Primary central nervous system diffuse large B-cell lymphoma (PCNSL-DLBCL) is a highly aggressive malignancy accounting for over 80% of primary CNS lymphomas, with an annual incidence of 0.4-0.6 per 100,000 people globally and a rising trend in immunocompetent patients. First-line high-dose methotrexate-based chemotherapy causes severe toxicities and nearly 50% of patients relapse within 1-2 years, developing relapsed/refractory (R/R) disease.

Treatment options for R/R PCNSL are scarce, with low response rates, median survival of only 3-6 months, and 5-year survival below 5%. The blood-brain barrier and tumor heterogeneity further worsen outcomes. This prospective, multicenter, single-arm phase II study evaluates the efficacy and safety of pomalidomide, PD-1 inhibitor, and selinexor (PPS) in R/R PCNSL, aiming to provide a new effective treatment.

Primary central nervous system diffuse large B-cell lymphoma (PCNSL-DLBCL) is a highly aggressive and uncommon extranodal non-Hodgkin lymphoma that exclusively or predominantly involves the central nervous system. As the predominant subtype of primary central nervous system lymphomas, it accounts for more than 80% of all cases, representing a major clinical challenge in neuro-oncology. Epidemiological studies indicate a global annual incidence of 0.4 to 0.6 per 100,000 individuals, with a gradual increase observed in immunocompetent populations in recent decades. This rising incidence, coupled with its malignant biological behavior, has placed substantial pressure on clinical diagnosis and management.

Currently, high-dose methotrexate (HD-MTX)-based combination chemotherapy remains the standard first-line treatment for PCNSL. Some patients may receive consolidation with local radiotherapy or autologous hematopoietic stem cell transplantation to improve disease control. Nevertheless, this therapeutic strategy has significant limitations. High-dose chemotherapy frequently induces severe adverse events, including myelosuppression, liver and renal toxicity, which are poorly tolerated by elderly patients or those with multiple comorbidities. Despite standardized first-line therapy, approximately 50% of patients experience disease relapse or progression within 1 to 2 years, eventually developing relapsed/refractory (R/R) PCNSL.

For patients with R/R PCNSL, therapeutic options are extremely limited. Existing second-line chemotherapy regimens yield unsatisfactory and inconsistent efficacy, with objective response rates generally below 50%. The median overall survival is only 3 to 6 months, and the 5-year survival rate is less than 5%. In addition to poor survival outcomes, patients often suffer from headache, neurological deficits, cognitive impairment, and other neuropsychiatric symptoms, severely impairing quality of life. Furthermore, the physiological barrier of the blood-brain barrier prevents most conventional chemotherapeutic agents from reaching effective intratumoral concentrations. Meanwhile, the high genetic and phenotypic heterogeneity of tumor cells further compromises treatment efficacy and contributes to drug resistance.

Collectively, the clinical demand for safe and effective treatments in R/R PCNSL remains drastically unmet. Therefore, we designed this prospective, multicenter, single-arm phase II clinical trial to systematically investigate the efficacy and safety of the triplet regimen consisting of pomalidomide, PD-1 monoclonal antibody, and selinexor (PPS) in patients with R/R PCNSL-DLBCL. This study aims to establish a novel and practical therapeutic approach, improve survival and quality of life, and fill the current therapeutic gap for this refractory patient population.

Inclusion Criteria:

• Histologically confirmed primary central nervous system diffuse large B-cell lymphoma (PCNSL-DLBCL).
• Disease progression or relapse after prior treatment with high-dose methotrexate and/or BTK inhibitors.
• Age between 18 and 75 years.
• ECOG performance status score 0-4.
• Expected overall survival > 3 months.
• No known hypersensitivity to any study drug.
• White blood cell count ≥ 3×10⁹/L; absolute neutrophil count ≥ 1.0×10⁹/L; platelet count ≥ 50×10⁹/L.
• Serum creatinine ≤ 1.5 mg/dL; creatinine clearance ≥ 50 mL/min.
• ALT and AST ≤ 3× upper limit of normal (ULN); total bilirubin ≤ 2× ULN.
• Signed written informed consent.

Exclusion Criteria:

• Presence of another malignant tumor requiring active pharmacological or surgical intervention at present;
• Female patients who are pregnant or breastfeeding;
• Patients (male or female) of reproductive potential who are unwilling to use or fail to use effective contraceptive measures;
• Known hypersensitivity to any study drug or any excipient ingredients of these products;
• Active infection (determined by the investigator);
• History of immunodeficiency, including positive HIV status, other acquired or congenital immunodeficiency disorders, or history of organ transplantation;
• Documented history of neurological or psychiatric disorders, including epilepsy or dementia;
• Documented history of autoimmune diseases (except Hashimoto's thyroiditis or thyroid dysfunction);
• Any severe comorbidity that, in the investigator's judgment, would compromise patient safety or interfere with the completion of the study.