Real-World Data on Clinical Characteristics, Prognosis and Outcome of Primary Plasma Cell Leukemia: A Study of the Greek Myeloma Study Group in the Era of Novel Agents

Primary plasma cell leukemia (pPCL) is an aggressive plasma cell disorder with poor outcome. We and others have previously demonstrated in a limited number of pPCL patients that novel agents and mainly bortezomib-based regimens (BBR) improve response rates and survival; in addition, two recent prospective studies have confirmed the efficacy of lenalidomide-dexamethasone and BBR respectively, followed by autologous transplantation (ASCT) in pPCL; however, the prognostic impact of the induction therapy was not evaluated in both studies. Herein, we explored the clinical characteristics and the impact of current treatments and biological markers on the outcome of an extended cohort of primary PCL (pPCL) patients treated upfront with novel agents, outside clinical trials.

We analyzed the medical records of 50 patients with pPCL (M/F: 25:25; median age 65.5 years, range: 32-86 years; IgG: 19, IgA: 9, light-chain only: 14, IgD: 2, non-secretory: 6; ISS1: 5, ISS2: 16, ISS3: 29) out of 2711 myeloma patients (1.8%), registered in the Greek Myeloma study group database, between 2000-2015. Eastern Cooperative Group (ECOG) performance status was ≥2 in 52% of patients; 77% of patients presented with lytic bone disease and 11% with bone or soft tissue palsmacytomas. Bence-Jones protein was present in 68% of patients; 53% of patients had abnormal lactate dehydrogenase (LDH); 28% had hypercalcemia and 68% had hemoglobin <10 g/dL; fluorescent in situ hybridization (FISH) or conventional karyotype were available in 32/50 (64%) patients; high risk features were present in 65% of patients; 60% of patients had CD56(-) peripheral blood plasma cells; 49/50 patients received therapy: Thirty-eight out of 49 (77.5%) patients received BBR, one patient was treated with the combination of melphalan, prednisone and thalidomide and 10 patients with conventional chemotherapy (C/T); 14/38 (37%) of patients treated with BBR and one patient treated with C/T underwent ASCT consolidation; one patient received in addition an allogeneic transplantation; 48/49 treated patients were evaluated for response: 38/48 patients (79%) achieved objective response (≥PR) and 35% displayed at least very good partial response (≥vgPR), including 17% complete responses (CR). Achievement of ≥vgPR significantly correlated with BBR followed by ASCT (p=0.02). Median time to response was 2 months (range 1-11).

After a median follow up of 61 months (95% CI: 34.5-87.4), 38 (76%) patients have died (disease progression: 18, infection: 16, other causes: 4) and 12 patients remain alive. Early mortality (≤1 month) occurred in 3/38 (6%) deceased patients; 31/38 patients who responded in induction treatment progressed; 27/31 patients who progressed received 2^nd line treatment (lenalidomide-based: 7, BBR: 16, C/T: 4). Progression-free survival was 12 months (95% CI: 8.5-15.4) and it was marginally longer in patients treated with BBR+ASCT vs. others (18 months vs. 10 months, p=0.07). Median OS was 17 months (95% CI: 13-21 months) and it was double in patients treated with BBR+ASCT compared to others (33 months vs. 16 months); median survival after PCL progression was only 7 months (95% CI: 3-11 months). In the univariate analysis, performance status, LDH, induction treatment with BBR, or treatment with BBR+ASCT and quality of response (≥vgPR vs. <vgPR) were independent prognostic factors for OS. In the multivariate analysis quality of response and LDH were the only significant predictors for OS (p<0.05). The median OS for patients who achieved ≥vgPR was 39 months (95% CI: 22-55) vs. 13 months (95% CI: 9-17) for those achieved <vgPR (p=0.02, HzR: 0.46). The median OS for patients with LDH ≥300 U/L was 11 months (95% CI: 7-15 months) vs. 24 months (95% CI: 8-40 months) for those with LDH <300U/L (p=0.03, HzR: 0.5).

These real-world data, based on the largest reported national multicenter series of pPCL patients to-date, support that treatment with BBR plus ASCT is the best currently available option that offers deep and durable responses and reduces early mortality in this setting. Quality of response and high LDH were the strongest independent prognostic factors for OS. We conclude that pPCL requires an aggressive upfront therapeutic approach with a bortezomib-based regimen followed by ASCT that would lead to maximum response and eventually to prolonged OS.