The emergence of cellular-based therapies represents a major opportunity to improve outcomes in the heavily pretreated and refractory myeloma population.
Multiple myeloma is a plasma cell malignancy that accounts for approximately 1% of new cancer diagnoses per year. The development of a combination approach of mainstay therapies including immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and anti–CD-38 antibodies has greatly improved up-front remission rates and response duration and prolonged overall survival in the past decade. However, for patients who have been heavily exposed to or are triple or penta-refractory to these classes of therapy, survival is under 1 year.1 Therefore, the emergence of cellular-based therapies represents a major opportunity to improve outcomes in the heavily pretreated and refractory myeloma population.
Chimeric antigen receptor (CAR) T-cell therapies approved by the FDA for several relapsed and refractory B-cell lymphomas are presently under investigation in a variety of treatment line settings for multiple myeloma. As more patients in the community become eligible for CAR T-cell therapies, community oncologists will need to be increasingly familiar about the various products, including their immediate and longer-term risks. In addition, it is key to understand the optimal time for referring these patients to an academic institution, as well as how to manage the requisite post CAR T-cell therapy in the community setting.
The major CAR T-cell therapies in trials for multiple myeloma are directed toward B-cell maturation antigen (BCMA), a surface antigen expressed on B cells starting from their period of development in the germinal centers onward and persisting through the time of plasma cell differentiation. BCMA is minimally expressed in normal human tissues but is heavily expressed on myeloma plasma cells. This allows for safe and intentional targeting of neoplastic myeloma cells using CAR T-cell technology.
The first FDA-approved commercial CAR T-cell therapy will likely arrive in the first quarter of 2021. Patients enrolled on the initial BCMA CAR T-cell trials were required to have had 3 or more prior lines of therapy with exposure to a PI, an IMiD, and an anti-CD38 monoclonal antibody.
The earliest trial was the KarMMa-1 study (NCT03361748) of idecabtagene vicleucel (ide-cel, previously bb2121), which demonstrated an overall response rate (ORR) of 73% and a median progression-free survival (PFS) of 8.8 months in all dose levels. Additionally, a median PFS of 12.1 months was observed in the highest dose level of CAR T cells (450 × 106).2,3 Patients on this trial (n = 128) had a median of 6 prior lines of therapy, and 84% were triple refractory.
A concurrent trial, CARTITUDE-1 (NCT03548207), studying JNJ-4528 (ciltacabtagene autoleucel in China), also targeting BCMA, demonstrated an unprecedented 100% ORR in patients, with 86% achieving stringent complete response (sCR), the deepest response level by International Myeloma Working Group criteria.4 In the most recent evaluation of PFS, 86% of patients on CARTITUDE-1 had not progressed in disease at a median follow-up time of 9 months.5 New data for JNJ-4528 and the other CAR T-cell therapies being investigated will be made available during the 2020 American Society of Hematology Annual Meeting and Exposition in December and should further reinforce the potential for CAR T-cell therapy to deliver deep and durable responses to patients with multiple myeloma who are heavily pretreated.
What Type of Patients Might Benefit the Most From CAR T?
As in the case of BCMA, antigens for CAR T cells are chosen for their unique expression in tumor tissue and low expression in normal, healthy tissue. The complications that occur in patients receiving CAR T-cell therapy will be largely specific to the targeted antigen. Patients must undergo a multistep process to safely and effectively undergo CAR T-cell treatment and should know up front about the process involved.
The initial step involves leukapheresis, or collecting the patient’s T cells. Once this is completed, the patient must wait 3 to 5 weeks for typical manufacturing of their CAR T cells at a production facility. If required, patients typically can undergo bridging chemotherapy during this waiting period to maintain their disease, particularly if myeloma progression is accelerating. Once the patient’s CAR T cells are produced, the patient will undergo lymphodepletion (typically with fludarabine/cyclophosphamide) for 3 days before being infused with prepared CAR T cells. Patients must have sufficient health reserve to withstand the potential adverse effects (AEs) associated with CAR T-cell therapy, including cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). Therefore, early referral to an academic center is key to getting these patients on therapy at the optimal time.
