Improved Survival of Patients with Primary Plasma Cell Leukemia with VRD or Daratumumab-Based Quadruplets: A Multicenter Study By the Greek Myeloma Study Group

Primary plasma cell leukemia (pPCL) is a rare plasma cell disorder with poor outcome. Recently, the International Myeloma Working Group revised its definition proposing cPCS of ≥5% as the new cut-off value. There is still limited information regarding the impact of novel effective anti-myeloma combinations, i.e., bortezomib-lenalidomide triplet (VRd) or daratumumab-based quadruplets (DBQ) on pPCL outcome. Therefore, considering the lack of prospective trials, our aim was to compare retrospectively treatment approaches, and to evaluate prognostic factors of overall survival (OS) in an extended cohort of pPCL patients including those fulfilling the new criteria, in the real-world setting. We analyzed the medical records of 110 pPCL patients (M/F: 51/59; median age 65 years, range: 44-86; IgG: 47, IgA: 17, light-chain: 32, IgD: 3, IgM: 2, non-secretory: 9; ISS1: 9, ISS2: 32, ISS3: 69) out of 3324 myeloma patients (3%), registered in our database, between 2001-2021; 51% of patients were ≤65 years; Eastern Cooperative Group (ECOG) was ≥2 in 46%; 65% had advanced bone disease and 15% had bone/soft tissue plasmacytomas; 72% had Bence-Jones proteinuria, 45% had abnormal LDH, 27% had hypercalcemia, 72% had hemoglobin <10 g/dL and 24% had estimated glomerular filtration rate <30ml/min/1.73m2. High-risk molecular abnormalities i.e., del17p, t(4;14), t(14;16) and 1q21+ tested by FISH hybridization were detected in 56%; 30% had t(11;14). Revised ISS (RISS) was distributed as follows: RISS1: 4%, RISS2: 58%, RISS3: 38%. Median cPCs % was 11% (range: 5-71%), in line with multiparameter flowcytometry findings (10%; range: 4,5-71%). Immunophenotype of PCs was similar in bone marrow and peripheral blood in 92% of patients; CD56(-) and CD27(+) cPCs was found in 52% and 35%, respectively. 37% had cPCS 5-20%; Patients' characteristics did not correlate with cPCs %, except from platelets (PLT) that were significantly lower in patients with >20% cPCs; 89% of patients received novel therapies; DBQ: 21%, VRd: 16%, bortezomib standard combinations (BSC): 52%, conventional chemotherapy (CT): 11%; 35% underwent autologous stem cell transplantation (ASCT). Regarding response to treatment 83% achieved objective response (≥PR); 24% had very good partial response (vgPR), and 26% had complete response (CR). Median time to response was one month (range 1-5). Treatment with VRd/DBQ or ASCT strongly correlated with higher CR rates (45% vs. 19%; p=0.007; 52% vs. 11%; p<0.001, respectively). After a median follow up of 51 months (95% CI: 45-56), 67 patients died (progression: 42, infection: 20, other: 5) and 43 patients remain alive. Early mortality (≤1 month) occurred in 4/67 deceased patients; 51/110 (46%) patients received 2nd line therapy (lenalidomide-based: 17, proteasome inhibitor-based: 12, daratumumab-based: 9, pomalidomide-based: 4, CT: 9). Median number of treatment lines was 1 (range: 1-5). Progression-free survival was 16 months (95% CI: 12-19.8), significantly longer in patients treated with VRd/DBQ vs. BSC/CT (25 months 95% CI: 13.5-36.5, vs. 13 months 95% CI: 9-16.8; p=0.03). Median OS was 29 months (95% CI: 19.6-38.3), significantly longer in patients treated with VRd/DBQ vs. BSC/CT (not reached vs. 20 months, 95% CI: 14-26; 3-year OS: 70% vs. 32%, respectively; p<0.001; HR: 3.88). Median survival after pPCL progression was 8 months (95% CI: 3.5-13.5). In the univariate analysis, ECOG ≥2, PLT <100.000/μL, cPCs (5-20% vs >20%), del17p(+), upfront treatment with VRd/DBQ, ASCT and CR were independent prognostic factors for OS; treatment with VRd/DBQ, del17p(+) and PLT <100.000/μL, significantly predicted for OS in the multivariate analysis (p<0.05). Median OS for patients with del17p(+) vs. del17p(-) was 17 months (95% CI: 11.7-22) vs. 48 months, respectively (95% CI: 27.8-68) (p=0.01, HR: 3.1). Median OS for patients with PLT <100.000/μL vs. ≥100.000/μL was 16 months (95% CI: 9-23) vs. 46 months (95% CI: 28-64) respectively (p=0.01; HzR: 0.34). These real-world data, based on the largest reported national multicenter series of pPCL incorporating the new criteria, has shown that treatment with VRd or antiCD38-based quadruplets induces deep and durable responses and is one of the strongest prognostic factors for OS representing currently the best therapeutic approach for pPCL; ASCT maintained its therapeutic value. Del17p (+) and thrombocytopenia were negative predictors for OS.