P804: plasma cell leukemia-like transcriptome of bone marrow plasma cells and circulating tumor cell levels in peripheral blood complementarily define high-risk in newly diagnosed multiple myeloma

Topic: 13. Myeloma and other monoclonal gammopathies - Biology & Translational Research Background: Despite the introduction of many effective treatment options for newly diagnosed multiple myeloma (NDMM), a subgroup of high-risk patients remains challenging to treat. Early identification of these patients is essential to enable enrollment in risk-adapted trials. Recently, two novel high-risk markers have been established with independent prognostic value in the context of conventional prognostic tools in NDMM: (1) high levels of circulating tumor cells (CTCs) in peripheral blood (PB), defined by a threshold of >0.07% (Bertamini et al, JCO 2022); (2) plasma cell leukemia-like (PCL-like) status of bone marrow (BM) tumor cells, defined by a combined transcriptomic score of 54 genes (Hofste op Bruinink et al, JCO 2022). Even though PCL-like status is associated with high CTC levels, it remains unclear if these markers have complementary prognostic value. Aims: To assess if PCL-like status and high CTC levels have independent prognostic value in a combined model with conventional risk markers in NDMM. Methods: At baseline, both PCL-like status and CTC levels were determined in transplant-eligible NDMM patients enrolled in the phase 2, randomized controlled FORTE trial (NCT02203643). Off label use of drugs was involved. All patients provided informed consent and received carfilzomib-based induction-consolidation with or without transplant and maintenance with lenalidomide with or without carfilzomib. RNA Seq data of CD138-enriched BM tumor cells were generated within the framework of the MMRF CoMMpass study (NCT01454297). CTC quantification was performed with multiparameter flow cytometry (sensitivity 4×10–5). Progression-free survival (PFS) and overall survival (OS) were analyzed, hazard ratios (HRs) for PCL-like status and CTC levels were estimated using a Cox proportional hazards model including both markers and adjusted for ISS, cytogenetic risk, LDH levels and first randomization arm. Results: Transcriptomic data were available of 122 patients. PCL-like status was found in 33/122 (27%) patients, with the remainder being classified as intramedullary MM (i-MM). PCL-like status was associated with a higher rate of LDH levels above the upper limit of normal (30% in PCL-like MM vs 9% in i-MM, P=0.007), while no statistically significant differences in the distribution of ISS, cytogenetic risk [del(17p) or t(4;14) or t(14;16)], gain(1q), amp(1q), R2-ISS group or randomization arm were found. Of 95/122 (78%) NDMM patients, baseline CTC levels were also available. PCL-like MM patients had higher CTC levels (median 0.97%, interquartile range [IQR] 0.28%–1.62%) than i-MM patients (median 0.03%, IQR 0.01%–0.14%, P<0.001). In the PCL-like cohort, 74% of patients had high CTC levels, as compared with 36% in the i-MM cohort (P=0.002). After a median follow-up of 68 months, in a multivariate model for PFS, both PCL-like status (HR 2.18, 95% CI 1.16–4.11, P=0.016) and high CTC levels (HR 2.20, 95% CI 1.09–4.47, P=0.028) retained independent prognostic value. Combining these two factors, median PFS was not reached in i-MM patients with low CTC levels, 54.2 months in PCL-like MM with low CTC levels, 37.9 months in i-MM with high CTC levels and 23.5 months in PCL-like MM with high CTC levels (Figure). In a multivariate model for OS, a statistically significant effect was found for PCL-like status (HR 3.12, 95% CI 1.26–7.69, P=0.014), while a borderline significant effect was found for high CTC levels (HR 2.88, 95% CI 0.93–8.96, P=0.068). Summary/Conclusion: PCL-like status and high CTC levels are complementary prognostic markers to define high-risk disease in a cohort of transplant-eligible NDMM patients.Keywords: Multiple myeloma, High risk, Plasma cells, Transcription