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

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