CRS is the most common acute AE that occurs in patients treated with CAR T-cell therapy. It occurred in nearly 9 out of 10 patients in the KarMMa-1 and CARTITUDE-1 trials, though severe CRS occurred only in 5% to 7% of patients.3,5 CRS is the phenotypic presentation of a supraphysiologic production of cytokines prompted by immune cell activation, including T cells, macrophages, and monocytes (Table 16 ). Preclinical models have shown that macrophages amplify CRS severity and are the source of several of the culprit cytokines of CRS, including interleukin (IL) 6, IL-1, and IFN-γ. CRS onset occurs variably depending on the CAR construct used.
Table 1. ASTCT Criteria for CRS6
For example, CRS occurred at median 1 day after infusion of ide-cel, whereas CRS occurred at median 7 days after infusion of JNJ-4528. Our primary treatment for CRS is tocilizumab (Actemra), a monoclonal antibody directed against IL-6; its use does not diminish efficacy of CAR T cells. Subsequent agents such as the IL-1 receptor antagonist anakinra (Kineret), anti–IL-5 monoclonal antibody siltuximab (Sylvant), and corticosteroids may be employed for severe cases of CRS.
The second notable AE associated with CAR T-cell therapy is ICANS, which is defined by the American Society for Transplantation and Cellular Therapy as “a disorder characterized by a pathological process involving the central nervous system….Symptoms or signs can be progressive and may include aphasia, altered level of consciousness, impairment of cognitive skills, motor weakness, seizures, and cerebral edema.”6 A primarily encephalopathic picture appears when patients develop ICANS, which typically occurrs later than CRS. The primary treatment for ICANS involves corticosteroids such as dexamethasone, initially every 6 hours with a quick taper as symptoms start resolving.
Signs and symptoms of neurotoxicity should be screened at least daily during the acute CAR T-cell treatment period and can be assessed with validated tools such as those from CAR T-cell therapy-associated TOXicity (CARTOX) Working Group or the Immune-Effector Cell-Associated Encephalopathy (ICE) tool.6 Severe neurotoxicity occurred at only a 3% rate in KarMMa-1 and CARTITUDE-1 and can be treated readily if caught early with close monitoring.
Other common AEs such as cytopenia and infection may occur during and after the period of CAR T-cell infusion and expansion. Anemia, thrombocytopenia, or neutropenia may occur for months after the initial treatment period, and clinicians should utilize supportive transfusions and/or granulocyte colonystimulating factor and thrombopoietin mimetics as indicated.
Cytomegalovirus quantitative polymerase chain reaction should be checked monthly. If the patient is persistently neutropenic, opportunistic infections should be considered. Intravenous immunoglobulin should be administered before initial lymphodepletion, but also every month for 6 months after CAR T-cell infusion and during winter months if the patient has a history of recurrent infections. In addition, patients should be vaccinated at 1-year post CAR T-cell therapy; a recommended vaccine schedule is included in Table 2.
Table 2. Recommended Vaccine Schedules After CAR T-Cell Therapy
The multiple myeloma treatment landscape is rapidly evolving, with many exciting new therapies on the forefront for relapsed and refractory multiple myeloma. CAR T-cell therapy is a 1-time treatment that allows patients to achieve deep and durable remissions without the need for the usual continuous cancer-directed treatments. The aforementioned trials and therapies have paved the way for subsequent iterations of cellular therapies. These include non–BCMA-targeted CAR T cells; next-generation CAR T cells with improved costimulatory domains for improved safety, efficacy, or faster production; and allogeneic CAR T cells derived from pluripotent stem cells available off the shelf to patients. In the coming year, as commercially available myeloma CAR T-cell therapies are approved, it will be even more important for community oncologists to better understand these therapies so they can offer them to their patients.