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    Plasma Cell precursor and Other Disorders

    Category: Plasma Cell precursor and Other Disorders

    BTK Inhibitors and Bendamustine-Rituximab Demonstrate High Efficacy in Secretory Non-IgM Lymphoplasmacytic Lymphoma

    (PA-339) BTK Inhibitors and Bendamustine-Rituximab Demonstrate High Efficacy in Secretory Non-IgM Lymphoplasmacytic Lymphoma

    Thursday, September 18, 2025
    Introduction: Non-IgM lymphoplasmacytic lymphoma (LPL) is a rare subtype defined by marrow infiltration without IgM paraprotein. Despite biological overlap with Waldenström macroglobulinemia (WM), it is often mistaken for multiple myeloma (MM). Due to its rarity, there are no prospective studies, and evidence is limited to case reports and small series. No comparative data support current treatment approaches, and clinical outcomes with modern agents such as BTK inhibitors (BTKi) remain anecdotal.

    Methods:

    We retrospectively identified patients with secretory non-IgM LPL (IgG or IgA) diagnosed at our institution from 2005 to 2025. Diagnosis and response assessment followed IWWM-12 criteria. The primary objective was to compare VGPR rates and PFS with bendamustine-rituximab (BR) vs. BTKi in the frontline setting. Secondary objectives included evaluating outcomes with BR/BTKi vs. rituximab monotherapy and MM-regimens. Multivariable logistic and Cox models were adjusted for age, sex, and isotype (IgG vs. IgA).

    Results:

    Seventy-two patients were included: 57 (79%) had IgG and 15 (21%) IgA monoclonal protein. Median age at diagnosis was 63.5 years (range 42–87); 38 (53%) were female. MYD88 mutations were detected in 60/63 patients (95%) and CXCR4 mutations in 11/36 (31%). With a median follow-up of 69 months (95% CI 52–85), the 5-year overall survival rate was 96%. Fifty-seven patients (79%) received treatment, with a median time to first treatment of 8.4 months (95% CI 2-28). First-line regimens included BR (n=16), BTKi (n=12; zanubrutinib n=8, ibrutinib ± rituximab n=4), rituximab monotherapy (n=11), MM-regimens (n=5; triplet combinations n=3, doublets n=2), and other chemo-immunotherapy/proteasome inhibitor-based combinations (n=13). Median follow-up after frontline therapy was 49 months for BR and 39 months for BTKi.

    In the frontline setting, BR and BTKi demonstrated similar efficacy: VGPR rates were 47% with BR and 36% with BTKi (p=0.60), and the 3-year PFS rate was 76% with BR and 77% with BTKi (p=0.57). Both therapies outperformed rituximab monotherapy, which showed a VGPR rate of 22% (p=0.28 vs. BR/BTKi) and a 3-year PFS rate of 34% (median PFS 13 months; p=0.01 vs. BR/BTKi). Among the few patients treated with MM-regimens, none achieved a VGPR, and PFS was significantly shorter compared to BR/BTKi (3-year PFS rate of 33%; p=0.04). On multivariable analysis, receipt of either BR or BTKi was independently associated with improved PFS compared to rituximab monotherapy (HR 0.16; 95% CI 0.04-0.69; p=0.01). No variables were associated with VGPR attainment.

    Conclusions:

    In the largest reported cohort of non-IgM LPL, BR and BTKis were comparable in efficacy and associated with superior PFS compared to rituximab monotherapy and other non-standard approaches. These findings provide the first evidence-based foundation for treatment selection in this rare population and support aligning therapeutic strategies with those established for WM.