Persistence of Monotypic Plasma Cells after Chemoimmunotherapy in Patients with Waldenström Macroglobulinemia: A Matter of Time?
Authors: Varettoni Marzia , Cappello Emilia , Boveri Emanuela , Ferretti Virginia Valeria , Zibellini Silvia , Favrin Gianmarco , Varraso Chiara , Lucioni Marco , Picone Cristina , Facchetti Giulia Vittoria , Palladini Giovanni O. , Paulli Marco , Arcaini Luca 
Published: December 2024

Background. Waldenström Macroglobulinemia (WM) is defined as a lymphoplasmacytic lymphoma involving bone marrow (BM) associated with a serum IgM paraprotein. BM infiltrate is typically composed of small B lymphocytes, plasmocytoid lymphocytes and plasma cells in variable proportions. Chemoimmunotherapy (CIT) has represented the mainstay of treatment of WM in the last 20 years, and overall response rates (ORR) exceeding 80% have been consistently reported with the most widely used regimens. Despite high chemosensitivity, the persistence of monotypic plasma cells in WM in absence of demonstrable monotypic B lymphocytes has been reported in up to 24% of patients after treatment (Barakat FH et al, Am J Clin Pathol 2011), but the impact on patients' outcome is currently unknown.
Aim. The aim of this study was to assess the frequency and the prognostic impact of persistence of monotypic plasma cells after CIT in patients with WM.
Methods. We retrieved the clinical, histologic and molecular data of 92 WM patients consecutively treated with CIT at the Division of Hematology of Fondazione IRCCS Policlinico San Matteo from June 2005 to September 2023. For the purposes of this study, the degree of BM infiltration by B-lymphocytes and plasma cells was assessed by immunohistochemistry (IHC) using respectively B-cell markers CD20, PAX5, CD79a, and plasmacytic differentiation markers MUM1, CD38, CD138. Immunoglobulin light chains antibodies were used to demonstrate light-chain restriction. MYD88 (L265P) mutation was assessed using allele-specific quantitative PCR (AS-qPCR) and CXCR4 mutations were assessed using next-generation sequencing. Progression-free survival (PFS) was defined as the time between BM biopsy after therapy and progression or death (events) or last follow-up, and was estimated via Kaplan-Meier method. All statistical analyses were performed using Stata 18 software
Results. The median age of patients was 65.7 years (IQR: 58.2-72.2), 91% harbored the MYD88 (L265P) mutation and 37% a CXCR4 mutation. Eighty-three patients (90.2%) received CIT as their primary therapy. Fifty-four patients (59%) received Rituximab-Bendamustine, 32 (35%) Rituximab+Cyclophosphamide-Prednisone (R-CP), 4 (4%) Fludarabine+Cyclophosphamide+Rituximab (FCR) and 2 (2%) Rituximab+Cyclophosphamide-Doxorubicine+Prednisone (R-CHOP). Before treatment, the median IgM paraprotein level was 2730 mg/dL (IQR: 1260-4740), the median B-cell infiltration was 40% (IQR: 30-70%) and median plasma cell infiltration was 10% (IQR: 7.5-15%). CXCR4 mutations were significantly more common in patients with 10% or more plasma cells as compared with those having &lt;10% plasma cells before therapy (45% vs 15%, P = 0.028). The ORR according to the 6th International Workshop on WM (IWWM-6) criteria was 91%. Bone marrow biopsy was available in 84/92 patients and was performed after a median time of 1.9 months after the last cycle of CIT (IQR: 1.4-2.3). After treatment the median B-cell infiltration was 5% (IQR: 2-10%) and the median plasma cell infiltration was 5% (IQR 5-15%). In 49/84 patients (58.3%), post-treatment BM biopsy showed the persistence of residual monotypic plasma cells without evidence of monotypic B lymphocytes. With a median follow-up of 4.4 years (IQR: 1.7-6.8) from the end of treatment, the median PFS of patients showing only residual plasma cells after therapy was not significantly different as compared with PFS of patients without evidence of monotypic plasma cells (P=0.649).
Conclusions. In this study, the persistence of monotypic plasma cells after CIT was commonly observed and was not associated with earlier progression. A late clearance of plasma cells, known to be more resistant to chemotherapy as compared with B lymphocytes, could explain these findings and may account for the deepening of response measured by IgM levels which is often observed especially after treatment with FCR or Rituximab-Bendamustine. Our findings may have practical implications, i.e. postponing BM evaluation after CIT, and question the need of additional treatment aimed at eliminating residual plasma cells.