CAR-T Cell Therapy in Advanced Myeloma with Extramedullary Disease - an In Vivo Imaging and Molecular Monitoring Study (CARAMEL): First Results of Cu-64 Radiolabelled Nanoparticle PET-CT and PET-MRI

Aim: Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy has demonstrated outstanding response rates and durability in heavily pre-treated (³3) myeloma patients (CARTITUDE-1), and superiority compared to standard-of-care in lenalidomide-refractory myeloma patients after 1-3 prior lines of therapy (CARTITUDE-4). Patients with extramedullary myeloma appear to have a reduced progression-free survival as compared to their respective counterparts in subgroup analyses. We aimed to study the early biodistribution of cilta-cel using a novel nanoparticle-based tracking technology, combined with immunological correlative studies on blood, bone marrow and plasmacytoma biopsies, in order to elucidate the biology of resistance in extramedullary myeloma and identify opportunities for novel interventions to improve outcomes.

Method: Copper-64 (Cu-64) super paramagnetic iron oxide nanoparticles (SPION) is a dual PET-CT PET-MRI cell tracking technology that is suited for studying early in vivo trafficking after adoptive cellular therapies. We performed pre-clinical studies to assess the effect of Cu-64-SPION labelling on in vitro CAR T-cell function. We then initiated CAR-T cell therapy in Advanced Myeloma with Extramedullary disease - an in vivo imaging and molecular monitoring study (CARAMEL). Myeloma patients with measurable extramedullary disease and ³2 prior lines of therapy (including a proteasome inhibitor and an immunomodulatory imide drug (IMiD) are eligible. Patients receive 70% unmanipulated cilta-cel, followed by 30% Cu-64 SPION-loaded cilta-cel. Dual Cu-64 PET-CT and PET-MRI imaging is performed over the first 4 days, followed by MRI alone at later time points.

Results: Pre-clinical studies demonstrated no deleterious effect of Cu-64 SPION labelling on cilta-cel viability, phenotype, killing or cytokine release in vitro. To date, three Caucasian, male patients, ranging in age from 55 to 59, have been enrolled and treated on CARAMEL. Preliminary imaging analysis demonstrates dynamic biodistribution initially within lung with trapping in the pulmonary vasculature, and migration of cells into the systemic circulation over time, including liver, spleen and bone marrow. In patient 1 the distribution of radioisotope at 12 hrs was 21% to liver, 47% to spleen, 3% to bone marrow. On the pre-infusion FDG-PET a distinct lesion was visible in the right pelvis, indicative of a bone-based plasmacytoma. On day 1 and day 3 post infusion, a rim of activity was seen on the Cu-64 PET, suggesting Cu64-SPION labelled cilta-cel tracking. The patient also had a soft-tissue plasmacytoma in the left axilla, with no tracking observed over the first four days, despite achieving a partial response on the D+28 FDG-PET. Patient 2 had numerous nodal as well as soft-tissue sites of myeloma involvement. The distribution of radioisotope at 12 hrs was 51% to liver, 14% to spleen, and 2.5% to bone marrow. Patient 3 had numerous subcutaneous and soft-tissue lesions in his pancreas and nasopharynx. The distribution of radioisotope at 12 hrs was 53% to liver, 16% to spleen, and 3% to bone marrow. Specific uptake at the soft-tissue plasmacytomas was not observed over the first 4 days. Analysis of longer-term tracking on MRI by the SPION component of the nanoparticles and correlative immunological studies on blood, marrow and plasmacytoma biopsies is ongoing.

Conclusion: First results from CARAMEL confirm the ability of Cu-64 SPION tracking technology to visualise the dynamic biodistribution of Cu-64 SPION-loaded cilta-cel. Enrolment in CARAMEL is ongoing and further research is needed to ascertain the sensitivity for detecting migration to bone-based or soft-tissue plasmacytomas. (NCT05666700).

Dowling:Abbvie: Patents & Royalties; Novartis: Consultancy; Kite/Gilead: Consultancy. Scott:Kite/Gilead: Honoraria, Other: Travel funding. Domingues:Cell Therapies Pty Ltd: Current Employment. Dickinson:Cyclotek: Current Employment. Schobben:Cyclotek: Current Employment. Frazzetto:Cyclotek: Current Employment. Hofman:Janssen: Consultancy; MIM: Research Funding; MSD: Consultancy; Isotopia: Research Funding; Bayer: Research Funding; Novartis: Research Funding. Santamaria:Cyclotek: Current Employment. Hao:J&J: Current Employment. Wall:Currus Biologics Pty Lrd: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Cell Therapies Pty Ltd: Current holder of stock options in a privately-held company; BMS: Patents & Royalties. Harrison:Haematologix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genetech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Eusa: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Terumo BCT: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.