OVERVIEW OF CAR-T THERAPY IN MULTIPLE MYELOMA
Kathryn Alexander, PharmD, PGY1, Mercy Hospital, Springfield
he American Cancer Society estimated that 35,730 new cases and 12,590 deaths occurred in 2023 due to multiple myeloma (MM). Multiple myeloma is a hematological cancer characterized
by abnormal growth in monoclonal plasma cells. Tese cells produce excessive monoclonal immunoglobulin, commonly called M-protein. Patients typically present with anemia and lytic lesions on X-ray and a combination of hypercalcemia, lymphadenopathy, leukopenia, and thrombocytopenia. Te initiating event is typically genetic alterations that lead to asymptomatic precursors such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Not all patients with MGUS or SMM progress to MM. Only 1% of MGUS and 10% of SMM patients progress yearly. Current mainstays of treatment include
proteasome inhibitors (e.g., bortezomib and carfilzomib), immune modulators (e.g., lenalidomide and pomalidomide), and anti- CD38 antibodies (e.g., daratumumab) in addition to dexamethasone or prednisone. Tere is currently no cure for MM, yet survival has continued to improve over the past two decades. With increased survival and longer courses of disease, there is tendency for MM to relapse and become resistant to available therapies. Te prognosis of patients with refractory MM who have been exposed to at least three treatment lines is poor, with median overall survival estimated to be 9.3 months and response
Amanda Carlson, PharmD, BCPS, Clinical Pharmacy Specialist, Mercy Hospital, Springfield
rates of 31%. Novel therapies such as chimeric antigen receptor T-cells (CAR-T) have begun to play a key role as they offer new treatment options for patients with refractory MM. Chimeric antigen receptors (CARs) are
engineered proteins designed to attack specific antigens on malignant cell surfaces and mediate cell destruction. Due to the personalized nature of CAR-T therapy, the creation process is complex. White blood cells are collected from the patient through leukapheresis and apheresis, and T cells are separated. DNA is inserted into the T cells through inoculation with a CAR virus or a non-infectious vector. T cells must undergo ex vivo proliferation, purification, and testing for quality and sterility. Te entire process can take several weeks. Tis personalization allows for targeted killing of cancer cells without involvement of the major histocompatibility complex. To further prevent the immune system from destroying engineered T cells, patients will usually undergo lymphodepletion. Regimens are typically cyclophosphamide and fludarabine for three days. As of today, out of the six FDA-approved CAR-T therapies, two are approved for refractory or relapsing MM: idecabtagene vicleucel (Abecma), and ciltacabtagene autoleucel (Carvykti). Te target antigen in MM is B-cell maturation antigen (BCMA). BCMA is part of the tumor necrosis factor (TNF) receptor family and is highly expressed on the surface of malignant plasma cells in MM patients. BCMA is undetectable in most normal human tissues
except plasma cells, making it an ideal therapy target. Idecabtagene vicleucel (ide- cel) was the first CAR-T therapy targeting BCMA to receive FDA-approval in 2021 for refractory or relapsed MM aſter two or more prior lines of treatment that included an immune modulator, a proteasome inhibitor, and an anti-CD38 antibody. Ciltacabtagene autoleucel (cilta-cel) was FDA-approved in 2022 for patients with MM refractory to lenalidomide and have failed one prior regimen that includes an immune modulator and a proteasome inhibitor. Unlike ide-cel, cilta-cel expresses two BCMA-targeting single-domain antibodies. Current guidelines recommend ide-cel as an option aſter two prior treatment lines including an immune modulator, an anti- CD38 antibody, and a proteasome inhibitor. Guideline recommendations for cilta-cel are for patients' refractory to lenalidomide and have trialed one prior therapy including an immune modulator and proteasome inhibitor. Tere have been no head-to-head trials comparing ide-cel to cilta-cel. KarMMa, an open-label single-arm
phase 2 study, assessed safety and efficacy of ide-cel in patients with MM refractory to their last regimen and had received at least three treatment lines. Patients recruited and received ide-cel (n = 128) were on average 61 years old, diagnosed for 6 years, and received six prior lines of treatment. 88% of patients received bridging therapy. Tere were three different doses of ide-cel evaluated. At a median follow-up of 13.3 months, 73% of patients had a response, with 33% of patients
36 Missouri PHARMACIST | Volume 98, Issue II | Summer 2024
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