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

This is a single-center, open-label, non-randomized, Phase Ib trial evaluating dose escalation of low-dose total body irradiation (LD-TBI) combined with standard-of-care CAR T-cell therapy in patients with relapsed or refractory large B-cell lymphoma (LBCL) or multiple myeloma (MM). The study includes two disease-specific cohorts: Cohort 1 (LBCL) receives commercial CD19-directed CAR T-cell therapy (axicabtagene ciloleucel or lisocabtagene maraleucel), and Cohort 2 (MM) receives commercial BCMA-directed CAR T-cell therapy (ciltacabtagene autoleucel). In CAR T-cell therapy, T-cells are removed via apheresis, modified to target the tumor, and infused back into the patient after lymphodepleting chemotherapy. On the same day as CAR T-cell infusion, prior to infusion, patients receive a single dose of LD-TBI.

Each cohort follows a standard 3+3 dose-escalation design (Part 1) to identify the maximum tolerated dose (MTD) across three planned dose levels (0.5 Gy, 1.0 Gy starting dose, and 2.0 Gy), based on dose-limiting toxicities occurring within 28 days of treatment. Once the MTD is identified, an expansion cohort (Part 2) of up to 10 additional participants per cohort will be randomized 1:1 to the MTD or a dose level below it to further evaluate safety and activity. Approximately 16-22 participants are anticipated per disease cohort. Participants will be followed for up to 2 years after treatment.

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