Pseudoprogression and Sarcoidosis-like Phenomena after CART-Cells and Bispecific Antibodies in Multiple Myeloma

Introduction: CAR T-cell therapy is establishing itself as a new standard of care in relapsed and refractory multiple myeloma (RRMM). Yet, there are a number of open issues including the lack of data on optimal follow-up assessments post CAR T therapy. Appreciating the high incidence of extramedullary lesions and patchy disease patterns seen in the RRMM setting, whole body 18F-Fluorodeoxyglucose (FDG) PET/CT imaging is increasingly used. Whether FDG is the best tracer in this setting has yet to be determined, as the technique is being based not only on the quantification of increased glucose uptake by tumor cells but also by others such as inflammatory cells. A phenomenon linked to this issue is pseudoprogression, which refers to an increase in the target lesion size due to influx of immune cells that may be misinterpreted as disease relapse. Pseudoprogression is a well-known event after checkpoint blockade therapy, seen in up to 10% of patients with solid cancers. Whether myeloma patients treated with CAR T or bispecific antibodies are at risk for pseudoprogression is, to the best of our knowledge, unknown.

Methods: We present a case study of a RRMM patient who experienced pseudoprogression twice during his course of disease treatment that included BCMA CAR T cells Idecabtagene vicleucel and GPRC5DxCD3 bispecific antibody talquetamab. We performed a comprehensive molecular analysis including single cell RNAseq from bronchoalveolar lavage as well as PET imaging using the three PET tracers 18F-FDG, 68Ga-DOTATOC, and 68Ga-Pentixafor (binds to CXCR4) to unravel the biology underlying pseudoprogression in this case.

Results: A 61-year-old Caucasian male was diagnosed with biopsy-proven pulmonary MM and treated with BCMA targeting CAR T cells in his 4th line of therapy. Ten days after CAR T infusion, the patient started violent coughing and a FDG-PET revealed full resolution of focal bone lesions but disseminated FDG uptake at the lung and mediastinal lymph nodes reminiscent to sarcoidosis. We performed a PET using 68Ga-DOTATOC that usually detects sarcoidosis with high sensitivity and specificity, which was negative. Negative results were also seen for 68Ga-Pentixafor, which is an alternative tracer to FDG in the detection of MM. Bronchoalveolar lavage (BAL) along with endobronchial ultrasound guided biopsy was done, showing noncaseating granuloma formation in the biopsy without evidence of residual MM cells. Single cell RNA-seq on the BAL sample revealed CD4-positive T cells exhibiting simultaneous expression of genes associated with Th1 T-cells (TBX21, CXCR3, IFNG, TNF) and genes associated with Th17 T-cells (RORC, IL23R, CCR6, CCL20, KLRB1), indicative for a Th1-polarized Th17 phenotype. Furthermore, these cells expressed IL4I1, ABCB1, and CSF210-12 , while IL17A, IL17B, IL17E (IL25), and or IL17F was not expressed, highlighting presence of Th17.1 cells. This cell type has been described to be pro-inflammatory and pathogenic and implicated in several auto-immune diseases, including sarcoidosis. Together, our data suggest a non-infectious, Th17.1 T-cell driven sarcoidosis-like auto-immune phenomenon located in the lungs following anti-BCMA CAR T-cell therapy. Respiratory symptoms completely resolved following high-dose inhalative steroids. The patient relapsed from complete remission (CR), and FDG PET showed the known sarcoidosis-like pulmonary changes, but also revealed a number of new soft-tissue lesions, suspicious for extramedullary relapse. In contrast to the previous scans, these lesions were CXCR4 positive, suggesting a role of using multiple PET tracers in this setting.

Later, the patient was enrolled on a trial investigating talquetamab. One week after dosing, the patient experienced severe pain crisis and a diffusion-weighted MRI revealed increase in size of multiple extramedullary lesions, but no new lesions. M- protein levels were decreasing at that time suggesting either mixed response or pseudoprogression. The patient was treated with painkillers and all lesions disappeared on a follow-up scan 6 weeks later, confirming pseudoprogression, and he is in an ongoing CR for 6 months at the time of writing.

Conclusion: We present two educating episodes of pseudoprogression in one patient following immune oncology drugs in MM. While one event was transient and self-limiting, the pulmonary manifestations were similar to sarcoidosis and required treatment with steroids.

Duell:Regeneron: Research Funding; Incyte: Consultancy; MorphoSys: Consultancy, Research Funding. Einsele:BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Other: travel grants. Rasche:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.