This study aims to evaluate the efficacy and safety of the VPX regimen, a novel combination of teniposide, PD-1 monoclonal antibody and selinexor, in patients with relapsed/refractory (R/R) primary central nervous system lymphoma (PCNSL) who have progressed after high-dose methotrexate (HD-MTX)-based systemic therapy. By investigating this therapeutic approach, we seek to establish a new treatment paradigm that may improve clinical outcomes of this high-risk population.

This study will enroll patients aged 18-75 years with R/R PCNSL who have progressed after HD-MTX-based systemic therapy. Eligible participants will receive induction therapy with 2 cycles of VPX regimen followed by evaluation of contrast-enhanced magnetic resonance imaging (MRI) of the brain. Patients who got disease progression of stable disease will be withdrawn from this study. Patients who achieved partial remission(PR) or complete remission（CR）will receive consolidation treatment stratification as followings:

Group A (ASCT-eligible): Patients will proceed to autologous stem cell transplantation (ASCT) as consolidation therapy.

Group B (ASCT-ineligible): Patients will receive four additional cycles of VPX regimen, followed by whole-brain radiotherapy (WBRT) consolidation.

After consolidation therapy, all responders will receive PD-1 monoclonal antibody therapy maintenance for up to 2 years, or until disease progression or unacceptable toxicity occurs.

Inclusion Criteria:

1. Age between 18 and 75 years old (inclusive).

2. Participants must be able to understand and willing to sign a written informed consent form.

3. The Eastern Cooperative Oncology Group is in a state of 0 to 3.

4. The expected lifespan is ≥ 3 months (according to researchers).

5. Primary central nervous system lymphoma of B-cell origin confirmed by pathology (histology or cytology).

6. Measurable diseases are defined as having a short diameter of at least 1.0cm through enhanced MRI.

7. Recurrent/refractory PCNSL: Must have received at least one systemic treatment based on high-dose methotrexate.

8. Any non hematological toxicity related to previous treatment should be restored to grade 1 or normal (excluding hair loss according to NCI CTCAE 5.0).

9. Bone marrow and organ function meet the following criteria (no blood transfusion, no G-CSF, no medication correction within 14 days prior to screening):

   Bone marrow function: absolute value of neutrophils ≥ 1.5 × 10 ^ 9/L, platelets ≥ 80 × 10 ^ 9/L, hemoglobin ≥ 80 g/L; Liver function: serum total bilirubin ≤ 1.5 × ULN (≤ 3.0 × ULN, if there is liver metastasis); Glutamate oxalate transaminase (AST) and glutamate pyruvate transaminase (ALT) ≤ 2.5 × ULN (≤ 5.0 × ULN, if there is liver metastasis); Coagulation function: International normalized ratio (INR) and activated partial thromboplastin time ≤ 1.5 × ULN; Renal function: serum creatinine ≤ 1.5 × ULN or estimated creatinine clearance rate ≥ 60 mL/min (male: Cr (ml/min)=(140 years old) × body weight (kg)/72 × serum creatinine concentration (mg/dl); Female: Cr (ml/min)=(140 years old) x body weight (kg)/85 x serum creatinine concentration (mg/dl)

10. Women with reproductive potential must agree to use efficient contraceptive methods during treatment and within 6 months after the last study drug administration. Sexually active males must agree to use highly effective contraceptive measures during treatment and within 6 months after the last dose of medication.

11. Can accept multiple MRI/CT and lumbar puncture examinations.

12. Swallowing oral tablets/capsules is not difficult.

13. Good compliance, willing to follow inspection procedures such as visit schedule, medication schedule, laboratory tests, etc.

Exclusion Criteria:

1. Chemotherapy, radiotherapy, immunotherapy, or antibody therapy for anti-tumor treatment, or herbal medicine with anti-tumor indications, small molecule targeted therapy within 2 weeks, monoclonal antibody conjugate drug or cytotoxic therapy within 10 weeks.
2. Participate in another clinical study using the research product within 4 weeks prior to the first day of treatment.
3. Patients who have used systemic corticosteroids for more than 5 days within 14 days prior to medication or require daily administration of>10mg dexamethasone or equivalent medication to control central nervous system disorders.
4. Active concurrent malignant tumors that require active treatment.
5. Patients who have received previous treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, selenidazole, and tiniposide drugs within 6 months prior to initial administration.
6. Suffering from uncontrolled or severe cardiovascular disease, including (but not limited to): any of the following: congestive heart failure (NYHA class III or IV); miocardial infarction; Unstable angina pectoris; Or there may be arrhythmia requiring treatment during screening, and the left ventricular ejection fraction (LVEF) within 6 months prior to initial administration is less than 50%; Primary cardiomyopathy (e.g. dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, undefined cardiomyopathy); A clinically significant medical history of QTc prolongation, grade II type II atrioventricular block or grade III atrioventricular block, or QTc interval (Method F)>470 milliseconds (females) or>480 milliseconds (males); Atrial fibrillation (EHRA ≥ 2b); Uncontrollable hypertensive patients are considered unsuitable to participate in this study.
7. Uncontrolled infections or infections requiring intravenous antibiotic treatment.
8. Chronic hepatitis B carriers with active hepatitis B or C infection (hepatitis B: acute hepatitis B, untreated chronic hepatitis B virus infection, HBV-DNA ≥ detection limit of each center; hepatitis C: HCV RNA positive) or syphilis. Attention: Non active carriers of HBV surface antigen (HBsAg), active HBV infection and persistent anti HBV suppression (HBV DNA\