ETD

• CAR-T
• multiple myeloma
• real life

Multiple myeloma (MM) is a malignant plasma cell disorder characterized by clonal proliferation within the bone marrow, leading to progressive organ damage. Despite significant therapeutic advances over recent decades, MM remains incurable, with most patients eventually experiencing relapse and refractory disease. Chimeric antigen receptor T-cell (CAR-T) therapy, targeting B-cell maturation antigen (BCMA), has emerged as a breakthrough treatment for relapsed/refractory MM, demonstrating promising efficacy and safety in pivotal registration clinical trials.
The approval and availability of CAR-T cell therapies for MM differ significantly between the United States and Italy, reflecting variations in regulatory frameworks and healthcare systems. In the United States, the Food and Drug Administration (FDA) granted accelerated approval to idecabtagene vicleucel (ide-cel) in March 2021 and ciltacabtagene autoleucel (cilta-cel) in February 2022. Both approvals target adult patients with relapsed or refractory MM who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
As of April 2024, the U.S. Food and Drug Administration (FDA) approved ciltacabtagene autoleucel for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, and are refractory to lenalidomide.
The European Medicines Agency (EMA) approved ide-cel in August 2021 and cilta-cel in September 2022, for patients who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Following EMA authorization, Italy’s regulatory body, the Agenzia Italiana del Farmaco (AIFA), conducts additional evaluations on reimbursement. Ide-cel received AIFA approval in June 2024, for patients who have received at least three prior lines of therapy while cilta-cel approval is ongoing. Both EMA and AIFA require administration in specialized centers certified for CAR-T therapy. In March 2024, the EMA expanded the indication of ide-cel to include earlier lines of therapy, i.e. for relapsed/refractory MM who had received at least two prior lines of therapy. Regarding cilta-cel, the EMA granted approval in 2024 for its use in adult patients with relapsed and refractory MM who have received at least one prior line of therapy.
This thesis aims to provide a comprehensive overview of MM patient management at Fred Hutchinson Cancer Center (FHCC) in Seattle, where I completed a six-month period as a visiting physician, focusing on the diagnostic workup, therapeutic journey, and outcomes of patients undergoing CAR-T therapy. Fred Hutch is distinguished by its long-standing expertise in immunotherapy and hematopoietic stem cell transplantation. It hosts a dedicated Immunotherapy Clinic that has been administering CAR-based therapies for over 15 years—making it one of the most experienced centers in this field globally. Additionally, the institution is internationally recognized for its pioneering role in stem cell transplantation, with decades of leadership in both clinical care and translational research. The presence of a specialized inpatient team devoted exclusively to cellular therapies further supports the delivery of complex treatments. Moreover, the center serves a broad and diverse patient population, with individuals routinely referred from an average of seven different U.S. states, underscoring its role as a national and international referral hub for advanced hematologic care. Fred Hutch’s integration of multidisciplinary care enables personalized treatment plans aligned with clinical trial protocols and real-world evidence.
Reviewing key registration studies, this work examines CAR-T cell products’ clinical trial results, highlighting response rates, durability of remission, and treatment-related toxicities such as cytokine release syndrome and neurotoxicity. These data form the foundation for evolving clinical practices at Fred Hutch, where specialized teams manage CAR-T infusion, monitor adverse events, and implement supportive care strategies.
The management of CAR-T recipients at Fred Hutch involves careful patient selection, pre-infusion conditioning, and post-treatment surveillance including minimal residual disease (MRD) assessment. Challenges such as antigen escape, CAR-T cell persistence, and long-term toxicities are addressed through ongoing research and clinical innovation.