Low-Dose TBI Plus CAR T-Cell Therapy for Relapsed/Refractory DLBCL and Multiple Myeloma

This is a clinical trial to evaluate the safety of combining CAR T-cell therapy with low-dose total body irradiation (LD-TBI) in patients with previously treated large B-cell lymphoma (LBCL) or multiple myeloma (MM). The investigators' hypothesis is that the combination will make the immune system more active in fighting cancer by increasing the display of antigens and activating pathways that lead to cell death, including death receptors like FAS and TRAIL2. This approach is expected to help the CAR T cells grow and last longer, leading to stronger anti-tumor effects and more cancer cell deaths. Participants will receive LDTBI treatment before their CAR T cell therapy and will be followed up for 2 years.

Inclusion Criteria: For Diffuse Large B-Cell Lymphoma (DLBCL) Cohort: * Diagnosis of DLBCL that is refractory to first-line chemoimmunotherapy, relapses within 12 months of first-line chemoimmunotherapy, relapses after 12 months in a transplant-ineligible patient, or is relapsed/refractory after two or more lines of systemic therapy. Eligible histologies include DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from indolent lymphoma (follicular lymphoma, marginal zone lymphoma, or chronic lymphocytic leukemia) * Age ≥18 years * ECOG performance status ≤2 * Measurable disease on PET/CT or CT per Lugano Criteria * Adequate organ function: ANC ≥1000 cells/mm³; platelet count ≥75,000 cells/mm³; creatinine clearance or eGFR ≥45 mL/min; total bilirubin ≤2.0x ULN; AST or ALT ≤3.0x ULN; left ventricular ejection fraction \>40% For Multiple Myeloma (MM) Cohort: * Relapsed or refractory multiple myeloma after ≥1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, with disease refractory to lenalidomide (progression within 60 days of last lenalidomide dose) * Age ≥18 years * ECOG performance status ≤2 * Adequate organ function: ANC ≥1000 cells/mm³; platelet count ≥75,000 cells/mm³; creatinine clearance or eGFR ≥30 mL/min; total bilirubin ≤2.0x ULN; AST or ALT ≤3.0x ULN; left ventricular ejection fraction \>40% Exclusion Criteria: For DLBCL Cohort: * History of previous total body irradiation * Prior CAR T-cell therapy * Clonal cytopenia of uncertain significance (CCUS) * Prior history of myeloid malignancies (MDS/AML or MPN), T-cell lymphoblastic lymphoma/leukemia, or B-cell acute lymphoblastic leukemia * Current or prior CNS involvement by lymphoma * Significant cardiovascular impairment (CHF greater than NYHA Class II, uncontrolled hypertension, unstable angina, MI or stroke within 6 months, or cardiac ventricular arrhythmia) * Decompensated cirrhosis * Active HIV, hepatitis B, or hepatitis C infection * Active uncontrolled systemic fungal, bacterial, or viral infection * Pregnancy For MM Cohort: * History of previous total body irradiation * History of myelodysplastic syndrome, CCUS, or concurrent active hematological malignancy with bone marrow involvement * Active HIV, hepatitis B, or hepatitis C infection * Active uncontrolled systemic fungal, bacterial, or viral infection * Prior CAR T-cell therapy * Active or history of CNS myeloma or leptomeningeal infiltration * Pregnancy