CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: April 04, 2022
Expiration: April 03, 2023
CAR T‑cell therapy is now approved for patients with various hematologic malignancies, including high‑risk leukemias, lymphomas, and R/R MM.CAR T-cell therapy can be engineered to target various tumor antigens, including BCMA for R/R MM. CAR T-cell therapy for patients with R/R MM are available through REMS programs at authorized centers. The process for navigating through this program includes everything from patient referral to the logistics of bridging therapy, lymphodepletion, CAR T-cell infusion to toxicity management after CAR T-cell therapy has been administered.
The 2 CAR T-cell therapies approved for R/R MM are idecabtagene vicleucel and ciltacabtagene autoleucel.
The FDA approved idecabtagene vicleucel for the treatment of adults with R/R MM after 4 or more lines of therapy (including IMiD, PI, and anti-CD38 agent) based on the findings of the phase II KarMMa study, which looks at idecabtagene vicleucel in R/R MM.13,14
KarMMa was a multicenter, phase II, single‑arm trial open to patients progressing after ≥3 prior regimens, each with ≥2 consecutive cycles, prior IMiD, PI, and anti-CD38 monoclonal antibody, and refractory to their last therapy. In this trial, 140 patients underwent leukapheresis for CAR T-cell manufacturing. During CAR T-cell production patients were allowed to receive bridging therapy until lymphodepletion. After lymphodepletion with cyclophosphamide and fludarabine, 128 patients received CAR T‑cell infusion. Idecabtagene vicleucel was given at various doses, including a flat dose of 150, 300, and 450 million CAR T-cells. The primary endpoint for this trial was ORR, and secondary endpoints included complete remission rate, DoR, PFS, OS, and safety.
Patients enrolled in this trial were heavily pretreated, with a median of 6 prior lines of therapy.13,14 Approximately one third (35%) of patients had high‑risk cytogenetics, and 51% had a high tumor burden with at least 50% involvement of their bone marrow. Tumor BCMA expression was identified by immunohistochemistry in all patients. Most patients (84%) were triple-class refractory, and 26% were penta‑refractory. Most patients required bridging therapy (88%), and only 5% of these responded to that therapy.
Among the overall patient group, the ORR was 73% with idecabtagene vicleucel.13,14 The response rate was 82% among the 54 patients receiving the highest dose of 450 million CAR T-cells, which is the recommended dose based on the FDA approval (range of 300 to 460 x 106 CAR-positive T-cells). The rate of CR was 33% in the overall population and 39% in the high-dose group.
Median PFS in the overall population was 8.8 months (95% CI: 5.6-11.6), and 12.1 months (95% CI: 8.8-12.3) in the group receiving the 450 million dose.13,14 Patients who achieved a CR or sCR did better than those with a partial or nonresponse, with a median PFS of 20.2 months (95% CI: 12.3 to NR) compared with 5.4 months and 1.8 months, respectively.
The FDA also approved ciltacabtagene autoleucel for the treatment of adults with R/R MM after 4 or more lines of therapy (including IMiD, PI, and anti-CD38 agent) based on the findings of the phase II CARTITUDE-1 study.15,16
Ciltacabtagene autoleucel was first assessed in R/R MM in the phase I LEGEND-2 trial, which reported an ORR of 88% among patients who had received an IMiD or a PI, or both.17 This therapy, which consists of 2 BCMA single-domain antibodies, has since been evaluated in R/R MM in the phase Ib/II CARTITUDE‑1 trial.15,16 Patients with R/R MM with measurable disease, ECOG PS 0-1, ≥3 prior therapies including PI, IMiD, and an anti-CD38 therapy, or double refractory to PI and IMiD underwent screening, enrollment, leukapheresis, optional bridging therapy, and subsequent lymphodepletion with fludarabine, cyclophosphamide, followed by a ciltacabtagene autoleucel infusion of 0.5 to 1.0 million CAR T-cell/kg (target 0.75 million/kg). The primary endpoints were safety and establishment of a recommended phase II dose in phase IB, and efficacy in phase II.
Similar to the KarMMa trial, patients who were enrolled in CARTITUDE-1 were heavily pretreated, with a median of 6 prior lines of therapy.16 Two thirds of patients had received more than 5 prior lines of therapy and 88% were triple-class refractory, and 42% were penta‑drug refractory. High‑risk cytogenetics were present in 24% of patients, and 13% of patients had extramedullary disease. Overall, then, this was a challenging patient population.
The ORR with ciltacabtagene autoleucel was an impressive 98%, and 95% of patients achieved at least a VGPR.16 Stringent CR rates have deepened over time, increasing to 83% after a median follow-up of 2 years. Responses occurred quickly, with a median of 1 month, and the median DoR was not evaluable at this point.
The 2-year rate of PFS in the overall study population was 60.5%.16 Median PFS has not yet been reached but will likely be longer than 24 months, based on the PFS rate. For comparison, in the KarMMa study, median PFS for the highest dose of idecabtagene vicleucel was 12 months.13,14 The 2-year rate of OS was 74% and the median OS has not yet been reached in CARTITUDE-1, but we look forward to longer‑term data.
