CD19-Targeted CAR T Cell Therapy for Concomitant Diffuse Large B Cell Lymphoma and Myeloma
Authors: D'Ovidio Tyler J , Ciccolini Kathryn , Kalac Matko , Osman Keren , Steinberg Amir 
Published: November 2021

Abstract
While DLBCL and myeloma comprise a large fraction of annual hematologic malignancies, the co-occurrence of these malignancies is particularly rare. The FDA has approved three CD19-targeted CAR T cell therapies for B-cell lymphoma (Kymriah, Yescarta, and Brenyazi) and more recently a single CAR T cell therapy for myeloma (Abecma). We present a case of concurrent multiply r/r DLBCL and non-r/r myeloma treated exclusively with CD19-targeted CAR T cell therapy.
A 77-year-old female was admitted to an outside hospital with a chief complaint of one week of constipation, incidental labs demonstrating hypercalcemia and AKI, and a bone marrow biopsy consistent with myeloma (phenotype lamda, CD138-, MUM01+, CD56- and CD117, KITE-). There were 20% lambda-restricted plasma cells with no evidence of lymphoma. She also had concomitant anemia with a hemoglobin of 9.6 g/dL best attributed to the plasma cell dyscrasia, thus fulfilling criteria from the International Myeloma Working Group.Beta-2-microglobulin was 6.8 mg/L, consistent with stage 3 disease. She demonstrated two M proteins at time of diagnosis; each was 0.40 g/dL. Interestingly these monoclonal proteins were IgG-Kappa and an IgM protein. The patient was transferred to our institution for management after receiving a single cycle of bortezomib, cyclophosphamide and dexamethasone. A right inguinal lymph node biopsy of an existing right thigh mass revealed atypical cells with findings consistent with non-GC DLBCL [CD20+, PAX5+ (weak), MUM1+, BCL2+, CD10-, CD5-, BCL6-, BCL1-, cMYC-; R-IPI 4, CNS-IPI 4, Stage IV]. Chemotherapy with R-CHOP for four cycles resulted in a mixed response. Upon subsequent hospitalization, a second right inguinal lymph node biopsy was consistent with refractory DLBCL [positive for CD79a, CD20 (weak), MUM1, BCL2, BCL6, MIB1 Ki67 60-70% proliferative fraction, CD30 (1-2%), negative for CD10, CD3, CD5, BCL1, MYC]. Radiation followed by RICE given as second line therapy had no meaningful response on imaging. However, monoclonal protein resolved after a second cycle of RICE. Pathology indicated a CD19+ specimen on review. Polatuzumab vedotin was given as bridging therapy, followed by lymphodepletion regimen and ultimately CD19-targeted CAR T cell infusion. A partial response for lymphoma was seen at 90-day evaluation (Deauville 3). Immunofixation was positive as late as 16 days post infusion with no abnormality detected at subsequent testing 32 days post infusion. At three months, the M protein level was 0.00 g/dL with no detectable monoclonal protein on immunofixation or electrophoresis testing. Flow cytometry peripheral blood smear was negative for plasma cells by CD38 and CD138 labeling seven months post CAR T infusion.
CD19-targeted CAR T cell therapy is established as an accepted standard of care for multiply r/r DLBCL when it is available. However, the role of HSCT in r/r DLBCL is standard of care after second line salvage. In our patient, however, she failed to adequately respond to salvage chemotherapy. Though there is data supporting the use of HSCT in chemorefractory patients, it is not as successful as in chemosensitive disease. Several trials have investigated BCMA-targeted CAR T cell therapy in r/r myeloma and have reported high response rates, however there is a lack of data supporting these immunologic therapies in non-r/r myeloma. Data regarding CD19 CAR T cell's effect on myeloma is limited as secondary malignancies typically exclude subjects from enrollment; however, CD19-mediated responses have been reported in vitro and CD19-targeted clinical trials are underway in r/r myeloma. Based on emerging data regarding the effectiveness of CAR T, our team elected to pursue CD19 CAR T cell therapy. One critique is that the monoclonal protein detected in the blood was different from the lambda-restricted plasma cell population that was noted in the initial bone marrow biopsy. However, given the lack of detectable myeloma based on labs and imaging, we have elected to defer a bone marrow biopsy at this time.
Our patient case shows that directing toward the more aggressive malignancy, typically the lymphoma with CAR T cell therapy, can target the myeloma as well. This has significant implications on guiding treatment decisions in future patients presenting with concomitant malignancies. Furthermore, new data from studies investigating CD19-targeted therapies' effect on myeloma will have amplified clinical relevance.

Disclosures
Ciccolini: Currant Insights, LLC: Consultancy; Techspert.io.: Consultancy; Guidepoint: Consultancy; Atheneum: Consultancy; First Thought: Consultancy; GLG: Consultancy; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; JADPRO: Honoraria. Kalac: Astra Zeneca: Consultancy; Kyowa Kirin: Consultancy; Gilead: Consultancy; Jannsen: Research Funding; Guidepoint: Consultancy; GLG: Consultancy.