survival with frontline therapy was significantly better for the NCPF-High cohort [HR 0.69 (95% CI: 0.53-0.9), p=0.006], with comparable induction, transplant and maintenance strategies in the two cohorts.

Conclusions: Among patients with NDMM, a higher non-clonal plasma cell fraction at diagnosis is independently associated with improved overall survival, suggesting its potential as a novel prognostic biomarker. Characterization of the immune microenvironment in these patients would be important to understanding the biologic rationale for these findings.