Patients who achieved measurable residual disease (MRD) negativity on ciltacabtagene autoleucel responded particularly well.16 Two‑year rate of PFS in this subset was 91% for those who sustained MRD negativity for at least 6 months, and 100% in those with at least 12 months of MRD negativity. The 2-year rate of OS in this latter group was 100%. So, we are looking forward to following these patients to evaluate whether we can predict those who will respond well, and so how to select patients for this very effective therapy.
Cytokine-release syndrome (CRS) is a key concern with use of CAR T-cell therapies, occurring in 95% of patients receiving ciltacabtagene autoleucel in CARTITUDE-1, and including 1 fatal event.18 Median time to onset of CRS was 7 days (range 1 to 12) and the median duration of CRS was 4 days (range 1 to 97).
Immune effector cell–associated neurotoxicity syndrome (ICANS) is also a concern with use of CAR‑T therapy, occurring in 16.5% of patients overall, and in 2.1% at grade 3 or higher. The rate of any neurotoxicity was 20.6%, with 12.4% of patients experiencing non-ICANS neurotoxicity. In the primary analysis, 1 of these non-ICANS events was fatal.15 There were no further such events with additional follow-up,11 which is reassuring and may indicate that management has improved.
Numerous other BCMA CAR T‑cell therapies are currently in development and under investigation in patients with R/R MM. As well as ciltacabtagene autoleucel and idecabtagene vicleucel that are reviewed above, early clinical studies of bb21217, CT053, BCMA-101, and the novel dual CAR T-cell therapy that targets BCMA and CD19, GC012F have reported impressive ORRs between 67% and 95%.14,16,19-22 All-grade CRS has been observed at frequencies between 70% and 95% for these agents, and much lower for BCMA-101. Most CRS and neurotoxicity reported in these studies is generally grade 1 or 2 and is easily managed with steroids in the case of neurotoxicity, or with tocilizumab and/or steroids for CRS.
As we have seen from the studies above, the major toxicity seen with use of CAR T‑cell therapy is CRS, which generally occurs in the first 2‑3 weeks of treatment.23 This event can be managed well with tocilizumab, steroids, and sometimes with anakinra.
Neurotoxicity can happen later, but generally is seen within the first month after CAR T-cell infusion. Steroids are the mainstay of management, but seizure prophylaxis can also be considered. Patients with severe, steroid-refractory neurotoxicity may require cyclophosphamide to reduce the number of CAR T-cells.
Prolonged cytopenias may also be seen with CAR T-cell therapy, probably due to bone marrow‑based inflammation.23 Cytopenia, including neutropenia, can be managed with growth factors and blood product transfusion support, as needed based on institutional guidelines.
B‑cell aplasia is an on-target, off-tumor effect of CAR T-cell therapy.24 Removal of B-cells does, of course, lead to hypogammaglobulinemia, increasing risk for infection. This can be managed with IV IgG,25 but this presents other challenges, such as inability to respond to COVID vaccines. Prophylactic anti‑COVID antibody is available for people who do not mount a specific response to COVID vaccines.26 Infections are always a concern with use of CAR T-cell therapies, and may be managed with acyclovir prophylaxis, or prophylaxis for Pneumocystis jirovecii pneumonia.27
Macrophage activation syndrome (MAS)-–like manifestations have been described with use of anti-BCMA CAR T-cell therapies.28 This syndrome is characterized by decreased fibrinogen and elevated ferritin and lactate dehydrogenase, and may also be managed with anakinra and steroids.
Overall, after several years of managing these AEs of CAR T‑cell therapy we have learned that these AEs are manageable and that CAR T-cell therapies may even be less toxic than traditional therapies like stem cell transplant.
CRS can manifest with a wide range of symptoms, much like a flulike syndrome.29 Patients will be febrile, usually with a rapid onset. They may also present with other symptoms, such as hypotension, hyponatremia, or other electrolyte dysregulations. However, the hallmark is fever, which is required for diagnosis of CRS.
Although we have clear evidence of the efficacy of BCMA‑directed CAR T‑cell therapy in heavily pretreated MM, relapses do occur.16,30 As we’ve seen in the KarMMa update and will probably eventually see in the CARTITUDE-1 study, patients may still progress after an initial response. Why this occurs and how it may be predicted and prevented are important questions for the future.
Next-generation CAR T-cell therapies are expected to build on the lessons from early therapies, for example, by incorporating more than 1 antigen to increase the depth of response, or by using a synthetic receptor or nanobodies to improve binding.31 Universal allogenic CARs might enhance logistics and allow better access.32
Different strategies for enhancing target antigens include use of γ‑secretase inhibitors, dual targeting, or a switch technology, which allows for CARs to be transcribed only in the presence of certain antigens.33
Third-generation CARs might find ways to enhance the activating motifs intracellularly or involve novel methods of engineering T‑cells to be more efficacious against the target. For example, the anti-BCMA CAR T-cell therapy, bb21217 was cultured in the presence of a PI3 kinase inhibitor to enhance the T‑cell memory-like phenotype.34
All of these potential developments are shaping the next generation of CAR T‑cell therapy in ways that will help to improve DoR and maybe reach a plateauing of response, as we have seen with CD19 CAR T‑cell therapies.
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