Primary plasma cell leukemia (pPCL) is a rare variant of plasma cell malignancy characterized by at least 5% of circulating plasma cell (cPC), aggressive behavior and ominous prognosis. Though to the rarity of the disease, up to now only three prospective studies have been conducted, consequently, the choice of treatment is most based on expert consensus. To overcome the lack of information, several real-world evidence data have been collected but in a heterogenous population including both transplant eligible (TE) and ineligible (TIE) patients. Moreover, the roles of daratumumab (Dara) and chemotherapy-based (Chemo) combinations as induction therapy is not well established.

The aim of this observational study is to retrospectively and prospectively evaluate in real-life the first-line treatment and the outcome of transplant eligible pPCL patients.

From 2009 to 2025 we collected data from 143 pPCL patients (54 with 5-19% cPC and 89 with ³20% cPC) followed in 27 Italian centers. Median age was 60 years (28-77). As expected, the cohort was enriched in high-risk disease features, including ISS III in 67.2% of cases (88/131), R-ISS III in 53.2% of cases (67/126) and R2-ISS IV in 42.9% of cases (42/98). Additionally, high LDH levels and extramedullary disease (EMD) were detected in 56.2% (77/136) and 20.5% (28/137) of patients, respectively. Finally, considering the cytogenetic status, 57.7% (64/111) of cases were high-risk, with 36.3% (37/102) displaying >1 alteration. Compared to patients with 5-19% of cPC, patients with ≥20% cPC were characterized by higher frequency of R-ISS III (48.2% vs 32.2%, p=0.096), high LDH levels (p=45.6% vs 30.1%, p=0.099) and lower frequency of EMD (33% vs 55.6%, p=0.0513).

Considering the induction treatment, 60/143 (42%) patients received Dara and 59/143 (41.3%) patients a Chemo-based induction. In detail, 42/143 (29.4%) received D-VTD, 13/143 (9.1%) D-VTD-PACE, 5/143 D-VRD (3.5%), 38/143 V(T)D-PACE (26.6%), 31/143 VTD (21.7%), 3/143 KRD (2.1%), 2/143 VRD (1.4%), 8/143 (5.6%) PAD/VCD and only one patient RD. Only 53.1% of cases (76/143) underwent at least a stem cell transplantation (SCT) in first line, with 30/76 (39.5%) receiving single AutoSCT, 33/76 (43,4%) tandem AutoSCT and 13/76 (17.1%) AlloSCT, mostly tandem AutoSCT-AlloSCT (10/13, 76.9%). Moreover, after SCT, 28/64 (43.8%) patients started maintenance while 36/64 (56.2%) begun observation.

With a median follow-up of 15 months, the median progression free survival (PFS) and overall survival (OS) were 18 months and 31 months, respectively. Overall, major predictor of worse OS were HR cytogenetic (20 vs 73 months, p=0.0018), >1 HR abnormalities (20 vs 52 months, p=0.0344) and EMD (16 vs 31 months, p=0.0382). As previously reported, no PFS and OS differences were found between cases with 5-19% cPC and those with ≥20% cPC (PFS: 17 vs 16 months, p=0.4222; OS: 30 vs 31 months, p=0.9442).

An increased PFS, although not statistically significant, was demonstrated in patients treated with Dara-based compared to Dara-sparing regimens (36 vs 16 months, p=0.1337) or Chemo-based compared to Chemo-sparing regimens (29 vs 15 months, p=0.1246). Of notice, D-VTD-PACE treatment showed superior PFS with respect to D-VTD (not reached vs 15 months, p=0.0152). Patients receiving tandem AutoSCT or AlloSCT showed higher PFS and OS compared to those who received single AutoSCT (tandem AutoSCT vs single AutoSCT: PFS=38 vs 15 months, p=0.0011; OS=72 vs 23 months, p<0.0001; AlloSCT vs single AutoSCT: PFS=98 vs 15 months, p=0.0121; OS=102 vs 23 months, p=0.0136). However, there was no significant difference in PFS and especially OS between AlloSCT and tandem AutoSCT (p=0.2399 and p=0.8638, respectively). Finally, patients who received maintenance displayed a significant improvement in PFS (45 vs 18 months, p=0.0019) and OS (not reached vs 29 months, p=0.0042) with respect to observation.Herein we reported one of the largest cohorts of TE pPCL patients. The preliminary data presented prove efficacy for Dara-based or Chemo-based combinations as induction treatment, with promising efficacy for D-VTD-PACE regimen. Most importantly, we confirmed the benefit in terms of PFS and OS for tandem AutoSCT or AlloSCT and maintenance therapy in the first line treatment, as recently suggested in EMN pPCL guidelines.

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2025
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